- Leading our days #2-3 highlights for ACC 2018 are two new analyses, a CANVAS post-hoc and the first results from CVD-REAL 2. CANVAS participants with baseline heart failure may have garnered greater benefit from SGLT-2 inhibitor canagliflozin: The heart failure cohort (n=1,461) saw a 39% risk reduction in CV death or hospitalization for heart failure (HR=0.61, 95% CI: 0.46-0.80), while the cohort without known heart failure (n=8,681) did not see a significant drop on this composite endpoint (HR=0.87, 95% CI: 0.72-1.06). The trial wasn’t powered to show superiority in this way, so the non-significant effects of canagliflozin in the no-heart failure group should be taken with a grain of salt – but this also makes the benefit in patients with heart failure all the more exciting. CVD-REAL 2 included type 2 patients from the Middle East, Asia, and North America (n=470,128), and used real-world data to demonstrate a 49% lower risk of all-cause death and a 36% lower risk of hospitalization for heart failure associated with SGLT-2s vs. other glucose-lowering drugs. These results compellingly corroborate the results of CVD-REAL 1 (in the US and western Europe) as well as SGLT-2i CVOTs. Suffice it to say, ACC was another big meeting for SGLT-2 inhibitor data … and cardiologists are showing distinct enthusiasm for this therapy class, which clearly does so much more than lower A1c.
- We also attended a dinner symposium on diabetes management for cardiologists, and were thrilled to note that the session was absolutely p-a-c-k-e-d (they actually had to turn people away!). Speakers included Drs. Mikhail Kosiborod, Robert Eckel, Laurence Sperling, and Ms. Melissa Magwire. Dr. Kosiborod suggested that the amputation signal in CANVAS is probably real, and he implied that the pressing question now is whether or not this is an SGLT-2 class effect. Dr. Eckel addressed the SUSTAIN 6 retinopathy signal, describing early worsening phenomenon in which dramatic drops in A1c are associated with exacerbation of background retinopathy (to be sure, semaglutide is a particularly potent glucose-lowering agent, leading to rapid A1c decline once patients start on this GLP-1 agonist). Dr. Kosiborod also cited a SUSTAIN 6 post-hoc showing that a rapid A1c drop was associated with heightened retinopathy risk in both treatment arms, semaglutide and placebo. There’s so much more below in our coverage of this session, including Dr. Kosiborod’s practical advice on how to prescribe SGLT-2 inhibitors and GLP-1 receptor agonists as a cardiologist.
- We also saw posters on baseline characteristics in VERTIS-CV (the CVOT for Merck/Pfizer’s SGLT-2 inhibitor ertugliflozin), the implications of enrollment criteria for SGLT-2 inhibitor CVOTs (and their generalizability to the real-world type 2 patient population), and the potential mechanisms of SGLT-2 inhibitor cardioprotection (touching on ketone metabolism, inflammation, and proteomics).
Sunday and Monday were incredible days for diabetes learning at ACC 2018, with Sunday featuring the one-two punch of a new CANVAS post-hoc evaluating benefit from canagliflozin based on baseline heart failure status, followed by exciting CVD-REAL 2 results confirming the mortality and heart failure benefits associated with SGLT-2 inhibitors. Indeed, you’ll notice that SGLT-2 inhibitors are featured heavily throughout this report, in line with the high level of interest they continue to receive in the cardiology community.
If you missed our day #1 highlights (including a notable diabetes presence in the exhibit hall), you can check those out here. Our day #1 report features the very first ODYSSEY Outcomes results, plus some interesting commentary on CVOT design from Dr. Lawrence Leiter and the notion of diabetes as a CV risk equivalent from Dr. Peter Wilson. Happy reading!
- Top 10 Highlights
- 1. CANVAS Post-Hoc Finds Amplified Benefit of Canagliflozin on CV Death/Heart Failure in Patients with History of Heart Failure; Builds on Evidence for SGLT-2s in Heart Failure Prevention
- 2. CVD-REAL 2 Highlighted Real-World Outcomes associated with SGLT-2 Inhibitors in Asia, Middle East, North America: 49% Lower risk of All-Cause Death and 36% Lower Risk of Hospitalization for Heart Failure vs. Other Glucose-Lowering Drugs, In Line with CVD-REAL 1
- 3. Drs. Eckel and Kosiborod Discuss Amputation (CANVAS) and Retinopathy (SUSTAIN 6) Safety Signals; Encourage Cardiologists to Get More Involved in Diabetes Care; Dr. Eckel Criticizes Latest ACP Guidelines
- 4. Anti-Inflammatory Therapy Canakinumab Does Not Prevent New-Onset Diabetes, but Significantly Lowers the Biomarkers of Inflammation that Predict Type 2 – CANTOS Post-Hoc from Dr. Everett
- 5. Dr. Scirica Reinforces Value of CVOTs (Phase 2/3 Clinical Trials Are Not Enough); Argues that SGLT-2 and GLP-1 CVOTs Should Drive Treatment Focus in Diabetes Toward Minimizing CV Risk
- 6. Dr. Kosiborod Delivers Passionate Argument for Shifting Diabetes Treatment Paradigm Toward CV Risk Reduction; EMPA-REG OTUCOME “Changed the World”
- 7. Are Diabetes CVOT Results Generalizable? Analysis of Eligibility Requirements of SGLT-2 Inhibitor CVOTs (EMPA-REG, CANVAS, DECLARE) Suggests Not
- 8. VERTIS-CV Design and Baseline Characteristics (Merck/Pfizer’s CVOT for SGLT-2 Ertugliflozin): 99% with Baseline CV Disease, Including a High Proportion (22%) with Heart Failure
- 9. Posters Hypothesize Mechanisms of CV Benefit Underlying SGLT-2 Inhibitors: (i) A Shift to Ketone Metabolism with Empagliflozin, (ii) Greater Efficacy of Empagliflozin vs. Canagliflozin in Reducing Inflammatory Cytokines, (iii) Widespread Effects of Empagliflozin on the Proteome
- 10. Lilly/BI’s “For Your Sweetheart” Survey Shows Low Patient Understanding of the Diabetes/CV Disease Connection
Top 10 Highlights
In an absolutely packed late-breaking session, Dr. Gemma Figtree presented a new post-hoc analysis of CANVAS showing that certain CV benefits with SGLT-2 Invokana (canagliflozin) were greater in patients with a history of heart failure. These data were simultaneously published in Circulation, and were also called out in a dedicated press release from J&J. For the composite endpoint of CV death or hospitalization for heart failure, CANVAS participants with a history of heart failure at baseline (n=1,461) experienced a 39% relative risk reduction (HR=0.61, 95% CI: 0.46-0.80) with 203 observed events, while participants without prior heart failure (n=8,681) did not experience a significant risk reduction (HR=0.87, 95% CI: 0.72-1.06) with 449 observed events. The p-value for this interaction was significant at 0.021. For reference, the full CANVAS population experienced 22% risk reduction for CV death or heart failure hospitalization with canagliflozin vs. placebo (HR=0.78, 95% CI: 0.67-0.91). It’s encouraging that the effect in the no heart failure group trended in the right direction, favoring Invokana, despite being underpowered. Moreover, these are exciting results for patients with diabetes/heart failure (which overlap substantially in the real world), who may garner even greater benefit from canagliflozin than initial results indicated. Heart failure has been too-long ignored as a CV complication of diabetes, but it’s now gaining more attention because of the protective effects of SGLT-2 inhibitors, including Invokana. We certainly view heart failure in diabetes as an unmet need, and it would be a huge win to have a therapy class (SGLT-2s) that demonstrates convincing benefits on hard outcomes (!) in this patient population.
