September 16-20, 2019; Barcelona, Spain; Full Report – Draft

Executive Highlights

In this report, we provide our full coverage of diabetes/obesity therapy, diabetes technology, and big picture topics from EASD 2019. Dive into 14 chapters, ranging from GLP-1s and SGLT-2s, to diabetes technology and novel therapies. Titles highlighted in blue represent new or expanded coverage that wasn’t included in our daily highlights (day #1, day #2, day #3, day #4, and day #5).

Note that some talks may appear in multiple sections. Navigate through all 170 pages of reporting using our table of contents below – happy reading!

Themes

Diabetes Therapy

1. Heart Failure Keeps SGLT-2 Inhibitors in the Spotlight: Endocrinologist vs. Cardiologist Perspective; Patient-Centric DEFINE-HF Study; Real-World Results from EMPRISE

There’s no doubt that heart failure is receiving more attention than ever at EASD, following SGLT-2 inhibitor dapagliflozin’s landmark DAPA-HF results at ESC 2019. As a reminder, dapagliflozin conferred a 26% relative risk reduction on the primary composite outcome of CV death/HF hospitalization/urgent HF visit when compared to placebo (HR=0.74; 95% CI: 0.65-0.85; p=0.00001; NNT=21) in HFrEF patients (both with and without diabetes, with consistent effects across both subgroups). The trial came up again and again during the various corporate symposia that opened the conference, and with results that University of Toronto’s Dr. Subodh Verma says, “truly usher in a new day in the way we think of SGLT-2 inhibitors in the treatment of heart failure,” we fully understand why.

• Looking ahead, an important question for the diabetes community appears to be which specialty will be at the forefront of using SGLT-2 inhibitors, given the sustained benefit across both participants with and without diabetes. In a presentation on the metabolic outcomes of DAPA-HF, Yale’s Dr. Silvio Inzucchi asked, “have we ‘lost’ drug class to cardiologists?” There’s certainly increased enthusiasm for the drug class amongst the cardiology community, but Dr. Inzucchi gave a fuller picture by explaining that (i) yes, SGLT-2s will see increased focus in cardiology because of their effects on heart failure regardless of diabetes status, but such usage will require collaboration with endocrinologists; and (ii) 90% of the patients without baseline HF that still experience positive CV effects with the class are primarily seen by endocrinologists, and it will be the job of endocrinologists to treat these patients with risk factors in order to prevent HF from developing (or presumably worsening). Dr. Mark Petrie (University of Glasgow, Scotland, UK) also supported a future of collaboration between endocrinologists and cardiologists during an AstraZeneca symposium. Dr. Petrie’s remarks struck a hopeful tone, noting that greater collaboration could yield a better understanding of how these impressive benefits are conveyed, along with ensuring that the right patients are benefitting from these treatments. With the recent news that J&J’s SGLT-2 Invokana (canagliflozin) has received FDA approval to reduce the risk of (i) end-stage kidney disease; (ii) worsening of kidney function; and (iii) CV death + hospitalization for heart failure in people with type 2 diabetes and CKD, we’re also curious to see how nephrologists will soon play into the equation.

• New results from DEFINE-HF, a mechanistic study of Farxiga in HFrEF, shined a light on the always-important patient perspective. No statistically significant difference was seen in the first primary endpoint of average of 6- and 12-week mean adjusted NTproBNP, a biomarker for HF, (HR=0.95; 95% CI: 0.84 to 1.08). However, on the second primary endpoint of patients that achieve a meaningful improvement in health status (≥5-point increases in average of 6- and 12-week Kansas City Cardiomyopathy Questionnaire (KCCQ) overall scores; or ≥20% decrease in average of 6- and 12-week NTproBNP), an HR of 1.8 (95% CI: 1.0-3.1, p=0.0386) favoring dapagliflozin was found. More specifically, dapagliflozin treatment significantly improved total symptom, physical limitation, and quality of life KCCQ scores (but not social limitation). As the KCCQ is a patient-filled questionnaire, these results suggest that even after just 12 weeks of treatment with dapagliflozin, patients felt that their HF-related health status had significantly improved – a hugely clinically meaningful finding!

• Though dapagliflozin took center stage at this year’s meeting, Dr. Elisabetta Patorno also presented compelling real-world data on Lilly/BI’s Jardiance, detailing a 26-34% risk reduction in hospitalization for heart failure vs. GLP-1 agonists from the EMPRISE study. These findings were fairly consistent with hHF outcomes from EMPA-REG, which found a 35% risk reduction (HR = 0.65; 95% CI = 0.50-0.85; p=0.002) compared to placebo, on top of standard of care. Importantly, Dr. Patorno pointed out that EMPRISE is an ongoing study, and the results presented today are only representative of the two-year endpoint and participant enrollment number. Looking ahead, additional results on MI and CV death in EMPRISE will be reported at AHA 2019 in November (see you there!)

• More broadly speaking, the state of heart failure is clearly alarming, and prevention is key to moving the needle on this serious condition. New data from AZ’s 38-nation observational DISCOVER trial (>15,0000 participants), examining the state of heart failure in people with type 2 diabetes, found that nearly 2% of the DISCOVER population had heart failure at baseline. The people with HF tended to be older (67 vs. 57 years), have a longer diabetes duration (8.2 vs. 5.5 years), and a greater prevalence of coronary artery disease (45% vs. 6%) and chronic kidney disease (23% vs. 4%). Furthermore, 60% of the DISCOVER population had the obesity-associated and harder-to-treat HFpEF. At the two years follow-up, 2.6% of DISCOVER participants developed heart failure, but this proportion rose to 15.3% for the subgroup of participants with baseline coronary artery disease. In a rousing call-to-action on heart failure prevention, Stony Brook University’s Dr. Javed Butler presented similarly alarming HF statistics, but specifically encouraged the audience to not get lost in distinctions between HFpEF and HFrEF when considering prevention. He stated, “we sometimes get really lost in the HFpEF, HFrEF, and HFmEF ‘this and that’ but for the purposes of my talk, it is an absolutely unimportant discussion. Whether you have this ejection fraction or that ejection fraction HF has therapeutic implications for management of HF, but when you’re talking about prevention of HF in a person who does not have HF, it does not matter which HF you are preventing because the outcomes for all forms once you develop it are horrible.”

2. The Case for Earlier Combination Therapies: Will VERIFY Help to Turn the Tide?

Results from the VERIFY study, investigating early combination therapy of DPP-4 Galvus (vildagliptin) and metformin, brought forward the first pieces of evidence from long-term clinical trials of the benefits of such combination therapy. As a reminder, results from the trial showed that initial combination therapy conferred a significant, 26-month delay in the primary outcome of treatment failure (A1c > 7%; HR: 0.51; 95% CI: 0.45-0.58; p<0.0001). Those on early combination surpassed 7% A1c at 62 months versus 36 months on monotherapy and also showcased a delay in insulin initiation (p<0.0001). Interestingly, initial combination therapy was associated with fewer CV events – sparking interest for future exploration of CV outcomes.

• How will VERIFY results impact therapeutic inertia? In November 2018, ADA convened over 125 stakeholders to discuss this topic, and we think that VERIFY results will importantly influence any future discussions regarding therapeutic inertia. In the publication of VERIFY results in The Lancet, the study’s authors note that “The findings of VERIFY support and emphasize the importance of achieving and maintaining early glycemic control… However, durable A1c values below 6.5% are unlikely to be achieved with monotherapy alone…Real-world evidence has shown how delayed treatment intensification after monotherapy failure results in increasing time spent with avoidable hyperglycaemia, raising a crucial barrier to optimized care. The durable effect we observed with an early combination strategy therefore provides initial support for such an approach as an effective way to combat clinical inertia.” Many KOLs have similarly reacted to VERIFY results: Prof. Stefano Del Prato was optimistic in his independent commentary that these results could help overcome therapeutic inertia in treatment practice, Dr. Dan Drucker interpreted results as a reason to “think like an oncologist” and adopt combination treatments earlier on in disease in order to successfully treat the complex disease that is type 2 diabetes, and Dr. Kamlesh Khunti similarly emphasized the implications of VERIFY in addressing inertia. We’re glad to see this push for earlier combination therapies to take the place of sequential treat-to-failure paradigms.

• Generic DPP-4s on the horizon should allow VERIFY results to soon be broadly applied. To be sure, DPP-4s currently remain unaffordable for many patients (especially those uninsured or underinsured). As a result, access and pricing issues have consistently plagued the use of currently available combination therapies, resulting in far too few patients actually using these efficacious treatments. However, generic DPP-4s are expected soon on the market ahead of SGLT-2s and GLP-1s, and we imagine that pricing on generic combinations of DPP-4s/metformin could represent a massive opportunity for patients. We’re curious as to whether future guidelines may even promote such combos of generic DPP-4/metformin as first-line therapy. Looking even further ahead, we’re highly optimistic about the potential of triple therapy generics of SGLT-2s/DPP-4s/metformin.

• A potential signal for CV benefit in VERIFY prompts the need for further study of the effects of early combo therapy on CV endpoints. VERIFY was not designed as a CVOT, but it was observed that there were CV events in the earlier combination arm – this was nominally significant, but the numbers in each group were understandably quite small. Nevertheless, these results are hypothesis-generating, and are backed by several putative mechanisms that could be underlying a potential CV benefit of earlier combo therapy with metformin and DPP-4s. Several commentators at EASD, including Prof. Del Prato and Dr. Cliff Bailey, were highly intrigued by this potential signal and called for larger studies investigating this possible benefit. We sincerely hope to see such studies conducted that may further add to the evidence base of benefits of earlier combination therapy, and are especially keen on what the possible effects of early combo SGLT-2/GLP-1 therapy could be.

3. Support for SGLTs in Type 1 Strong as Ever, But Debate on BMI >27 kg/m² Cutoff Continues

• Germany’s Dr. Thomas Danne was as vocal as ever on the SGLTs in type 1 front, again petitioning for a dedicated type 1 CVOT and presenting a post-hoc analysis from sotagliflozin’s inTandem program. Dr. Danne began his appeal for SGLT usage in type 1 patients with an impassioned, off-script plea to not be over cautious to the point of withholding important benefits to patients: “I’m a little bit angry. I completely understand with all the data that we have that we need to be cautious. But we also have situation where people are starting to be over cautious. Tell me, if you would have a child with type 1 diabetes – at age 10, and you look through the data of the Swedish Diabetes Registry – you realize that your child will lose 17 years of life (if a girl) or 14 years of life (if a boy), and you know that this loss of life is due to increased CV mortality risk. Yes, there is a risk of DKA, and yes we are doing a bad job so far, and yes I hope we will do a better job – but why are we so cautious that we have not yet started trials in this very vulnerable pediatric population with a drug that has shown positive CV mortality and renal outcomes effects in type 2 diabetes and in those without diabetes? Is it so difficult to believe that they will have similar benefits in type 1 diabetes?” On a more positive note, Dr. Danne highlighted several new interventions aimed at improving risk mitigation including (i) the EASD e-learning module on adjunct type 1 therapy; (ii) ATTD education portal for industry education on the subject; (iii) the KetoAWARE program for structured DKA education in type 1; (iv) several HCP-focused DKA education programs; and (v) JDRF’s call-in requesting research grant proposals investigating safe use of SGLTs in type 1 diabetes. Many of Dr. Danne’s talking points certainly echoed themes from EASD 2018, and while we think that being cautious about using the drug is of the utmost priority, we believe that it’s time for SGLTs to reach the type 1 community (of course, along with the right education).

• As always, much of the SGLT in type 1 conversation centered on the contentious BMI >27 kg/m² number. Data from the new inTandem post-hoc analysis demonstrated greater efficacy in the BMI >27 kg/m² group in terms of A1c reductions, time in range, and weight loss, as well as slightly lower rates of DKA. Comparatively, results from the DEPICT program for dapagliflozin in type 1 presented at ENDO 2019 showed that patients with a BMI ≥27 kg/m² did not have significantly different CGM-based outcomes compared to the entire cohort, though DKA rates were lower than the overall, pooled population. So far, it’s been fairly unclear as to how exactly the EMA chose the >27 kg/m² BMI cut-off for both dapagliflozin and sotagliflozin’s European approval in type 1, so we’d be eager to know what data might be supporting these guidelines. Dr. Danne seemed hopeful that the EMA will eventually ease its current BMI restriction and open up SGLT therapy to most patients with type 1. We also learned at EASD that there is a requirement (minimum dosage) of daily insulin intake. Dr. Danne noted that he “likes the idea of caution, but we now need to see if our risk mitigation strategy works in the real world. Then, I think EMA will reconsider their original guidelines and approve this drug for those with normal body weight as well.”

• Several posters documented the effects of SGLTs on patients with type 1.  Both the INCLIVIA Biomedical Research Institute in Valencia, Spain and Sanofi tackled real-world evidence, focusing on (i) efficacy and safety of sotagliflozin and dapagliflozin in Spain; and (ii) DKA in patients treated off-label in the US. The DEPICT program for dapagliflozin in type 1 also produced a plethora of new findings including (i) pooled outcomes from DEPICT-1 and DEPICT-2; (ii) pooled efficacy and safety; (iii) subgroup analysis by method of insulin administration; and (iv) subgroup analysis by A1c.

Diabetes Technology

1. Smart Pens: New CGM-Insulin Partnerships for Sanofi/Abbott, Medtronic/Novo Nordisk; Whose pens will launch first?

• EASD began with two major partnerships between insulin manufacturers and CGM companies: Sanofi with Abbott and Novo Nordisk with Medtronic.  Both partnerships seek to combine CGM data with insulin injection data, and we’re hopeful that the data combination will substantially improve insulin dosing and time-in-range – especially paired with smart titration and compelling business models. The smart pen field remains nascent, but these major partnerships indicate the continued march towards broad commercialization.

  • Novo Nordisk now has access to data from the three largest global CGM manufacturers, following previous partnerships with Dexcom (EASD 2018) and Abbott (February 2019). As part of the Medtronic announcement, Novo Nordisk updated that its first two reusable, NFC-enabled smart pens, NovoPen 6 and NovoPen Echo Plus, will launch “starting in 2020” – at least a one-year delay from the initial plan to launch in “early 2019.” The two devices have been CE-Marked since EASD 2018 and will support cartridges of basal and bolus insulin. The pens have displays to show insulin on board and time since last injection, an 800-injection dose memory, and five-year battery life. It was great to see them on display in both Novo Nordisk and Abbott exhibit hall booths. Also in the NN booth, we got a first look at a Bluetooth-enabled pen cap attachment (referred to as “Dialogue”) for disposable insulin pens. The device is not yet CE-Marked and did not appear to have a built-in display, meaning users would view all data on their smartphones. The Bluetooth cap has a 1,200-injection memory and a remarkable two-year battery life. This will be the more exciting device, in our view, as Bluetooth has more potential to deliver on the continuous connected experience vs. using NFC to manually “scan” a pen.

  • For Sanofi, FreeStyle Libre is a critical CGM partner to enhance its earlier stage connected ecosystem. In Sanofi’s partnership announcement, a vague timeline for “next few years” was given for launch, suggesting Sanofi’s smart pen efforts may not come to market until ~2022 – likely a couple years behind Novo Nordisk and Lilly. Sanofi is also “partnered” with Dexcom to some extent through Onduo (a Sanofi/Verily joint venture, where Dexcom is the preferred CGM).

  • Lilly did not share smart pen updates at EASD, though its connected pen was submitted to the FDA as of 1Q19. We’ll hear more about it at DTM 2019 in a few weeks – when will we see a US launch, especially relative to Novo Nordisk? We aren’t sure whether a disposable pen attachment or a reusable pen with built-in connectivity was submitted to the FDA. At Lilly’s Diabetes Blogger Summit (May 2018), the company said it was focused on a device that fits onto the disposable KwikPen. Lilly’s smart pen will presumably launch with Dexcom first, though there is certainly potential for other partners, and Abbott’s FreeStyle Libre was mentioned at the time. Lilly is also an investor in Companion Medical (already on the market and growing nicely), and its own hybrid closed loop system is also in development. All in all, Lilly may emerge of the three companies as having the most comprehensive automated insulin ecosystem – its own pens and own pump

2. Large CGM Studies Continue to Show Benefits Across Age Groups, SMBG Frequencies, Insulin Deliveries

• Building off momentum from ADA 2019, we saw recaps and post-hoc analyses of large, randomized studies demonstrating CGM’s effectiveness at improving glycemia. Jaeb Center’s Dr. Kellee Miller recapped the WISDM study (n=203) investigating CGM in older adults (≥60 years) with type 1 diabetes: CGM conferred a significant advantage over BGM in every outcome measured, including a two-hour per day advantage on time-in-range (70-180 mg/dl). Full three-year data from COMISAIR affirmed the one-year results presented at EASD 2016: adding CGM to MDI drives similar glycemic outcomes as adding CGM to a pump. A post-hoc analysis of the Swedish GOLD study (n=161) found that CGM effectiveness was not affected by baseline SMBG frequency. The momentum for CGM is the strongest it has ever been, and we’re hopeful that subsequent EASDs will devote more attention to CGM and time in range – this meeting continues to lag behind ADA in focus on technology. 

