This document contains our coverage of outcomes trials at EASD 2016, organized into themes, symposia, corporate symposia, and oral presentations (in that order). The meeting ended on a very high note with SUSTAIN 6 full results presented on Friday morning in the grand Minkowski Hall, and we also heard diabetes experts sound off on LEADER, EMPA-REG OUTCOME, and the impact of CVOTs more broadly. Moreover, this chapter includes new data and important insights on renal outcomes in diabetes. See below for all of these learnings!
Talk titles highlighted in yellow were some of our favorites from the meeting, reflecting what we found to be most notable. Talk titles highlighted in blue are new full report additions, and were not part of our daily highlights coverage during the conference.
- Detailed Discussion and Commentary
- Symposium: SUSTAIN 6
- Study Design and Baseline Characteristics
- Cardiovascular Outcomes
- Clinical and Metabolic Outcomes
- Safety Outcomes
- Close Concerns Questions
- Symposium: EMPA-REG OUTCOME: One Year Later
- Introduction and Context
- Macrovascular and Heart Failure Outcomes: An Update
- Microvascular and Renal Outcomes
- Implications for the Management of Patients with Type 2 Diabetes and High CV Risk
- Symposium: Liraglutide Effect and Action in Diabetes
- Evaluation of Cardiovascular Outcome Results – A Long-Term Evaluation (LEADER)
- EASD/ADA Symposium: Changing Paradigms: The Role of SGLT-2 Inhibitors
- Symposium: Diabetes Prevention
- Corporate Symposium: Type 2 Diabetes: Beyond the Beta Cell (Sponsored by AZ)
- Can We Reduce the Incidence of Macrovascular Complications?
- Cardiovascular Outcomes Trials: Current Status
- Cardiovascular Outcomes Trials: Implications for Clinical Practice
- Panel Discussion
- Oral Presentations: SGLT-2 Inhibitors: Metabolic Effects
- Symposium: SUSTAIN 6
Future and Impact of Cardiovascular Outcomes Trials
§Following an exciting year of positive cardiovascular outcomes trial (CVOT) results, much discussion centered on Cardiovascular Outcomes Trials
- hHow they should CVOT results affectchange drug labelings, regulatory processes, and clinical practice.? This is a looming question in the field and was a looming question at EASD 2016. We heard opinions from numerous esteemed experts on what needs to happen in order for EMPA-REG OUTCOME, LEADER, and SUSTAIN 6 data to realize its real-world implications. Dr. Juris Meier (Ruhr University of Bochum, Germany) pushed for multi-agent CVOTs and head-to-head comparisons of newer drugs with relatively older agents. Data showing the relative CV benefits of different available diabetes drugs would be tremendously valuable for high-risk patients, he argued, and would give CVOT findings more direct purpose in clinical decision-making. Dr. Meier also advocated for a greater emphasis on primary CV prevention. Participants in published CVOTs have largely been very high-risk (understandably, as this helps a trial reach the necessary number of CV events for a sufficiently small confidence interval in a shorter amount of time), but enrolling lower-risk participants will be important for the future of CVOTs, Dr. Meier explained, noting that AZ’s DECLARE (for SGLT-2 inhibitor dapagliflozin) and EXSCEL (for GLP-1 agonist exenatide) will each include a cohort of patients without prior CV history. In his view (and ours), positive results on primary CV prevention could be a major win in two ways: (i) by promoting greater utilization of these agents across a much wider spectrum of the diabetes patient population, and (ii) by providing even more compelling evidence for cardioprotection in a broader population. Maybe this is what we need to get positive CV data on drug labels. We see expanding CVOTs into primary prevention as a worthwhile goal, although we acknowledge the enormous associated cost would be enormous that would be associated.
EMPA-REG OUTCOME: One Year Later
- We heard much discussion on the potential mechanism of cardioprotection seen in EMPA-REG OUTCOME, one-year after the groundbreaking CVOT was presented at EASD 2015. Dr. Silvio Inzucchi (Yale University, New Haven, CT) – who also presented the cardiovascular outcomes from the study at last year’s meeting – admitted that the initial thinking on why empagliflozin might offer CV benefit was off-base. “With a great deal of modesty, we had it all wrong.” The early divergence of the Kaplan- Meier curves suggests that the SGLT-2 inhibitor works not by an overarching atherosclerotic effect (which is more likely for GLP-1 agonist liraglutide based on LEADER data), but rather by some other mechanism. Dr. Bernard Zinman (University of Toronto, Canada) later presented a univariate mediation analysis of EMPA-REG OUTCOME (first presented at ADA 2016), which attributed 52% of empagliflozin’s cardioprotection to volume contraction, as reflected by an increase in hematocrit. The same analysis attributed 25% to decreased uric acid concentration and only 3% to between-group A1c differences – this last point underscores that the CV benefit is independent of glycemic effects. Dr. Zinman shared that a multivariate analysis, which will prove more accurate in illuminating mechanism, is underway – we’re glad to see this hypothesis-generating work underway, though we recognize it may be quite a while before we have an consensus mechanism for the cardioprotective benefit. we’re curious about this, as the answer still escapes us as to how empagliflozin conferred such remarkable 38% risk reduction for CV death and 14% risk reduction for the primary three-point MACE.
- That said,On the other hand, many speakers wondered aloud: how crucial is it that we understand mechanism? Several speakers felt that while it’s interesting and important to investigate the mechanism, it’s nNot so crucial that we must wait for a definitive answer before affecting clinical practice or adding positive CV results to drug labels for Lilly/BI’s Jardiance (empagliflozin) and, hopefully coming soon before the FDA,or Novo Nordisk’s Victoza (liraglutide). Dr. Inzucchi urged the committee charged with authoring the next iteration of the ADA/-EASD diabetes treatment guidelines to consider EMPA-REG OUTCOME and other recent CVOTs, including LEADER, SUSTAIN 6, and even IRIS (for the TZD pioglitazone, perhaps at low doses), in crafting its next position statement for the diabetes field, despite lingering mechanism questions. Having data from EMPA-REG OUTCOME and LEADER readily available on the label for these drugs would be hugely helpful for busy patients and HCPs, and so we agree wholeheartedly with what these renowned thought leaders had to say:
- “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.” – Dr. Hertzel Gerstein
- “One excuse at the Jardiance Advisory Committee was ‘we’re not quite sure about the mechanism’ – who cares?! While I applaud conservatism, it’s time to take action.” – Dr. Neil Poulter
- “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.” – Dr. Juris Meier
Renal Outcomes in CVOTs
- We noticed growing interest in renal complications of diabetes at this year’s EASD, as highlighted by encouraging renal outcomes results from the SUSTAIN-6 trial and a new sub-analysis of the LEADER trial. In SUSTAIN-6, renal complications appeared at a rate of 3.6% in the semaglutide group (59 events) vs. 6.0% in the placebo group (99 events), an impressive 36% risk reduction. The renal benefit was driven primarily by a difference in the diagnosis of persistent macroalbuminuria, which occurred at a rate of 2.5% in the semaglutide group, versus 4.9% with placebo. This parallels the 22% risk reduction in renal complications reported in the LEADER trial (HR=0.88; 95% CI: 0.67-0.92, p=0.003), which were driven by a 26% reduction in the onset of persistent macroalbuminuria (HR=0.74, 95% CI: 0.60-0.91) and a 19% reduction in urinary albumin-creatinine ratio, a measure of microalbuminuria (HR=0.31, 95% CI: 0.76-0.86). Two new findings from the ongoing subgroup analysis of the LEADER trial’s renal data further revealed that: (1) Among participants with kidney disease (eGFR <60 ml/min/1.73 m2) there was a 22% reduction in time to first renal event (HR: 0.78; 95% CI: 0.56-1.09); (2) Among participants with severe kidney disease (30-60 ml/min/1.73 m2) or end-stage renal disease there was a 27% reduction in time to next additional composite renal outcome (HR: 0.73; 95% CI: 0.50-1.07). These two findings provide the intriguing suggestion that liraglutide’s renal benefits may be particularly applicable to patients already experiencing renal disease.