- There were no significant, or even borderline significant, interactions between heart failure history and three-point MACE, MI, stroke, all-cause death, or serious decline in renal function. When splitting the study population by heart failure status, enough power was lost such that few significant effects were seen on these endpoints in either cohort individually, but the group with baseline heart failure did retain a statistically significant benefit on all-cause mortality (30% relative risk reduction, HR=0.70, 95% CI: 0.51-0.96), while the group without baseline heart failure retained a statistically significant benefit on the composite renal endpoint (48% relative risk reduction, HR=0.52, 95% CI: 0.37-0.72).
- Dr. Figtree also presented new data showing that canagliflozin decreased risk for the composite of fatal heart failure or heart failure hospitalization by 30% vs. placebo (HR=0.70, 95% CI: 0.55-0.89). For comparison, canagliflozin reduced risk for heart failure hospitalization alone by 33% vs. placebo (HR=0.67, 95% CI: 0.52-0.87), according to the initial full results presentation at ADA, so this post-hoc finding lends additional evidence for the SGLT-2 inhibitor’s heart failure benefit. Experts in diabetes and cardiology alike are enthusiastic about the SGLT-2 class and its applications in heart failure. Although J&J isn’t currently pursuing a dedicated heart failure indication for Invokana, to our knowledge, both Lilly/BI and AZ are – for Jardiance (empagliflozin) and Farxiga (dapagliflozin), respectively.
- Dr. Figtree emphasized that the heart failure cohort was fairly small, comprising only 14.4% of the sample (n=1,461). At baseline and compared to the cohort without a history of heart failure, the heart failure cohort had significantly more participants who were female, a shorter mean duration of diabetes, a higher mean A1c, and more hypertension, CV disease, atrial fibrillation, and atherosclerotic CV disease, suggesting an overall sicker subgroup of patients (p<0.001 for all comparisons). Despite this, there were no significant differences on safety endpoints. The amputation signal was maintained across the split cohorts (HR=2.32, 95% CI: 1.10-5.51 for those with prior heart failure, and HR=1.90, 95% CI: 1.33-2.78 for those without prior heart failure).
- These analyses affirmed that canagliflozin reduced risk for CV death and heart failure hospitalization across most baseline characteristics, which is an important finding in terms of expanding the spectrum of type 2 patients who take the drug. Dr. Figtree reviewed various subgroups to show that no significant interactions existed for region, CANVAS vs. CANVAS-R, age (split at 65 years, though p=0.09 suggesting borderline significance), blood pressure (split at 140/90 mmHg), diabetes duration (split at 10 years), baseline eGFR, insulin use, atrial fibrillation, DPP-4 inhibitor use, TZD use, or history of CV disease. There were borderline significant interactions with BMI (p=0.03) when split at 30 kg/m2, baseline A1c (p=0.04) when split at 8%, and baseline metformin use (p=0.03); these indicate that those with higher BMI, higher baseline A1c, and who aren’t using metformin may benefit more from canagliflozin in terms of CV death and heart failure hospitalization – we’d be curious for additional investigations into these effects, and we’re intrigued by the possibility that SGLT-2s could be effective first-line agents for people with higher starting A1c and/or BMI.
- Neither CANVAS nor EMPA-REG OUTCOME (the CVOT for Lilly/BI’s Jardiance) measured baseline heart failure status with a cardiac echo or another formal diagnostic assessment; rather, this was an investigator-reported comorbidity. As such, it’s possible that far more patients had heart failure at baseline (i.e. the 14.4% of CANVAS participants is an underestimate). Indeed, Dr. David Aguilar asserted that heart failure is comorbid with diabetes in 25%-40% of patients, depending on the population studied, so the 14% prevalence in CANVAS does seem low. Dr. Figtree shared that, for the hospitalizations that occurred in CANVAS, only ~60% have echo data; she pointed to EMPEROR HF as an important prospective trial program for clearing things up. Also notable, DECLARE (CVOT for AZ’s Farxiga) is recording baseline cardiac echo or other formal assessments of heart failure if they were conducted, and the trial features a co-primary endpoint that includes heart failure. As such, DECLARE seems poised to give us the best evidence yet on SGLT-2 inhibitors and heart failure in diabetes, and we look forward to this readout anticipated in 2H18.