GLP-1 Agonists and DPP-4 Inhibitors Highlights

SUSTAIN 8 Full Results: Head to Head Trial Shows Superior A1c Reductions and Weight Loss with Ozempic vs. Invokana

Dr. Ildiko Lingvay (UT Southwestern) presented full results from the SUSTAIN 8 trial of Ozempic (injectable semaglutide) vs. Invokana (canagliflozin), demonstrating superior A1c lowering and body weight reductions associated with semaglutide treatment. Full results were also published today in The Lancet Diabetes & Endocrinology. On A1c from a baseline of 8.3%, semaglutide 1.0 mg drove a 1.5% reduction vs. 1.0% for canagliflozin 300 mg (p=0.0001), while on weight from a base of 90 kg, semaglutide gave a 5.3 kg drop vs. 4.2 kg for canagliflozin (p=0.0029). Impressively, semaglutide helped a higher proportion of patients reach ADA’s A1c target of 7% (66% reaching goal vs. 45% for canagliflozin) and AACE’s more aggressive A1c target of 6.5% (53% vs. 24%). On this point, Dr. Lingvay noted that this 6.5% target is an especially challenging goal to achieve in clinic, and the fact that it was met by over half of patients on semaglutide is very noteworthy.

• Semaglutide truly differentiated itself on weight loss outcomes, with 22% of patients achieving ≥10% weight loss (vs. 9% for canagliflozin, p<0.0001). Moreover, a post-hoc analysis showed that 7% of patients on semaglutide achieved ≥15% weight loss vs. 1% for canagliflozin (p<0.0001) – this is highly notable, as Dr. Lingvay explained that it’s the first time ever that a glucose lowering agent has shown such weight loss. This impressive weight loss isn’t surprising per se (after all, Novo Nordisk has initiated a dedicated obesity program for semaglutide (Phase 3a STEP program (four trials) initiated 2Q18; SELECT CVOT in obesity launched 3Q18; Positive phase 2 data in obesity in 2Q17) but is striking to see against another efficacious therapy that also has significant weight loss effects itself. Interestingly, the authors of the study, in the discussion section of the full paper in The Lancet Diabetes & Endocrinology, point to potential synergistic weight loss effects with SGLT-2s + GLP-1s given their putative distinct mechanisms of driving weight loss. Synergistic weight loss effects with these two drugs would be a major win for patients and we hope to see studies further exploring this possibility.

• Regarding clinical implications, SUSTAIN 8 results heartily support the notion of using semaglutide over canagliflozin (and other SGLT-2s) as second-line therapy when A1c lowering and weight loss are the primary concerns. However, an individualized approach for each patient must still be applied, and we note that SGLT-2s may be favored in situations where patients have established heart failure, are at risk for heart failure, or have CKD. Patient preferences regarding using a once-weekly injectable therapy vs. a daily oral pill must also be considered. Regardless of head to head comparisons between the class, it’s clear that agents from both classes are highly efficacious and that the broader community should continue working to ensure as many patients as possible who can derive benefit are getting onto these drugs.

• Full results from SUSTAIN 8 dovetail nicely with those from PIONEER 2 (oral semaglutide vs. empagliflozin) in generating a larger evidence base for semaglutide vs. the SGLT-2 class. As a reminder, full results from PIONEER 2 were presented at ADA 2019, showing that  from a baseline of 8.1%, mean A1c declined to 6.8% for those on the oral GLP-1 agonist (n=411) and to 7.2% for those on Lilly/BI’s SGLT-2 inhibitor Jardiance (n=410) over 26 weeks (p<0.05). In PIONEER 2, weight loss was similar in both groups: From a baseline 202 lbs, mean body weight fell by 8 lbs with both molecules (non-significant p-value) – a majority of this weight loss occurred in the first 26 weeks and was maintained through the full year. 

VERIFY Full Results: Early Combo Therapy of DPP-4 Galvus + Metformin Superior to Monotherapy and Sequential Intensification; Doubles Time to Treatment Failure, Provides Added Glycemic Durability, and Shows Intriguing Potential CV Risk Reduction

Very positive full results from VERIFY (n=2,001) revealed that early combination therapy of metformin and Novartis’ DDP-4 inhibitor Galvus (vildagliptin) doubled the time to initial treatment failure vs. metformin monotherapy. Full results were also published in The Lancet (see here). Treatment with combination therapy resulted in a significant 26-month delay in the primary outcome of treatment failure (defined as reaching A1C > 7%) and treatment intensification compared to monotherapy (p<0.0001). Specifically, those on initial monotherapy received surpassed an A1c of 7% at a median 36 months, compared to 62 months for those on early combination (vildagliptin + metformin). Treatment with combination therapy also resulted in significantly delayed insulin therapy (p<0.0001), meeting the secondary outcome in favor of combination therapy. Results from VERIFY are highly notable, as they present strong evidence for the first time regarding benefits of early combination therapy on durable glycemic control. Moreover, exploratory analysis of the trial also demonstrated intriguing cardiovascular outcomes – in a small sample, but hypothesis generating nonetheless (see below for more). KOL reaction was positive toward VERIFY, and Dr. Dan Drucker summed up implications from the trial quite well in his Twitter musings: “What does VERIFY teach us about treating type 2 diabetes? Diabetes is a serious disease! Think more like an oncologist (early combination therapy) rather than a traditional treat to failure approach. Well tolerated drug combinations with established safety profiles should be used earlier.” This is a brilliant approach – many are already viewing VERIFY as an important evidence base for tackling therapeutic inertia through early combo therapy use. Moreover, with DPP-4 inhibitors soon becoming generic, we see immense possible for accessible and affordable combination therapies of DPP-4s + metformin. And, investments should be made now. For historical context, see in yellow below from a talk by Dr. John Buse what we were writing about DPP-4 inhibitors back in 2007

• VERIFY Introduction and Research Question: Dr. Chantal Mathieu started the session off with an overview of the premise of the VERIFY trial, which aims to answer the question of whether providers should initiate combination therapy at the start of glucose-lowering treatment in patients with type 2 diabetes. This overarching theme distills into three clinical questions: (i) Do those with type 2 diabetes benefit from combined therapy at the beginning of pharmacological treatment; (ii) Do they benefit more from combination therapy versus additive therapy; and (iii) Does it matter clinically? Early combination therapy has potential to synergistically target many of diabetes’ pathophysiological mechanisms and lead to better outcomes by preventing or slowing beta-cell function decline without increasing the risk of adverse events or comorbidities. There’s currently little evidence on whether coupling medications as first line therapy creates an additive or protective effect in health outcomes.

• Background, Design, and Outcomes: Dr. Michael Stumvoll explained that starting combination therapy early may provide an opportunity for reaching glycemic targets before A1c rises to hard to manage levels. Very notably, treatment in VERIFY, a randomized, double-blind, two arm, parallel-group trial that spanned five years, starts at the earliest time and the lowest A1c of all other large-scale anti-hyperglycemic drug efficacy trials (!). All enrolled patients were between 18 and 70 years old, drug-naïve, recently diagnosed with type 2 diabetes (≤24 months), and had eGFRs ≥60 mL/min, BMIs between 22 and 40 kg/m², and A1cs between 6.5% and 7.5%.

• VERIFY’s unique trial design featured three periods, with two transition points aligned with the primary and secondary outcomes. Patients were randomized to the early combination therapy group (metformin and Vildagliptin) or monotherapy group (placebo and metformin) in “period one.” If a patient’s A1c surpassed 7%, they either stayed on combination therapy (if started on combination therapy) or progressed to combination therapy (if started on monotherapy) for “period two.” The primary outcome, time to failure, was measured if a patient’s A1c increased above 7% during period one; otherwise, they stayed on period one treatment. The secondary outcome, time to second failure, was measured if a patient’s A1c remained greater than 7% for at least six months during period two. The patient then advanced to insulin treatment during “period three.” Time to first failure determined if there was benefit to combination therapy at the beginning of pharmacological treatment, while time to second failure determined if there was more benefit from initial combined therapy versus sequential additive therapy. Failure is confirmed or denied by a practitioner at a visit every three months, and rate of failure is calculated in each strategy group as a proportion of those failing out of all present in each treatment strategy group.

• Results: Early combination therapy delayed both time to initial treatment failure (median difference in time-to-failure vs. placebo: +25.8 months; HR: 0.51; 95% CI: 0.45-0.58; p<0.0001) and time to second failure (HR: 0.74; 95% CI: 0.63-0.86; p<0.0001). Rate of loss of glycemic control was also lower in the early combination therapy group, and in future studies, will be analyzed to determine beta cell function and insulin resistance. Both treatment options showcased similar success rates, with early combination therapy showing slightly higher success rates that became more pronounced when target A1c amount was lowered. Dr. David Matthews emphasized that this trend means that early combination therapy is more beneficial if A1c goals are lower. Very notably, there did appear to be fewer CV events in the early combination group than in the initial monotherapy group. Of course, VERIFY was not a CVOT, and was not powered for such analyses, making these results exploratory at best. Nonetheless, they are very intriguing, and prompted much discussion during commentary (see below).

• Discussing clinical implications of VERIFY, Prof. Stefano del Prato noted that these results could help minimize therapeutic inertia and enhance use of earlier combo therapy. Prof. del Prato also appeared quite bullish regarding potential CV benefits of such a strategy. He emphasized that the finding of fewer CV events in the early combo group is hypothesis-generating only, and certainly not a proof that early combo therapy could decrease CV risk. However, the opening of the two curves (especially at such early time points, as seen in the curves above) surely represent ground for future investigation in his view – we would surely love to see such CVOTs of combo therapies done, especially with combinations of therapies that have proven CV benefits on their own (i.e. SGLT-2s and GLP-1s). In his independent commentary, Dr. Cliff Bailey also honed in on this exploratory outcome of CV events. Dr. Bailey was especially intrigued by the early separation of curves and wonders whether we could see effects in primary prevention, given the relatively healthy patient population enrolled in the trial.

SGLT-2s or GLP-1s for Renal Protection? KOLs Compare Data Between Classes; Currently Favor SGLT-2s, But Future Data on GLP-1s (Namely Semaglutide’s FLOW Trial) Could Shift Debate

In reviewing renal outcomes data for SGLT-2 inhibitors and GLP-1 agonists, Dr. David Cherney (Toronto General Hospital Research Institute) expressed more confidence with SGLT-2s given their impressive benefits in outcomes trials on hard renal endpoints. Dr. Cherney asserted that renal outcomes data for the GLP-1 class is “very interesting,” as the class has been shown to reduce renal composite endpoints that include reducing macroalbuminuria. However, the effect of the class does appear to be driven by this endpoint, as removing macroalbuminuria considerations for these composite endpoints results in no significant benefits with GLP-1s. Dr. Cherney noted that it’s “still an open question that needs to be addressed in dedicated trials” and pointed to Novo Nordisk’s FLOW trial investigating semaglutide on renal outcomes as an important step for the field in helping to answer this question. As a reminder, the FLOW trial was initiated in June 2019 and will enroll 3,160 patients with type 2 diabetes and CKD (eGFR 25-75 ml/min/1.73 m²) for up to five years. Expected completion is August 2024, and the primary endpoint is a composite of persistent eGFR decline of ≥50%, reaching ESRD, and CV or renal death. Traditional MACE endpoints will also be measured and we hope Time in Range and PROs will be also. This is a highly notable, first-ever renal outcomes trial among GLP-1s, and it’s clear that enthusiasm is high for the trial’s potential in further informing renal benefits of the GLP-1 class. We’ve sensed optimism from Novo Nordisk that more efficacious GLP-1s (such as semaglutide) may be able to compete in the future with renal outcomes data from the SGLT-2 class, along with providing the additional benefit of not losing their glucose lowering abilities in patients with a lower eGFR.

• Dr. Cherney’s assessment of the GLP-1 class on renal outcomes aligns with broader KOL consensus that we’ve gathered on the topic. In light of REWIND results, KOLs appeared a bit underwhelmed by dulaglutide’s efficacy on renal endpoints, and noted that data for the GLP-1 class on these endpoints somewhat pale in comparison to those shown by the SGLT-2 class, to date.

• Later on in the day, University of Helsinki’s Dr. Per-Henrik Groop made this same point in a Lilly/BI sponsored session, noting that GLP-1 renal outcomes data is primarily driven by macroalbuminuria reductions and not on the same hard renal outcomes that the SGLT-2 inhibitor class has so impressively shown benefits on.

• Dr. Hiddo Heerspink also weighed in on the subject during AZ’s symposium, asserting that if he had to choose between a GLP-1 and an SGLT-2 in terms of protecting kidney health in a post-ACS type 2 diabetes patient, he would surely choose the SGLT-2.

• Dr. Cherney also commented on the usage of SGLT-2s in patients with low eGFRs, asserting that renal-protective effects are likely preserved across all eGFR levels. Indeed, although SGLT-2 inhibitors remain contraindicated for those with severe renal impairment (eGFRs below 45 mL/min/1.73 m²), their benefits on renal outcomes have been significant in those with lower eGFR levels. Dr. Cherney noted that CANVAS, EMPA-REG, DECLARE, and CREDENCE all enrolled patients down to an eGFR of 30 (with benefit still seen here), while ongoing dedicated CKD trials in Dapa-CKD and EMPA-KIDNEY are going down even further in terms of eGFR (25 and 20, respectively). Of course, the current contraindication for SGLT-2 inhibitors in those with eGFRs below 45 is not because of potential safety concerns, but because of the attenuation of glycemic benefits at lower eGFRs. Dr. Cherney predicted that the future of SGLT-2 inhibitors will include broader use of the class in these patients with lower eGFRs, seeing as their impressive effects on renal and CV outcomes are significant in these patients. We’re curious whether results from Dapa-CKD and EMPA-KIDNEY (along with those from CREDENCE) may help regulatory agencies reconsider this contraindication. Dr. Cherney appeared confident on this front, noting that it’s likely that these labels will be changed to recommend usage in patients with eGFR’s as low as 30 (he also commented that this is already the case in Canada).

PIONEER Analysis Shows Consistent Efficacy with Oral Semaglutide Across Baseline A1c Levels; Greatest Effects with Highest Doses + Higher Baseline A1c

Dr. Juris Meier presented a new analysis of the PIONEER trials for oral semaglutide demonstrating the therapy’s consistent effect on glucose and weight across a wide spectrum of baseline A1c levels. In the analysis, all patients from PIONEER 1-5, 7, and 8 were included (n=5,657) and binned into baseline A1c groups of ≤8%, between 8% and 9%, and >9%. A1c reductions associated with oral semaglutide showed consistent benefit across each baseline A1c group, with larger A1c drops understandably seen in the higher baseline A1c groups. Results reinforce oral semaglutide’s potential in a wide patient population, allowing HCPs to confidently prescribe the therapy across a broad spectrum of patients, ranging from those achieving relatively decent glucose control (A1c <8%) to those who might be experiencing greater challenges with glucose control (A1c >9%). Notably, this analysis further confirmed oral semaglutide’s robust superiority on glycemic effects when compared to the active comparators it was tested against in the PIONEER program: oral semaglutide at a higher dose (7 mg and 14 mg) achieved greater A1c reductions across baseline A1c levels when compared to active comparators of empagliflozin in PIONEER 2, sitagliptin in PIONEER 3, and liraglutide in PIONEER 4. See summary table below:

Prof. Philip Home’s Independent Commentary on CAROLINA: “Beautiful” Clinically Relevant Study; CAROLINA Published in JAMA this AM with Editorial from Dr. Wexler

Even for those who had seen the presentation of the CAROLINA CVOT (n=6,033) –showing non-inferiority on three-point MACE for Lilly/BI’s DPP-4 inhibitor Tradjenta (linagliptin) vs. the sulfonylurea glimepiride – at ADA 2019, independent commentary from Newcastle’s Prof. Philip Home made attendance at the European presentation well worth it. Following a series of talks on the study rationale, design, results, and significance from the same exact lineup present at ADA (Drs. Julio Rosenstock, Mark Espeland, Steven Kahn, Nikolaus Marx, Bernie Zinman, and Darren McGuire), Prof. Home took to the podium to offer his interpretation, which was largely positive: “Sadly, as I really love to criticize Julio [Dr. Rosenstock], I actually loved CAROLINA from the moment I heard of its conception. The reason really being because it was an active comparator study pitting linagliptin against an active comparator.” The bullets below delineate Prof. Home’s more specific takeaways. Note, too, that CAROLINA was published just this morning in JAMA alongside an editorial by Dr. Deborah Wexler asserting that CAROLINA represents “one of the most important findings to emerge from this set of trials [post FDA 2008] regarding the CV safety of SUs” and that “the perennial concern regarding the CV safety of SUs raised by the UGDP more than 40 years ago may finally have been assuaged by CAROLINA trial.”

