The 6th CODHy World Congress was held February 21-22 in Tel Aviv, Israel. This series of international meetings only continues to grow stronger, and we were treated to tons of compelling commentary and insights while in Tel Aviv (which is now one of our team’s very favorite conference cities!).
We begin this full report with themes from the meeting: CV risk mitigation is becoming a central piece of diabetes care in this CVOT era, and other comorbidities of diabetes like obesity and NASH are also moving into the spotlight. Several CODHy sessions also dealt with gaps in evidence and how to fill them: For instance, which diabetes drugs might be effective in prediabetes? Should we be prescribing GLP-1 agonists and SGLT-2 inhibitors earlier on in disease progression, even to patients who don’t yet have established CV disease? Our immediate answer to this latter question is “yes!” because of the compelling efficacy of GLP-1s and SGLT-2s even beyond cardioprotection (glucose-lowering, weight loss), but we acknowledge that CVOT data isn’t generalizable to the entire real-world diabetes population, and we’re eager for real-world studies and other research that closes this gap.
Highlights from CODHy include Dr. Mikhail Kosiborod on selecting diabetes drugs based on CV risk and Dr. Ralph DeFronzo offering a vehement defense of TZD pioglitazone, also debuting his “Fab Four” of diabetes drugs. We attended a fascinating panel on diabetes drugs for prediabetes (is there hope for DPP-4s, SGLT-2s, or GLP-1s?), and heard about the link between hypoglycemia and CV risk from the always-outstanding Professor Simon Heller.
While we were excited that this iteration of CODHy included four sessions featuring digital health startups, we were underwhelmed by the presentations that we were able to catch – though it’s still certainly exciting to see a very therapy-focused conference and crowd reaching “across the aisle” to the digital health world.
The 6th CODHy World Congress took place in late February in Tel Aviv, Israel. This full report ties together the highlights we published (day #1, day #2) by detailing a few key themes we noticed from the jam-packed two days. Talk titles highlighted in yellow represent some of the most notable from CODHy 2018, in our opinion, while those highlighted in blue were not included in our initial highlights reports – enjoy!
We spent President’s Day taking in the sights of Jerusalem’s Old City, and we highly recommend a stroll through the port of Jaffa if you find yourself in Tel Aviv. Along with IDF 2017 in Abu Dhabi, we’ve spent a fair amount of time in the Middle East these past few months, learning about the issues HCPs and patients with diabetes face worldwide – and how they’re more similar to than they are different from the US.
Shifting the Focus of Diabetes Treatment to CV Risk Management in the Wake of CVOTs
Now that the diabetes field has multiple positive CVOTs in the books, thought leaders are discussing how to most effectively and efficiently prevent the CV complications of diabetes. To this end, CODHy 2018 featured even more content on CV risk reduction vs. CODHy Latin America in 2017, which goes to show how fast things are changing and improving in our toolkit of cardioprotective diabetes drugs. Since last year’s gathering, CANVAS reported and gave us a second SGLT-2 inhibitor with apparent MACE and heart failure benefits. What should all this accumulating CVOT information mean to a healthcare provider? Dr. Mikhail Kosiborod presented a new evidence-driven paradigm for choosing diabetes therapy based on where a patient falls on the spectrum of CV disease. Importantly, he didn’t discard glucose management, but rather argued that the way glucose is lowered (i.e. which drug is chosen) is perhaps more important than how much glucose is lowered. To be sure, guidelines have started to reflect this shift in thinking: The ADA’s 2018 Standards of Care include a recommendation for patients with established atherosclerotic CV disease to receive an agent known to lower CV risk, but guidelines across the board could certainly be more precise, personalized, and forward-thinking. Later on that same day, Dr. Enzo Bonora echoed this sentiment, adding that renal benefits should also be considered; he presented his own decision tree that takes CV disease status, CKD status, and heart failure into account. Indeed, treatment of heart failure with SGLT-2 inhibitors surfaced as perhaps the most exciting result to come out of the recent CVOTs. In a second presentation on Thursday, Dr. Kosiborod emphasized that heart failure is probably the most deadly, morbid, and costly of diabetes complications – and he was particularly excited about the potential for SGLT-2s in heart failure management/prevention.
We also saw this newfound focus on CV disease reflected in Dr. Ralph DeFronzo’s brand-new “Fab Four,” comprised of the four drugs he thinks are worth using in treating someone with type 2 diabetes: GLP-1 agonists, SGLT-2 inhibitors, TZD pioglitazone, and metformin. Dr. DeFronzo said he’s most excited about GLP-1 agonists, and he suggested that they should be first-line therapy. Very notably, he has chosen only the drugs/classes with a demonstrated impact on lowering CV risk. Cardioprotection is likely a class effect of SGLT-2 inhibitors, as seen in EMPA-REG OUTCOME for Lilly/BI’s Jardiance (empagliflozin), CANVAS for J&J’s Invokana (canagliflozin), CVD-REAL, and EASEL. While class effect for GLP-1 agonists is still hotly debated, Dr. DeFronzo argued in favor at WCTD 2017, attributing EXSCEL’s neutral result to its pragmatic study design and calling it “probably positive” overall – several other thought leaders have echoed this view, and we agree as well. As Dr. Kosiborod has argued, the goal of diabetes treatment shouldn’t be to just lower glucose values, but to make people live longer and healthier. We hope this way of thinking is only furthered as more outcomes studies in diabetes, heart failure, and CKD read out in the coming months and years.
Gaps in Evidence and How to Fill Them
Can the drugs we use to treat diabetes prevent the progression of prediabetes? Do SGLT-2 inhibitors or GLP-1 agonists lower CV risk in people who haven’t yet developed CV disease? It’s easy to forget that research hasn’t actually answered these questions, which would affect the treatment of tens of millions of people. On day #1 of CODHy, Drs. John Wilding, Agostino Consoli, and Baptist Gallwitz discussed the possibility of using diabetes drugs to prevent diabetes. Despite the fact that this is an “evidence-free zone,” all three speakers seemed intrigued by the potential for DPP-4 inhibitors, SGLT-2 inhibitors, and GLP-1 agonists to prevent or slow progression to diabetes – and also to lower CV risk. That said, the cost and required length of an event-driven trial in prediabetes are huge barriers to an outright prediabetes CVOT, though the VA is sponsoring VA-IMPACT, a trial of the much cheaper metformin in patients with high CV risk and prediabetes. Similar cost and time barriers exist in studying primary prevention populations in diabetes: It simply takes longer to demonstrate benefit in a lower-risk population, so CVOTs have historically enrolled fewer of these patients. Dr. Enzo Bonora pointed out how difficult it is to choose diabetes therapies for primary CV prevention, as most CVOTs have enrolled a majority secondary prevention cohort. That said, DECLARE (for AZ’s Farxiga) and REWIND (for Lilly’s Trulicity) have enrolled majority primary prevention cohorts. Though some have cast doubt on the ability of these trials to show CV superiority, both will report this year and could seriously change how providers view the CV benefits of SGLT-2 inhibitors and GLP-1 agonists. In a way, DECLARE and REWIND are high-risk, high-reward trials for the field – it may be more difficult for Farxiga and Trulicity to show significant CV benefit because of a presumably lower event rate in a “less sick” study population, but positive results would transform conception of SGLT-2s and GLP-1s, potentially shifting how and when we address CV risk in patients with diabetes.