- Renal complications are among the costliest of diabetes complications, so it is very encouraging to see evidence of renal- protective effects in not one but two members of the GLP-1 agonist class. As of now it remains unclear whether these renal benefits are due to improvements in glucose control and blood pressure or are instead the product of a direct effect of semaglutide on the kidney. We will be awaiting further dissection of these renal findings, and perhaps even a dedicated chronic kidney disease trial for liraglutide and semaglutide. We were also impressed by the renal outcomes from EMPA-REG OUTCOME for Lilly/BI’s SGLT-2 inhibitor Jardiance (empagliflozin), first presented at ADA 2016. We’re hopeful that improvements in our understanding of the renal impact of diabetes drugs can direct patients with diabetic nephropathy to treatment options most likely to help address this area of high unmet need.
Detailed Discussion and Commentary
Symposium: SUSTAIN 6
Study Design and Baseline Characteristics
Lawrence Leiter, MD (St. Michael’s Hospital, Toronto, Canada)
Dr. Lawrence Leiter provided an overview of the trial design and baseline population characteristics in the SUSTAIN 6 cardiovascular outcomes trial (CVOT). SUSTAIN 6 was a double-blind, randomized, placebo-controlled, time- and event-driven trial: 3,297 individuals with type 2 diabetes from 230 sites across 20 countries were enrolled so long as they were (i) ≥ 50 years old with evidence of CVD (83% of subjects) or ≥ 60 years old with subclinical evidence of CVD (17% of subjects); (ii) diabetes drug-naïve, or on 0-2 oral diabetes agents with or without basal or premix insulin; and (iii) had an A1c ≥ 7.0%. Clinicians were repeatedly encouraged to treat according to local standard of care guidelines to achieve optimal glycemic control. Participants were randomized in a 1:1:1:1 fashion to 1.0 mg semaglutide, 0.5 mg semaglutide, or volume-matched placebos and were observed for 109 weeks (104-week treatment period followed by a 5-week follow-up period). The trial required at least 122 primary events (cardiovascular death, non-fatal MI, and non-fatal stroke) to achieve appropriate statistical power, though the trial yielded more than double that minimum number of events. Key secondary outcomes included time to first occurrence of an expanded composite CV outcome (CV death, non-fatal MI, non-fatal stroke, revascularization, unstable angina requiring hospitalization, and hospitalization for heart failure). All-cause death and each individual component in the expanded composite CV outcome were pre-specified secondary outcomes as well. The outcomes addressing secondary safety and efficacy objectives included glycemic control, body weight, patient-reported outcomes, microvascular outcomes (retinopathy and nephropathy), and adverse events (including hypoglycemia). Dr. Leiter noted that the study was extremely well-executed, given that 98.0% of patients completed the trial (those in the semaglutide group were slightly more likely to drop out, most commonly due to the documented GI consequences of GLP-1 therapy), and the vital status of 99.6% was known at trial’s end.
- Baseline characteristics were well-balanced between the semaglutide-treated arms and placebo. The study population had a mean age of 65 years, body weight of 92 kg (~202 lbs), 14-year diabetes duration, and 8.7% baseline A1c. Notably, a high proportion of patients had hypertension (~93%) and ischemic heart disease (~61%) at baseline, and many were taking CV medications – ~94% were on anti-hypertensive agents, ~73% on statins, and ~76% on anti-thrombotics. In addition, ~58% of the subjects were on some sort of insulin therapy, and ~84% were taking non-insulin glucose-lowering medications, the most prevalent being metformin (~73%) and sulfonylureas (~43%).
Steven Marso, MD (UT Southwestern, Dallas, TX)
Cardiologist Dr. Steven Marso presented the headlining cardiovascular outcomes from SUSTAIN 6. Novo Nordisk’s next-generation once-weekly GLP-1 agonist semaglutide demonstrated a 26% (!) risk reduction for the primary endpoint of three-point MACE (CV death, non-fatal MI, and non-fatal stroke), eliciting a loud round of applause and joyful murmuring from the audience. This primary outcome occurred in 7% of semaglutide patients (n=1,648) titrated to a dose of either 0.5 mg or 1.0 mg of the agent vs. 9% of the placebo group (n=1,649) over 104 weeks, producing a hazard ratio of 0.74 (95% CI: 0.58-0.95; p<0.001 for non-inferiority; p=0.02 for superiority). Dr. Marso emphasized that the point estimates for the primary outcomes continued to favor placebo across subgroup analyses for sex, baseline age, baseline BMI, baseline A1c, baseline duration of diabetes, and region, with hazard ratios ranging from 0.58 to 0.84. The p-value for interaction among subgroups within each category was non-significant, suggesting that the results are consistent across all subgroups. Similarly, the point estimates for subgroup analyses of race, ethnicity, baseline heart failure status, history of MI/stroke, cardiovascular disease status, insulin treatment at baseline, and eGFR at baseline (<60 ml/min/1.73m2 and <30 ml/min/1.73m2) were all to the left of or right at unity and the p-values for interaction for all were non-significant.
- The 26% risk reduction for the composite primary endpoint is remarkable! For comparison, LEADER showed a 13% risk reduction for Novo Nordisk’s Victoza (liraglutide) and EMPA-REG OUTCOME showed a 14% risk reduction for Lilly/BI’s SGLT-2 inhibitor Jardiance (empagliflozin), with both CVOTs relying on the same three-point MACE used in SUSTAIN 6. That said, in a conversation with us, Dr. Philip Home (Newcastle University, UK) suggested that reporting the relative risk reduction as being in the range of 5%-42% would be more accurate, given the large confidence intervals. Within this context, the SUSTAIN 6 results are consistent with the LEADER results. We also can’t overlook the shorter span and smaller number of MACE events incurred during this CVOT. Follow-up on the primary endpoint continued for only two years in SUSTAIN 6, whereas LEADER followed-up for a minimum of 3.5 and a maximum of five years and EMPA-REG OUTCOME followed-up for four years. The direct impact of a shorter CVOT is fewer MACE events – 254, 1,302, and 772 in SUSTAIN 6, LEADER, and EMPA-REG OUTCOME, respectively. As a result, it wouldn’t be possible to say that the results would definitely support a cardioprotective indication, given the complexities of the regulatory system - indeed, Novo Nordisk has already shared that it intends to conduct a larger CVOT powered for superiority for semaglutide. Despite the differences in trial size, Dr. Marso emphasized to us that SUSTAIN 6 has more in common with LEADER than not in terms of the patient population enrolled, the endpoints, etc.