• Prof. Home lauded the study for its clinical relevance. First, it compared the two most commonly-used second-line therapies (and most probable in those with mild CV risk). Second, the enrolled population was more representative of the general diabetes population: “Most CVOTs don’t apply to 80%+ of the people we see in clinics…This trial event rate [2.1 per patient-year] is quite close to the unselected population in the RECORD study” (see slide below). Third, it included a reasonably ethnically and geographically diverse population, unlike other recent CVOTs; he specifically pointed to the fact that 18% and 17% of participants were Asian and Hispanic/Latino, respectively. That said, just 5% of the population was black. Fourth, median 6.3-year follow-up with median drug exposure of 5.9 years was appropriate to detect adverse event for a therapy likely to be used long term, and the power was adequate to give smooth, “non-erratic” Kaplan-Meier curves, unlike you’d see in “say, EMPA-REG [OUTCOME].”

  • One instance in which the study may have strayed from clinical relevance, in his view, is in the at-first-glance concerning data on recurrent hypoglycemia. As Dr. Zinman presented, the rate ratio of a second blood glucose ≤70 mg/dl or severe hypoglycemia was 0.09 (95% CI: 0.07-0.11; p=0.0001) for linagliptin vs. glimepiride, confirming that recurrent hypoglycemia was significantly more common with the SU. Prof. Home reasoned that this data is not reflective of real clinical practice, since providers wouldn’t keep people on SUs after one year if they had had two events. (If only that were true in all geographies! We believe heaps of patients go on SUs and stay on them due to a variety of factors – even though of course what Professor Home says is what should be done.)

• “I believe results can be extrapolated to other DPP-4 inhibitors, I see no reason why not. For other SUs, we’re still uncertain.” The independent commentator at ADA, Dr. Matthew Riddle, aligned with Prof. Home on lack of generalizability to other SUs, but was more cautious about applying the linagliptin data to the DPP-4 inhibitor class. Dr. McGuire, too, agreed that this study does not assuage concern of all SUs: “It may be that others would behave similarly, but that is not a complete certainty.” All that said, he cautioned that we still haven’t demonstrated glimepiride’s safety in a high-risk population.

• Though he appreciated the design and premise of CAROLINA, Prof. Home lamented the fact that UGDP trial influenced the field so strongly for so long, quipping that such hesitation was “frankly silly” given the miniscule number of events in UGDP. He went on to cite plentiful evidence from UKPDS, ADOPT, RECORD, ADVANCE, and TOSCA.IT that SUs are safe from a CV perspective (if not hypoglycemia and weight). “Albeit not from a direct study like this beautiful one, we were already reasonably confident these drugs were safe.”

  • Dr. McGuire noted, on the other hand, that cardiologists have been very concerned about SUs, “probably more so than diabetologists,” in the wake of UGDP. “Never have 36 events caused so much confusion and consternation. Here we are 50 years later, finally with an answer.”

• Prof. Home noted that the A1c trajectories were in line with expectations for both medications. In ADOPT and RECORD, he said, SUs were the most effective glucose-lowering drug early on, but they then lose their effect. Prof. Home noted that linagliptin had a similar impact on A1c over the first six to eight months of use as do metformin and rosiglitazone.

• Prof. Home who was a major advisor in the development of glimepiride, noted that the SU seems to have been titrated correctly in CAROLINA. By the end of the study, 66% of patients were on the maximum 4 mg/day dose, which he called “very reasonable.”  

• Echoing Dr. Zinman during his safety presentation, Prof. Home proclaimed: “I think the pancreatitis data puts the potential risks attributed to DPP-4 inhibitors to rest.”

• Prof. Home’s one complaint was that the reported lipid and A1c data stops at five years in the paper, whereas the CV, mortality, and other results extend to seven years. We’re not sure why this is the case, and the investigators did not respond. We’d like to see the additional two years of data as well – while some say they wouldn’t expect significant divergence, it’s hard to say what A1c data will show in terms of long-term durability without seeing it upfront and close. 

Phase 3a GLP-1 data Shows Favorable A1c-lowering Profile for Hansoh Pharma’s Novel Once-Weekly GLP-1 Agonist PEX 168

A poster showed favorable phase 3a data for Hansoh Pharma’s once-weekly GLP-1 agonist PEX168 (polyethylene glycol loxenatide) in people with type 2 diabetes. The trial randomized people with type 2 diabetes (n=406) to either 100 or 200 µg PEX168 or placebo for 24 weeks. At the end of the study, participants on PEX168 experienced significant improvements in A1c: -0.99% from baseline for the 100 µg dose and -1.34% for the 200 µg dose(vs. a non-significant -0.15% with placebo). Furthermore, the proportion of patients who achieved an A1c <7% by the end of the 24 weeks stood at 35% and 47% in the 100 µg and 200 µg dose groups, respectively, both significantly higher than in the placebo group (16%). No serious adverse events or severe hypoglycemia events occurred in the trial, and most adverse reactions were mild to moderate GI reactions, as is expected for the GLP-1 agonist class. According to the study’s ClinicalTrials.gov page, a 28-week extension period is planned, where participants randomized to placebo will cross over to one of the active comparator arms. We look forward to following up on the full readout and will be particularly eyeing the weight loss data, which is listed as a secondary outcome. While the phase 3a data presented here look encouraging, we note that the GLP-1 agonist space is highly competitive, and PEX168 will have a high bar to clear if it is to compete against heavyweights like Trulicity, Victoza, and Ozempic – market leaders with impressive profiles for combination glucose-lowering, weight-loss, and CV protection. Notably, PEX168 is already approved in China, launched earlier this year under the brand name Fu Laimei.

New REWIND Stroke Outcomes Data: Dulaglutide Reduces the Risk of Non-Fatal (But Not Fatal) Stroke and Protects Against Ischemia (But Not Hemorrhage)

Dr. Hertzel Gerstein unveiled new REWIND data, diving deep into stroke outcomes with Lilly’s GLP-1 agonist Trulicity (dulaglutide). Released only a few months ago at ADA 2019, the REWIND trial demonstrated a 12% relative risk reduction on 3-point MACE (HR=0.88, 95% CI: 0.79-0.99) with dulaglutide vs. placebo, with strong consistency between both the primary (69% of participants) and secondary (31%) prevention cohorts. Overall, dulaglutide showed a 24% relative risk reduction for fatal and non-fatal stroke (HR=0.76, 95% CI: 0.62-0.94; p=0.010). This effect seems to be driven primarily by nonfatal stroke (HR = 0.76, 95% CI: 0.61-0.95; p=0.017), as there was no significant effect of dulaglutide on fatal stroke (HR = 0.78, 95% CI: 0.47-1.30; p=0.34), and only a very small number of fatal strokes occurred in the trial. Furthermore, dulaglutide’s protective effects apply only to ischemic stroke (HR: 0.74, 95% CI: 0.59-0.94; p=0.012), not hemorrhagic stroke (HR: 1.05, 95% CI: 0.55-1.99). According to Dr. Gerstein, although the mechanistic insights that can be gleaned from CVOTs are limited, this finding suggests that dulaglutide’s protective effects relate to ischemia, or diminished blood supply, rather than ruptured blood vessels. The investigators additionally examined the impact of dulaglutide on “disabling stroke” – that is strokes with a modified Rankin severity score ≥3. Interestingly, dulaglutide showed an impressive 26% risk reduction for disabling stroke (HR: 0.74, 95% CI: 0.56-0.99; p=0.042), but the overall distribution of Rankin scores between the strokes that occurred in the dulaglutide and placebo groups were not significantly different (p=0.18). This indicates that while dulaglutide does reduce the risk of disabling strokes (and strokes in general) from occurring, if a stroke does occur the drug does nothing to reduce its severity. As Dr. Gerstein put it “there is a comparable distribution of stroke severity if you’re unfortunate enough to have a stroke, regardless of which drug you were on.” Finally, in exploratory subgroup analyses there appeared to be no heterogeneity in dulaglutide’s stroke-protective effects according to sex, BMI, A1c level, or absence vs. presence of existing CV disease (i.e. primary vs. secondary prevention).

• Highlighting a 2019 meta-analysis of all five reported GLP-1 agonist CVOTs, Dr. Gerstein pointed out that risk reduction for stroke was the highest of any MACE component (HR = 0.84, 95% CI: 0.76-0.93, p<0.0001). In fact, the only GLP-1 agonist not to show significant risk reduction for stroke was ELIXA (for Sanofi’s lixisenatide), although we’ve heard ample commentary that the entirely post-recent-ACS population enrolled in ELIXA was likely too sick for lixisenatide to confer any benefit (i.e., the population was ‘too far gone’). While the overall CV benefits of GLP-1 agonists are clear, Dr. Gerstein suggested that the especially potent effect on stroke risk reduction may point to a particular effect of GLP-1 agonists on the brain. (To this end, just yesterday we saw promising preclinical data on GLP-1 agonists for the treatment of neurodegenerative disease).

Novo Nordisk Symposium Highlights GLP-1 + SGLT-2 Combo Therapy and Lack of GLP-1 Penetration – Could Oral Sema Move the Needle?

GLP-1s stole the show at Novo Nordisk’s packed corporate symposium on moving beyond the standard in diabetes and obesity care, led by a star-studded cast including Drs. Rory McCrimmon, Subodh Verma, Ofri Mosenzan, Thomas Wadden, Melanie Davies, Vanita Aroda, and more. Themes from the session included (i) optimized use of GLP-1s for patients with type 2 diabetes; (ii) optimized use of GLP-1s for patients with obesity; and (iii) the future of GLP-1s. Read on for some top highlights below!

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Dr. Rory McCrimmon focused on the potential benefits of combining GLP-1s and SGLT-2 inhibitors for patients with type 2 diabetes, displaying a particularly helpful table of the two drugs’ possible counterbalancing effects. For example, hepatic glucose output is negatively impacted by the use of an SGLT-2 inhibitor; however, adding a GLP-1, which beneficially decreases glucose production, can neutralize the effect for patients. Dr. McCrimmon cited the AWARD 10, DURATION 8, and LIRA-ADD2SGLT-2i clinical trials as evidence of the combination’s success.

• Dr. Thomas Wadden and Dr. Ofri Mosenzan tackled GLP-1 usage in patients with obesity – the former focusing on intensive behavior therapy (IBT) and the latter on combination usage with basal insulin. Dr. Wadden presented data from the SCALE IBT trial (n=282), which combined liraglutide 3.0 mg with IBT (prescribed exercise of 250 min/week, reduced caloric intake based on body weight, and 23 IBT counseling visits) for patients with a BMI ≥30 kg/m² but without diabetes. In the study, behavioral counseling with placebo induced a mean reduction in baseline weight of 5.4% at six months, confirming the effectiveness of brief IBT alone. Although six-month results did not differ greatly for those additionally on liraglutide, patients who stayed on the therapy at week 56 saw an impressive loss of 9.1% of baseline weight. Dr. Mosenzan focused on the SCALE Insulin trial (n=396) which looked at liraglutide 3.0 mg + IBT vs. placebo + IBT in patients with overweight/obesity and basal insulin-treated type 2 diabetes. Cumulative results showed that patients also on liraglutide were 3.3x more likely to achieve ≥5% weight loss, A1c <7%, and no documented symptomatic hypoglycemia (p=0.0006) – these results are incredibly encouraging, and overall, we see tremendous potential for GLP-1s in the evolving field of diabetes treatment.

• In terms of the future of GLP-1s, oral semaglutide was the obvious center of attention. While the overall audience opinion on oral semaglutide was generally positive (praise for the PIONEER trials received light but spontaneous applause), the question of pricing, and more broadly why only ~10% of eligible patients are on GLP-1s, did seem to be a hot topic from the audience. In response to this query, both Dr. Melanie Davies and Dr. Vanita Aroda pointed to lack of provider comfortability as a major factor. Dr. Davies noted that while DPP-4 inhibitors are similarly priced to GLP-1s in her native UK, DPP-4 inhibitors are still far more often prescribed. Dr. Aroda added that some practitioners feel less prepared to put their patients through careful dose escalation and explain GI side effects compared to other drugs. We’re hopeful that oral semaglutide could help to bend the curve here by reducing injection burden (perceived or real). To end Q&A, the panel collectively agreed that the challenges with GLP-1 accessibility are not just in the United States and Europe but also in Africa and Asia – we wholeheartedly agree and hope that the conversation on access is not just limited to those who have the means to speak about it!

Post-Hoc Analysis of DURATION-8 Trial Hints at NAFLD/NASH Benefits with GLP-1/SGLT-2 Combination Therapy

A post-hoc analysis of the DURATION-8 trial showed improvements in liver fat and fibrosis with combination therapy of the GLP-1 agonist exenatide and SGLT-2 inhibitor dapagliflozin. As a reminder, DURATION-8 compared exenatide/dapagliflozin combination therapy against both monotherapies alone, finding significantly greater A1c reductions and weight loss with two agents vs. one over two years follow-up. At baseline, >81% of the DURATION-8 population (mean age 55 years; mean A1c 9.3%; mean BMI 33%) had fatty liver/steatosis and >9% had more severe liver fibrosis. In participants on exenatide/dapagliflozin combination therapy, the prevalence of fatty liver fell 10.5% and the prevalence of steatosis fell 6.1% after 28 weeks of therapy. Also at this time point, the proportion of patients with liver biomarker scores indicating the presence of advanced fibrosis fell 4% for those on the combination therapy regimen.

• Several individual GLP-1 agonists and SGLT-2 inhibitors have been investigated in NAFLD/NASH, but to our knowledge this is the first large-scale examination of GLP-1/SGLT-2 combination therapy. The study author, Dr. Cristian Guja (Carol Davila University, Bucharest, Romania) underscored that DURATION-8 wasn’t powered to investigate NAFLD/NASH outcomes and didn’t include any histological examination or imaging of the liver, so these findings are by no means definitive and must be validated in a dedicated prospective trial. That said, we find the results very encouraging. About half of people with type 2 diabetes and obesity are estimated to have NAFLD, so it is a very attractive proposition for diabetes combination therapy to double as therapy for liver disease. Of course there is also no shortage of novel agents in development for NAFLD/NASH in the ever-expanding competitive landscape.  

Ellipse Trial Shows Encouraging Results for Liraglutide in Adolescents with Type 2 Diabetes

University of Birmingham’s Dr. Timothy Barrett presented results from the Ellipse trial, demonstrating the efficacy of GLP-1 agonist liraglutide as an add-on to metformin in adolescents with type 2 diabetes (n=134). After 26 weeks, from a baseline A1c of 7.5%, average A1c fell 0.64% with liraglutide vs. a 0.42% rise in A1c with placebo (p<0.001). This difference persisted at the 52 week mark: A1c reductions with liraglutide stood at -0.50%, vs. +0.80% with placebo (p<0.001). Liraglutide also produced improvements in other key secondary outcomes, including FPG (-19 mg/dl vs. +14 mg/dl with placebo at 52 weeks) and proportion of patients who attained an A1c <7% (64% vs. 37% with placebo at 26 weeks). Over the full study period, the most common adverse events were nausea, vomiting, and diarrhea, as is typical for GLP-1 agonists. As for hypoglycemia, there were more symptomatic (19 vs. 6) and asymptomatic (21 vs. 12) events in the liraglutide-treated group vs. the placebo-treated group. During Q&A Dr. Barrett elaborated that this is something to further explore to ensure the safety of liraglutide in this patient population. Liraglutide is not associated with increased hypoglycemia risk in adults, and one likely explanation is that the majority of these hypoglycemia events occurred in patients who were additionally taking insulin (one of the only medications approved for adolescents with type 2 diabetes). Overall, the Ellipse results are encouraging for the use of liraglutide in this under-served patient population. In the ensuing Q&A, Dr. Barrett affirmed that the results of this trial will change his own clinical practice. In his words, “I’d much rather use liraglutide than insulin.” As a reminder, FDA approved Victoza in this patient population in June 2019.