Conference chair Dr. Itamar Raz made a strong argument for the use of real-world evidence (RWE) to fill the gaps left by RCTs, in terms of patient population, study design, and use of combinations. In addition to showing how a drug works in the real world, RWE can help us glean more information on more patients than an RCT could ever enroll. With programs like CVD-REAL (sponsored by AZ) and LIGHTNING (sponsored by Sanofi) already producing compelling results, manufacturers seem keen on using real-world data to reinforce the benefits of their products.
Obesity and NASH Move into the Spotlight
While CODHy is by definition a multidisciplinary conference, it’s hard for diabetes not to dominate at center-stage. But the whole field is shifting toward an understanding of diabetes, obesity, NASH, and other comorbidities as manifestations of a cardiometabolic syndrome, and CODHy 2018 reflected this shift. On Wednesday, Dr. Ran Oren framed NASH as the epitome of “controversies to consensus,” shedding light on debates over the definition, diagnosis, epidemiology, prognosis, and treatment of fatty liver disease. NASH continues to shine as one of the hottest areas in biotech, as a handful of companies race to bring the first therapy to market, but Dr. Oren’s presentation reminded us that clinical understanding of the disease is still very much emerging. Nevertheless, it’s so important for endocrinologists and others working in diabetes to be aware of: NASH affects anywhere from 16-64 million Americans and is commonly comorbid with type 2 diabetes. We shifted gears slightly the next day, when Dr. Luc Van Gaal gave a master class in obesity pharmacotherapy, characterizing the current state of the field as striving to break the >10% weight loss wall. Excitingly, Dr. Van Gaal hypothesized that semaglutide (Novo Nordisk’s second-gen GLP-1 agonist) could be the drug that finally does so, since it has shown a “new level of weight loss efficacy” thus far. Phase 3 trials of semaglutide in obesity, including the first-ever obesity CVOT, will begin later this year. To be sure, the obesity epidemic is driving the diabetes epidemic; empowering HCPs to help their patients with more significant weight loss, partly through the use of pharmacotherapy, will certainly improve their ability to treat diabetes as well.
- Detailed Discussion and Commentary
- Diabetes Tomorrow
- Identifying Subjects at Risk
- Treatment Individualization
- New Anti-Hyperglycemic Agents and Diabetes Prevention
- New Players in T2DM
- Fighting Obesity
- Be Aware Of…
- Residual CV Risk in Diabetes
- Treatment Evolution in Type 1 Diabetes
- Diabetes and Heart Failure
Detailed Discussion and Commentary
SGLT-2 Inhibitors and CVD-REAL, The Complete Story
Mikhail Kosiborod, MD (Saint Luke’s Health System, Kansas City, MO)
Dr. Mikhail Kosiborod presented a new diabetes management paradigm, where treatment is determined based on a patient’s status of CV disease – see the image below for an overview. He arrived at this algorithm based on findings from CVOTs of GLP-1 agonists, SGLT-2 inhibitors, DPP-4 inhibitors, and TZD pioglitazone. For people with CV risk factors only, Dr. Kosiborod suggested that GLP-1s and SGLT-2s are appropriate. Individuals with recent stroke should take pioglitazone, per his guidelines, while GLP-1s and SGLT-2s are also ideal for diabetes patients with a history of stroke/MI or with established coronary disease. Why should therapy be chosen according to the CV disease spectrum? As Dr. Kosiborod put it, CV disease remains the leading cause of death for people with type 2 diabetes, and it’s well-accepted that a diabetes diagnosis leads to residual CV risk. While comorbidities, contraindications, and A1c/glycemic targets should also be factored into treatment decisions, Dr. Kosiborod pointed out happily that the agents we now know to reduce CV risk are also some of the more effective glucose-lowering drugs. This paradigm shift in diabetes care, with cardioprotection at the center, is starting to take hold: The ADA’s 2018 Standards of Care contains a formal recommendation for cardioprotective drugs (SGLT-2 empagliflozin and GLP-1 liraglutide are specifically called out) in people with established CV disease. Despite the fact that better glucose control has not been empirically linked to improved CV outcomes or lower all-cause mortality, we do see value in the two-for-one combination of glucose-lowering and cardioprotection, especially when it comes to convincing regulators, payers, and diverse HCPs of the utility of these newer agents. As Dr. Kosiborod explained, the way you lower glucose is extremely important: DPP-4 inhibitors don’t improve CV outcomes, but GLP-1 agonists and SGLT-2 inhibitors do.
- Dr. Kosiborod also spoke in favor of cardioprotective class effects for GLP-1 agonists and SGLT-2 inhibitors. He defined a class effect as results from multiple trials going in the same direction. Across LEADER (liraglutide), SUSTAIN 6 (semaglutide), ELIXA (lixisenatide), and EXSCEL (exenatide), GLP-1 agonists have given a 10% relative risk reduction (HR=0.90, 95% CI: 0.82-0.99, p=0.033) in three-point MACE (non-fatal MI, non-fatal stroke, CV death) and a 12% relative risk reduction in all-cause mortality (HR=0.88, 95% CI: 0.81-0.95, p=0.002) – Dr. Kosiborod reviewed this meta-analysis, which we also saw at IDF. The notion of a cardioprotective class effect around GLP-1 agonists has generated some controversy in the field since AZ’s Bydureon (exenatide once-weekly) just missed the threshold for MACE superiority in EXSCEL (HR=0.91, 95% CI: 0.83-1.00, p<0.001 for non-inferiority, p=0.06 for superiority). Since then, however, we’ve heard several experts attribute EXSCEL’s neutral result to its pragmatic trial design, and thought leaders seem to be leaning toward class effect (this is certainly our view, and Dr. Ralph DeFronzo argued at WCTD 2017 that EXCEL was “probably positive”). We were pleased to hear additional commentary in support from Dr. Kosiborod. Consensus on CV benefit to GLP-1s could improve uptake of all products in this class.