Dr. Mikhail Kosiborod presented very reassuring CVD-REAL 2 results (just published in JACC), demonstrating that the impressive real-world CV outcomes associated with SGLT-2 inhibitors observed in the first iteration of CVD-REAL extends into a population representing South Korea (n=336,644), Japan (n=67,780), Australia (n=27,442; only included in all-cause death analysis), Israel (n=19,472), Canada (n=16,064), and Singapore (n=2,726). In the multinational cohort (n=470,128), SGLT-2 inhibitors were associated with a 49% lower risk of all-cause death (HR=0.51, 95% CI: 0.37-0.70, p<0.001 vs. other glucose-lowering drugs); 5,216 events were observed in total. SGLT-2i were also associated with 36% lower risk of heart failure hospitalization (HR=0.64, 95% CI: 0.50-0.82, p=0.001 vs. other glucose-lowering drugs); 5,997 events were observed in total. For the composite outcome of all-cause death/heart failure hospitalization, SGLT-2i were associated with40% lower risk (HR=0.60, 95% CI: 0.47-0.76, p<0.001 vs. other glucose-lowering drugs); 9,788 events were observed in total. Dr. Kosiborod also presented original CVD-REAL results at last year’s ACC meeting, reporting 51% lower risk of all-cause death with SGLT-2i, 39% lower risk of heart failure hospitalization, and 46% lower risk of the composite (all p<0.001) – we note similar findings from CVD-REAL and CVD-REAL 2, adding to the robustness of this real-world evidence. Dr. Kosiborod continued by showing heterogeneity p-values of <0.001 for all three endpoints in CVD-REAL 2 across regions; the only individual region to cross the line of unity (into non-significance) was Singapore for all-cause death (HR=0.75, 95% CI: 0.38-1.47) and heart failure hospitalization (HR=0.62, 95% CI: 0.38-1.02), and we note the wide confidence intervals due to small sample size; with n=2,726, Singapore had the lowest number of participants among all countries. We continue to be very positive about the results coming out of this AZ-sponsored program, which supports both a cardioprotective class effect for SGLT-2 inhibitors and the real-world benefit of these agents outside the rigorous clinical trial setting. CVD-REAL and CVD-REAL 2 additionally show the potential effects of SGLT-2oi in a broad, diverse population. Even with different event rates between populations with and without CV disease at baseline, similar effects were observed with SGLT-2i in CVD-REAL 2 across all endpoints and regions. Dr. Kosiborod acknowledged that real-world studies come with inherent risk of residual confounding, even though the results were consistent in sensitivity analyses. Events were not adjudicated, and safety was not evaluated. It’s important to keep in mind that our experience with SGLT-2 inhibitors in the real world is still relatively short – will these potential benefits hold up over decades? In the shorter-term, these results have only made us more excited for the DECLARE CVOT on AZ’s Farxiga (dapagliflozin), expected to read out in 2H18, and for the now-underway Dapa-HF trial in chronic heart failure. Many thanks to AZ for sponsoring such a groundbreaking real-world program!
- Of particular note, CVD-REAL 2 also found a significant 19% lower risk of MI with SGLT-2 inhibitors (HR=0.81, 95% CI: 0.74-0.88, p<0.001) and a 32% lower risk of stroke (HR=0.68, 95% CI: 0.55-0.84, p<0.001). All five individual regions saw significantly lower risk of stroke with SGLT-2i, compared to only two regions for MI. Dr. Kosiborod positioned the stroke results as all the more notable considering a higher prevalence of stroke in Asia, and we’re certainly excited about the potential implications of lower stroke risk in a population where diabetes is becoming so much more prevalent. Dr. Kosiborod characterized these athero-thrombotic events as “not well studied” in previous CVD-REAL datasets, and he thus explained that these results should be seen as more reassuring. Following EMPA-REG OUTCOME results at EASD 2015 (this was the first positive diabetes CVOT, for Lilly/BI’s SGLT-2 inhibitor Jardiance), there was some talk about the above 1.00 hazard ratio for non-fatal stroke (HR=1.24, 95% CI: 0.92-1.67; p=0.16), even though this did not meet statistical significance. No increase in the risk of stroke was seen with canagliflozin in the CANVAS Program. To this end, we think it’ll be valuable to have a large real-world dataset showing lower stroke risk among patients starting SGLT-2 inhibitor therapy vs. other diabetes drugs, to address any lingering concerns among real-world HCPs, patients, or payers.
- CVD-REAL 2 compared new users of SGLT-2 inhibitors vs. new users of other glucose-lowering drugs using propensity scores to match 235,065 sets of treatment episodes 1:1 in each participating country. National registries, insurance claims, and EMR records combined for the total study of 470,128 treatment initiation episodes. Dr. Kosiborod explained that an intent-to-treat analysis was used, so patients were followed even if index treatment was discontinued . He shared that mean follow-up was ~400 days. He reviewed baseline characteristics to show that the cohorts were well-matched. Dr. Kosiborod also highlighted high metformin (74%-75%) and, unfortunately, high sulfonylurea (51%-52%) utilization across the entire real-world study population.
- Dapagliflozin accounted for 75% of SGLT-2 exposure time in CVD-REAL 2, which reflects the ex-US dominance of AZ’s Farxiga. Empagliflozin (Lilly/BI’s Jardiance) accounted for 9% of SGLT-2 exposure time, while ipragliflozin accounted for 8%, canagliflozin (J&J’s Invokana) for 4%, tofogliflozin for 3%, and luseogliflozin for 1%. This stands in contrast to the original CVD-REAL conducted in the US, UK, Norway, Denmark, Sweden, and Germany, in which 53% of participants were on canagliflozin (first-to-market in the US), 42% on dapagliflozin (first-to-market in Europe), and 5% on empagliflozin. Even in that dataset, 92% of EU patients were taking dapagliflozin and 76% of US patients were on canagliflozin, mirroring the first-to-market therapies in those geographies.
- Dr. Kosiborod also shared hopes to potentially use the CVD-REAL dataset to analyze safety events in the future. He does think this is a good venue in which to do so, but understandably stipulated that this must be undertaken with a great deal of care. We remain convinced that amputation risk should be manageable in the real world, primarily with careful patient selection (e.g. Dr. Lawrence Leiter suggested on ACC day #1 that HCPs avoid prescribing canagliflozin to people with peripheral artery disease), diligent monitoring of the feet, and strong patient education. Given the low base rate of amputations, even in the canagliflozin arm of CANVAS, we don’t think this risk holds a candle to the tremendous benefits of Invokana (and other SGLT-2s) on heart failure, other CV events, and overall mortality. That said, the J&J’s sponsored real-world study EASEL did find a higher amputation rate in patients on SGLT-2s vs. other diabetes drugs, so we can’t ignore that this is a safety issue that needs to be concertedly addressed.