- Individual components of primary outcome: Among the components of the primary outcome, semaglutide significantly reduced the risk of non-fatal stroke by 39% (HR=0.61; 95% CI: 0.38-0.99; p=0.04). Non-fatal MI also trended toward reduction, though the result was not significant (HR=0.74; 95% CI: 0.51-1.08; p=0.12). Notably, the Kaplan-Meier curves for cardiovascular death in the semaglutide and placebo arms were virtually superimposable (HR=0.98; 95% CI: 0.65-1.48; p=0.92). For comparison, the LEADER trial for Novo Nordisk’s other GLP-1 agonist, Victoza (liraglutide), found a highly significant 22% reduction in cardiovascular death with liraglutide (HR = 0.78; 95% CI: 0.66-0.93; p=0.007). We expect the lack of clear cardiovascular mortality benefit might be due to the small size and short duration of the trial, contributing to a very low event number (44 adjudicated CV deaths and 46 adjudicated CV deaths).
- Key secondary endpoints: Semaglutide demonstrated a significant 26% risk reduction for the expanded composite outcome (cardiovascular death, non-fatal MI, non-fatal stroke, revascularization, and hospitalization for unstable angina or heart failure) (HR=0.74; 95% CI: 0.62-0.89; p=0.002). The composite endpoint of non-fatal MI, non-fatal stroke, and all-cause mortality (replacing cardiovascular mortality) was reduced by 23% (HR=0.77; 95% CI: 0.61-0.97; p=0.03). Like the cardiovascular mortality results, the Kaplan-Meier curves for all-cause mortality were largely superimposable with 62 deaths in the semaglutide group and 60 deaths in the placebo group (HR=1.05; 95% CI: 0.74-1.50; p=0.79).
- Revascularization: Revascularization, including both coronary and peripheral revascularization, was also significantly reduced by 35% with semaglutide treatment (HR=0.65; 95% CI: 0.50-0.86; p=0.003). This event occurred in 83 participants in the semaglutide group and 126 participants in the placebo group, driving event rates of 5% and 8%, respectively. All other individual components were not significantly different from placebo.
- Hospitalization for unstable angina and for heart failure: Neither hospitalization for unstable angina nor for heart failure with semaglutide treatment achieved a significant difference from placebo. The hazard ratio point estimate for unstable angina requiring hospitalization was 0.82 (95% CI: 0.47-1.44; p=0.49), with 22 events in the semaglutide arm and 27 events in the placebo arm. The hazard ratio for hospitalization for heart failure slightly favored placebo, but the wide confidence intervals suggest no significant relationship between semaglutide treatment and increased risk of hospitalization for heart failure (HR=1.11; 95% CI: 0.77-1.61; p=0.57).
- As expected, semaglutide treatment produced modest increases in heart rate and decreases in systolic blood pressure. Pulse increased 2.1 beats/min and 2.4 beats/min in the 0.5 mg and 1.0 mg dose groups, respectively. Systolic blood pressure decreased 1.27 mmHg with semaglutide 0.5 mg and 2.59 mmHg with semaglutide 1.0 mg.
Clinical and Metabolic Outcomes
Tina Vilsbøll, MD (University of Copenhagen, Copenhagen, Denmark)
Dr. Tina Vilsbøll presented the key clinical and metabolic outcomes from the SUSTAIN 6 trial, overviewing semaglutide’s efficacy outcomes (in terms of A1c and weight reductions) and microvascular outcomes (encompassing renal and opthalamic complications). At the pre-specified time point of two years post-randomization, mean A1c in the semaglutide vs. placebo groups was 0.66% lower for the 0.5 mg dose and 1.05% lower for the 1.0 mg dose, both of which were statistically significant (baseline A1c=8.7%; p<0.0001). Similarly, mean body weight (baseline = 92 kg) in the semaglutide vs. placebo groups was 2.87 kg (~6.3 lbs) lower for the 0.5 mg dose and 4.35 kg (~10 lbs) lower for the 1.0 mg dose (baseline=92 kg [~203 lbs); p<0.0001 for both). The microvascular outcome measures collected were a double-edged sword, showing an encouraging decreased risk of nephropathy (HR= 0.64; 95% CI: 0.46-0.88; p=0.005) and a concerning increase in the risk for retinopathy (HR=1.76; 95% CI: 1.11-2.78; p=0.02).
- Retinopathy complications appeared at a rate of 3% in the semaglutide group (50 events) vs. 1.8% in the placebo group (29 events), a 1.2% absolute risk increase and a 76% relative risk increase. Of course, these are very small event numbers but the increased risk of retinopathy complications (which were defined in this study as vitreous hemorrhage, onset of diabetes-related blindness, or need for treatment with an intravitreal agent or retinal photocoagulation) will surely be worrisome for some, including potentially regulatory agencies. That said, Dr. Visbøll emphasized that all of the patients that experienced worsening retinopathy had pre-existing retinopathy at baseline. Among the five semaglutide-treated patients with onset of diabetes-related blindness during the trial, all had proliferative retinopathy at baseline according to Dr. Visbøll. There is nothing possible to say at this stage – there are equal chances this is “spurious correlation” or chance – or that this is a negative finding – and a trial will need to be done to ascertain this (perhaps a two-year trial – hard to say at this stage). 50 vs. 29 events are simply too small numbers to confidently assess, especially given the multiple endpoints at play in this trial. A larger trial would certainly be able elucidate this potential connection. It is concerning that in the LEADER trial, treatment with liraglutide also hinted at a trend toward increased retinopathy (HR=1.15; 95% CI: 0.87-1.52; p=0.33), although those results were non-significant.
- Certainly these findings are disturbing on the face of it, but they do not come completely unexpectedly. Dr. Visbøll mentioned that rapid glucose lowering is associated with worsening of retinopathy, as reported in the DCCT/EDIC study – although the applicability of this finding to the SUSTAIN 6 results is not yet clear, it’s important to think about this particularly related to the very small numbers shown. In a conversation with us, Dr. Philip Home (Newcastle University, Newcastle, UK) echoed this sentiment, also noting a similar finding in the Kroc study in the 1980s. He explained that the mechanism is believed to be reduction of blood flow in a damaged vasculature previously protected by the high blood flow (through vascular dilatation) of hyperglycemia, which is consistent with the large improvement in A1c also seen after intensive glucose lowering. It will be great to hear opinions on various approaches, keeping in mind what will keep things easy for patients and HCPs – we would not want to see complicated regimens that would threaten adherence. We wondered if possibly a slower dose titration or if more gradual treatment intensification (perhaps to a DPP-4 inhibitor or an SGLT-2 inhibitor, or even a less potent GLP-1 agonist before initiating semaglutide) could help ameliorate some of this risk among patients with pre-existing retinopathy but this is pure speculation and we will look forward to amassing expert views.