- For SGLT-2 inhibitors, Dr. Kosiborod emphasized that both CANVAS (canagliflozin) and EMPA-REG OUTCOME (empagliflozin) demonstrated significant reductions in three-point MACE with the SGLT-2 vs. placebo. That said, canagliflozin (J&J’s Invokana) was not found to significantly reduce CV or all-cause death, and empagliflozin (Lilly/BI’s Jardiance) is now indicated for the reduction of CV death. Given this mild heterogeneity, Dr. Kosiborod suggested that all eyes are on DECLARE, the CVOT for dapagliflozin (AZ’s Farxiga) expected to read out in 2H18. DECLARE will be the largest and longest CVOT when it completes in July 2018, enrolling only ~40% of participants with baseline CV disease, compared to 100% in EMPA-REG and 66% in CANVAS. We hope there is lots of sub-group analysis. Moreover, DECLARE is the first-ever CVOT with a co-primary endpoint that includes heart failure, so results could help clear up (i) what CV benefit SGLT-2 inhibitors offer in primary prevention and (ii) the impact of SGLT-2s on heart failure. We look forward to both these insights, and the latter could help fill an unmet need in diabetes care – as you can see on Dr. Kosiborod’s graphic below, he listed symptomatic heart failure, hospitalization for heart failure, and end-stage heart failure as “not adequately studied.” To share optimism for positive DECLARE results, Dr. Kosiborod pointed out that CVD-REAL (for which he was a primary investigator) found significant mortality and heart failure benefits with SGLT-2 inhibitors in both initial and recurrent heart failure patients in the real world. We’re eager for findings from CVD-REAL 2 (encompassing Asia Pacific, Canada, and the Middle East), reporting at ACC 2018 in just a couple of weeks!
Pharmacologic Therapy: What’s Next?
Ralph DeFronzo, MD (University of Texas, San Antonio, TX)
Dr. Ralph DeFronzo challenged diabetes treatment algorithms and current prescription habits by introducing his “Fab Four” of therapy – SGLT-2 inhibitors, GLP-1 agonists, TZD pioglitazone, and metformin. He particularly praised GLP-1 agonists: “Why would you not use this as first-line therapy in every single one of your patients?” While this line of thinking isn’t new from Dr. DeFronzo (read about his ringing endorsements of GLP-1s, SGLT-2s, and pioglitazone at last year’s CODHy gathering in Buenos Aires and at the WCTD conference in Berlin), this was the debut of the term “Fab Four.” We have to say: The name is catchy, highlighting the superior effectiveness of more advanced drug classes (GLP-1s, SGLT-2s), as well as the growing importance of cardioprotection in diabetes care. As Dr. DeFronzo pointed out, gut peptides GLP-1 and GIP account for 60%-70% of the insulin secreted after a meal, making them absolutely essential for normal glucose tolerance. Moreover, they counteract beta cell failure, which is an important role of anti-hyperglycemic therapy and is all but necessary for sustained A1c reduction. Dr. DeFronzo pointed to a 2003 study showing that liraglutide (Novo Nordisk’s GLP-1 agonist Victoza) returns beta cell function to the levels expected of someone without diabetes. He expressed distinct enthusiasm for Novo Nordisk’s oral semaglutide as well as Intarcia’s ITCA 650 (implantable exenatide mini pump). While we think most patients (and providers) would be resistant to first-line therapy with an injectable, we also fully appreciate and endorse the ethos of earlier, more aggressive treatment to fight diabetes progression. Oral semaglutide and an implantable mini pump that lasts for three-six months (initiation phase and maintenance phase, respectively) could very well increase the number of patients who start on GLP-1 earlier in the course of disease, if not first-line, given the reduced or eliminated injection burden. That said, before we get too far ahead of ourselves, we note that awareness of and reimbursement for GLP-1s will have to improve remarkably to increase prescription volume. According to a Diabetes Care article published last year, only 7% of second-line diabetes prescriptions in the US go to a GLP-1 agonist; the majority (46%) still go to an SU, and only 7% go to an SGLT-2 inhibitor.
- Turning to SGLT-2 inhibitors, Dr. DeFronzo highlighted a key advantage of SGLT-1/2 dual inhibitors (like Sanofi/Lexicon’s sotagliflozin) – these dual inhibitors block nearly 100% of glucose reabsorption, while SGLT-2 inhibitors only block ~55% of reabsorption. Sotagliflozin is in phase 3 for type 2 diabetes, and we’re interested to see what glycemic and weight loss data look like in patients with type 2. Notably, the agent will also be filed with FDA and EMA shortly for a type 1 indication (FDA submission is scheduled for 1Q18, per Sanofi’s 4Q17 update).
- Dr. DeFronzo maintained his status as one of diabetes’ most outspoken proponent of TZDs (specifically, pioglitazone). While pioglitazone gives a ~35% increase in insulin sensitivity (and is the only available drug for sensitization), he explained that he sees the TZD as most useful for increasing insulin secretion. Pioglitazone has also been shown to reduce MI/stroke in people with and without diabetes, in PROactive and IRIS. On the horizon, Dr. DeFronzo forecast a serious gap in the development of new insulin sensitizers. He acknowledged early-stage Lyn kinase activators, but said he is otherwise disappointed at the lack of therapeutic options for this aspect of diabetes pathophysiology, for this aspect of the ominous octet.
- In Dr. DeFronzo’s view, pioglitazone and its effects continue to be misunderstood. Dr. Itamar Raz challenged Dr. DeFronzo’s argument for combination therapy, noting that pioglitazone worries some doctors due to lingering concern over heart failure. Dr. DeFronzo seemed quite disappointed at this “misperception.” He pointed out that pioglitazone is actually a potent insulin sensitizer in the myocardium, and has been shown to markedly improve both systolic and diastolic function. However, as the label stipulates, pioglitazone should not be given to those with class III or IV heart failure because it causes sodium retention, increasing fluid volume and “[throwing people into heart failure]." Dr. DeFronzo actually cast doubt over whether some participants in PROactive had heart failure, as it was never adjudicated – he attributed some events to fluid retention. As Dr. DeFronzo has previously stated, the weight gain associated with pioglitazone is also partially due to fluid retention and can be combated with distally-acting diuretics. Moreover, lower doses of pioglitazone – never above 30 mg – are preferred, and weight gain can even be countered with a GLP-1 agonist. Other thought leaders have similarly advocated for low-dose pioglitazone at 15 mg (never above 30 mg) for type 2 diabetes, including Drs. Jay Skyler, Robert Eckel, and George Bakris at CMHC 2016. In our view, it’s important to think about how patients experience and perceive weight gain, because this can lower treatment satisfaction, adherence, and overall health outcomes. We hope providers are vigilant in explaining and treating these effects when prescribing pioglitazone, and we’d love more concrete guidance for HCPs on what this communication should look like.