Drs. Robert Eckel and Mikhail Kosiborod gave a master class in diabetes management for the cardiologist during a packed dinner symposium. Dr. Eckel clarified that while glycemia is absolutely relevant in treating people with diabetes, HCPs can now lower glucose while simultaneously mitigating CV risk, with cardioprotective diabetes drugs like Novo Nordisk’s GLP-1 Victoza (liraglutide) and Lilly/BI’s SGLT-2 Jardiance (empagliflozin). This hit on an all-important conference theme – that it’s a tremendous victory to have multiple diabetes drugs with CV benefit, to have a choice (!) among glucose-lowering, weight loss-promoting, cardioprotective medicines, and that people with diabetes and comorbid CV disease need multidisciplinary care, coordinated among specialists. Drs. Eckel and Kosiborod addressed two safety signals, for amputations in CANVAS and retinopathy in SUSTAIN 6. Dr. Kosiborod argued that the amputation signal seen with canagliflozin (J&J’s SGLT-2 inhibitor Invokana) is probably real: A near-doubling of risk is a big difference, even from a low base, and the hazard ratio was consistent across CANVAS and CANVAS-R, making it unlikely to be a statistical fluke. A post-hoc safety analysis of CANVAS was presented at EASD 2017, and even after controlling for other known risk factors (peripheral vascular disease, neuropathy, etc.), canagliflozin treatment increased the likelihood of a lower limb amputation nearly two-fold. Dr. Kosiborod talked about adjudication and collection of amputation events, explaining that while people “mistrust” EMPA-REG OUTCOME’s amputation data because it didn’t label amputations an event of special interest, amputations only became of special interest in CANVAS after an early signal and action by the independent data monitoring committee. The main question now, in Dr. Kosiborod’s view, is whether amputations are an SGLT-2 inhibitor class effect – there’s no compelling evidence that supports this to date, but other trials are now collecting that data more thoroughly. Turning to SUSTAIN 6 and the retinopathy signal seen with semaglutide (Novo Nordisk’s GLP-1 Ozempic), Dr. Eckel described early worsening phenomenon, in which rapid drops in A1c are associated with a risk of progressive retinopathy in those with background retinopathy – and background retinopathy is often missed. He highlighted that early worsening is only a theoretical explanation right now, though our sense is that most thought leaders seem to agree with it. Dr. Kosiborod referenced additional analyses of SUSTAIN 6, showing that people with more dramatic A1c-lowering were at higher risk for retinopathy regardless of treatment arm. Further, the absolute increase in retinopathy risk was much greater for those who already had retinopathy at baseline, even though semaglutide appeared to increase risk relative to placebo regardless of baseline retinopathy status. We don’t anticipate that retinopathy-related concerns will impede Ozempic uptake in the real world, given how powerful and potent this drug seems to be on A1c and weight loss, but this will unfold in the coming months as the product was just launched in the US in February. Meanwhile, amputation-related concerns have been a significant headwind for the Invokana business, ever since FDA issued a black box warning in May 2017. For our part, we believe amputation risk should be manageable in the real world, but Invokana sales have trended sharply down in recent quarters.
- We were happy that Dr. Eckel immediately criticized the new ACP guidelines recommending an A1c target of 7%-8% for the majority of type 2s, which is not consistent with any endocrinology organization’s guidelines. We heard some hallway chatter about these guidelines, and attendees did seem a bit wary of the recommended A1c goals, so we’re glad Dr. Eckel discussed the potential negative impact that these ACP guidance statements could have on diabetes care. We think it’s so important to spread the message that these are not widely-applicable guidelines for type 2 diabetes.
- The dinner conversation spanned a range of other topics as well. Dr. Eckel shared that he’s not a fan of SUs, as the insulin secretion they promote likely causes earlier beta cell burnout, and the lack of glucose-dependent function can cause hypoglycemia. We agree wholeheartedly with this view, and we wish the majority of second-line diabetes prescriptions in the US weren’t still going to a sulfonylurea. Dr. Kosiborod noted that eGFR restrictions for SGLT-2 inhibitors (contraindicated below 30 mL/min/1.73 m2) don’t necessarily arise from a safety concern as much as a worry that glycemic efficacy will be lost at very low renal function. That said, there’s no evidence to-date that the blood pressure, weight loss, or even CV benefits are attenuated for people with lower eGFR. Dr. Eckel added that the story is starting to change, with SGLT-2 manufacturers beginning to show that patients with eGFR <40 mL/min/1.73 m2 still benefit. Indeed, we think upcoming trials of SGLT-2i in kidney disease will elucidate the full range of benefits for this advanced, oral therapy class: This includes CREDENCE for Invokana, Dapa-CKD for Farxiga, and a planned study for Jardiance in CKD. We also heard distinctly positive commentary on fixed-ratio basal/GLP-1 combinations. Dr. Eckel cited Dr. John Buse in talking about these combo drugs replacing basal insulin and even basal-bolus – we’re thrilled by this concept.
- Shifting perspective, Dr. Kosiborod offered practical advice on how to prescribe diabetes medications as a cardiologist without stepping on a PCP’s or endocrinologist’s toes. He shared a story in which a cardiology colleague prescribed an SGLT-2 inhibitor and shortly after received a call from the patient’s PCP for trying to manage diabetes. To avoid such scenarios, Dr. Kosiborod recommended explicitly putting in the patient note that the prescription is not for the management of blood glucose, but for minimizing CV risk: “I put nothing about A1c and glucose control in the note because that’s not why I’m doing it.” In his view (and ours), it’s absolutely under the purview of cardiologists to prescribe medications to lower CV risk even if they were originally diabetes medications. He urged cardiologists in the room to familiarize themselves with SGLT-2 inhibitors and GLP-1 agonists: “If you think you’re using these drugs to control blood glucose, it’s going to be a no-go for most of us. If you’re using them to lower CV risk, we know what to talk about with the patient.” Kansas City’s Ms. Melissa Magwire shared her own experience in which a PCP asked a cardiologist to assess whether a patient would be a good candidate for an SGLT-2 inhibitor or GLP-1 agonist so that the PCP could start them on it. While this setup certainly requires more organization and structure, Ms. Magwire emphasized that communication is paramount in provider-provider relationships, not just patient-provider relationships. Finally, Dr. Kosiborod underscored the HCP’s responsibility to explain to patients what they should expect on these medications: For SGLT-2 inhibitors, this is one extra bladder void per day and a higher risk of yeast infections, and men should be asked if they’re circumcised (with an explanation why, since the risk of genital infections with SGLT-2i is higher in uncircumsized men); for GLP-1 agonists, patients should be warned about nausea and other potential GI side-effects.