- Renal complications appeared at a rate of 3.6% in the semaglutide group (59 events) vs. 6.0% in the placebo group (99 events), an impressive 36% risk reduction. The renal benefit was driven primarily by a difference in the diagnosis of persistent macroalbuminuria, which occurred at a rate of 2.5% in the semaglutide group, versus 4.9% with placebo. This parallels the nature of the renal benefits reported in the LEADER trial (HR=0.88; 95% CI: 0.67-0.92, p=0.003), which were also driven by reductions in macroalbuminuria. Renal complications (which were defined in this study as new onset of persistent macroalbuminuria, persistent doubling of serum creatinine, need for continuous renal replacement therapy, or death due to renal disease) are among the costliest of diabetes complications, so it is very encouraging to see evidence of renal protective effects in a second member of the GLP-1 agonist class. As of now it remains unclear whether these renal benefits are due to improvements in glucose control and blood pressure or are instead the product of a direct effect of semaglutide on the kidney. We will be awaiting further dissection of these renal findings, and perhaps even a dedicated chronic kidney disease trial for semaglutide (which has been suggested for liraglutide). If Novo Nordisk does undertake a dedicated chronic kidney disease trial, we expect it would be for semaglutide as management has stated that it will focus more of its resources on semaglutide, which it views as the more efficacious and potent GLP-1 agonist molecule – it’s also, presumably, easier to prescribe for HCPs and use for patients. We’re curious if it would be possible to conduct a single combined outcomes trial that both rigorously assesses the cardiovascular benefit (as Novo Nordisk is already planning on initiating) and the potential renal benefit. Of course, this trial would be massive and likely very costly, though we expect less costly than conducting two separate outcomes trials. Compared to the overall costs of kidney disease, it is very very low.
- Dr. Home noted that these nephropathy findings are encouraging, but do not directly address renal function. This would require assessment of eGFR, which we hope will appear in later analyses of the SUSTAIN 6 data.
- Semaglutide demonstrated significant improvements in a variety of additional efficacy outcomes related to A1c and weight reduction, which were sustained over the 2 year treatment period. Semaglutide was efficacious in reaching A1c goals: 39% and 49% of participants in the semaglutide 0.5 mg and 1.0 mg arms respectively achieved an A1c <7% vs. 16% and 15% with equivalent doses of placebo (p<0.0001 for both); 23% and 34% of participants on semaglutide 0.5 mg and 1.0 mg respectively achieved an A1c <6.5% vs. 7% and 8% with equivalent doses of placebo (p<0.0001 for both). Furthermore, after 104 weeks, a higher proportion of semaglutide-treated patients were able to achieve 5% and 10% weight loss. 36% (versus 18%) of patients in the low dose arms and 47% (versus 19%) of patients in the high dose arms achieved 5% weight loss. 13% (versus 6%) of patients in the low dose arms and 20% (versus 7%) of patients the high dose arms achieved 10% weight loss. Dr. Vilsbøll highlighted this latter finding as particularly notable; indeed, it is quite impressive that 1.0 mg semaglutide produces such substantial weight loss in as many as 1 in 5 patients.
- Additionally, semaglutide demonstrated significant improvements on a range of patient-reported outcomes (PROs), as assessed by the SF-36v2 survey. Encouragingly, the 1.0 mg semaglutide demonstrated statistically significant improvements on ALL (!) patient-reported outcomes assessed, including physical functioning, bodily pain, general health, vitality, social functioning, and mental health (The 0.5 mg semaglutide dose produced positive trends in these PROs, but only general health reached statistical significance). We applaud the trial designers for including PROs in this analysis. To our knowledge (and we need to check this!) this is the first time such outcomes have been assessed in a CVOT, and we hope this more holistic and patient-centered approach becomes the standard going forward.
- Patients in the semaglutide and placebo groups alike experienced similar low rates of hypoglycemia. Severe or blood-glucose confirmed hypoglycemia occurred at a rate of 23.1% (191 events) and 21.7% (178 events) in the 0.5 mg and 1.0 mg semaglutide groups, respectively, and 21.5% (177 events) and 21.0% (173 events) in the corresponding placebo groups. Severe hypoglycemia occurred at a rate of 1.7% (14 events) and 1.3% (11 events) in the 0.5 mg and 1.0 mg semaglutide groups, respectively, and 1.5% (12 events) and 2.1% (17 events) in the corresponding placebo groups.
Stephen Bain, MD (Swansea University, UK)
Dr. Stephen Bain stepped up next to discuss additional safety outcomes of interest. Treatment discontinuation due to an adverse event was higher among semaglutide patients (214 cases amounting to 12% of the 0.5 mg group and 15% of the 1.0 mg group) vs. placebo (110 cases amounting to 6% of the 0.5 mg group and 8% of the 1.0 mg group), although the total numbers of adverse events and serious adverse events were greater for placebo vs. semaglutide. Adverse events occurred in 90% of patients on 0.5 mg semaglutide vs. 91% of their placebo counterparts, and in 89% of patients on 1.0 mg semaglutide vs. 89% of their placebo counterparts. Serious adverse events (including death, life-threatening episodes, and hospitalizations) occurred in 35% of patients on 0.5 mg semaglutide vs. 40% of their placebo counterparts, and in 34% of patients on 1.0 mg semaglutide vs. 36% of their placebo counterparts. Researchers focused on many adverse events in SUSTAIN 6 that have been raised as points of consideration for GLP-1 agonists and other incretin-based therapies, such as GI side-effects, pancreatitis, and neoplasms, particularly in the pancreas.
- Nausea was the no. 1 factor leading to discontinuation of treatment, accounting for nearly 5% of premature cessation in the 1.0 mg semaglutide arm. There were 233 nausea events reported in the 0.5 mg semaglutide group (75% mild, 21% moderate, 5% severe) vs. 79 in the 0.5 mg placebo group (72% mild, 27% moderate, 1% severe), and 285 nausea events in the 1.0 mg semaglutide group (66% mild, 28% moderate, 5% severe) vs. 95 in the 1.0 mg placebo group (82% mild, 18% moderate, 0% severe).
- Diarrhea occurred 279 times in the 0.5 semaglutide group vs. 161 times in placebo, and 251 times in the 1.0 mg semaglutide group vs. 113 times in placebo. As was the case for nausea, a majority of these events were mild.
- There were 128 vomiting events among patients on 0.5 mg semaglutide vs. 53 in the corresponding placebo group; there were 173 vomiting events among patients on 1.0 mg semaglutide vs. 43 in the corresponding placebo group. Once again, as was seen in the data on nausea and diarrhea, a majority of these cases were mild.
- Acute pancreatitis occurred in 0.7% of patients on 0.5 mg semaglutide vs. 0.4% of their placebo counterparts, and in 0.4% of patients on 1.0 mg semaglutide vs. 1.1% of their placebo counterparts. In total, there were nine semaglutide-treated patients and 12 placebo patients who experienced acute pancreatitis. There were no instances of severe pancreatitis observed during the trial.
- Adverse events related to the gallbladder were reported in 4%, 3%, 5%, and 3% of the 0.5 mg semaglutide, 1.0 mg semaglutide, 0.5 mg placebo, and 1.0 mg placebo arms, respectively. Gallbladder adverse events included cholelithiasis and cholecystitis acute.