- Dr. DeFronzo once again denounced sulfonylureas and over-reliance on metformin, noting that they correct none of the triumvirate leading to hyperglycemia (impaired insulin secretion, decreased glucose uptake, increased hepatic glucose production) and none of the ominous octet. A compilation of long-term studies on SUs demonstrates that they are completely ineffective in the long term, Dr. DeFronzo explained. This is a crucial point – many clinical trials, and even head-to-head studies, show strong A1c-lowering efficacy with sulfonylureas because of study duration <two years, but beta cell burnout is a known side-effect of SUs and this attenuates their efficacy over time. Interestingly, Dr. DeFronzo laid out a similar argument for metformin. He suggested that metformin is commonly misperceived as an insulin sensitizer (rather, the generic drug prevents gluconeogenesis at the liver). He pointed out that UKPDS is traditionally cited as evidence for metformin use, but the CV analysis contained only 342 participants and A1c slowly rose over time, surpassing baseline levels at ~five years. Indeed, we were somewhat surprised by Dr. DeFronzo’s inclusion of metformin in the Fab Four – he’s called its use “archaic” in the past – though he later clarified it was the least important of the four. Metformin has been incredibly well studied, is remarkably affordable (just dollars a month), and has a mild side-effect profile, keeping it at the top of treatment algorithms. In the end, even Dr. DeFronzo isn’t ready to say goodbye to metformin, though he argued that it should only be used in combination with other agents. We imagine the inclusion of metformin could actually promote faster acceptance of the Fab Four within the diabetes world (patients, providers, and payers alike), since the agent is so familiar to this community.
Identifying Subjects at Risk
To Screen or Not To Screen?
Jaakko Tuomilehto, MD (University of Helsinki, Finland)
In a compelling session on diabetes prevention, Dr. Jaakko Tuomilehto discussed the surprising controversy that surrounds diabetes screening and its potential benefits. As the lead investigator on the first-ever diabetes prevention RCT, the Finnish Diabetes Prevention Study, Dr. Tuomilehto is an esteemed expert on prevention, a field that is still very much emerging. When it comes to screening for hyperglycemia, Dr. Tuomilehto highlighted several unresolved questions: What measure or combination of measures should be used as the basis of diabetes screening? Should we screen for prediabetes as well as overt diabetes? How often should screening take place within a population, or for an individual? Perhaps most importantly, does screening actually produce long-term improvements in health outcomes?
- On which screening method to use, Dr. Tuomilehto expressed a preference for the one-hour, 50 g oral glucose tolerance test, which is low-cost and shows excellent sensitivity in identifying people with undiagnosed diabetes (whereas A1c and fasting plasma glucose, though easier, may occasionally miss some diabetes cases). We are wondering about a two-week blinded wear of Libre Pro …
- On the nuances of “to screen or not to screen,” things are less conclusive, according to Dr. Tuomilehto. He noted that while prevention studies (his own Finnish DPS, the US DPP study, and the Chinese Da Qing study) show convincingly that screening for prediabetes can prevent or delay the onset of type 2, it has not been definitively shown that screening for diabetes itself improves hard outcomes. Though it seems intuitive that diabetes screening would lead to earlier detection and therefore a wider therapeutic window to slow disease progression, Dr. Tuomilehto pointed out subtleties in how we assess the outcomes of screening programs. Due to the phenomenon of “length bias,” screening can appear to correlate with better prognosis as a byproduct of the fact that screening tends to preferentially pick up slow progressors (since they have a longer window of opportunity to be screened), whereas rapid progressors with a more aggressive form of the disease are more likely to already have a clinical diagnosis and therefore not be included in the screening cohort. Also at play is “lead time bias,” the idea that early disease detection only prolongs the length of time a person is aware that they have a disease, not necessarily the length of time they live with the disease (i.e. two people who live until age 80 with diabetes could “survive” 30 years or 10 years with the disease depending on whether they were diagnosed at age 50 or age 70, without any difference in actual lifespan).
- “Screening sounds simple, but it’s not.” This session certainly opened our eyes to the hidden complexities of diabetes screening, and we’re left with the open question of whether screening programs are actually the best avenue to diabetes prevention. Still, we note that under-diagnosis of diabetes (and obesity, for that matter) is a serious public health problem. Education and awareness should not be overlooked or de-prioritized, even though there are kinks to be worked out. For instance, we’d love to find solutions to “length bias” (could better detection methods identify even the rapid progressors?) and “lead time bias” (this seems very solvable, by setting standards for data analysis in screening/prevention studies), rather than shying away from screening altogether.
Treatment Personalization after the CVO Trials
Enzo Bonora, MD (University of Verona, Italy)
Echoing earlier sentiments from Dr. Mikhail Kosiborod, Dr. Enzo Bonora argued that the number of different therapy classes now available enables genuine personalization of diabetes care, but that CV and renal benefits should dominate therapy selection (as below). Dr. Bonora called this “treat to benefit” rather than “treat to target,” which we love and will be repeating. He drew the most significant distinction in therapy choice between primary and secondary prevention of CV disease. Evidence for secondary prevention (i.e. those with established CV disease) is quite robust given positive SGLT-2 and GLP-1 CVOTs, despite the fact that this reflects only ~25% of patients with type 2 diabetes in the real world. Nevertheless, Dr. Bonora characterized the evidence as quite strong for adding SGLT-2 inhibitors, GLP-1 liraglutide (Novo Nordisk’s Victoza), or TZD pioglitazone to metformin (unless not indicated/contraindicated) to prevent subsequent CV events in these patients with a prior history. In contrast, he suggested that there’s a relative dearth of CVOT evidence when it comes to patients without established CV disease: While there are many options to choose from, there are few certainties and few head-to-head comparisons to inform decision-making. By our count, all reported CVOTs of GLP-1 agonists and SGLT-2 inhibitors enrolled 66%-100% secondary prevention cohorts, with most enrolling >80% in secondary prevention. As such, choosing therapy for primary prevention is complicated and less evidence-based right now (studies like DECLARE for AZ’s SGLT-2 dapagliflozin and REWIND for Lilly’s GLP-1 dulaglutide could start to change this, as both CVOTs – reporting this year – have recruited a majority primary prevention population). For the primary prevention patient today, an HCP might balance various benefits (glucose-lowering, CV risk factor improvement, microvascular disease prevention) and risks (hypoglycemia, other adverse effects) – there’s room for more personalization here, but also more room for interpretation.