• At ADA 2016, we were warned that the incidence of early onset type 2 will increase in the coming years, especially in underserved minority groups. This adds additional urgency to the need for therapies beyond metformin and insulin in this patient population, especially given the increased risk of especially aggressive diabetes complications with such an early onset of disease. We would imagine that liraglutide’s CV benefits are especially meaningful for this population as well.

Dulaglutide Treatment in People with Type 2 and Binge Eating Disorder: A New Parameter in Prescriber Decision Making?

Dr. Andrea Da Porto discussed how GLP-1 agonists may confer superior weight loss by reducing binge eating behaviors in people with type 2 diabetes and binge eating disorder. After 12 weeks of treatment, non-drug naïve patients with diabetes and binge eating disorder given Trulicity (dulaglutide) showed greater decreases in binge eating behavior, more weight loss, and better glycemic control than patients given the sulfonylurea gliclazide. Specifically, patients on dulaglutide lost a median 1.9% of fat mass (p<0.0001; vs. 0.2% fat loss in the gliclazide group) and showed a median A1c drop of 1.07 (p=0.009; vs. 0.75 drop in the gliclazide group). Change in binge eating symptoms was also significantly associated with change in weight (p<0.0001) and change in A1c (p=0.033). Results potentially support the theory suggested by preclinical studies and clinical case reports that GLP-1s can influence appetite regulation by counteracting food cravings and overeating. Interestingly, the effects on body weight reported in the GLP-1 group were superior to what was expected from 12-weeks of treatment, further supporting the need to study appetite regulation and identify binge eating disorder in the diabetes population. Overall, binge eating disorder could represent a parameter for clinicians to consider in choosing among different therapeutic options to treat people with type 2.

• Though results could mean promising strides in the future of both diabetes and binge eating disorder treatment, results may have been affected by methodological limits. This study’s limitations include small sample size, brief follow-up period, and the known magnified effects of GLP-1s on weight early in treatment. With this, no patients on dulaglutide stopped the therapy prematurely due to side effects, which is often seen in clinical practice. During Q&A, an audience member brought up a great point: SU use is often associated with weight gain. In response, Dr. Da Porto stated that he doesn’t believe such short use of gliclazide caused any confounding weight gain and agrees that the study should be extended to determine if this confounder exists.

A Role for GLP-1 Agonists and GLP-1/GIP Dual Agonists in Treating Alzheimer’s and Parkinson’s?

Henan University’s Dr. Christian Hölscher discussed early evidence that incretin analogues such as GLP-1 agonists and GLP-1/GIP dual agonists could be neuroprotective in Alzheimer’s and Parkinson’s diseases. In rodent models of Alzheimer’s disease, both lixisenatide (Sanofi’s Lyxumia) and liraglutide (Novo Nordisk’s Victoza) improved memory, boosted synaptic plasticity, decreased the load of beta-amyloid plaques in the brain, and reduced the number of activated microglia (suggesting an anti-inflammatory mechanism). Similarly, in rodent models of Parkinson’s disease lixisenatide and liraglutide improved motor activity, preserved neurons in the substantia nigra (the main area of damage in Parkinson’s disease), and reduced activated microglia (again, pointing to anti-inflammation). On the heels of these results, in-human trials of GLP-1 agonists in Parkinson’s disease are underway. A 2013 trial showed improvements in motor skills and cognitive performance with exenatide (AZ’s Bydureon) in people with Parkinson’s disease, and these lasted three months after the drug treatment was stopped. Three additional phase 2 trials are currently underway examining liraglutide (completion expected in 2019), lixisenatide, and semaglutide. Dr. Hölscher showed additional data demonstrating that GLP-1/GIP dual agonists have an even more powerful effect on rodent models of Alzheimer’s and Parkinson’s diseases. He has developed two novel GLP-1/GIP dual agonists that are able to cross the blood-brain-barrier (not true for all diabetes drugs, particularly peptides) and founded a new company, Kariya Pharmaceuticals, to advance these candidates through toxicology and dose-response studies in humans.

• Why the beneficial effect for incretins? Dr. Hölscher noted that incretins normalize energy utilization, reduce inflammation, and enhance cell repair. In the brain, this could translate to protection against neurodegenerative disease.

• Although these results are incredibly early-stage, needless to say we are extremely intrigued and eagerly look forward to watching the first in-human trials. Dr. Hölscher noted that type 2 diabetes is a hypothesized risk factor for both Parkinson’s and Alzheimer’s, so these findings could add one more item to the (long) list of diabetes complications that are lessened with GLP-1 agonists.

NAFLD/NASH Overview Stresses Need for Better Screening and Clinical Phenotyping + Optimism for GLP-1

Dr. Elisabetta Bugianesi emphasized that clinical phenotyping needs to place focus on type 2 diabetes, hypertension, and metabolic syndrome in diagnosing NAFLD and determining which patients need immediate attention. As obesity and type 2 diabetes make patients more likely to develop liver fibrosis, which increases the risk of liver-related mortality, screening needs to start early to prevent the subsequent progression of mild to severe fibrosis. Screening also needs to become more dynamic and take the metabolome, proteome, and microbiome into account. Current screening modalities, like biopsies and ultrasounds, are a snapshot in time and do not give clear indications of trends in liver health that are usually non-linear. Dr. Bugianesi believes that markers of fibrolysis and fibrogenesis, if validated, may better suit diagnosis and treatment monitoring. However, accuracy and accessibility of use need to be balanced in these new screening methods.

• There is currently no long-term data on the efficacy of lifestyle, pioglitazone, and vitamin E treatment on NAFLD, but GLP-1 agonists may hold promise. In the phase 2 LEAN trial, liraglutide showed safety and a 39% resolution in NASH (vs. 9% on placebo; p=0.019). However, methodological issues like small sample size and low placebo response rate limit validity of findings, and results could be confounded by weight loss effects. Looking ahead, the entire field is excited for results of Novo Nordisk’s phase 2 trial of semaglutide in NASH, expected to complete in November 2019. See the complete NASH landscape here.

• Clinically meaningful outcomes in pre-cirrhotic NASH should prevent cirrhosis and improve CVD-associated metabolic risk factors. This would shift clinical focus from resolution of NASH and fibrosis to prevention. In the long-term, this translated to decreased rates of liver and CVD morbidity and mortality.

GLP-1 Agonists and DPP-4 Inhibitors Poster Highlights

SGLT Inhibitors Highlights

SUSTAIN 8 Full Results: Head to Head Trial Shows Superior A1c Reductions and Weight Loss with Ozempic vs. Invokana

Dr. Ildiko Lingvay (UT Southwestern) presented full results from the SUSTAIN 8 trial of Ozempic (injectable semaglutide) vs. Invokana (canagliflozin), demonstrating superior A1c lowering and body weight reductions associated with semaglutide treatment. Full results were also published today in The Lancet Diabetes & Endocrinology. On A1c from a baseline of 8.3%, semaglutide 1.0 mg drove a 1.5% reduction vs. 1.0% for canagliflozin 300 mg (p=0.0001), while on weight from a base of 90 kg, semaglutide gave a 5.3 kg drop vs. 4.2 kg for canagliflozin (p=0.0029). Impressively, semaglutide helped a higher proportion of patients reach ADA’s A1c target of 7% (66% reaching goal vs. 45% for canagliflozin) and AACE’s more aggressive A1c target of 6.5% (53% vs. 24%). On this point, Dr. Lingvay noted that this 6.5% target is an especially challenging goal to achieve in clinic, and the fact that it was met by over half of patients on semaglutide is very noteworthy.

• Semaglutide truly differentiated itself on weight loss outcomes, with 22% of patients achieving ≥10% weight loss (vs. 9% for canagliflozin, p<0.0001). Moreover, a post-hoc analysis showed that 7% of patients on semaglutide achieved ≥15% weight loss vs. 1% for canagliflozin (p<0.0001) – this is highly notable, as Dr. Lingvay explained that it’s the first time ever that a glucose lowering agent has shown such weight loss. This impressive weight loss isn’t surprising per se (after all, Novo Nordisk has initiated a dedicated obesity program for semaglutide (Phase 3a STEP program (four trials) initiated 2Q18; SELECT CVOT in obesity launched 3Q18; Positive phase 2 data in obesity in 2Q17) but is striking to see against another efficacious therapy that also has significant weight loss effects itself. Interestingly, the authors of the study, in the discussion section of the full paper in The Lancet Diabetes & Endocrinology, point to potential synergistic weight loss effects with SGLT-2s + GLP-1s given their putative distinct mechanisms of driving weight loss. Synergistic weight loss effects with these two drugs would be a major win for patients and we hope to see studies further exploring this possibility.

• Regarding clinical implications, SUSTAIN 8 results heartily support the notion of using semaglutide over canagliflozin (and other SGLT-2s) as second-line therapy when A1c lowering and weight loss are the primary concerns. However, an individualized approach for each patient must still be applied, and we note that SGLT-2s may be favored in situations where patients have established heart failure, are at risk for heart failure, or have CKD. Patient preferences regarding using a once-weekly injectable therapy vs. a daily oral pill must also be considered. Regardless of head to head comparisons between the class, it’s clear that agents from both classes are highly efficacious and that the broader community should continue working to ensure as many patients as possible who can derive benefit are getting onto these drugs.

• Full results from SUSTAIN 8 dovetail nicely with those from PIONEER 2 (oral semaglutide vs. empagliflozin) in generating a larger evidence base for semaglutide vs. the SGLT-2 class. As a reminder, full results from PIONEER 2 were presented at ADA 2019, showing that  from a baseline of 8.1%, mean A1c declined to 6.8% for those on the oral GLP-1 agonist (n=411) and to 7.2% for those on Lilly/BI’s SGLT-2 inhibitor Jardiance (n=410) over 26 weeks (p<0.05). In PIONEER 2, weight loss was similar in both groups: From a baseline 202 lbs, mean body weight fell by 8 lbs with both molecules (non-significant p-value) – a majority of this weight loss occurred in the first 26 weeks and was maintained through the full year. 

DAPA-HF from the Endocrinologist’s Perspective: Dr. Silvio Inzucchi Breaks Down Divergent Metabolic Outcomes in People w/ and w/o Diabetes, Solidifying Glucose Independent Mechanism of CV Benefit

Yale’s Dr. Silvio Inzucchi presented metabolic outcomes from DAPA-HF, showing divergent effects in people with and without baseline type 2 diabetes and reinforcing the notion that cardiovascular benefits of SGLT-2s have little to do with glucose lowering effects.  As a reminder, DAPA-HF enrolled 45% of its participants with type 2 diabetes (3% were previously undiagnosed), with the rest having prediabetes or no diabetes status. Importantly, treatment effect in terms of the primary endpoint (CV death/HF hospitalization/urgent HF visit) was consistent across both subgroups of people with and without diabetes. Metabolic outcomes between these two groups told a different story, however. On A1c, people with diabetes saw a 0.2% drop compared to placebo at 8 months (the lower A1c drop than normally expected was attributed to lower eGFR in the patient population), while people without diabetes barely saw any difference at all with placebo (see graphs below). Weight outcomes told a similar story, with significant reductions in the diabetes group and nearly identical curves in the group without diabetes (see graphs below). Conversely, while effects on weight and A1c were different between the two groups, there were similar effects on blood pressure and hematocrit levels. Based off of these findings, Dr. Inzucchi posited that there may be a divergence of hemodynamic effects vs. metabolic effects in these two populations, with the possibility that consistent hemodynamic effects across subgroups could be driving the consistent cardiovascular benefit.

• Dr. Inzucchi answered the question that appeared to be on the minds of many endocrinologists in attendance: “Have we ‘lost’ this drug class to cardiologists?” Indeed, in light of the numerous positive CVOTs for the class, now along with DAPA-HF results, we’ve sensed (without question) heightened attention and enthusiasm from cardiologists regarding SGLT-2s. Dr. Inzucchi acknowledged this and tempered these fears, noting that (i) yes, SGLT-2s will see increased focus in cardiology because of their effects on heart failure regardless of diabetes status, but such usage will require collaboration with endocrinologists; and (ii) 90% of the patients without baseline HF that still experience positive CV effects with the class are primarily seen by endocrinologists, and it will be the job of endocrinologists to treat these patients with risk factors in order to prevent HF from developing (or presumably worsening). After all, heart failure remains an underrecognized complication of diabetes, as it represents the complication with the largest excess risk of mortality—even larger than MI and other ischemic events. It will be the job the endocrinologist to recognize risk factors for heart failure early on and have conversations with patients about initiating SGLT-2 therapy before heart failure develops. (Of course, we could imagine cardiologists having the same conversations.)

• Excitingly, Dr. Inzucchi hinted that future analysis of DAPA-HF will look at subgroup effects in participants with prediabetes, along with potential evaluation of diabetes prevention with SGLT-2s. When asked during Q&A about the prediabetes cohort in DAPA-HF and whether any future analysis of this subgroup will be conducted, Dr. Inzucchi answered in the affirmative and also seemed to indicate that Farxiga’s potential in diabetes prevention could also be studied. We’re particularly intrigued by this possibility of SGLT-2s in people with prediabetes, and whether such usage could represent an efficient diabetes prevention strategy that also exerts important CV and renal protective effects. It’s quite notable that DAPA-HF represents the largest study to date that has used SGLT-2s in people without diabetes, and we hope to see further analysis comparing Farxiga’s effect in this population vs. in people with diabetes.

Dr. Javed Butler Gives Call to Arms for HF Prevention: “From My Perspective, All Patients with Diabetes Are at Risk for Heart Failure” at Joint EASD/ESC Symposium

An impassioned Dr. Javed Butler (Stony Brook University Hospital) pushed for further investment into prevention of heart failure (HF), underscoring that HF prevention indications should be given equal, if not more, weight than MACE outcomes. Dr. Butler was quick to note that the crux of his argument is not to say certain diseases are more important than others, but rather, to draw attention to the often-overlooked field of heart failure. According to Dr. Butler, while the prevention of CV disease has been of interest for quite some time (the landmark Framingham Heart Study was initiated in 1948), the focus has always been on atherosclerotic cardiovascular disease (ASCVD), and consequently myocardial infarction (MI) and stroke. HF was simply viewed as a product of ASCVD, and therefore, if ASCVD could be treated, HF did not need to be its own independent target. In reality, recent statistics paint a startlingly more negative picture of the state of HF. Dr. Butler cited that there will be 1,000,000 new onset cases and rising of HF in the US in 2019, compared to 790,000 new/recurrent MIs and falling. In addition, the risk of dying after hospitalization for heart failure (hHF) is 3x higher than that following hospitalization for MI. Heart failure in patients with type 2 diabetes is even worse. A 2004 paper in Diabetes Care denoted an astonishing 10-fold increase in mortality rate (HR=10.6; 95% CI: 10.4 to 10.9) in patients ≥65 years old (n=151,738) with type 2 diabetes and HF, as opposed to those without HF. 

• Dr. Butler listed numerous ways HF prevention has being neglected in the past, including (i) lack of research, grants, and publications; (ii) its absence from the Framingham Risk Score and ACC/AHA Pooled Cohort Equation; (iii) non-requirement in FDA Guidance on CV safety in diabetes medications; (iv) perception as a “soft,” subjective, and less important endpoint than MACE; and (v) lack of ACC/AHA, HFSA, ESC, or ACP guidelines on HF prevention. Of note, even when trials successfully reduce HF, these findings are often considered neutral or even negative unless MACE is reduced.