- Ms. Magwire advocated for coordinated, multidisciplinary teams to improve chronic disease management and patient outcomes. The hospital where she practices, Shawnee Mission Health in DC, established a glycemic steering committee in 2008, later adding half a dozen other interdisciplinary teams and specialist positions aimed at coordinating care. To underscore the need for improved communication, Ms. Magwire introduced a single patient who was receiving care from more than a dozen providers, including an endocrinologist, RN, PA, CDE, cardiologist, PCP, the PCP nurse practitioner, a vascular surgeon, a nephrologist, a pharmacist, social services, cardiac rehabilitation, a retinal specialist, a podiatrist, and a dietician. In situations with even far fewer people in the mix, communication is often sub-optimal, and that missing link negatively impacts outcomes, fragments care, and leads to questions and uncertainty surrounding treatment plans (for both provider and patient). Improved multidisciplinary communication should involve (i) organization of care, (ii) medication management, and (iii) promotion of patient-centered care and shared decision-making, which in and of itself improves satisfaction and outcomes. Above all else, however, Ms. Magwire emphasized the need to keep patient expectations in mind: Patients are content to receive care from multiple team members as long as there’s a perception of coordination, which is good news because no one person can offer best practice care for all aspects of diabetes.
- In the same session, Dr. Laurence Sperling noted that there are ~7,000 endocrinologists in the US (and only ~half really involved in diabetes care) compared to ~30,000 cardiologists. Thus, it makes basic sense for cardiologists to help minimize the CV risk conferred by diabetes. How can all HCPs help affect change in the diabetes arena? Dr. Sperling advocated for frequent examination of diabetes patients for nephropathy, smoking history, retinopathy, and foot complications. He also placed major emphasis on shared decision-making between the patient/provider. Dr. Sperling envisions “an extension of the existing healthcare paradigm,” and he put forth the idea of a Collaborative Care Command Center to encourage home and remote care provisions, enabled by the growing reach of different facets of digital health. While intensive lifestyle intervention seems to be the most effective way to reduce CV risk, Dr. Sperling underscored that we also have at least 12 medication classes proven to treat diabetes – and two that we know can reduce CV risk – so we need to work to maximize the benefit of all the treatment tools (pharmacological, technological, and personal).
While baseline biomarkers of inflammation can predict the progression from prediabetes to diabetes, anti-inflammatory drug canakinumab (an interleukin-1ß inhibitor) does not prevent that progression in patients with prior MI and high baseline inflammation – these findings from a pre-specified analysis of the CANTOS trial (n=10,061) were presented by Dr. Brendan Everett. He showed that baseline hsCRP and IL-6 were both significantly associated with incident type 2 diabetes (p=0.0002 and p<0.001) at five years, even after multivariable adjustment. However, only the IL-6 association remained significant after adjusting for baseline A1c. Treatment with canakinumab did significantly reduce both hsCRP (at 50 mg, 150 mg, and 300 mg doses) and IL-6 (at 150 mg and 300 mg doses), but this drop in inflammatory biomarkers did not translate to a drop in incident diabetes at five years. Adjudicated diabetes incidence per 100 person-years across all three canakinumab arms of the trial was 4.23 vs. 4.2 in the placebo arm (p=0.86). Incidence was 4.24/100 person-years in the 50 mg canakinumab group, 4.35 in the 150 mg canakinumab group, and 4.12 in the 300 mg canakinumab group (p=0.70-0.80 vs. placebo). That said, canakinumab did reduce risk for three-point and four-point MACE in this population of high-risk patients with pre-existing atherosclerotic CV disease, and this benefit was seen regardless of baseline glycemic status (p=0.86 for heterogeneity). In a somewhat surprising effect, canakinumab provided a significant (p<0.0001) but fleeting A1c reduction in people with prediabetes, in dose-dependent fashion. This benefit rapidly attenuated over ~9-12 months, and was not clinically-meaningful in our opinion. Overall, it seems that canakinumab is likely effective in reducing CV but not diabetes risk, despite an effect on inflammation. In CANTOS (n=10,061), 4,057 participants had baseline diabetes, 4,960 had baseline prediabetes, and 1,044 had normal glucose.
- Dr. Laurence Sperling highlighted this CANTOS analysis in a talk on the top three presentations in diabetes most likely to impact clinical or research practice. Despite seemingly negative results overall, Dr. Sperling was very positive about the fact that glycemia didn’t interfere with canakinumab’s MACE benefit in CANTOS. He also emphasized that this trial contributes to our ability to predict diabetes. Indeed, we think this analysis supports the importance of inflammation as a risk factor for diabetes, even if modification of that risk factor with canakinumab didn’t reduce diabetes incidence per se. To our understanding, the inflammation predicting development of diabetes is possibly more of a symptom than a cause of the pathophysiology underlying diabetes. More work certainly need to be and is being done to puzzle apart the role of inflammation in cardiometabolic disorders – it’s been implicated in insulin resistance and impaired insulin production, according to Dr. Everett – and Dr. Sperling urged the audience not to abandon the idea of anti-inflammatory therapy.
In two CVOT-focused talks on Sunday, Dr. Benjamin Scirica argued first that these outcomes studies are absolutely necessary (offering insight above and beyond phase 2b/3 trials), and second that positive diabetes CVOTs are convincing evidence of the CV benefit associated with SGLT-2 inhibitors and GLP-1 agonist and should impact clinical practice. To the first point, Dr. Scirica presented pooled phase 2b/3 data for saxagliptin (AZ’s DPP-4 inhibitor Onglyza): 41 total MACE events translated into a 56% risk reduction vs. placebo at 76 weeks (HR=0.44, 95% CI: 0.24-0.82). On the other hand, the SAVOR-TIMI CVOT gave a resoundingly neutral hazard ratio of 1.00 for three-point MACE, out to 24 months. Without this RCT, our conception of the CV profile of saxagliptin would have been incredibly different. This evokes the point with which Dr. Scirica opened both of his talks: Before five years ago, the best randomized data on CV risk prevention in diabetes came from UKPDS, which is now 20 years-old and suggests a CV benefit for metformin with only 342 patients (a sample size that would never fly these days). He explained that the field needs to keep conducting large and lengthy CV outcomes trials in diabetes because there’s simply no other way to gain a more accurate or precise understanding of drug benefit. This echoed commentary from Dr. Darren McGuire at ESC 2017. Dr. McGuire described how prior to FDA’s 2008 CVOT guidance, diabetes therapies were approved for the market with as few as 250 patient-years of drug exposure, compared to the ~15,000 patient-years of drug exposure afforded through a CVOT. This is clearly a substantial investment for diabetes manufacturers, but we ultimately agree with Drs. Scirica and McGuire in their point that these outcomes studies paint a comprehensive picture on safety while also uncovering “surprise” CV benefits.