- Interestingly, Dr. Bonora contextualized this current focus on CV and renal outcomes as the next step in a long series of treatment foci, starting with an emphasis on body weight in the 1980s and progressing through postprandial glucose, insulin resistance, beta and alpha cell dysfunction, and then multiple targets and hypoglycemia before present-day. This historical perspective piqued our interest. What might be the focus of diabetes treatment in 10 or 20 years, as science furthers our understanding of the etiology and mechanisms underlying the disease? For example, what role will inflammation play in the future? In the meantime, we think CV disease, CKD, and heart failure are particularly efficacious targets for reducing morbidity and mortality, and we’d still like to see greater focus on hypoglycemia risk reduction in diabetes care. Dr. Bonora has developed the flow chart below to illustrate the concept of treatment personalization with respect to these various factors. We imagine most providers use similar mental heuristics when selecting therapy, but we would love to see more detailed and formal decision support tools aimed at medication selection.
New Anti-Hyperglycemic Agents and Diabetes Prevention
The “Evidence-Free Zone” of Repurposing Diabetes Drugs for Prevention; Arguments for SGLT-2s, GLP-1s, and DPP-4s; Regulatory Challenges Persist
John Wilding, MD (University of Liverpool, UK); Agostino Consoli, MD (University of Chieti, Italy); Baptist Gallwitz, MD (University of Tuebingen, Germany)
During an afternoon panel, Drs. John Wilding, Agostino Consoli, and Baptist Gallwitz discussed the plausibility of using SGLT-2 inhibitors, GLP-1 agonists, and DPP-4 inhibitors to treat prediabetes. Said Dr. Wilding: “This is an evidence-free zone, but that doesn’t prevent any of us from having something to talk about.” We love this perspective, and we agree that productive conversation should continue around possible prediabetes drugs, despite resistance from regulators to consider a prediabetes indication (to be sure, there are challenges here, but many thought leaders have criticized FDA’s hesitation to approve metformin for prediabetes). Outlining the case for SGLT-2 inhibitors, Dr. Wilding cited compelling reductions in A1c and body weight (a key risk factor for type 2) with these agents in the diabetes population, though there are no published trials to-date on the use of SGLT-2s in prediabetes. Additionally, Dr. Wilding pointed to the much-discussed CV benefit of two SGLT-2 inhibitors – Lilly/BI’s Jardiance (empagliflozin) and J&J’s Invokana (canagliflozin) – as seen in EMPA-REG OUTCOME and CANAS. He suggested that these benefits for people with diabetes at high CV risk could very well extend to the prediabetes population. Risk reduction for atherosclerotic CV events might be somewhat muted if prediabetes patients face lower CV risk to start; then again, prediabetes is a known risk factor for CV disease, and these individuals may already have significant atherosclerosis. Moreover, there have been some hints that SGLT-2s may exhibit a heart failure benefit entirely independent of glycemia: A post-hoc of CANVAS found significant risk reduction for heart failure in the primary prevention cohort (whereas three-point MACE was not significantly reduced among these lower-risk patients), and Dr. David Fitchett shared data from EMPA-REG OUTCOME attributing empagliflozin’s heart failure benefit to volume effects, which apply outside the context of diabetes. Dr. Subodh Verma has explained that diastolic dysfunction (a precursor to heart failure) appears earlier in the course of diabetes progression than does atherosclerosis, defending earlier use of SGLT-2 inhibitors – possibly even in prediabetes. All this said, Dr. Wilding returned to the issue of plausibility. He noted that SGLT-2s for prediabetes is a milestone “unlikely to happen in the foreseeable future,” given the time it would take to complete a large-scale trial in prediabetes and the steep cost of SGLT-2 inhibitors relative to other candidate drugs for prevention, namely metformin. There may be some opportunity to investigate the impact of SGLT-2 therapy in prediabetes within the EMPEROR and Dapa-HF trials, of course, and we very much hope this is happening. These studies are recruiting participants with chronic heart failure, with or without type 2 diabetes, so presumably, there will be a cohort of patients with prediabetes at baseline randomized to SGLT-2 inhibitor (Jardiance or Farxiga) or to placebo. We’re eager to find out how these advanced oral agents perform as heart failure treatment distinct from diabetes and glucose-lowering, and to probe for effects in the prediabetes population. We’ll have to wait until June 2020 for the EMPEROR program to wrap up, while Dapa-HF is expected to complete in December 2019. We are counting the months …
- Dr. Consoli presented a similar argument for GLP-1 agonists, adding that beyond glycemic and weight loss benefits, this therapy class also boasts strong evidence for the potential to improve beta cell function and “comfort” the beta cell failure that drives type 2 pathogenesis. That said, he acknowledged that it is still an open question if GLP-1 agonist therapy can truly restore beta cell function and prevent beta cell failure – we would be happy, of course, for some preservation of beta cell function. As for investigating a GLP-1 molecule in prediabetes, we see opportunity in the upcoming SELECT CVOT of Novo Nordisk’s semaglutide in people with obesity (n=~17,500). This trial is slated to start sometime in 2018, and will presumably enroll a decent cohort of patients with baseline prediabetes, allowing for interesting sub-group analyses. Novo Nordisk’s SCALE program has already shown high-dose liraglutide (branded Saxenda for obesity) to effectively delay type 2 diabetes onset over three years in people with prediabetes – so, perhaps we shouldn’t call this area an entirely “evidence-free zone,” though certainly much more research is needed.
- Given the particularly high cost of SGLT-2 and GLP-1 products, we found Dr. Gallwitz’ argument for DPP-4 inhibitors to be quite compelling. As another incretin-based therapy (alongside GLP-1s), these agents could potentially foster a similar beta cell-protective effect in a more adherence-friendly oral (rather than injectable) formulation and at lower cost. We add that generic DPP-4s are closer around the corner than are generic GLP-1s, and widespread access will be key in promoting any prediabetes therapy (given that this patient population is even more numerous than the type 2 diabetes patient population). On the other hand, DPP-4 inhibitors are less potent than GLP-1 agonists and do not come with weight loss benefit or CV/renal protection, though they do boast a solid safety profile and excellent tolerability.
- With rising prediabetes prevalence (estimated at 84 million adults in the US alone, according to CDC) we imagine the pursuit of a prediabetes indication could be a worthy investment for any company with an SGLT-2 inhibitor, GLP-1 agonist, or DPP-4 inhibitor on the market. That said, we understand that the lack of a clear regulatory pathway for prediabetes (which is not yet classified as a disease) represents a substantial obstacle – for now. In all likelihood, it will take collaboration from multiple manufacturers to sway regulatory authorities in the US and elsewhere to consider any prediabetes indication, regardless of therapy class.