• “We sometimes get really lost in the HFpEF, HFrEF, and HFmEF ‘this and that’ but for the purposes of my talk, it is an absolutely unimportant discussion. Whether you have this ejection fraction or that ejection fraction HF has therapeutic implications for management of HF, but when you’re talking about prevention of HF in a person who does not have HF, it does not matter which HF you are preventing because the outcomes for all forms once you develop it are horrible.” Dr. Butler warned audience members to not get lost in the semantics of HF when considering prevention, as over-complication can sometimes impede meaningful results. As an example, Dr. Butler brought up the controversy surrounding the HF reductions seen in SGLT-2 inhibitor CVOTs, calling the criticism of “we don’t know baseline ejection fraction in these populations” that has often been brought up as “completely meaningless.” In another light, he added, “If you prevent MI in someone with clean arteries or prevent MI in someone with 50-70% stenosis, how many times in a study that prevents MI would you say, ‘I’m not going to believe it because there was no hard cap on stenosis’?…If you’ve prevented an MI, you’ve prevented an MI” – just as any prevention of HF is a meaningful result.

• Dr. Butler finished his talk by highlighting the current tools available to patients with type 2 diabetes to prevent HF. From his perspective, all patients with diabetes are at high risk for heart failure, so there is less of a need to dissect if risk is high or low. Measures like not smoking, exercising, weight loss, and now perhaps SGLT-2 inhibitors are universally helpful across the population. We commend Dr. Butler on his call to action and certainly agree – it’s time to make HF a real priority. We would love to see more investment in clinical trials that address HF prevention in patients with type 2 diabetes who not only have had HF, but also those who have not, along with trials in type 1. That being said, we are of course looking forward to results from DELIVER (dapagliflozin in HFpEF), EMPEROR-Preserved and EMPEROR-Reduced (empagliflozin in HFpEF and HFrEF), and SOLOIST-WHF (sotagliflozin post-worsening HF) on the heels of landmark positive results from DAPA-HF.

Excitement Abound for DAPA-HF: KOLs Highlight “Transformative” Results, Note Disconnect Between CV Benefits and Glucose Lowering; Could Dapa-HF Help Overcome Inertia?

Across many of the industry symposia running during Day #1 of EASD 2019, we sensed tremendous excitement for the just-presented AstraZeneca Dapa-HF results, with multiple KOLs today commenting on the landmark nature of the trial. As a reminder, on the primary composite outcome of CV death/HF hospitalization/urgent HF visit, dapagliflozin treatment delivered a 26% relative risk reduction when compared to placebo (HR=0.74; 95% CI: 0.65-0.85; p=0.00001; NNT=21) in HFrEF patients (both with and without diabetes, with consistent effects across both subgroups) in Dapa-HF. Today, Canada’s Dr. Subodh Verma characterized the trial as “transformative” and asserted that these results will “truly usher in a new day in the way we think of SGLT-2 inhibitors in the treatment of heart failure in the presence or absence of diabetes.” During multiple presentations over the course of the day, Dr. Verma came back to Dapa-HF time and time again, stressing the magnitude these results will have in shifting treatment paradigms in the space. We sensed that Dr. Verma wanted to convey the impressiveness of Dapa-HF results, especially in regard to the “high hurdle” it had to clear to show significant benefits: the benefit it demonstrated was on top of excellent standard of care therapy (no kidding, including 11% of patients that were on Novartis’ highly effective Entresto). Dr. Verma underscored that “it’s not always that you come across such a profound efficacy signal” – and we couldn’t agree more, especially considering the buzz that Dapa-HF generated at ESC 2019 where results were first presented. The fact that dapagliflozin still displayed such a robust effect beyond standard of care is what prompted Dr. Verma to posit that dapagliflozin will become a “foundational therapy” for heart failure, regardless of diabetes status. Whoa – over 25 million people globally are estimated to have heart failure and it’s mounting.

• Dr. Verma also believes that Dapa-HF will help solidify the fact that CV benefits associated with SGLT-2 inhibitors are completely decoupled from glucose lowering effects. A potential benefit of this is that it seems to be helping cardiologists overcome therapeutic inertia in their patients with ASCVD in whom they have been somewhat reluctant to prescribe SGLT-2s (and GLP-1s) to. Dr. Verma asserted: “Dapa-HF will help cardiologists overcome inertia in patients with ASCVD. We have patients with ASCVD who deserve these therapies, but the fact that these agents were presumed to be glucose lowering per se and agents that cardiologists should not dabble with, has been demystified after Dapa-HF. If anybody thinks that these effects are related to glucose after Dapa-HF, they need to think about that some more time.” We note that prescription rates of SGLT-2s and GLP-1s among cardiologists remain troublingly low (see Dr. Mikhail Kosiborod’s talk on this topic at ESC 2019 for more), and we are hopeful – actually, we’re optimistic - that Dr. Verma’s prediction on Dapa-HF turning the tide may come to fruition.

  • During a Lilly/BI symposium, Dr. Kausik Ray (a very highly regarded preventive cardiologist from Imperial College, London) emphasized a similar point. He noted that Dapa-HF demonstrates the disconnect of its mechanism of action in terms of CV benefit from glucose lowering: “Glucose lowering is important but for this endpoint it’s not really relevant. What we should be thinking about is organ preservation and improving outcomes.” From our view, of course glucose-lowing is important, but it’s not the mission of cardiologists – allowing that to be a bonus is more than fine.

• University of Glasgow’s Dr. Mark Petrie echoed many of Dr. Verma’s sentiments while also pointing out that these results should prompt greater collaboration between cardiologists and diabetologists. Dr. Petrie noted that since not all the patients in Dapa-HF had diabetes, there must be more involved teamwork between diabetologists and cardiologists about thinking how to fit these traditional “diabetes drugs” into cardiology. He struck a hopeful tone, noting that greater collaboration could yield a better understanding of how these impressive benefits are conveyed, along with ensuring that the right patients are benefitting from these treatments. On a separate note, Dr. Petrie also underscored the reassuring safety data from Dapa-HF: “When I talk to diabetologists, there’s some concern about adding dapagliflozin to ‘sick’ patients that are already taking a lot of other medications. The patients in Dapa-HF were these ‘sick’ patients. Despite this, there were no adverse safety data – this is very, very reassuring data in the use of this drug in ‘very sick’ patients.”

Fortifying this enthusiasm for Dapa-HF was the news Monday morning (the timing could not have been better) that FDA has granted a Fast Track designation to Farxiga in heart failure. Our understanding is that this designation allows for more frequent communication between FDA and AZ, as well as for rolling review of any future sNDA submission (meaning that FDA would review application materials as they are ready, rather than waiting for the complete application). A Fast Track designation also means that if Farxiga meets certain eligibility criteria in clinical findings, it could be granted Priority Review for an expedited approval process (we think this might be likely given the landmark nature of Dapa-HF results). This is a huge win for AZ and also comes on the heels of Farxiga earning a similar Fast Track designation in CKD earlier this year. Elsewhere in the SGLT-2 inhibitor in heart failure landscape, Lilly/BI’s Jardiance gained a Fast Track designation in chronic heart failure in July 2019 – ultimately, this new designation is a positive for the class.

SGLT-2 Inhibitors in Heart Failure Landscape: Ongoing Outcomes Trials

EMPRISE: Additional Real-World Data Shows 26-34% Risk Reduction for Jardiance vs. GLP-1 Agonists in Drug Initiators with Type 2

Dr. Elisabetta Patorno (Brigham & Women’s Hospital) gave an engaging poster presentation on EMPRISE, Lilly/BI’s real-world evidence program for SGLT-2 inhibitor Jardiance, detailing a 26-34% reduced risk of hospitalization for heart failure (hHF) vs. GLP-1 agonists in patients with type 2 diabetes. These findings were fairly consistent with hHF outcomes from EMPA-REG, which found a 35% risk reduction (HR = 0.65; 95% CI = 0.50-0.85; p=0.002) compared to placebo, on top of standard of care. Importantly, Dr. Patorno pointed out that EMPRISE is an ongoing study, and the results presented today are only representative of the two-year endpoint and participant enrollment number. Study participants (n=52,824) were pulled from two commercial (Optum Clinformatics; Truven Health MarketScan) and one federal (Medicare fee-for-service) database, then 1:1 propensity-score matched between empagliflozin initiators and GLP-1 initiators. Patients were ~60 years old, 25% had a history of CV disease, and ~5% had a history of HF. In terms of GLP-1 agonists being used, 56% of patients were on liraglutide, 24% on exenatide, 16% on dulaglutide, and 4% on albiglutide. Primary outcomes were (i) hHF-broad, a heart failure discharge diagnosis in any position; and (ii) hHF-specific, a heart failure discharge diagnosis in the primary position. In the broad category, a 26% risk reduction was seen (HR=0.74; 95% CI: 0.60 to 0.90), while the more specific definition gave a 34% risk reduction (HR=0.64; 95% CI: 0.40 to 0.996). Due to the small number of events, further sub-analysis by type of GLP-1 could not yet be performed. Generally, we’re glad to see such robust results in what appears to be a lower risk population than was enrolled in EMPA-REG.

• During Q&A, Dr. Patorno noted that additional results on MI and CV death in EMPRISE are to be reported at AHA 2019 in November.

• See past data from EMPRISE below:

  • CV efficacy and safety of empagliflozin vs. DPP-4 inhibitors (ADA 2019)

  • hHF benefit of empagliflozin vs. DPP-4 inhibitors (AHA 2018)

Dr. Itamar Raz’ Call to Action: “We Should Be Using SGLT-2s in Every Patient w/ A1c >6.5%” – Conversely, Dr. Melanie Davies Urges More Careful Use in Patients Who Can Benefit Most

Dr. Itamar Raz advocated for broader use of SGLT-2s, proclaiming a “Call for Action” in terms of earlier combination therapy with disease modifying drugs and personalized therapy based off of cardiorenal status. In the wake of the DECLARE CVOT for Farxiga demonstrating benefit in a broader patient population than previous trials have, Dr. Raz asserted that “I think we now have enough evidence about efficacy and SGLTs and the need to put these drugs in the forefront of diabetes therapy. Actually, in my mind, we should be using these in every patient with diabetes with an A1c above 6.5%.” We note that although DECLARE showed Farxiga’s consistent benefit across a wide variety of subgroups – including patients without established CVD in terms of hHF benefit – the large NNT for benefit in these patients with treatment might make its efficient use intractable in clinical practice. In fact, Prof. Stefano Del Prato brought this point up a few months ago at CODHy 2019. Dr. Melanie Davies also touched on this concern in her independent commentary—see below.

• Dr. Raz commented on guidelines for treatment algorithms, with a broad message of simplification so that the average family physician or GP “who has to already follow 50 different guidelines” can easily follow them. On the newly updated ESC/EASD guidelines, Dr. Raz noted that he supports the idea of earlier use of SGLT-2s and GLP-1s, but worries that the guidelines are too “CV and renal” focused – “we also have to focus on the pancreas, and we shouldn’t forget that glucose is also related to macrovascular and microvascular disease.” It’s clear that Dr. Raz thinks that patients early on in the course of type 2 diabetes progression should be prescribed SGLT-2 inhibitors, regardless of the presence of multiple CV or renal risk factors. Presenting his own idea for what the thrust of guidelines should be, Dr. Raz focused on the idea of simplicity with his “SIMPLE” guidelines: Simple, (early) Intervention, Multiple risk reduction, Patient centric/Personalized, Life changing, re-Evaluation. See below for Dr. Raz’ proposed guidelines, which he argues are simple, help to avoid therapeutic inertia, and help get patients on SGLT-2s and GLP-1s depending on their personalized cardiorenal status.

• In an independent commentary, Dr. Melanie Davies rebutted some of Dr. Raz’ points, emphasizing that its “critical that future guidelines target those patients most likely to benefit.” Instead of Dr. Raz’ broad vision of using SGLTs in nearly every patient with diabetes, Dr. Davies outlined a more measured approach that focused on identifying the patients that may benefit the most from these currently expensive therapies. We’re hopeful about the potential of new risk stratification tools—such as one presented based off of DECLARE data at ESC 2019—in carrying out this ideal. Dr. Davies also noted that a new update to ADA/EASD consensus guidelines is in the work to reflect data from DECLARE and CREDENCE, and that the committee is striving to be “evidence based and proactive while also cognizant of the risk/benefit.” We admire Dr. Davies’ commitment to progressive diabetes care. 

DEFINE-HF: Farxiga Improves KCCQ But Not Primary Endpoint of NTproBNP

In one of the most packed sessions of the day, Dr. Mikhail Kosiborod and Dr. Michael Nassif (both of Saint Luke’s Health System) revealed new results from the DEFINE-HF trial, demonstrating improved KCCQ (symptoms, function, and QOL) at 12 weeks for dapagliflozin vs. placebo in patients with established HFrEF. Crucially, no significant difference in the primary endpoint of NTproBNP (a biomarker for HF) was found, so secondary outcome results, including effect on KCCQ, are considered exploratory. These findings further add to the outstanding 26% RRR on CV Death/HHF in HFrEF patients seen in DAPA-HF. Although DEFINE-HF results notably did not generate the “ooh’s and ahh’s” heard at ESC 2019 for DAPA-HF, we were excited to see a study specifically aimed at the patient perspective (KCCQ is a patient-filled questionnaire). Check out the study’s recent publication in Circulation here.

• Background and rationale. Dr. Kosiborod opened the session with what he described as the “key goals for treating patients with heart failure:” (i) reduce death and hospitalization rate; and (ii) improve health status, including symptom burden, physical limitations, and QOL. Dr. Kosiborod noted that for HFrEF specifically, although there are some treatment options available that reduce death and hospitalization (namely Novartis’ Entresto), ones that reduce symptom burden are essentially nonexistent. As no previous trials have focused on the early effects of SGLT-2 inhibitors on HF-specific health status, DEFINE-HF was designed to fill this need.

• Inclusion criteria and patient characteristics. Key inclusion criteria included (i) HF for at least 16 weeks (with or without type 2 diabetes); (ii) LVEF ≤40%; (iii) NYHA Class II or Class III symptoms; and (iv) NTproBNP ≥400 pg/mL (or BNP ≥100 pg/mL). Patients were ~60 years of age, obese (BMI ~32), with ~2/3 of patients having Class II HF and 1/3 having Class III HF. Uniquely, nearly 40% of patients were African American, much higher than contemporary HF studies, which we see as a big win for a traditionally underserved population in clinical trials. About 60% of patients had type 2 diabetes (individuals with type 1 diabetes were excluded).

• Trial design. Following a 2-week screening period, participants (n=263) were randomized to either dapagliflozin or placebo. Participants underwent the intervention for a relatively short time period of 12 weeks. 

• Results. No statistically significant difference was seen in the first primary endpoint of average of 6- and 12-week mean adjusted NTproBNP (HR=0.95; 95% CI: 0.84 to 1.08). On the second primary endpoint of patients that achieve a meaningful improvement in health status (≥5-point increases in average of 6- and 12-week KCCQ overall scores) or NTproBNP (≥20% decrease in average of 6- and 12-week NTproBNP) an HR of 1.8 (95% CI: 1.0-3.1, p=0.0386) favoring dapagliflozin was found. Although Dr. Kosiborod warned of very small sample size during subgroup analysis, of note, there was no difference between (i) those with or without diabetes; or (ii) different types of RAAS treatment (ACE/ARB, ARNI, or neither). In terms of memorable secondary endpoints, there were significant improvements in KCCQ total symptom, physical limitation, and quality of life scores but not social limitation score. NNT for overall KCCQ was just 10. No significant change was seen in 6-minute walk test, A1c, or weight. Safety events were well-balanced in each group.

• During Q&A, Dr. Kosiborod remedied the inconsistencies between KCCQ and 6-minute walk test results by noting that KCCQ is much more specific to HF-related limitations. He commented that the 6-minute walk test can also be affected by study coordinator, as well as non-HF-related limitations such as “a knee hurting, having a cold, or not sleeping well.” In general, he pointed out that strong correlations between KCCQ and 6-minute

SGLTs in Type 1: Are We Being Overcautious + Not Considering Potential CV and Renal Benefits? Impassioned Calls for a Type 1 CVOT Grow!

Dr. Thomas Danne gave a passionate and powerful overview concerning the safe use of SGLTs in type 1 diabetes. SGLTs in type 1 have been discussed at length over the past few years, and we were glad to see Dr. Danne highlight several new initiatives in his talk aimed at improving safe use of these efficacious agents, with many major points dovetailing nicely with his similar recent talk at Keystone 2019. First, Dr. Danne reviewed several of the published risk mitigation strategies that have emerged recently: these include the STICH Protocol published by Dr. Satish Garg and colleagues, the International Consensus document spearheaded by Dr. Thomas Danne, and the recently published STOP DKA protocol authored by Drs. Irene Hramiak, Bernie Zinman, and others. Excitingly, he also touched on multiple new efforts being undertaken on this front: (i) the EASD e-learning module on adjunct type 1 therapy; (ii) ATTD education portal for industry education on the subject; (iii) the KetoAWARE program for structured DKA education in type 1; (iv) several HCP focused DKA education programmes; and (v) JDRF’s call in requesting research grant proposals investigating safe use of SGLTs in type 1 diabetes. Broadly speaking, we’re enthusiastic about how this emphasis on DKA prevention is spilling over into broader efforts toward DKA education and risk mitigation, and are confident that with this focus that SGLTs can truly deliver its potential benefits to a wide range of people with type 1.