- Dr. Scirica divided diabetes CVOTs into two waves, the first including all three DPP-4 inhibitor trials (TECOS for sitagliptin, SAVOR-TIMI for saxagliptin, and EXAMINE for alogliptin) plus ELIXA (for GLP-1 lixisenatide). For the most part, these were reassuring safety trials, although Dr. Scirica did highlight the unexpected finding of a 27% increased risk for heart failure hospitalization with saxagliptin vs. placebo. Now, these studies are “quaint,” in his view. His second wave of diabetes CVOTs includes EMPA-REG (for SGLT-2 empagliflozin), LEADER (for GLP-1 liraglutide), SUSTAIN 6 (for GLP-1 semaglutide), CANVAS (for SGLT-2 canagliflozin), and also IRIS for TZD pioglitazone in patients with recent stroke. What these trials have in common is positive results, indicating cardioprotection. Dr. Scirica asserted that thought leaders would not have bet on CV superiority if someone asked them to put money down, meaning these were “surprise” findings for the field at first. Both empagliflozin and canagliflozin showed 14% risk reduction vs. placebo for three-point MACE (non-fatal MI, non-fatal stroke, CV death), while liraglutide gave a 13% relative risk reduction on the same endpoint and semaglutide gave a 26% relative risk reduction (with a much wider confidence interval). These results are “remarkable in a time we’re finding it harder and harder to reduce CV death,” Dr. Scirica said. For people who think the results are too good to be true, he pointed to the consistent signals across multiple trials and the fact that A1c reduction in CVOTs is much lower than in trials of glycemic efficacy, indicating glucose-independent mechanisms.
- To conclude, Dr. Scirica laid out a philosophy for cardiologists in prescribing diabetes therapies. With the explosion of new drugs classes in recent decades, how do cardiologists and other practitioners integrate them into clinical practice? As Dr. Scirica put it, providers need to fundamentally shift away from thinking that the goal of therapy is to lower A1c. HCPs should focus more on how a therapy lowers glucose rather than by how much, since SGLT-2s and GLP-1s have demonstrated CV benefit independent of A1c improvements.
- Dr. Scirica also listed some outstanding questions that he hopes will be addressed in the next, third wave of diabetes CVOTs. Should metformin still be first-line therapy? Dr. Scirica suggested a “modern UKPDS” that investigates A1c normalization in newly-diagnosed patients. He posited another question recently addressed in a JCI viewpoint: Can we still do placebo-controlled trials when we know SGLT-2 inhibitors and GLP-1 agonists are cardioprotective, helping patients avoid heart attacks, strokes, and CV death? See our take here. Lastly, Dr. Scirica considered class effects and their potential implications: At what point (if ever) can we say something is a class effect and that new class members don’t need full CVOTs? Separately, Dr. Mikhail Kosiborod explained that there are plenty of examples in medicine where members of the same class have very different safety or efficacy signals. Additionally, Dr. Scirica emphasized the need for more studies in people with obesity, CKD, and prediabetes, as well as more endpoints on eGFR and hospitalization for heart failure.
“Does a cardiologist need to be a diabetologist, or does a diabetologist need to be a cardiologist?” Session chair Dr. Robert Eckel posed this question, and speaker Dr. Mikhail Kosiborod outlined a compelling case for both, advocating for greater collaboration in general between diabetes care specialists and CV medicine specialists. Dr. Kosiborod spoke to the paradigm shift taking place in diabetes, from a hyper-focus on glycemic control to a central focus on CV risk reduction: “No one wants people walking around with an A1c of 10% or 11%, but it’s more about how you do it [lower glucose] than just doing it.” At recent meetings, we’ve heard Dr. Kosiborod argue with increasing zeal that the ultimate goal of treatment in type 2 diabetes is to let patients live longer and feel better doing it, not to make lab values like A1c look better; in order to do this, treatment needs to target CV outcomes first and foremost, rather than glycemia. For us, this argument evokes the outcomes beyond A1c movement, highlighting the importance of hard outcomes that impact patient wellbeing, longevity, and quality of life – this includes hypoglycemia as well as CV events, and indeed, the two may be related. Comparing people with and without diabetes, Dr. Kosiborod explained that both populations have experienced improvements in CV outcomes over the last 20 years, and yet the size of the gap between the two groups isn’t closing. Ischemic heart disease remains the #1 killer of people with diabetes by far. While glucose control unequivocally improves microvascular outcomes, Dr. Kosiborod noted that the same notion hasn’t panned out for macrovascular, CV outcomes: Aggressive, rapid lowering of A1c without paying attention to how you accomplish this has not impacted CV events in a substantial way. Dr. Kosiborod named CV death and heart failure as “arguably, the two most important CV events for diabetes patients”, and he asserted that no evidence to-date has shown that a general strategy of A1c lowering improved these outcomes. That’s why positive diabetes CVOTs represent such a major advance, because cardioprotection with molecules such as liraglutide, empagliflozin, and canagliflozin, is likely unrelated to A1c reduction per se. In Dr. Kosiborod’s words, EMPA-REG OUTCOME “changed the world” as the first positive read out, followed by IRIS, LEADER, SUSTAIN 6, CANVAS, and, in part, also by large real world studies such as CVD-REAL. Suddenly, there was a new classification of glucose-lowering compounds – those that reduce CV risk, and even CV death – and we wholeheartedly share Dr. Kosiborod’s excitement about SGLT-2 inhibitors and GLP-1 agonists for their CV (and renal) benefits.