- It’s also worth mentioning that the ACE CVOT recently showed the potential for diabetes prevention with alpha-glucosidase inhibitor acarbose (Bayer’s Glucobay, also generic). Though Glucobay did not meet any of its CV endpoints in the study, it showed a compelling 18% risk reduction vs. placebo for the secondary endpoint of new-onset type 2 diabetes (HR=0.82, 95% CI: 0.71-0.94, p=0.005) in a Chinese population with prediabetes and a previous history of CV events (n-6,526). We found it notable that acarbose was absent from this discussion, because it is low-cost and it’s commonly-used in China, where prediabetes affects an astonishing 500 million people (half the adult population). We’d expect this from a meeting like CODHy with such a global focus, especially.
New Players in T2DM
Ran Oren, MD (The Hebrew University of Jerusalem, Israel)
Israeli gastroenterologist Dr. Ran Oren outlined the numerous disputes surrounding NAFLD/NASH (fitting for a conference on “controversies to consensus”). As a relatively uncharted and under-recognized disease state, NAFLD/NASH is riddled with controversy at every level – from screening to diagnosis to management to recommended health systems approaches to the growing epidemic of fatty liver disease. Dr. Oren hit on the following key issues:
- Defining NAFLD. The current definition (>5% liver fat in people who drink little to no alcohol) is very vague and does not systematically encompass any concrete measure of alcohol intake to differentiate NAFLD from alcoholic liver diseases.
- NAFLD vs. NASH. Less urgency surrounds NAFLD than full-fledged NASH, but Dr. Oren argued that NAFLD deserves serious attention in and of itself, given that it’s a precipitating risk factor for the more severe NASH. Emerging evidence suggests that improvement or resolution of NAFLD can have beneficial effects for comorbid diabetes, all the more reason that NAFLD should be taken seriously in its own right.
- Understanding the prognosis of lean NAFLD/NASH. Studies counterintuitively suggest that the progression of NAFLD to NASH is much more aggressive in lean people with fatty liver disease, despite their lower prevalence of fibrosis and more favorable risk factor profile.
- Epidemiology of NAFLD/NASH. Prevalence of NAFLD in the general population is commonly estimated at around 25%-30%, of which 20%-30% eventually progress to NASH. Due to the difficulty of diagnosis, the “real” prevalence statistics are yet to be determined.
- How to diagnose NAFLD/NASH. Non-invasive diagnostic tools such as MRI and liver enzyme tests provide an incomplete picture of NASH, largely because its three pathophysiological features – steatosis, inflammation, and cirrhosis – are difficult to simultaneously assess. Composite measures like the NAFLD fibrosis score, the BARD score, and the Hepascore (which integrate various combinations of liver biochemistry, glycemic measures, and anthropometric measurements) are not sufficiently sensitive and are typically unable to definitively characterize >15% of people. According to Dr. Oren, even the gold standard liver biopsy diagnostic is “neither gold, nor standard” because there can be incredible variability between different biopsy samples of the same liver. What’s more, liver biopsy is quite expensive and invasive, adding another deterrent for an already under-diagnosed disease.
- Population health. Given what appears to be epidemic rates of fatty deliver disease, should countries call for nationwide NAFLD/NASH screening? Would such a policy be cost-effective, given the lack of available treatments? (In other words, after screening, what next? There are no FDA-approved treatments for NASH on the market.) Would population-level screening be feasible given the lack of consensus over diagnosis?
- Treatment for NAFLD/NASH (in the context of no formally-approved therapies). Currently, the only officially-recommended treatments for fatty liver disease (besides diet and exercise) are pioglitazone and vitamin E, though preliminary evidence suggests that GLP-1 agonists and metformin could also be effective. A wide array of therapies studied specifically for NAFLD/NASH are in various stages of development, but even the most advanced phase 3 candidates (Allergan/Norvartis’ cenicriviroc, Genfit’s dual PPAR alpha/gamma agonist elafibranor, Intercept’s FXR agonist obeticholic acid, and Gilead’s ASK-1 inhibitor selonsertib) are years away from reaching the market (and much further from being affordable and well-reimbursed).
- As Dr. Oren described, NAFLD/NASH represents the epitome of controversy and lack of consensus in the field metabolic disease. We’d even add one more key issue to this list: Anticipating regulatory behavior. As the NASH field heats up and as more drug candidates advance into late-stage clinical development, companies are especially attentive to designing clinical trials with regulatory agencies’ positions in mind. This is a difficult proposition, however, because no real consensus among different agencies exists, and most advice is asset-specific without pertaining to NASH drug development as a whole. Indeed, drug developers and regulatory agencies alike are wrestling with questions such as what stage of fibrosis constitutes a “treatable” NASH patient, whether NASH drugs will be chronic treatments, how to best define the efficacy of a NASH candidate, and the list goes on. This makes clinical trial design an enormous challenge, and, as our understanding of NASH evolves, it is not uncommon for a trial’s primary endpoint to shift from “important to not-important” from a regulatory standpoint before its completion date. Once NASH therapies reach the market, we imagine this uncertainty will likely spill over to the payer landscape. Additional uncertainty comes from the fact that outcomes for NASH patients all play out over the course of decades. Without hard data from long-term outcomes trials in NASH, it may be an uphill battle to convince payers that these likely pricey drugs would be cost-saving for the healthcare system in the long run. To this end, the Global Liver Institute’s Dr. Brian Harvey has advocated that hepatic data be systematically collected in diabetes CVOTs (~10,000-patient datasets ripe for the picking). The complexity here is great, and we view this as an invitation for greater conversation and collaboration among basic science researchers, drug developers, regulators, payers, and of course, patients, in order to foster more communication and eventually standardization at every level – from identifying gold-standard mouse models for preclinical research, to agreeing on a set of NASH outcomes, to defining which classes of NASH patients these drugs will be geared toward.