• Dr. Danne opened his talk with an impassioned, off-script plea to not be over cautious to the point of withholding important benefits to patients: “I’m a little bit angry. I completely understand with all the data that we have that we need to be cautious. But we also have situation where people are starting to be over cautious. Tell me, if you would have a child with type 1 diabetes – at age 10, and you look through the data of the Swedish Diabetes Registry – you realize that your child will lose 17 years of life (if a girl) or 14 years of life (if a boy), and you know that this loss of life is due to increased CV mortality risk. Yes, there is a risk of DKA, and yes we are doing a bad job so far, and yes I hope we will do a better job – but why are we so cautious that we have not yet started trials in this very vulnerable pediatric population with a drug that has shown positive CV mortality and renal outcomes effects in type 2 diabetes and in those without diabetes? Is it so difficult to believe that they will have similar benefits in type 1 diabetes?”

  • We couldn’t agree more with Dr. Danne’s passionate call to better study potential CV and renal long term outcomes associated with SGLTs in type 1s, as we believe this to be a major consideration in the risk/benefit profile of this therapy that has not been assessed adequately. Earlier on in this same session, Dr. Thomas Pieber similarly called for CV and renal outcomes studies for SGLTs in type 1 diabetes: “I think we have to do an outcomes trial, a well-designed trial that looks into the implications of SGLT-2 inhibitors in long term outcomes for CV and renal outcomes in type 1 diabetes.” Of course, Drs. Danne and Pieber are surely not the first thought leader to emphasize the need for a type 1 CVOT. At EASD 2018, we heard Dr. Julio Rosenstock echo a similar sentiment, saying that “if there was ever a need for a pragmatic CVOT, this is it – SGLT inhibitors in people with type 1 diabetes at high risk for CV disease.” At ADA 2018, Dr. David Cherney offered an analogous call for a cardio/renal outcomes trial in type 1 diabetes, and Dr. Anne Peters shared that many of her type 1 patients ask for an off-label SGLT-2 inhibitor primary for the cardioprotective benefits – this is clearly a topic on people’s minds, from patients to providers to KOLs. To be sure, we currently have zero hard evidence on organ protection with these agents in type 1, though the mechanisms of SGLT inhibition – which are not thought to be glucose-mediated – should theoretically play out in type 1 diabetes much like they do in type 2 – see Dr. Per-Henrik Groop speak on this this topic, from ATTD 2019 for more.

• Dr. Danne is also hopeful that EMA will eventually ease its current BMI restriction and open up SGLT therapy to most patients with type 1. Currently, both dapagliflozin and sotagliflozin have been approved by EMA, but with the stipulation that it can only be used in people with a BMI ≥ 27. Dr. Danne noted that he “likes the idea of caution, but we now need to see if our risk mitigation strategy works in the real world. Then, I think EMA will reconsider their original guidelines and approve this drug for those with normal body weight as well.”

• Dr. Danne firmly believes that DKA risk can be mitigated to the point of achieving lower rates of DKA than seen in the many clinical trial programs of SGLTs in type 1. We agree here, and are excited to see real-world evidence collected with dapagliflozin in type 1 patients in Europe once it is fully rolled out.

• The EASD released two, no-cost e-learning modules for healthcare providers on adjunct type 1 therapy, with informational videos narrated by Drs. Danne and Mathieu. The Rationale for Adjunct Therapies module began with a comparison of total mortality between type 1 and type 2 diabetes from the Swedish Registry study to contextualize the importance of type 1 adjunct therapy. This was further emphasized with a focus on unmet needs in glycemic control (mean US A1c of 8.3% in type 1), severe hypoglycemia (7% surveyed reported severe hypoglycemia in the last year), and DKA (8% reported DKA in the last year) from T1D Exchange data. As higher A1c is linked with higher mortality, new adjunctive, non-insulin therapies like metformin, amylin analogues, GLP-1 agonists, DPP-4 inhibitors, and SGLT inhibitors can improve type 1 outcomes. The module states that SGLT inhibitors sotagliflozin and dapagliflozin are pertinent treatment options for adults with type 1, but do come with the risk of DKA. Dr. Danne concluded with a reminder that attaining glycemic control in type 1 is difficult, and that new treatments are needed to complement intensive insulin therapy or CGM. SGLT inhibitors are of promise given that they promote more TIR, promote weight loss, as well as potentially promote beta cell preservation, renal protection, and CV risk reduction. These modules provide a holistic view of the type 1 diabetes drug landscape, with information on the less often discussed risk of DKA. Resources like these, which include many short and informative videos with relevant data, are ideal for physicians who may not have the time to sift through years of clinical trial data.

• ATTD also provides similar free, educational resources for those in industry with their education portal. The SGLT-2 Inhibitor Use in Type 1 resource provides a plethora of information for both endocrinologists and healthcare educators. Information is available via PowerPoint, and topics include (i) disease burden in those with uncontrolled type 1; (ii) the DEPICT trial; (iii) dapagliflozin’s EU approval for type 1; (iv) dapagliflozin’s vascular and renal outcomes in type 1; and (v) managing DKA for patients with type 1 on SGLT inhibitors. The DKA management presentation provided clarity on what DKA is, risk factors for DKA specific to those on SGLTs, and required patient education before use. The presentation also highlighted the STITCH and STOP DKA protocols, which are integral for providers to know when prescribing SGLTs to those with type 1. Materials for facilitating a peer-to-peer education program on SGLT use were also available for download in ten languages, with an option to request more translations. This slide deck led HCPs through expected, normal insulin physiology, insulin’s role as a type 1 therapy, the roles of different adjunct therapies, and the mechanism, evidence, and safety of SGLT-2 inhibitors.

  Combined, these resources made up ~300 slides of material, definitely ample for learning more about what can lead to DKA and how to mitigate it. We hope other large diabetes organizations as well as patient nonprofits join both ATTD and EASD in providing free, downloadable materials for individuals to learn about advancements in diabetes clinical practice online. It is with resources like these that the field is able to learn altogether, allowing HCPs to practice in unison when prescribing newer medications, as well as preparing for and treating emergencies that may be linked to novel therapies.

• The KetoAWARE Program is a free, downloadable educational program for structured DKA education in type 1 diabetes, all the way from the biological mechanisms of DKA to creating personal treatment plans for people at higher risk of DKA. The program uses the metaphor of a factory to describe glucose metabolism, making it suitable for HCPs like diabetes educators and community health workers who do not have extensive experience in medicine and biomedical science. The program also heavily emphasizes euglycemic DKA, stressing the importance of regular blood and urine ketone monitoring for those on SGLT inhibitors whenever they feel slightly ill or “off.” While the danger of DKA is underscored, the program provides information on the physical signs of DKA to look out for, guidance on when to perform ketone measurements, and ways to treat early stages of DKA with insulin and carbs. KetoAWARE also goes great lengths to outline why one may be at increased risk for DKA (i.e. if they omit insulin, participate in intense physical activity, or fast), along with using SGLT inhibitors. The program stresses that when in doubt, patients should discontinue SGLT use until DKA or symptoms subside. If increasing bolus insulin does not help symptoms subside, the program suggests finding caretaker support and getting medical help to treat DKA properly. KetoAWARE importantly takes a holistic approach to explain DKA, and we hope to see the resource translated for use by patients in the future, as well as in languages beyond English and German. 

• Beyond online educational programs, JDRF announced a call-in request for research grant proposals investigating safe use of SGLTs in type 1 diabetes. The full announcement requested letters of intent from researchers to study safe and effective use of SGLT inhibitors for people with type 1. JDRF highlighted DKA risk as the biggest hurdle for SGLT use, with special focus on euglycemic DKA. Letters of intent were due by October 28, 2019, and full applications are due on January 8, 2020 with awardees receiving notification starting May 31, 2020. Projects are set to begin on August 31, 2020.

• Also, at Keystone 2019, renowned endocrinologist Dr. Anne Peters revealed her personal DKA risk mitigation protocol, notably without any initial changes to insulin dosing or BMI requirements, and with the added patient selection criterion of an A1c <9.0%. This protocol was inspired by an impactful story with one of her patients. An “ideal” patient with diabetes on an SGLT inhibitor underwent DKA and would have continued to if not for Dr. Peters’ informing doctors on call to increase insulin dosage instead of decreasing it as they had been since the patient was hospitalized. Dr. Peters underscored that patient and provider education is a crucial first step, and “even with the best job that I can do, I can’t prevent DKA unless the rest of the world understands this as well.” She will be teaching her DKA risk mitigation protocol at this year’s upcoming Emergency Department Physicians meeting to inform this group about what to do when low glucose levels are seen in tandem with high ketone levels. Patients who follow her protocol need to be adherent with A1c <9.0% and an understanding of the risks of DKA and hypoglycemia from SGLT use. Ketones should be tested in the morning for two weeks to establish a baseline, only after this should low doses of SGLTs be initiated. Dosage should increase every 2 weeks based on ketone levels, and insulin does should not be altered. Ketone monitoring should persist until a patient is stable on their maximum dose but can be stopped two weeks after SGLT use has stabilized. Even after daily ketone monitoring has stopped, patients should have ketone testing supplies readily available. Patients should be advised to avoid a low-carb diet, hold SGLT use if sick, dehydrated, planning for intense exercise, or during insulin pump failure. Practitioners should also teach patients to increase carb and fluid intake and insulin dosage while holding SGLTs until ketones fall to baseline. It is integral for HCPs to be on the same page for DKA treatment protocols, and we hope the effort that doctors like Anne Peters take to share and distribute their successful protocols does not go unnoticed. Actions like these support standard, effective protocols, and individual changes can be made based on solid foundational approaches to provide the best care to patients.

SGLT-2s or GLP-1s for Renal Protection? KOLs Compare Data Between Classes; Currently Favor SGLT-2s, But Future Data on GLP-1s (Namely Semaglutide’s FLOW Trial) Could Shift Debate

In reviewing renal outcomes data for SGLT-2 inhibitors and GLP-1 agonists, Dr. David Cherney (Toronto General Hospital Research Institute) expressed more confidence with SGLT-2s given their impressive benefits in outcomes trials on hard renal endpoints. Dr. Cherney asserted that renal outcomes data for the GLP-1 class is “very interesting,” as the class has been shown to reduce renal composite endpoints that include reducing macroalbuminuria. However, the effect of the class does appear to be driven by this endpoint, as removing macroalbuminuria considerations for these composite endpoints results in no significant benefits with GLP-1s. Dr. Cherney noted that it’s “still an open question that needs to be addressed in dedicated trials” and pointed to Novo Nordisk’s FLOW trial investigating semaglutide on renal outcomes as an important step for the field in helping to answer this question. As a reminder, the FLOW trial was initiated in June 2019 and will enroll 3,160 patients with type 2 diabetes and CKD (eGFR 25-75 ml/min/1.73 m²) for up to five years. Expected completion is August 2024, and the primary endpoint is a composite of persistent eGFR decline of ≥50%, reaching ESRD, and CV or renal death. Traditional MACE endpoints will also be measured and we hope Time in Range and PROs will be also. This is a highly notable, first-ever renal outcomes trial among GLP-1s, and it’s clear that enthusiasm is high for the trial’s potential in further informing renal benefits of the GLP-1 class. We’ve sensed optimism from Novo Nordisk that more efficacious GLP-1s (such as semaglutide) may be able to compete in the future with renal outcomes data from the SGLT-2 class, along with providing the additional benefit of not losing their glucose lowering abilities in patients with a lower eGFR.

• Dr. Cherney’s assessment of the GLP-1 class on renal outcomes aligns with broader KOL consensus that we’ve gathered on the topic. In light of REWIND results, KOLs appeared a bit underwhelmed by dulaglutide’s efficacy on renal endpoints, and noted that data for the GLP-1 class on these endpoints somewhat pale in comparison to those shown by the SGLT-2 class, to date.

• Later on in the day, University of Helsinki’s Dr. Per-Henrik Groop made this same point in a Lilly/BI sponsored session, noting that GLP-1 renal outcomes data is primarily driven by macroalbuminuria reductions and not on the same hard renal outcomes that the SGLT-2 inhibitor class has so impressively shown benefits on.

• Dr. Hiddo Heerspink also weighed in on the subject during AZ’s symposium, asserting that if he had to choose between a GLP-1 and an SGLT-2 in terms of protecting kidney health in a post-ACS type 2 diabetes patient, he would surely choose the SGLT-2.

• Dr. Cherney also commented on the usage of SGLT-2s in patients with low eGFRs, asserting that renal-protective effects are likely preserved across all eGFR levels. Indeed, although SGLT-2 inhibitors remain contraindicated for those with severe renal impairment (eGFRs below 45 mL/min/1.73 m²), their benefits on renal outcomes have been significant in those with lower eGFR levels. Dr. Cherney noted that CANVAS, EMPA-REG, DECLARE, and CREDENCE all enrolled patients down to an eGFR of 30 (with benefit still seen here), while ongoing dedicated CKD trials in Dapa-CKD and EMPA-KIDNEY are going down even further in terms of eGFR (25 and 20, respectively). Of course, the current contraindication for SGLT-2 inhibitors in those with eGFRs below 45 is not because of potential safety concerns, but because of the attenuation of glycemic benefits at lower eGFRs. Dr. Cherney predicted that the future of SGLT-2 inhibitors will include broader use of the class in these patients with lower eGFRs, seeing as their impressive effects on renal and CV outcomes are significant in these patients. We’re curious whether results from Dapa-CKD and EMPA-KIDNEY (along with those from CREDENCE) may help regulatory agencies reconsider this contraindication. Dr. Cherney appeared confident on this front, noting that it’s likely that these labels will be changed to recommend usage in patients with eGFR’s as low as 30 (he also commented that this is already the case in Canada).

Additional Commentary on Positive Renal Data from DECLARE: Consistent Effects in Patients with Relatively Normal Kidney Function Emphasized

Ofri Mosenzon (Hadassah Medical Center) gave a very similar presentation to ADA 2019 on the positive renal outcomes from DECLARE, but seemed to focus today’s talk on the drug’s renal benefit even in participants with relatively normal kidney function. As a reminder, dapagliflozin conferred both (i) greater improvements in UACR and (ii) lower rates of UACR deterioration vs. placebo – demonstrating the drug’s potential in both CKD prevention and treatment for patients with type 2 diabetes. In today’s talk, Dr. Mosenzon specifically drew attention to dapagliflozin’s positive renal effects in the DECLARE cohort with relatively robust kidney function in terms of UACR (<30 mg/g) and eGFR (>60 mL/min/1.73 m²). She noted that even with more than 50% of participants having not just normal albuminuria, but either undetectable or albuminuria <15 mg/g at baseline, there were significant improvements in (i) renal-specific composite outcomes; (ii) sustained eGFR decrease ≥40% to eGFR <60; (iii) ESRD; and (iv) renal death (slide below). Dr. Mosenzon emphatically pointed out that for the renal-specific composite endpoint, there was “absolutely no relation to” baseline UACR and stated that dapagliflozin is effective on renal specific outcomes at all baselines UACR.

• Dr. Melanie Davies agreed during independent commentary that there is no relation between baseline UACR and the renal-specific composite endpoint but urged the crowd to also consider the high NNT values in the high eGFR and UACR individuals (NNT reaching up to 1250 in participants with the highest renal function). All in all, Dr. Davies emphasized making intentional choices about which populations will most benefit from treatment – we thought this was a very thoughtful qualification to make amongst the swath of positive renal DECLARE data!