- The frequency of malignant neoplasms was similar across treatment arms, and the hazard ratio for pancreatic cancer was 0.25 in favor of semaglutide (though this ratio was not statistically significant). In total, pancreatic cancer affected one individual in the semaglutide group and four individuals in the placebo group during the study period. The hazard ratio for total neoplasms, encompassing those that were benign, was 1.12 in favor of placebo; however, this value was once again not statistically significant.
Lars Rydén, MD, PhD (Karolinska Institute, Stockholm, Sweden)
Dr. Lars Rydén endeavored to contextualize the SUSTAIN 6 results, providing a historical perspective on the path to modern CVOTs and a comparison to other neutral and positive CVOTs for diabetes drugs that have reported in the last few years. Dr. Rydén congratulated the trial lead investigators for a “carefully planned, well performed, objectively reported” trial and underscored that he would not be nitpicking the details of the trial design or interpretation. Instead, he emphasized that both the 26% relative risk reduction and the 2.3% absolute risk (from 8.9% to 6.6%) in the primary endpoint with semaglutide treatment is substantial and clinically meaningful. He pointed out that cardiologists are often pleased if new platelet therapies are able to demonstrate a much smaller absolute risk reduction.
- Regarding the mechanism of action, Dr. Rydén emphasized that the results appear to be driven by a positive impact of semaglutide on non-fatal stroke and non-fatal MI. Considered along with the benefit on risk reduction for revascularization and the slow onset of benefit, Dr. Rydén suggested that semaglutide’s cardioprotective effect could be mediated through a delay in progression or even regression of atherosclerosis. Dr. Rydén also suggested that duration of action may account for the heterogeneity seen in the large 26% risk reduction observed in SUSTAIN 6 compared to the smaller – but still positive – 13% risk reduction of liraglutide in LEADER and to the neutral ELIXA results for lixisenatide (Sanofi’s Lyxumia/Adlyxin). Lixisenatide is a short-acting GLP-1 agonist, while liraglutide is a longer-acting GLP-1 agonist and semaglutide (as a once-weekly injection) is longer-acting still. He hypothesized that the bioavailability of the GLP-1 agonist must last at least through an entire day to demonstrate a cardioprotective benefit.
- In a comparison to the LEADER and EMPA-REG OUTCOME trials, Dr. Rydén highlighted that both the relative and absolute risk reduction was greater in SUSTAIN 6. Semaglutide’s relative risk reduction of 26% and absolute risk reduction of 2.3% compares to liraglutide’s relative risk reduction of 13% and absolute risk reduction of 1.9% and empagliflozin’s relative risk reduction of 14% and absolute risk reduction of 1.6%. Dr. Rydén also pointed out that the A1c reduction in SUSTAIN 6 was greater than in the LEADER and EMPA-REG OUTCOME trials: a placebo-adjusted difference of 0.8%, compared to 0.4% and 0.2%. As expected for a pre-approval safety trial, the follow-up duration in SUSTAIN 6 was shorter at 2.1 years compared to 3.8 years for LEADER and 3.1 years for EMPA-REG OUTCOME.
- Regarding the retinopathy data, Dr. Rydén largely deferred to future clinical or registry-based trials. He pointed out that the LEADER trial had also observed a 15% increase in retinopathy, though it was not statistically significant, but ultimately suggested that time will tell how much of a concern this finding is. We were a little disappointed that Dr. Rydén did not dig into the retinopathy outcomes more – though of course he was already fitting a lot into the mere 10 minutes he was allotted already! – and we expect we’ll hear much discussion of this finding in the coming months.
- Dr. Rydén concluded with three main areas of impact for the SUSTAIN 6 results in his view: (i) raising interest in mechanistic studies delineating mechanisms and refining treatment; (ii) catalyzing the initiation of new clinical trials investigating the combination of a GLP-1 agonist and an SGLT-2 inhibitor; and (iii) creating an immediate therapeutic option for a sizeable and vulnerable patient population.
Close Concerns Questions
Q: Is the remarkable 26% risk reduction for three-point MACE a product of smaller sample size of events? How much of this risk reduction should be attributed to the smaller number of MACE events?
Q: Will empirical support for semaglutide’s CV benefits make an even stronger case for the CV benefits of Victoza (liraglutide)? Will this influence the FDA’s decision to revise the Victoza label?
Q: What is the prospective timeline for a larger CVOT of semaglutide that includes a higher number of MACE events on par with LEADER or EMPA-REG OUTCOME?
Q: Does the physiological action of semaglutide directly increase retinopathy risk?
Q: How will follow-up research unpack the association between semaglutide and eye complications?
Q: Do the significant weight loss results foreshadow semaglutide’s potential as an obesity drug, paralleling Saxenda (high dose liraglutide)?
Q: Does SUSTAIN 6, in conjunction with LEADER, offer support for a cardioprotective class effect of GLP-1 agonists?
Q: Is there an aspect of the once-weekly formulation (perhaps improved adherence) that causes more powerful CV effects vs. the once-daily formulation?
Q: Given the more dramatic 24% risk reduction on three-point MACE vs. Victoza’s 13% risk reduction, does semaglutide have more potential as a cardioprotective agent in a lower-risk patient population vs. liraglutide?
Symposium: EMPA-REG OUTCOME: One Year Later
Introduction and Context
Bernard Zinman, MD (University of Toronto, Canada)
Dr. Bernard Zinman (University of Toronto, Canada) set the tone for this session, a one-year later update on EMPA-REG OUTCOME, by focusing attention on mechanism. Whenever the field sees a robust clinical finding, he explained, we’re understandably eager to know the underlying biology. Dr. Zinman reviewed data from a univariate mediation analysis of EMPA-REG OUTCOME which attributed 52% of the cardioprotection finding to volume contraction, as reflected by an increase in hematocrit. The analysis attributed 25% to decreased uric acid concentration and only 3% to between-group A1c differences – this last point underscores that the CV benefit of Lilly/BI’s Jardiance (empagliflozin) is independent of glycemic effects. That said, Dr. Zinman mentioned a few caveats: (i) this univariate analysis was post-hoc and should only be considered hypothesis-generating; (ii) variables that weren’t factored into the analysis, such as ketone bodies, might play a mediating role between empagliflozin and reduced CV death; and (iii) a multivariate model of combined mechanisms would be more accurate, though this analysis is also much more complicated. He remarked that a multivariate analysis is underway.
Macrovascular and Heart Failure Outcomes: An Update
David Fitchett, MD (University of Toronto, Canada)
Dr. David Fitchett (University of Toronto, Canada) discussed an interesting post-hoc analysis to EMPA-REG OUTCOME, zooming in on heart failure burden. He also presented these post-hoc results at this year’s European Society of Cardiology Congress in Rome. The recent analysis showed that empagliflozin reduces the risk of a variety of heart failure measures by a substantial margin: (i) the risk of investigator-reported heart failure declined by 30% with empagliflozin treatment; (ii) the risk of a composite endpoint of hospitalization for heart failure or investigator-reported heart failure also declined by 30%; (iii) the introduction of loop diuretics was delayed by 38%; and (iv) the risk of a composite endpoint of hospitalization for heart failure and introduction of loop diuretics declined by 37%. Dr. Fitchett emphasized that these risk reductions are clinically meaningful. He also underscored that the decrease in CV death with empagliflozin vs. placebo was similar in patients with and without heart failure at baseline or during the trial. For more on this data, see our coverage from ESC 2016.