Metabolic Surgery for Primary & Secondary Diabetes Prevention
Luc Van Gaal, MD (University Hospital Antwerp, Belgium)
Dr. Luc Van Gaal characterized the future of obesity pharmacotherapy as a “search to break the 10% weight loss target.” In reviewing the clinical data for all the major obesity drugs available today, he showed how each agent’s efficacy plateaus around 8%-10% weight loss. Even 5% weight loss is sufficient to produce improvements in insulin sensitivity, beta cell function, CV risk, and quality of life, but Dr. Van Gal emphasized that many patients and providers would like to see weight loss >10%. He thus set up this goal for next-generation obesity products: Meet the unmet need of more substantial weight loss in people with obesity. The obesity drug competitive landscape features a variety of promising candidates. Dr. Van Gaal specifically highlighted Novo Nordisk’s next-gen GLP-1 agonist semaglutide, underscoring this agent’s potential to surpass the current standard of efficacy in obesity care. In a phase 2 trial, semaglutide taken once-daily produced a game-changing ~16% weight loss (average drop of 39 lbs from a baseline 244 lbs) among participants who completed one full year of treatment vs. ~8% weight loss for patients randomized to Novo Nordisk’s existing obesity drug Saxenda (liraglutide 3.0 mg) and only 2% weight loss for patients on placebo (all adjunct to diet/exercise). Given this next-level efficacy, Novo Nordisk management decided to advance once-weekly injectable semaglutide into phase 3 for obesity. In 2018, the company will launch four phase 3a STEP studies, slated to read out in 2020. Particularly notable is that Novo Nordisk has also planned a dedicated CVOT for semaglutide in obesity – the upcoming SELECT trial (n=~17,500), also scheduled to begin this year. No trial to-date has “proven” that obesity and its complications are responsive to pharmacotherapy, and positive results in this first-of-its-kind CVOT could underscore once and for all that obesity is a treatable condition and that long-term outcomes can be improved with medical management.
- Dr. Van Gaal additionally highlighted GLP-1/glucagon dual agonists as a promising future avenue for the medical management of obesity. The most advanced of these agents is Sanofi’s SAR425899, which is slated to enter phase 3 studies for obesity in 2018. In phase 2, the agent stimulated >3.5 kg (~8 lbs) weight loss after only four weeks – Sanofi management has suggested that this could potentially be on par with semaglutide’s weight loss effects, and we eagerly await data from longer studies.
- Dr. Van Gaal’s remarks left us optimistic about a future of greater efficacy from obesity pharmacotherapy. Even if 5%-10% change in body weight leads to improved health for patients, we know that weight loss is a crucial element of treatment satisfaction, medication adherence over the long run, and even patient engagement in chronic disease self-management. From this perspective, a drug that offers >10% weight loss could be a very valuable addition to the current obesity treatment toolkit. In our view, current options for obesity care are simply not good enough, and of course issues of stigma and poor reimbursement persist.
Be Aware Of…
Simon Heller, MD (University of Sheffield, UK)
Hypoglycemia expert Professor Simon Heller shared evidence from his lab pointing to a potential pathophysiological mechanism by which hypoglycemia could be associated with subsequent CV events and mortality. When patients with type 2 diabetes were induced to either hypoglycemia (45 mg/dl) or euglycemia (100 mg/dl), clot absorbance and clot lysis time were significantly and immediately increased in those with hypoglycemia, a change sustained out to one week after the hypoglycemic event. When looking at C-reactive protein and fibrinogen, no changes were observed directly after induction, but these measures were significantly elevated in the hypoglycemia group at one week. Thus, in a small sample, induced hypoglycemia led to significantly thicker blood and higher levels of inflammation. While the implication is that severe hypoglycemia could have a causal relationship with CV events, Dr. Heller also interpreted these results to mean that, in some patients with tighter control and repeated episodes of mild hypoglycemia, the benefits of tight glucose control could be cancelled out (potentially explaining the increased mortality in ACCORD’s intensive control group). To be sure, further study is needed to support this theory and, as Dr. Heller laid out, there are important challenges with the ethics of lowering glucose and studying high risk patients, as well as in accounting for downstream mortality. That said, we think this is an incredibly important area of research with the potential to seriously impact clinical practice. Dr. Heller cited numerous case studies of arrhythmias during hypoglycemia, also showing evidence that asymptomatic nocturnal hypoglycemia commonly occurs in patients with type 2 diabetes at increased CV risk. Further, there’s evidence indicating that hypoglycemia is associated with bradycardia and lower T wave symmetry in people with diabetes, but the same effect isn’t seen in those without diabetes. Overall, the number of different measures linking hypoglycemia with a negative CV impact absolutely warrants further investigation and we look forward to seeing where this line of research goes.
- Notably, a post-hoc analysis of DEVOTE found a significant, outcomes-based correlation between hypoglycemia and CV death. Following an episode of severe hypoglycemia in the study (a CVOT comparing Novo Nordisk’s next-gen basal insulin Tresiba vs. Sanofi’s Lantus), patients faced increased risk for CV mortality (HR=2.14, 95% CI: 1.37-3.35). To be sure, there was a wide confidence interval for this finding, and three-point MACE (non-fatal MI, non-fatal stroke, and CV death composite) was actually not significantly affected by severe lows. That said, these post-hoc, hypothesis-generating results do underscore the importance of more research into this overlap between hypoglycemia/CV risk.
Residual CV Risk in Diabetes
Itamar Raz, MD (Hadassah Medical Center, Israel)
Dr. Itamar Raz, lead investigator of SAVOR-TIMI and the soon-to-report DECLARE trial, used these CVOTs as a springboard to discuss the complexities of modern clinical trial design and interpretation, underscoring the essential role of real-world evidence to address questions unanswered by RCTs alone. Dr. Raz pointed out vast differences in patient population, study design, and event adjudication across diabetes CVOTs. These factors make it impossible to truly compare the safety/efficacy of different agents, and they limit our understanding of how these drugs perform in a broader patient population, outside the context of a controlled clinical trial setting. “We’ve enrolled hundreds of thousands of patients and spent hundreds of millions of dollars, but no matter how much data we glean from RCTs, there will never be enough.” (As an aside, we actually think billions of dollars have been invested into CVOTs, and we prefer to see this as an investment rather than cost.) We found this argument to be incredibly profound. Even our dream CVOT of an “all-brand” trial that randomizes participants to all available drugs (within and across therapy classes) would leave countless unanswered questions: How do these therapies stack up in a slightly different patient population than the one investigated? How would they compare in various combinations? And the list goes on … Even with unlimited funds, time constraints would make it impossible to gather sufficient hard CVOT data to definitively answer every question in the medical management of diabetes. According to Dr. Raz, this is the beauty of real-world evidence, which can at least scratch the surface of the issues that CVOTs and other RCTs leave unaddressed. He explained how RWE goes a step further by answering not only the question of can a therapy work (under ideal conditions), but does it work when actually placed into patient hands. This talk certainly gave us a lot to think about, and we are curious about what it would take at the regulatory level for RWE to be considered synergistically alongside RCT data.