In a poster presentation, Dr. Eric Wittbrodt highlighted that ~half of patients with type 2 diabetes do not meet the eligibility criteria for any SGLT-2 inhibitor CVOT. Based on exclusion criteria related to A1c, chronic kidney disease (CKD) status, and CV history, only 21% of type 2s in the Diabetes Collaborate Registry (DCR) would be eligible for EMPA-REG OUTCOME, 30% for CANVAS, and 46% for DECLARE. Only 16% of patients were eligible for all three trials, Dr. Wittbrodt explained, while 46% of patients were eligible for none. Most notable in our opinion is that nearly half of the real-world population with type 2 diabetes is not eligible for any of these CVOTs, suggesting that results from these RCTs may not generalize to many patients seen in usual clinical practice. Moreover, there are typically eligibility criteria above and beyond these three categories of A1c, CKD, and CV history, so even fewer patients would likely qualify for these CVOTs in reality. While we don’t think this fact should diminish excitement about the CV efficacy of SGLT-2 inhibitors in any way (after all, EMPA-REG and CANVAS showed compelling CV safety, and there’s a chance for any patient to reap the CV benefits), it does show the unmet need for outcomes-based research in a very “real-world” patient population. According to Dr. Wittbrodt, the DCR is the first interdisciplinary diabetes database to monitor and boost care for diabetes and metabolic disease patients, covering ~two million patients and ~10,000 providers total; we’re intrigued to see what else might come out of this dataset. Patients in this study (n=407,410) were ³18 years of age with type 2 diabetes diagnosed between January 1, 2012 and March 31, 2017. Type 1 patients, people with type 2 diabetes managed with diet alone (without pharmacotherapy), and patients with prediabetes were not included. Dr. Wittbrodt mentioned a few limitations, including a potential gap in accurate US population illustration due to the fact that 29% of the data provided was from HCPs. This sample included patients from 689 sites and 9,266 providers. At baseline, patients had a mean age of 66 years, 49% were female, mean A1c was 7.9%, 53% had baseline atherosclerotic CV disease, and the 10-year risk for atherosclerotic CV disease in those without it at baseline was 25%. Among type 2 patients, there were high rates of hypertension and dyslipidemia (>80%), though only ~8% of the people in this category actually took SGLT-2 inhibitors (which matches data from another Diabetes Care publication pointing to only ~7% of second-line diabetes prescriptions in the US going to an SGLT-2 product). We agree with researchers when they say that these findings offer a chance for renewed attention to provision of SGLT-2 inhibitors for more sustainable patient health outcomes in the future.
- We also think it’s important to note significant differences in study population across trials: A1c criteria ~halved the eligible population for CANVAS and EMPA-REG, but had a much less sizable impact on DECLARE, though DECLARE did have more restrictive CKD criteria. Overall, these findings suggest that DECLARE will be a more “real-world” CVOT, similar to AZ’s other diabetes CVOT, EXSCEL for GLP-1 agonist Bydureon, which has been called out for its “pragmatic design.”
Dr. Christopher Cannon presented a poster on the design and baseline characteristics of VERTIS-CV, the CVOT for ertugliflozin (Merck/Pfizer’s SGLT-2 inhibitor Steglatro). An abstract detailing this info was also just published in JACC. VERTIS-CV (n=8,327) isn’t expected to complete until October 2019, but this will be a very important read out for Merck, Pfizer, and the long-term success of Steglatro on the market (considering that two SGLT-2 inhibitors have already demonstrated CV benefit – Lilly/BI’s Jardiance has this benefit reflected on its label, while J&J’s Invokana may also receive a CV indication by year-end). Dr. Cannon showed that a particularly high proportion of patients with baseline heart failure (22%) were enrolled in VERTIS-CV, compared to DECLARE (10%), CANVAS (14%), or EMPA-REG (10%). In line with inclusion criteria, 99% of patients had baseline CV disease, similar to EMPA-REG and in contrast to 41% in DECLARE and 66% in CANVAS. Coronary artery disease was known in 76% of VERTIS-CV participants at baseline, while cerebrovascular disease was known in 23% and peripheral arterial disease (PAD) in 19%. Stage 3 CKD was present in 22% of VERTIS-CV patients at study start, while micro- and macroalbuminuria were present in 30% and 9% of participants, respectively. Overall, we agree with Dr. Cannon’s characterization of this study population as representing high baseline CV risk. Participants were randomized 1:1:1 to placebo, 5 mg ertugliflozin, or 15 mg ertugliflozin once-daily. Like the other SGLT-2 inhibitor CVOTs, the primary endpoint is three-point MACE comprised of CV death, non-fatal MI, and non-fatal stroke. Key secondary endpoints include CV death or hospitalization for heart failure, CV death alone, and a renal composite of renal death, dialysis/transplant, or doubling of serum creatinine from baseline (to be sure, the renal benefits of SGLT-2s have been a wonderful surprise finding from CVOTs completed to-date, and we’ll be looking for this from ertugliflozin in VERTIS-CV as well). While most CVOTs over-represent white men, VERTIS-CV has the highest enrollment of white patients by eight percentage points (at 88%), and we expect criticism from some on this point.
From what we can tell, cardiologists are quite enthusiastic about the CV benefits that have been observed with SGLT-2 inhibitors, and they’re (understandably) curious about the mechanism underlying this cardioprotection. This topic of mechanism surfaced during nearly every ACC 2018 session dealing with SGLT-2s. Here, we highlight three posters aimed at identifying a cardioprotective mechanism of action. We’re certainly intrigued by the various hypotheses circulating, and it’ll be exciting when this answer is finally illuminated, but in any discussion of mechanism we feel it’s important to highlight two quotes from EASD 2016: Dr. Hertzel Gerstein said, “a stone falls today the same way that it fell 200 years ago, but our theory of gravity has changed dramatically. You don’t need to know how a drug works to benefit from it.” And Dr. Juris Meier said, “at a certain point it’s okay to be pragmatic and say even if we don’t know exactly how we’re saving lives, let’s save lives.” That is to say, while mechanism of CV benefit for SGLT-2s is a fascinating and important scientific question, we hope HCPs aren’t waiting for a clear mechanism before incorporating this drug class into their practice and prescribing SGLT-2 therapy to patients in-need of CV risk reduction.