Microvascular and Renal Outcomes
Christoph Wanner, MD (University of Würzburg, Germany)
Dr. Christoph Wanner (University of Würzburg, Germany) outlined findings on the positive renal effects of empagliflozin treatment regardless of baseline kidney function. He described how patients with healthy kidneys, microalbuminuria, or macroalbuminuria all experience clinically significant changes in urinary albumin creatinine ratio (UACR) over the course of 192 weeks on empagliflozin. Among patients who at baseline showed normoalbuminuria, there was a mean 7% decline in UACR at 12 weeks (p<0.05 vs. placebo) and a mean 21% decline at 192 weeks (p<0.01 vs. placebo). For patients with baseline microalbuminuria, these values were 25% (p<0.001) and 40% (p<0.001), respectively, while patients with baseline macroalbuminuria experienced an average 32% drop (p<0.001) and 38% drop (p<0.05) in UACR at 12 and 192 weeks, respectively. Though UACR is not yet accepted as an outcome parameter, Dr. Wanner emphasized that it is connected to renal outcomes and thus should hold weight in evaluations of empagliflozin’s renal benefits. Continuing on, he shared incidence rate ratios for adverse events, breaking down the study population into baseline eGFR <60 ml/min/1.73m2 and >60 ml/min/1.73m2. In patients with lower eGFR, signaling a higher risk for kidney complications or disease, the hazard ratios for adverse events, serious adverse events, and severe adverse events all favored empagliflozin vs. placebo. In fact, the only hazard ratios near unity were urinary tract infections (UTI) and complicated UTIs. Genital infections were markedly more common in the empagliflozin group. These trends were similar among patients with higher baseline eGFR. The important takeaway from this additional data, according to Dr. Wanner, is that there were pronounced benefits to empagliflozin among the patients at risk for kidney complications in EMPA-REG OUTCOME. Treatment with the SGLT-2 inhibitor slowed the progression of kidney disease and reduced clinically relevant renal events. Dr. Wanner ended his presentation with a brief explanation of the glomerular hypertension hypothesis for mechanism of renal protection, which he also discussed in relation to empagliflozin at ADA 2016. The expanded renal results presented at EASD were certainly encouraging and reassuring – we would love to see Lilly/BI tackle a dedicated renal outcomes trial for empagliflozin and potentially pursue a diabetic nephropathy indication given the high unmet need in this area. We’d also like to better understand regulatory requirements on this front – previously they have been quite challenging.
Implications for the Management of Patients with Type 2 Diabetes and High CV Risk
Hertzel Gerstein, MD (McMaster University, Ontario, Canada)
How important is the explanation of mechanism? Dr. Hertzel Gerstein (McMaster University, Ontario, Canada) suggested that understanding mechanism of cardioprotection for empagliflozin (Lilly/BI’s Jardiance) shouldn’t be a prerequisite for using this knowledge of the drug’s CV benefits in clinical practice. While he acknowledged that we need to support research to find out more about mechanism, he argued that this lingering uncertainty shouldn’t stop us from applying this evidence toward optimal diabetes care for patients with type 2 diabetes and high CV risk. “Empagliflozin reduces some extremely serious health outcomes,” he put simply, and even though “we’re not sure why, that shouldn’t stop us from offering these benefits to patients.” We so appreciated this commentary as we’d love to see improved prognosis for patients, especially those at high risk for CV morbidity and mortality who stand to benefit most from empagliflozin therapy. It seems like such a shame to be sitting on compelling evidence for cardioprotection without harnessing the latest clinical data to provide better patient care. Dr. Gerstein summed it up perfectly: “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.”
Symposium: Liraglutide Effect and Action in Diabetes
Evaluation of Cardiovascular Outcome Results – A Long-Term Evaluation (LEADER)
Rury Holman, MD (University of Oxford, UK); John Buse, MD (University of North Carolina, Chapel Hill, NC); Steven Marso, MD (UT Southwestern, Dallas, TX); Michael Nauck, MD (Diabeteszentrum Bad Lauterberg, Germany); Johannes Mann, MD (Friedrich Alexander University of Erlagen, Germany)
In a symposium largely recapping LEADER cardiovascular outcomes trial data for Novo Nordisk’s GLP-1 agonist Victoza (liraglutide), we saw several new sub-analyses of the cardiovascular, renal, and pancreatic data. The double-blind, randomized, placebo-controlled, time- and event-driven LEADER trial (n=9,340) results were originally presented ADA 2016, demonstrating a 13% relative risk reduction for the primary outcome of three-point MACE (cardiovascular death, non-fatal MI, and non-fatal stroke) and a 16% improvement in microvascular outcomes (driven entirely by a 22% improvement in renal outcomes), among a barrage of other secondary endpoints. See our detailed coverage of the ADA 2016 LEADER results presentation for more.
- Dr. Johannes Mann (Friedrich Alexander University of Erlagen, Germany) presented an expanded analysis of the microvascular outcomes from the LEADER trial. The microvascular benefit – or, perhaps more accurately, the renal benefit – was driven primarily by a 26% reduction in the onset of persistent macroalbuminuria with liraglutide (HR=0.74, 95% CI: 0.60-0.91) and a 19% reduction in urinary albumin-creatinine ratio, a measure of microalbuminuria (HR=0.31, 95% CI: 0.76-0.86). Dr. Mann also revealed two new findings from the ongoing subgroup analysis of the LEADER trial’s renal data: (1) Among participants with kidney disease (eGFR <60 ml/min/1.73 m2) there was a 22% reduction in time to first renal event (HR: 0.78; 95% CI: 0.56-1.09); (2) Among participants with severe kidney disease (30-60 ml/min/1.73 m2) or end-stage renal disease there was a 27% reduction in time to next additional composite renal outcome (HR: 0.73; 95% CI: 0.50-1.07). The trial investigators had previously shared that the hazard ratio point estimate for participants was 0.94 (95% CI: 0.83-1.07). The full subgroup analysis is expected in two months at the upcoming American Society of Nephrology meeting, but these two findings provide the intriguing suggestion that liraglutide’s renal benefits may be particularly applicable to patients already experiencing renal disease. The implications of this strong renal benefit are substantial, and may even prompt consideration of a dedicated chronic kidney disease trial for liraglutide. We are curious whether this effect of liraglutide is a consequence of improvements in renal risk factors like glucose and blood pressure, or whether it is a direct effect (GLP-1 is known to mediate the muscles around renal glomeruli, the functional filtering units of the kidney). These results should surely result in much more robust discussion on this front.