Treatment Evolution in Type 1 Diabetes
Yang Tao, PhD (Hohai University, China)
China’s Dr. Yang Tao called attention to an exciting new development (published just days ago!) in Dr. Zhen Gu’s work on glucose-responsive insulin. Dr. Gu’s high-profile project (backed by the prestigious ADA Pathway grant, $5.8 million from MicroPort Scientific Corporation, and a cut of a $4.6 million grant from JDRF/Sanofi) involves H2O2-responsive polymeric vesicles that sense glucose and deliver insulin accordingly. In this most recent study, Dr. Gu’s team fashioned these vesicles into a gel-based microneedle array device that is able to release insulin across a layer of skin in response to glucose in a mouse model with type 1 diabetes. The mechanism is ingenious: The gel reacts with glucose to produce an H2O2 byproduct, and the vesicles in turn interact with H2O2, stimulating the release of insulin. Notably, the microneedle array has completely pain-free insertion and to-date has shown excellent biocompatibility. Though this work is clearly very early-stage, it inspires hope for a future where complicated insulin therapy regimens can be replaced by a simple, decision-free patch worn on the body. Dr. Gu’s microneedle array patch is one of the most promising candidates in the glucose-responsive insulin competitive landscape. That said, there are substantial challenges in this arena – chief among them insulin’s narrow therapeutic range and the hypoglycemia risk that comes from expecting an insulin analog to turn “on” and “off.” At the recent ADA Pathway to Stop Diabetes symposium, Dr. Gu detailed some of these obstacles but positioned glucose-responsive insulin as the future of diabetes management. We’re cautiously optimistic. For a deeper dive, check out the full paper published earlier this week in ACS Nano.
Diabetes and Heart Failure
HF and Anti-Hyperglycemic Drugs
Mikhail Kosiborod, MD (Saint Luke’s Health System, Kansas City, MO)
Dr. Mikhail Kosiborod provided a comprehensive overview of how various diabetes drug classes affect heart failure – one of the costliest and most deadly complications of diabetes. We’ve noticed much more focus on heart failure at diabetes conferences of late, and very notably, the ADA also included information on how each therapy class impacts heart failure in its 2018 Standards of Care (do these agents increase/decrease risk for heart failure, or are they neutral?). At a high level, some SGLT-2 inhibitors have shown convincing evidence for heart failure risk reduction, while certain DPP-4 inhibitors (ADA lists both saxagliptin [AZ’s Onglyza] and alogliptin [Takeda’s Nesina]) have shown a signal for heart failure hospitalization. In between, insulin, SUs, GLP-1s, and metformin are considered neutral for heart failure outcomes. Naturally, much of Dr. Kosiborod’s discussion was centered on the promise of SGLT-2s. In fact, he emphasized that the notion of diabetes drugs with a beneficial effect on heart failure is a welcome change of pace, since historically, the conversation has been dominated by fear that a diabetes therapy may worsen heart failure outcomes. Both Lilly/BI’s Jardiance (empagliflozin) and J&J’s Invokana (canagliflozin) demonstrated compelling risk reduction for heart failure hospitalization in the EMPA-REG OUTCOME and CANVAS trials, respectively. These findings are complemented by real-world evidence from AZ’s CVD-REAL study, for which Dr. Kosiborod is a primary investigator. He reviewed how SGLT-2s as a class demonstrated significant mortality and heart failure benefits vs. other glucose-lowering drugs in both initial and recurrent heart failure patients outside of a clinical trial setting. These results have inspired dedicated investigations of SGLT-2 inhibitors for the treatment of heart failure (rather than the prevention of heart failure in people with diabetes), namely the EMPEROR HF program for Jardiance and the Dapa-HF study for AZ’s Farxiga (dapagliflozin). These studies are enrolling people with heart failure with or without diabetes. Speaking of Farxiga, Dr. Kosiborod noted that all eyes are on the DECLARE CVOT, which is expected to read out sometime in 2H18. DECLARE will be the largest and longest CVOT to-date, with only ~40% of participants having baseline CV disease (compared to 100% in EMPA-REG and 66% in CANVAS). This leaves ample statistical room to delve into the issue of what CV benefit Farxiga could offer in the setting of primary as well as secondary prevention. Once “the elephant in the room,” ignored as a meaningful CV endpoint for people with diabetes, heart failure is now a veritable hot topic in diabetes – largely thanks to such promising SGLT-2 inhibitor findings. Dr. Kosiborod also criticized the implication that heart failure is a class effect for DPP-4 inhibitors. He underscored that only SAVOR-TIMI for Onglyza showed a statistically significant increase in heart failure hospitalizations with saxagliptin vs. placebo; this data trended in the wrong direction (favoring placebo over Nesina) in EXAMINE, but did not reach statistical significance. What’s more, the TECOS trial for Merck’s Januvia (sitagliptin) found a resoundingly neutral hazard ratio for heart failure hospitalization of 1.00. FDA has added heart failure warnings to all DPP-4 inhibitor labels, and ADA lists “potential risk” next to DPP-4s in its treatment algorithm – Dr. Kosiborod questioned these decisions, which echoes commentary from Dr. Darren McGuire at ESC 2017. Indeed, our sense is that most thought leaders disagree with heart failure being a class effect of DPP-4s, and labeling these products as such could deter patients/HCPs from using a potentially very helpful diabetes drug that is safe, well-tolerated, and effective overall.
- Dr. Kosiborod also emphasized the distinction between heart failure with preserved ejection fraction (HFpEF) vs. reduced ejection fraction (HFrEF). Whereas HFrEF involves a decrease in cardiac output following an insult to the myocardium, Dr. Kosiborod positioned HFpEF as a systemic disease associated with excess adiposity and insulin resistance – the “cardiac manifestation” of obesity (alongside NAFLD as the hepatic manifestation of obesity, hypertension as the vascular manifestation, and so on). According to Dr. Kosiborod, this explains why HFpEF is less responsive to traditional myocardium-targeting treatments – unlike HFrEF, it is not simply a disease of the myocardium. Consistent with the global obesity pandemic, epidemiological evidence shows a steady uptick in the proportion of heart failure cases that feature preserved ejection fraction. This is a worrisome development given the lack of effective treatments for HFpEF. Hopefully, SGLT-2 inhibitors could provide a much-needed treatment option in this area of high unmet need. Lilly/BI have launched two separate EMPEROR studies, one in patients with HFpEF (EMPEROR HF-Preserved, expected to complete June 2020) and the other in patients with HFrEF (EMPEROR HF-Reduced, also expected to complete June 2020). AZ’s Dapa-HF trial is focused on heart failure with reduced ejection fraction, and is expected to complete in December 2019 according to ClinicalTrials.gov; we’ll be curious to see if the company initiates another study in patients with preserved ejection fraction.
-- by Ann Carracher, Abigail Dove, Payal Marathe, Maeve Serino, and Kelly Close