- A study from Mount Sinai used a pig model to show that empagliflozin shifts myocardial metabolism from glucose oxidation to ketone metabolism, improving myocardial energetics and lowering LV remodeling. After MI was induced via two-hour balloon occlusion of the proximal LAD, 16 pigs were randomized to either 10 mg empagliflozin daily or to placebo; they also received cardiac MRI and 3D-echo at one day and two months post-MI. Empagliflozin (Lilly/BI’s Jardiance) was associated with lower cardiac remodeling at two months, as well as reduced LV mass (p=0.02), volume (p<0.01), and sphericity (p=0.01). Empagliflozin also gave improved LV systolic function, as measured by LVEF and strain. Neurohormonal activation, as measured by BNP and catecholamine, was reduced in the empagliflozin group compared to the placebo group (p<0.01 and p=0.03, respectively). Moreover, sampling of myocardial metabolites from the LAD and coronary sinus was conducted, demonstrating that control pigs had higher myocardial glucose consumption (p=0.01), while empagliflozin raised plasma ketone levels (p<0.01) and myocardial ketone consumption (p<0.001), resulting in higher lactate levels (p<0.05). If that weren’t enough, empagliflozin treatment also improved ATP/ADP and NADH/NAD+ ratios in the myocardium (p<0.05 and p=0.02, respectively). We find the variety of measurements included in this study particularly compelling, and we think it’s quite likely that the ketone metabolism hypothesis plays some role in mediating the CV benefit associated with SGLT-2 inhibitors. That said, we also agree with Dr. Benjamin Scirica that SGLT-2 inhibitors (and GLP-1 agonists) are likely exerting their effects via multiple axes that compound into significant collective benefit.
- An in-human study found that empagliflozin but not canagliflozin (J&J’s Invokana) significantly reduced inflammatory cytokines. Interestingly, canagliflozin was more effective in lowering A1c, but empagliflozin had the edge on cytokine reduction. Thirty-two men with type 2 diabetes were randomized 1:1 to empagliflozin 10 mg or canagliflozin 100 mg for six months, then switched to the other therapy for another six months. At the first six-month mark, canagliflozin was associated with a 0.9% drop in A1c, while empagliflozin decreased A1c by 0.7%. After another six months, the group that went from canagliflozin to empagliflozin experienced a 0.1% increase in A1c, while the empagliflozin to canagliflozin group experienced an additional 0.1% A1c decline. Turning to the inflammatory biomarker data: At six months, canagliflozin dropped IFN-γ (inflammatory cytokines interferon gamma) from 23 pg/ml to 18 pg/ml (p=0.38), while empagliflozin reduced IFY- γ to 10 mg/ml from the same baseline (p=0.001). The numerical difference here between canagliflozin’s and empagliflozin’s effect is more than marginal, and of course, only empagliflozin showed a statistically significant change. On TNF-α (tumor necrosis factor alpha), canagliflozin reduced levels from 40 pg/ml to 33 pg/ml (p=0.29), but empagliflozin dropped the same to 25 pg/ml (p=0.002), reaching statistical significance for this improvement in inflammation. Finally, for IL-6 (interleukin 6), canagliflozin gave a reduction from 20 pg/ml to 16 pg/ml (p=0.27), compared to 10 pg/ml with empagliflozin (p=0.022). Thus, treatment with empagliflozin moved the needle on three inflammatory biomarkers into “normal” ranges. Moreover, similar magnitudes of reduction were seen in the group that received canagliflozin first once they were switched to empagliflozin. In the group to switch from empagliflozin to canagliflozin, inflammatory biomarkers had climbed back up by one year (to just below the six-month canagliflozin data), indicating to us that inflammation is a very modifiable pathology. To be sure, this is a small trial and did not assess CV outcomes, but we find the data incredibly interesting nonetheless. We still think much more science is needed to figure out the role inflammation plays in cardiometabolic disorders, but these data are certainly compelling.
- A third study assessed the impact of empagliflozin on biomarker plasma proteins (proteomics), identifying 43 altered plasma protein levels (using a p<0.05 cutoff) after four weeks of treatment with the SGLT-2 inhibitor, pointing to the widespread effect of this agent on physiology. In 144 paired plasma samples from 72 participants (one sample at baseline, one after four weeks of treatment with empagliflozin 25 mg) across a spectrum of glucose tolerance, 3,713 different protein levels were evaluated with a modified aptamer assay. Empagliflozin was found to impact 43 plasma proteins – seven related to cardiomyocyte contraction or relaxation, five to iron handling, and one to sphingosine/ceramide metabolism (which the authors clarified is a known pathway of CV disease). Fourteen more plasma proteins implicated are involved in metabolic and lipid pathway regulation, and the most significant changes were (i) an increase in IGFBP1 and desmocollin and (ii) a decrease in ferritin. There’s no doubt that “omics” hold great promise in understanding and treating cardiometabolic disease, and even though we don’t yet know the specific implications of each protein identified in this study, we’re very intrigued by these results. If nothing else, it’s clear that SGLT-2 inhibitors are having a widespread impact on metabolism.
BI’s Dr. Jonathan Pak presented new results from the Lilly/BI-sponsored online survey called “For Your SweetHeart,” and he emphasized low patient awareness of the correlation between type 2 diabetes and CV disease. Among people with type 2 diabetes (n=501), 52% were unaware of the heightened risk for CV disease and macrovascular events associated with their diagnosis, though they were more aware of risk for microvascular complications including retinopathy (57%), nephropathy (57%), and neuropathy (64%). Only 41% of the 501 patients were aware of their increased risk for MI, while only 43% were aware of their increased risk for stroke. Only 67% were aware that CV disease is the leading cause of death among people with diabetes. This adds color and detail to very preliminary survey results released by Lilly/BI in November 2016. While immensely disheartening, the survey – available from October 24, 2016 until November 1, 2016 – also found that 88% of patients with diabetes would modify their diet and 81% would talk to their healthcare provider if they knew about their increased CV disease risk. There is hope that with much better patient education, people with this chronic disease will be open to and engaged in CV risk reduction strategies, although we acknowledge that what individuals endorse in a survey doesn’t always align with behavior. These results parallel findings from Novo Nordisk/IDF’s “Taking Diabetes to Heart” survey, which also showed a greater understanding of microvascular rather than macrovascular complication risk. Selection bias may have played a role in these online surveys, with more engaged patients participating, so there’s a chance that awareness of CV risk was actually overestimated (and the reality is even worse). The “For Your SweetHeart” survey (n=1,505) included responses from 501 patients with type 2 diabetes, 364 who knew someone with type 2 diabetes, and 1,004 controls (neither). Adults ³18 years were encouraged to participate in the survey. Gender was largely balanced, and the 35-54 age range saw the most overall participants.
-- by Ann Carracher, Megan Clyne, Payal Marathe, and Kelly Close