- Highly regarded cardiovascular expert Dr. Steven Marso shared additional analyses of the heart failure data from LEADER. The combined endpoint of hospitalization for heart failure and all-cause death was reduced by 13% in the overall trial (95% CI: 0.77-0.97). Recognizing that heart failure is of particular interest to many given the conditions significant in EMPA-REG OUTCOME and DPP-4 inhibitor CVOTs thus far, Dr. Marso also shared two subgroup analyses examining cardiovascular outcomes in patients with and without heart failure at baseline. The hazard ratio for the primary three-point MACE endpoint among patients without heart failure at baseline was 0.85 (95% CI: 0.76-0.96) while the hazard ratio among patients with heart failure at baseline was 0.94 (95% CI: 0.72-1.21). While the risk reduction was not significant among patients with heart failure, the point estimate trended in the right direction and the p-value for interaction between the two subgroups was non-significant at 0.53. Among participants without heart failure at baseline, the hazard ratio for hospitalization for heart failure throughout the trial was 0.82 (95% CI: 0.65-1.04). Among participants with heart failure at baseline, the hazard ratio was 0.95 (95% CI: 0.71-1.28) – like the MACE results, the point estimate here trended in the right direction and the p-value for interaction between the two groups was non-significant at 0.45.
- A more detailed sub-analysis of the LEADER trial presented by Dr. Michael Nauck (Diabeteszentrum Bad Lauterberg, Germany) supported the initial finding that liraglutide does not increase the incidence of pancreatitis, though a wide confidence interval prevents us from ruling out the possibility entirely. Nineteen events of acute pancreatitis occurred in 18 patients on liraglutide, compared to 33 events in 25 patients on placebo. Dr. Nauck shared a graph depicting time to acute pancreatitis in the Victoza-treated vs. placebo groups and reported a hazard ratio of 0.78 over in favor of liraglutide. However, due to the confidence interval for the hazard ratio ranging from 0.42-1.44, Dr. Nauck stated that “we cannot rule out the possibility that liraglutide could have a minute enhancement of risk for pancreatitis.” Based on this sub-analysis, the worst case scenario would be a 44% greater risk of acute pancreatitis associated with liraglutide (or a best case scenario of a 58% risk reduction in pancreatitis). There were very low rates of neoplasms in LEADER, Dr. Nauck continued, which poses a challenge in precise determination of pancreatic cancer risk. The rate of pancreatic cancer was 0.3% in the liraglutide group and 0.1% in the placebo group, representing a hazard ratio of 2.59, though Dr. Nauck reiterated the high amount of uncertainty linked to this value. Overall, the results are reassuring and further support the general consensus that the benefits of GLP-1 agonist treatment outweigh the small possible risks of pancreatitis.
EASD/ADA Symposium: Changing Paradigms: The Role of SGLT-2 Inhibitors
SGLT-2 Inhibition and Cardiovascular Outcomes
Silvio Inzucchi, MD (Yale University, New Haven, CT)
Dr. Silvio Inzucchi (Yale University, New Haven, CT) presented cardiovascular results from EMPA-REG OUTCOME at last year’s EASD in Stockholm, Sweden – he returned this year with a focus on mechanism, and started off by admitting “with a great deal of modesty, we had it all wrong.” Dr. Inzucchi explained how the initial thinking on Lilly/BI’s SGLT-2 inhibitor Jardiance (empagliflozin) was that the agent would confer CV benefits through an overarching atherosclerotic effect. The early divergence of the Kaplan Meier curves in EMPA-REG OUTCOME suggests otherwise. Results from blood pressure and statins trials demonstrate that an atherosclerotic mechanism shows up as divergence much later, around 12-18 months, which is also what was seen in the LEADER trial for Novo Nordisk’s GLP-1 agonist Victoza (liraglutide). Despite lingering questions surrounding mechanism of cardioprotection, Dr. Inzucchi called upon the ADA and EASD to consider powerful CVOT data in drafting the next position statement for the diabetes field. He urged the committee charged with authoring the next ADA-EASD treatment guidelines to look closely at EMPA-REG OUTCOME and other recent CVOTs, including LEADER, SUSTAIN 6 (for GLP-1 agonist semaglutide), and even IRIS (for the TZD pioglitazone, perhaps at low doses), because in his view, these CV benefits should be making their mark and improving real-world diabetes care.
Questions and Answers
Q: Can you pick up on heart failure data from DPP-4 inhibitor CVOTs, SAVOR and EXAMINE? The FDA has listed a warning, but on this side of the Atlantic, our European agency has posted a statement saying that the changes seen in heart failure are too small and should not alter practice. What are your thoughts on this?
A: The effect with alogliptin was not statistically significant. I still don’t completely understand why the FDA compelled that label to change. There’s no reason to believe a DPP-4 inhibitor could increase heart failure hospitalization rates, but the data is the data. Could it be a chance finding? Perhaps. We’re still obligated to follow drug labels in the US.
SGLT-2 Inhibitors and Renal Outcomes
David Cherney, MD (University of Toronto, Canada)
Dr. David Cherney (University of Toronto, Canada) picked up on the topic of SGLT-2 inhibition and continued the conversation on mechanism, but shifted focus from the heart to the kidneys. Post-hoc analysis of a composite renal endpoint in EMPA-REG OUTCOME found an impressive hazard ratio of 0.54 in favor of empagliflozin (Lilly/BI’s Jardiance), representing a 46% risk reduction with the SGLT-2 inhibitor therapy (p<0.001). More specifically, Dr. Cherney mentioned that the drug was associated with fewer cases of acute kidney injury and acute renal failure. What were the mechanisms responsible for improved renal outcomes? The short answer, as Dr. Cherney put it, is “we don’t know yet.” Still, he discussed in great detail what is known about the impact of SGLT-2 inhibitors – including empagliflozin, dapagliflozin (AZ’s Farxiga), and canagliflozin (J&J’s Invokana) – on kidney function, summarizing the leading hypotheses related to hyperfiltration and how agents in this class consistently reduce hyperfiltration, now evidenced through both animal and human data. He pointed out an interesting observation that 80% of patients enrolled in EMPA-REG OUTCOME were on a background of RAAS blockers. RAAS inhibition tends to dilate the kidney’s efferent arteriole, while SGLT-2 inhibition constricts the afferent arteriole. Therefore, one interesting theory for the renal protection seen in the CVOT is an additive effect of empagliflozin plus RAAS blockade, which may have more effectively lowered intraglomerular pressure to provide long-term kidney benefits. Another intriguing explanation is that empagliflozin delayed time to introduction of loop diuretics for participants (hazard ratio 0.62, p<0.001). Dr. Cherney also presented a combined renal-cardio hypothesis for the kidney and heart benefits seen in EMPA-REG OUTCOME. While cardioprotection has been getting more overt attention from the field of late, he suggested that renal preservation with SGLT-2 inhibitor therapy could be the gateway to lowering CV morbidity and mortality. Dr. Cherney outlined four potential pathways for this renal-cardio hypothesis: Lowering intraglomerular hypertension and albuminuria could (i) decrease blood pressure, arterial stiffness, cardiac afterload, and left ventricular remodeling, the last of which is cardioprotective; (ii) reduce renal systemic inflammation which decreases left ventricular remodeling; (iii) preserve sodium/water homeostasis which enhances maintenance of euvolemia, which is cardioprotective; and/or (iv) decrease cardiac preload, myocardial wall tension, and arrhythmogenesis, which is directly cardioprotective.