Sotagliflozin in Type 1: Post-Hoc inTandem Analysis Confirms Greater Efficacy in BMI >27 Group (Greater A1c Reductions, Time in Range Benefits, and Weight Loss) with Potential DKA Risk Attenuation

Dr. Thomas Danne presented a post-hoc analysis of sotagliflozin’s type 1 program sub-grouped by BMI (above and below 27 kg/m², the cutoff point advised by EMA), demonstrating greater A1c reductions and time in range improvements with treatment in >27 BMI patients and slightly lower DKA rates between groups. We noted considerable enthusiasm for this presentation, which was part of a broader session on SGLTs in type 1 – in Europe, both dapagliflozin and sotagliflozin have been approved by EMA with the same guidelines, which understandably is driving increased interested here. Dr. Danne framed his talk by underscoring that any new type 1 therapy must balance its provided benefits with any risks it may introduce, and that the BMI cutoff proposed by EMA is attempting to better triangulate such a favorable risk/benefit profile. However, it’s been unclear so far how exactly that decision was made, and what data might support this guideline. We’ve seen pooled data from the DEPICT program for dapagliflozin in type 1 presented as a poster at ENDO 2019, which showed that patients with a BMI ≥27 kg/m² experienced less DKA than the overall, pooled population, while efficacy and CGM-based outcomes were similar between the ≥27 kg/m² subgroup and the entire cohort. Encouragingly, our understanding of the pooled data of inTandem presented by Dr. Danne for sotagliflozin in type 1 suggest a similar finding, with slightly lower DKA rates (low event rates surely complicate interpretation) accompanied by greater efficacy in the higher BMI group. See slides below for breakdown on DKA rates (slightly lower in higher BMI group), A1c differences (greater A1c drops in higher BMI group), time in range comparisons (large increase for higher BMI group taking highest dose), and body weight comparisons (greatest effect in higher BMI group taking highest dose). Of course, it’s paramount to keep in mind (especially on DKA endpoints) that these event rates are very, very low – a point that Dr. Danne emphasized when discussing the need for further investigation on this point.

• Baseline characteristics: patient characteristics were generally well-balanced between the two different BMI groups (above and below 27), with similar baseline age, male/female ratios, A1c, and time in range. Notably, and understandably, baseline total insulin doses were significantly higher in the BMI >27 group (~76 IU/day v s. ~46 IU/day). On this point, Dr. Danne speculated that this higher baseline insulin dose associated with a higher BMI may be “part of the protective effect of being overweight” in regard to DKA risk

Dr. Subodh Verma: Patients at Risk for Heart Failure Should Be Treated “Before the Horse Leaves the Barn” – No Need to Confirm Heart Failure Diagnosis Before Initiating Treatment

Jumping into a conversation regarding when targeted evaluations for heart failure might be initiated in an at-risk patient, Dr. Subodh Verma stressed that it’s not necessary to actually confirm a heart failure diagnosis before using SGLT-2 treatment. After all, the trials showing robust benefits in heart failure prevention (namely DECLARE) did not discriminate treatment for those with heart failure at baseline; instead, the trials were designed to show that at-risk patients could be treated and heart failure hospitalizations could be prevented without an actual heart failure diagnosis. Said Dr. Verma: “These patients are at risk for heart failure and they should be treated before the horse leaves the barn. That’s how the trials were done and that’s how the treatments should be used. Scientifically speaking, saying ‘let me find some heart failure before I start treating’ is a disservice to our patients.” This response came in regard to an ongoing discussion of how to better identify heart failure in clinical practice, and what steps may be necessary to make more targeted evaluations (such as completing an ECG). Dr. Verma felt that these steps may be unnecessary in the context of deciding whether to use an SGLT-2 or not and made an analogy to the use of statins not requiring such diagnosis before their use. We’re glad to see Dr. Verma emphasize this point, since we imagine that with data emerging on both the prevention (through DECLARE) and treatment (through Dapa-HF) of heart failure, there may be some ongoing confusion on how to best initiate and use these therapies and in which patients.

12-Week Dapagliflozin Treatment Significantly Improves CKD Urinary Proteomics Score

Dr. Mie Klessen Eickhoff (Steno Diabetes Center, Copenhagen, Denmark) presented an elegant diagnostic-focused study, documenting SGLT-2 inhibitor dapagliflozin’s (AZ’s Farxiga) beneficial effects on urinary proteomics score CKD273 in patients with type 2 diabetes and albuminuria. As background, CKD273 is a panel of 273 unique urinary peptides that allow for early detection of chronic kidney disease (CKD). The peptides are primarily derived from either (i) fragments from the kidney (thought to be a marker of kidney fibrosis); or (ii) fragments from the blood (suggested as a marker of glomerular leakage). Research by Zurbig et al. published in Diabetes has shown that CKD273 successfully predicts progression from normo- to macro albuminuria 1.5 years before the occurrence of microalbuminuria in patients with diabetes. A CKD273 score of 0.343 distinguishes those with CKD from controls, and a score of 0.154 

• In order to assess the effect of SGLT-2 inhibition on CKD273, a randomized, placebo-controlled, cross-over study (n=40) was performed comparing dapagliflozin (10 mg) and placebo. Patients were randomized to one arm of the study for 12 weeks, followed by crossover for a subsequent 12 weeks, with stable RAAS treatment throughout. Participants had to have (i) type 2 diabetes; (ii) A1c >7.5%; (iii) UACR ≥30 mg/g; and (iv) eGFR ≥45 mL/min/1.73 m².

• Treatment with dapagliflozin significantly lowered CKD273 by -0.217 vs. placebo (95% CI: -0.346 to -0.087; p=0.0014). This decrease in CKD273 score represented a significant change from those at high risk to not at risk of developing microalbuminuria from normoalbuminuria, as marked by a 0.154 cut-off value previously established by Lindhardt et al. No significant change was seen in the 0.343 cut-off value, documented by Good et al., distinguishing individuals with CKD from controls. We’d be curious to see how the values change in a more long-term study, considering the short study duration. 

• As a reminder, Farxiga is currently being studied in a larger, dedicated trial in CKD (Dapa-CKD) which is expected to complete in November 2020. Previously, renal outcomes analysis from DECLARE—presented at ADA 2019—highlighted Farxiga’s positive effects on both eGFR decline and UACR, with a 47% relative risk reduction on the renal-specific composite endpoint of preventing ≥40% sustained eGFR decline to less than 60 mL/min/1.73m², end-stage renal disease, or renal death. Farxiga has also recently obtained a Fast Track designation from FDA for a potential indication in CKD.

Novel Mechanisms of SGLT-2s: Increased BOHB Ketones in Type 1 Not Due to Lipolysis

Dr. David Russell-Jones (University of Surrey, Guilford, UK) unveiled new results from a small, mechanistic study aimed at investigating the pathophysiology of diabetic ketoacidosis (DKA) in type 1 diabetes, in the presence and absence of SGLT-2 inhibitors. Of most interest, the study uncovered that while patients on SGLT-2 inhibitor dapagliflozin did have significantly higher BOHB ketone levels both at baseline and through 180 minutes of testing (AUC_{0-180 min} BOHB 149 ± 26 mmol/L*min  vs. 12 ± 18 for placebo; p=0.044), rising ketones were not caused by increased lipolysis (a previously proposed mechanism of DKA) – both non-esterified fatty acids (NEFA) and rate of glycerol appearance (Ra), well-established markers of lipolysis, were consistent between both arms.

• The study was designed as a double-blind, crossover trial (n=12) of participants with type 1 diabetes using insulin pumps (40.7 ± 3.9 years old; BMI 26.2 ± 1.5 kg/m²). Participants were randomized to either dapagliflozin (1o mg) or placebo for seven days. On day seven, patients underwent variable intravenous insulin infusion to maintain blood glucose at 5 mmol/L. ²H₂ glucose was infused to measure glucose kinetics, as well as ²H₅ glycerol to measure rate of lipolysis. At isotopic steady state, participants had their insulin withdrawn and received either day seven dapagliflozin or placebo, allowing blood glucose to rise (mimicking DKA). The study was terminated at 600 minutes or upon reaching one of the pre-selected rescue parameters including (i) blood glucose >18 mmol/L; (ii) bicarbonate <15 mmol/; (iii) venous pH <7.35; or (iv) capillary BOHB >5.0 mmol/L. After a four-week washout period, the test process was repeated on the other arm of treatment.

• There was no difference in rate of glucose appearance (Ra) between the two treatment arms, however, dapagliflozin had a significantly greater rate of glucose disposal (Rd; 2727 ± 222 mmol/min/kg*min vs. 2006 ± 140 on placebo; p=0.0004), due to increased glucose clearance through the kidney, as measured by increased urinary glucose excretion during 0-120 minutes (5.10 ± 0.80 mmol/kg/min vs. 0.029 ± 0.01; p=0.003). No significant differences were seen in cortisol, growth hormone, or glucagon.

Merck Symposium Highlights SGLT-2 Inhibitor Steglatro; Anticipation for Early 2020 VERTIS CV Readout

A Merck-sponsored symposium provided a deep dive on the company’s portfolio of oral diabetes therapies: Pfizer-partnered SGLT-2 inhibitor Steglatro (ertugliflozin) and DPP-4 inhibitor Januvia (sitagliptin). Dr. Sam Dagogo-Jack (University of Memphis, Tennessee) provided a deep dive on the ongoing and highly-anticipated CVOT for Steglatro, VERTIS CV. The trial’s design has several notable features: (i) The trial is strongly positioned as a secondary prevention study, enrolling 99.9% of participants with established CVD; (ii) as we learned last year at EASD 2018, 23% of the VERTIS CV patient population has a history of heart failure, bolstering the statistical power to investigate this crucial secondary outcome. To this end, we believe VERTIS CV is also the only SGLT-2 CVOT to collect baseline heart failure status in all participants, further boosting the study’s ability to examine the increasingly apparent link between SGLT inhibition and heart failure outcomes. Dr. Dagogo-Jack confirmed that enrollment is complete (>8,000 participants) and the study is projected to complete in December 2019, with results available as early as January 2020 (at one point it was as early as 4Q19). Commenting on the wave of positive SGLT-2 CVOTs in general, nephrologist Dr. Ofri Mosenzon (Hebrew University Hospital, Jerusalem, Israel) provocatively argued that we should start referring to these agents as “disease-modifying therapies” for their ameliorating effect on the natural history of crucial diabetes complications like heart failure and CKD. Dr. Daniel Drucker (University of Toronto, Canada) contextualized that this is “something that five years ago none of us could have imagined” before the paradigm-shifting EMPA-REG OUTCOME readout at EASD 2015. Whew!

• Turning to Merck’s DPP-4 inhibitor franchise, Dr. Juan Frias (National Research Institute, Los Angeles, CA) highlighted the CompoSIT trial program. CompoSIT-R found superior A1c-lowering with Januvia (sitagliptin) over AZ’s SGLT-2 inhibitor Farxiga (dapagliflozin) in patients with mild renal impairment (to the tune of -0.15%). This makes sense given that the glucose-lowering mechanism of SGLT-2 inhibitors is strongly dependent on renal function. CompoSIT-I found greater reductions in A1c and FPG when sitagliptin was continued vs. withdrawn at the initiation of insulin glargine therapy, with no increase in hypoglycemia. Finally, CompoSIT-M showed A1c benefits for adding sitagliptin during metformin uptitration vs. metformin alone. Together, these trials show the relevance of Januvia for three common clinical situations: (i) As an alternative to SGLT-2 inhibitors in people with renal impairment, (ii) as complement to insulin therapy (that boosts the glucose lowering with no added risk of hypoglycemia), and (iii) as an addition to intensifying metformin therapy (sooner rather than later, to combat clinical inertia).

• Dr. Drucker kicked off the symposium with some words of wisdom for clinicians eyeing exciting advances in beta cell basic science. “Let’s apply the same stringent criteria to basic science that we do in the clinical arena,” he advised. Highlighting the poor replicability of early basic science studies (given methodological differences) and imperfect translation from mice and cell culture to humans, Dr. Drucker implored the audience not to “put too much faith in the latest, greatest basic science finding.” With exciting clinical trials, Dr. Drucker pointed out that people are quick to acknowledge that the effect may not hold up in subsequent, larger and differently-designed trials, or for other members of the same drug class. He argued that the same amount of nuance should be applied when interpreting basic science findings.

EXSCEL Post-Hoc Provides First Long-Term Evidence of Cardiorenal Benefits with GLP-1/SGLT-2 Combination Therapy

Dr. Lindsay Clegg presented results from a new post-hoc analysis of the EXSCEL CVOT for AZ’s GLP-1 Bydureon (once-weekly exenatide), demonstrating important potential cardiorenal benefits with exenatide + SGLT-2 combo therapy. This analysis included participants in EXSCEL that were also using open label SGLT-2 therapy during the trial (n=575), propensity matched with participants just taking exenatide and participants only on placebo. In total, 8.7% of participants on exenatide picked up an SGLT-2 inhibitor over the course of the trial, compared to 10.6% of placebo participants. On MACE, a non-significantly lowered hazard ratio was seen, driven by nominally significant reductions in CV death. Risk of all-cause mortality was also nominally significantly lowered with combo therapy vs. only exenatide and placebo. Rates of serious hypoglycemia trended toward the combo therapy group, but was not significant. On renal outcomes, improvements in eGFR slope were seen after SGLT-2 initiation in both the exenatide and placebo groups, consistent with the remarkable renal-protective effects the class has shown. We’re encouraged to see this continued improvement in eGFR decline even on top of GLP-1 therapy. Moving ahead, Dr. Clegg noted that an important question that needs to be answered is whether a patient needs to take both of these therapies at the same time to garner potential additive benefits, or to simply have exposure to both at different times. We hope to see further, more comprehensive, trials conducted to investigate these possibilities.

• Of course, it’s crucial to keep in mind that EXSCEL was not powered for this specific analysis, making these results hypothesis generating at best.

Novo Nordisk Symposium Highlights GLP-1 + SGLT-2 Combo Therapy and Lack of GLP-1 Penetration – Could Oral Sema Move the Needle?

GLP-1s stole the show at Novo Nordisk’s packed corporate symposium on moving beyond the standard in diabetes and obesity care, led by a star-studded cast including Drs. Rory McCrimmon, Subodh Verma, Ofri Mosenzan, Thomas Wadden, Melanie Davies, Vanita Aroda, and more. Themes from the session included (i) optimized use of GLP-1s for patients with type 2 diabetes; (ii) optimized use of GLP-1s for patients with obesity; and (iii) the future of GLP-1s. Read on for some top highlights below!

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Dr. Rory McCrimmon focused on the potential benefits of combining GLP-1s and SGLT-2 inhibitors for patients with type 2 diabetes, displaying a particularly helpful table of the two drugs’ possible counterbalancing effects. For example, hepatic glucose output is negatively impacted by the use of an SGLT-2 inhibitor; however, adding a GLP-1, which beneficially decreases glucose production, can neutralize the effect for patients. Dr. McCrimmon cited the AWARD 10, DURATION 8, and LIRA-ADD2SGLT-2i clinical trials as evidence of the combination’s success.

• Dr. Thomas Wadden and Dr. Ofri Mosenzan tackled GLP-1 usage in patients with obesity – the former focusing on intensive behavior therapy (IBT) and the latter on combination usage with basal insulin. Dr. Wadden presented data from the SCALE IBT trial (n=282), which combined liraglutide 3.0 mg with IBT (prescribed exercise of 250 min/week, reduced caloric intake based on body weight, and 23 IBT counseling visits) for patients with a BMI ≥30 kg/m² but without diabetes. In the study, behavioral counseling with placebo induced a mean reduction in baseline weight of 5.4% at six months, confirming the effectiveness of brief IBT alone. Although six-month results did not differ greatly for those additionally on liraglutide, patients who stayed on the therapy at week 56 saw an impressive loss of 9.1% of baseline weight. Dr. Mosenzan focused on the SCALE Insulin trial (n=396) which looked at liraglutide 3.0 mg + IBT vs. placebo + IBT in patients with overweight/obesity and basal insulin-treated type 2 diabetes. Cumulative results showed that patients also on liraglutide were 3.3x more likely to achieve ≥5% weight loss, A1c <7%, and no documented symptomatic hypoglycemia (p=0.0006) – these results are incredibly encouraging, and overall, we see tremendous potential for GLP-1s in the evolving field of diabetes treatment.

• In terms of the future of GLP-1s, oral semaglutide was the obvious center of attention. While the overall audience opinion on oral semaglutide was generally positive (praise for the PIONEER trials received light but spontaneous applause), the question of pricing, and more broadly why only ~10% of eligible patients are on GLP-1s, did seem to be a hot topic from the audience. In response to this query, both Dr. Melanie Davies and Dr. Vanita Aroda pointed to lack of provider comfortability as a major factor. Dr. Davies noted that while DPP-4 inhibitors are similarly priced to GLP-1s in her native UK, DPP-4 inhibitors are still far more often prescribed. Dr. Aroda added that some practitioners feel less prepared to put their patients through careful dose escalation and explain GI side effects compared to other drugs. We’re hopeful that oral semaglutide could help to bend the curve here by reducing injection burden (perceived or real). To end Q&A, the panel collectively agreed that the challenges with GLP-1 accessibility are not just in the United States and Europe but also in Africa and Asia – we wholeheartedly agree and hope that the conversation on access is not just limited to those who have the means to speak about it!

Novartis Symposium Highlights Heart Failure; Promise for SGLT-2s and Entresto in HFrEF; Unmet Need Persists in HFpEF

A Novartis-sponsored symposium shed light on the increasingly apparent intersection of diabetes and heart failure. Expectedly, a major focus of discussion was Novartis’ heart failure therapy, Entresto (sacubitril/valsartan), indicated for HFrEF. Great interest has surrounded the question of whether Entresto’s benefits extend to the increasingly common HFpEF, which is thought to be more tightly linked to adiposity, obesity, and diabetes. Sadly for the diabetes and cardiology community, hot-off-the-presses data from the newer PARAGON-HF trial indicate that this may not be the case. Entresto narrowly missed significance on the primary endpoint of reducing CV death and total HF hospitalizations (p=0.06), and subgroup analyses for hospitalization for HF and HF death were also not significant. Positive results in PARAGON-HF would have represented the first ever for a potential treatment of HFpEF, and the two cardiologists on the panel, Dr. Martin Cowie (Imperial College, London, UK) and Dr. Andriaan Voors (University Medical Center Groningen, Netherlands), took this as an opportunity to underscore the unmet need in this form of heart failure.

• Following promising signals for heart failure prevention in recent CVOTS, SGLT-2 inhibitors are also a source of great hope for the treatment of heart failure, particularly in people with diabetes. To this end, Leicester’s very highly regarded Dr. Melanie Davies highlighted the DAPA-HF trial, which stole the show at this month’s ESC meeting with a 26% risk reduction on CV death and hospitalization for heart failure with AZ’s Farxiga (dapagliflozin) in HFrEF patients with and without diabetes. These results solidified dapagliflozin as the first SGLT-2 inhibitor to show benefit in heart failure, and the first SGLT-2 inhibitor to demonstrate beneficial effects in a large-scale trial of people without diabetes. On this wave of excitement surrounding SGLT-2s, we note that two additional trials are ongoing to address HFpEF specifically: EMPEROR-Preserved for Lilly/BI’s Jardiance, DELIVER for AZ’s Farxiga.

• On the epidemiological front, Dr. Clifford Bailey (Aston University, Birmingham, UK) provided an important reminder of why these trial results matter so much: The combination of heart failure and diabetes is a “deadly duo.” Diabetes increases the risk of heart failure, and heart failure in turn increases the risk of diabetes. The combination of the two is associated with high mortality: According to data from the Swedish Heart Registry, median survival for patients with HF and diabetes is only 3.5 years (vs. 4.6 years for HF alone). Making matters worse, therapy for heart failure and diabetes can sometimes counteract each other. Dr. Bailey pointed out that thiazides, statins, and beta-blockers can potentially increase blood glucose, whereas diabetes therapies (certainly TZDs and potentially SUs and insulins) can negatively impact heart failure prognosis. This puts the importance of SGLT-2 inhibitors into perspective, with their beneficial impact on both diabetes and HF.

Post-Hoc Analysis of DURATION-8 Trial Hints at NAFLD/NASH Benefits with GLP-1/SGLT-2 Combination Therapy

A post-hoc analysis of the DURATION-8 trial showed improvements in liver fat and fibrosis with combination therapy of the GLP-1 agonist exenatide and SGLT-2 inhibitor dapagliflozin. As a reminder, DURATION-8 compared exenatide/dapagliflozin combination therapy against both monotherapies alone, finding significantly greater A1c reductions and weight loss with two agents vs. one over two years follow-up. At baseline, >81% of the DURATION-8 population (mean age 55 years; mean A1c 9.3%; mean BMI 33%) had fatty liver/steatosis and >9% had more severe liver fibrosis. In participants on exenatide/dapagliflozin combination therapy, the prevalence of fatty liver fell 10.5% and the prevalence of steatosis fell 6.1% after 28 weeks of therapy. Also at this time point, the proportion of patients with liver biomarker scores indicating the presence of advanced fibrosis fell 4% for those on the combination therapy regimen.

• Several individual GLP-1 agonists and SGLT-2 inhibitors have been investigated in NAFLD/NASH, but to our knowledge this is the first large-scale examination of GLP-1/SGLT-2 combination therapy. The study author, Dr. Cristian Guja (Carol Davila University, Bucharest, Romania) underscored that DURATION-8 wasn’t powered to investigate NAFLD/NASH outcomes and didn’t include any histological examination or imaging of the liver, so these findings are by no means definitive and must be validated in a dedicated prospective trial. That said, we find the results very encouraging. About half of people with type 2 diabetes and obesity are estimated to have NAFLD, so it is a very attractive proposition for diabetes combination therapy to double as therapy for liver disease. Of course there is also no shortage of novel agents in development for NAFLD/NASH in the ever-expanding competitive landscape.  

AZ’s 38-Nation Observational DISCOVER Trial Sheds Light on Global Heart Failure Trends

New data from AZ’s observational, >15,000 person, 38-nation DISCOVER trial reveals trends in the global prevalence of heart failure. DISCOVER is an observational longitudinal study of people with type 2 diabetes initiating second-line glucose-lowering therapy; to date, data has been collected for 2 years. This study determined that nearly 2% of the DISCOVER population had heart failure at baseline. The people with HF tended to be older (67 vs. 57 years), have a longer diabetes duration (8.2 vs. 5.5 years), and a greater prevalence of coronary artery disease (45% vs. 6%) and chronic kidney disease (23% vs. 4%). Furthermore, 60% of the DISCOVER population had the obesity-associated and harder-to-treat HFpEF. Heart failure guru Dr. Mikhail Kosiborod has emphasized the uptick in HFpEF in epidemiological studies, in line with the global obesity epidemic. This is a question from a clinical point of view, as none of the therapies approved for HFrEF have meaningful effects in HFpEF. Over the course of two years follow-up, 2.6% of DISCOVER participants developed heart failure, but this proportion rose to 15.3% for the subgroup of participants with baseline coronary artery disease. The speaker, Dr. Suzanne Arnold (University of Missouri, Kansas City, MO), elaborated that among these incident heart failure events, 74% were diagnosed in the outpatient setting and 56% in the absence of coronary artery disease. (Dr. Arnold commented that in real-world clinical practice  most heart failure diagnoses are made in an outpatient setting, so other trials that assess only HF hospitalizations are likely underestimating the true incidence.) One major limitation of the DISCOVER study is variation in screening for diabetes complications between the different nations involved, not to mention heterogeneity in the patient populations enrolled from each nation. That said, we admire the richness of this data set, and are troubled by the comparatively high rates of heart failure in such a relatively young population (mean=56.6 years old) with a relatively short duration of diabetes (mean=5.7 years).

• The ambitious DISCOVER program is proving to be a wealth of information about global trends in diabetes complications. At ADA 2019 a separate DISCOVER analysis revealed that people with type 2 diabetes initiating a second-line glucose-lowering therapy had a strikingly high prevalence of microvascular (27%) and macrovascular (15%) complications after two years, and people with macrovascular complications at baseline were at an extremely high likelihood for recurrent events (OR=382, 95% CI: 2.47-5.90).

DECLARE Analysis Confirms Safety and Efficacy of Dapagliflozin in Elderly Populations

Dr. Avivit Cahn presented a new analysis of the DECLARE CVOT, confirming Farxiga’s (dapagliflozin) safety and efficacy in older patients. The new analysis was spurred by authorities’ hesitance to prescribe dapagliflozin based on the lack of long-term safety data in patients over age 75 years. Sub-group analyses were divided by age into <65 years, 65-75 years, and ≥75 years groups. All sub-group analyses revealed homogeneity in renal and cardiovascular outcomes (save for slight heterogeneity in hHF) that were either neutral or in favor of dapagliflozin. A1c decreased similarly among these age groups, dropping most in the ≥75 year-old group potentially due to these patients starting with lower weight at baseline, according to Dr. Cahn. A larger majority of every age group on dapagliflozin showed A1c levels below 8% - a boundary Dr. Cahn deemed relevant for older age groups that most likely have had diabetes the longest and have more difficulties lowering A1c. Overall, dapagliflozin conferred lower serious adverse event incidence in the general DECLARE study population, with volume depletion and acute kidney injury observed at no increased risk between different age groups. Only diabetic ketoacidosis, urinary tract infections, and genetical infections, common class-wide side effects,  occurred more often among the elderly groups taking dapagliflozin. Overall, Dr. Cahn believes that safety and efficacy data is in favor of dapagliflozin in older populations and can even lead to an extended indication for the SGLT-2 inhibitor.

SGLT-2 Inhibitor Poster Highlights

Insulin Highlights

CONCLUDE Trial of Tresiba vs. Toujeo in Type 2 Finds No Significant Difference on Primary Endpoint of Overall Symptomatic Hypoglycemia; Exploratory Secondary Endpoints of Nocturnal Hypoglycemia and Severe Hypoglycemia Benefit Trend Toward Tresiba

Dr. Athena Philis-Tsimikas presented results from the Novo Nordisk-sponsored CONCLUDE trial (n=1,609) comparing next-gen basal insulins Tresiba (insulin degludec U200) and  Toujeo (insulin glargine U300) in type 2 patients, demonstrating no significant differences on the primary endpoint of overall symptomatic hypoglycemia. See slides below for a full rundown of the primary and exploratory secondary endpoints from the trial. For the primary endpoint, rates of overall symptomatic hypoglycemia trended toward lower rates with Tresiba but did not reach significance (RR=0.88; 95% CI: 0.73-1.06; p=0.17). Failure to meet significance on this primary endpoint rendered the following secondary outcome results as purely exploratory and hypothesis-generating: On both nocturnal symptomatic hypoglycemia (RR=0.63; 95% CI: 0.48-0.84; p=0.0014) and severe hypoglycemia (RR=0.20; 95% CI: 0.07-0.57; p=0.0027), Tresiba was associated with nominally significant reductions. Despite their exploratory nature, Dr. Philis-Tsimikas noted that these endpoints might still provide some value in interpretation, explaining that “interpretation of a trial should encompass totality of evidence not just one endpoint.” A more detailed presentation of CONCLUDE is set for EASD Day #4 on Thursday, and we’re looking forward to more commentary on this study.

• We sensed some pushback during Q&A regarding the interpretation of secondary endpoints in CONCLUDE. One audience member commented: “When interpreting secondary outcomes, we have to interpret them through the primary outcome. If the primary outcome is neutral, all of the alpha has been used up on that analysis. All of the additional outcomes that have been presented are exploratory. I would counter against the conclusions presented here, because the five percent critical alpha has been used up on the primary analysis. This is particularly depressing when we need these comparative clinical trials and we need to have a clear understanding of differences between therapies.” In fact, Dr. Philis-Tsimikas’ presentation of CONCLUDE stressed that interpretation of secondary endpoints must be done with caution and viewed as exploratory and hypothesis generating.  

• For context, Sanofi’s BRIGHT trial of Toujeo vs. Tresiba found overall similar A1c reductions with the two agents, but a predefined subgroup analysis (first presented at ADA 2019 and also at a poster here at EASD 2019) found significantly different mean A1c changes favoring Toujeo at lower baseline eGFR (p-value for interaction=0.02). On hypoglycemia, BRIGHT found a statistically significant decrease in incidence of hypoglycemia <70 mg/dl (OR=0.74, 95% CI: 0.57-0.97, p=0.03) and hypoglycemia <54 mg/dl (OR=0.63, 95% CI: 0.40-0.99, p=0.044) with Toujeo vs. Tresiba during the first 12 weeks of the study – the “titration period.” While there was no significant difference in the latter 12 weeks of the study – the “maintenance period,” from a patient perspective, going an extra three months with more hypoglcyemia if given a choice wouldn’t be the preference.  Ultimately, the implication from these data was that Toujeo conferred a 26% risk reduction for hypoglycemia when compared to Tresiba; the p-values of 0.03 and 0.044 were certainly well below 0.05 and the fact that this benefit lasted for 12 weeks was notable. That said, the hypoglycemia benefit disappeared during BRIGHT’s maintenance phase – this deserves further study. While some seemed to think this study was about whether Toujeo is truly superior to Tresiba on hypoglycemia, it was actually far more relevant to use of next-gen insulins in renally-impaired patients – we’d like to study these further. .

• Overall, we would like to see more evidence pointing to far more people using next-gen basal insulins, full stop – and then, within these populations, examine where notable differences might lie, such as in the case of renally impaired patients. Ultimately, as a community, the focus should be on bringing them to more patients. As Dr. Alice Cheng said at EASD 2018, “I don’t think the big takeaway from BRIGHT is that it demonstrated non-inferiority in terms of A1c reduction between the two next-gen insulins. The big takeaway is that both insulins were able to lower A1c from an average above 8.5% to 7.0% in just 24 weeks.” Notably, it also seems that the conclusion about which insulin is better depends significantly on sub-group analysis: While DELIVER D+ and BRIGHT found no significant difference between the two in hypoglycemia past the first 12 weeks in overall populations, sub-group analysis saw that renally compromised patients may see more benefit related to Toujeo. While the CONFIRM real-world study (n=4,056) suggested that hypoglycemia and treatment discontinuation were more common with Toujeo than Tresiba, we know that both next-gen insulins are associated with far less hypoglycemia than Levemir and Lantus.

Prof. Stefano Del Prato’s Commentary on CONCLUDE Emphasizes Inconclusive Results of Tresiba vs. Toujeo Comparison Trials

Following presentation of results from CONCLUDE (Novo Nordisk sponsored trial of Tresiba vs. Toujeo in type 2s, see our coverage from EASD Day #3), Prof. Stefano Del Prato provided his independent commentary, underscoring the inconclusive nature of the trial and other sources of evidence comparing these two next-gen basals. Indeed, we’ve sensed that CONCLUDE has generated extensive debate in the community, as its non-significant primary endpoint but intriguing secondary endpoint results  have called into question (i) how exactly to interpret trials where the primary endpoint may not be met but secondary endpoints are; and (ii) how to reconcile these results with the BRIGHT study (Sanofi’s sponsored trial of Tresiba vs. Toujeo – obviously, of course, starting with sub-group analysis and recognizing the different populations). Another point of major discussion was the accuracy of the glucose meters used in CONCLUDE, which further complicate interpretation and analysis.

• Prof. Del Prato took the audience through a thought experiment while trying to comprehend results from CONCLUDE: assuming that results do indicate a lower hypoglycemia risk with Tresiba, could there be a valid explanation for this finding? One possible explanation could be varying PK/PD profiles for both of these agents which could help differentiate their hypoglycemia effects. Prof. Del Prato reviewed PK/PD studies for Tresiba and Toujeo, with conflicting results in this space preventing a clean conclusion one way or the other. Some studies have shown better lower day to day variability with Tresiba, whereas others have demonstrated lower daily fluctuations with Toujeo. He noted that there exist tremendous amounts of intrinsic variability in PK/PD studies, with many variables (ranging from different primary endpoint to different bioavailability’s and metabolic effects) complicating interpretation and comparison. Without clear results in these studies, Prof. Del Prato finds it hard to connect evidence to the claim that CONCLUDE’s results indicate a lower hypoglycemia risk for Tresiba.

• Could past data (namely the BRIGHT trial) help contextualize CONCLUDE results? Important differences between the two trials make conclusions difficult. Prof. Del Prato emphasized study population differences between CONCLUDE and BRIGHT (see table below). The two trials had different designs, different endpoints, different populations in terms of age, baseline A1c and eGFR, diabetes duration, and more. Real-world evidence between the two agents do not help to differentiate them either: both DELIVER D+ (lower rates of hypoglycemia with Toujeo) and CONFIRM (showed lower rates of hypoglycemia with Tresiba) suggested different conclusions – again, the population being examined makes a big difference. Although Prof. Del Prato elicited laughs from the audience by joking at the start of his presentation: “You would expect that a trial named CONCLUDE would be more conclusive with its results …” it is certainly true that there’s so much that is different with the trials!