- Dr. Cherney picked up on Dr. Inzucchi’s call-to-action for guidelines committees as well. “In Canada, we do have exactly what’s suggested – in patients with high CV risk, SGLT-2 inhibitors are now indicated in guidelines as the next therapy of choice.” He endorsed this designation of SGLT-2 inhibitors as second-line therapy.
Symposium: Diabetes Prevention
What Has the ADDITION Trial Added?
Annelli Sandbaek, MD (University of Aarhus, Denmark); Simon Griffin, MD (University of Cambridge, UK); William Herman, MD (University of Michigan, Ann Arbor, MI)
Drs. Simon Griffin (University of Cambridge, UK) and Annelli Sandbaek (University of Aarhus, Denmark) presented five- and 10-year results from the ADDITION trial demonstrating a 12% reduction in risk of a composite cardiovascular endpoint and a 9% reduction in risk of all-cause mortality associated with small but statistically significant improvements in diabetes care of people with screen-detected diabetes in primary care. The trial examined the effect of early and intensive primary care-based diabetes treatment (vs. routine care) on time to first cardiovascular outcome over the course of a decade among people with type 2 diabetes detected by screening. The trial randomized clinics to provide either screening and routine care according to national standards or screening and intensive treatment (with target A1c£7% and a recommendation to initiate treatment at a threshold of 6.5%, intensive blood pressure and lipid targets, widespread aspirin use, and lifestyle modifications including diet, physical activity, and smoking cessation). The intensive care regimen also involved diabetes education classes, peer group meetings, and feedback about the course of each individual’s diabetes management. In total, 3,057 patients were included in the trial and the results were based on an impressive 96.9% follow-up rate at 10 years. After five years, intensive treatment non-significantly improved the primary CVD composite (cardiovascular mortality, non-fata MI, non-fatal stroke, non-fatal revascularization, and non-traumatic amputation) endpoint by 17% (HR: 0.83, 95% CI: 0.65-1.05; p=0.12), and reduced relative risk of all-cause mortality by 9% (HR: 0.91; 95% CI: 0.69-1.21). Additional intermediate outcomes include: (i) reduction of systolic blood pressure by 2.86 mmHg from a baseline of 151 mmHg; (ii) reduction of baseline A1c by 0.08% from a baseline of 7%; (iii) reduction of BMI by 0.02 kg/m2 from a baseline of 31.6 kg/m2; and (iv) a 2.02-fold smaller risk of cardiovascular disease (95% CI: 3.12-0.92). In terms of secondary endpoints, intensive treatment caused a downward, but non-significant, trend in the microvascular complications of diabetes, producing a 16% reduction in retinopathy (HR: 0.84, 95% CI: 0.64-1.10) and a 13% reduction in nephropathy, as measured by albuminuria (HR:0.87, 95% CI: 0.72-1.07). Furthermore, patient reported outcomes on the EQ-5D and EQ-VAS scales were also higher in the intensive treatment group, though the difference did not reach significance. Though the intensive intervention largely did not produce a statistically significant improvement in most of the outcomes measured, the consistent trend toward positive outcomes suggests that there may be some benefit to intensive treatment early in the course of disease.
- This trend toward decreased risk of cardiovascular disease and all-cause mortality persisted ten years following the initiation of the intensive primary-care diabetes treatment regimen. Intensive treatment improved the primary CVD composite endpoint by 12% (HR: 0.88; 95% CI: 0.73-1.06; p=0.17) and non-significantly reduced all-cause mortality by 9% (HR: 0.91; 95% Ci: 0.76-1.08). As was true in the five-year analysis, these trends in CVD risk and all-cause mortality were accompanied by modest but statistically significant improvements in systolic blood pressure, A1c, and total cholesterol; after ten years of treatment, 46%, 63%, and 85% of patients in the intensive treatment group respectively achieved target levels of these outcomes. Dr. Griffin shared that these data are quite new and more analyses (likely regarding overall cardiovascular burden and microvascular complications) are forthcoming.
- Interestingly, the early intensive treatment intervention appeared to have a stronger effect on older individuals (i.e. age >60 years), producing a 24% relative risk reduction (HR: 0.76, 0.60-0.96, p=0.07).
- Dr. William Herman (University of Michigan, Ann Arbor) discussed the cost-effectiveness of early intensive diabetes treatment as demonstrated by ADDITION. One of the study’s most pressing follow-up questions is “given the high baseline cardiovascular risk and the beneficial effects of early diabetes treatment, should diabetes screening and primary care treatment regimens become a part of standard policy?” In short, the answer is “yes.” The ADDITION study provided compelling evidence of the ability of early intervention with a dedicated primary care diabetes treatment regimen to meaningfully improve patient outcomes. Using statistical models based on the raw ADDITION study data, Dr. Herman determined what the 10-year incidence of the composite CV outcome would be with and without screening and early diabetes treatment. When compared to no screening and a 3 or 6 year delay in the initiation of diabetes treatment, screening and early intervention produced a dramatic 30%-40% relative risk reduction for the composite CV outcome at 10 years, clear evidence of the major health benefits that accrue as a result of early diagnosis and treatment of diabetes.
- In addition to having a positive effect on outcomes, screening and early intervention are affordable. Dr. Herman stated that with new guidelines for the diagnosis of diabetes, A1c can be used as both a screening and diagnostic test. The cost of an A1c test is small even considering the number needed to screen in order to detect one individual requiring treatment, and the total cost of medications for risk factor management for patients with newly diagnosed diabetes are small compared to the total costs of diabetes.
- This presentation of the ADDITION study’s full five-year and ten-year results marks the first time these data have been summarized together in entirety. Previously the results of this massive study had been spread among a series of presentations and publications (including Griffin et al., 2011, Donk et al., 2013, Black et al., 2014, and Sandbæk et al., 2014).
Corporate Symposium: Type 2 Diabetes: Beyond the Beta Cell (Sponsored by AZ)
Can We Reduce the Incidence of Macrovascular Complications?
Neil Poulter, MD (Hammersmith Hospital and Imperial College, London, UK)
Dr. Neil Poulter spoke first in trio of presentations on diabetes-related macrovascular complications, specifically the cardiovascular consequences of the disease. He advocated strongly for aggressive treatment for patients with type 2 diabetes, with lower A1c targets, lower systolic blood pressure goals, and statin therapy. “It’s a no brainer – if a patient has type 2 diabetes, they should be on a statin.” To support this view, Dr. Poulter highlighted data on how lipid-lowering reduces the risk of stroke for type 2 diabetes patients by ~48%. “We can certainly reduce macrovascular events via lipid-lowering,” he articulated, so “you have to find a very good excuse not to give a type 2 diabetes patient a statin, in my opinion.” He expressed doubts about the ADA’s decision to increase the recommended A1c target for macrovascular risk reduction to <7% – “I suspect that will go back down again with time, and I think it should.” Dr. Poulter also touched upon systolic blood pressure as a way to prevent macrovascular complications. In response to results from the ACCORD trial, which showed no significant benefits of tighter blood pressure control of <120 mmHg vs. <140 mmHg, many guidelines committees raised the recommended systolic blood pressure for type 2 diabetes patients to 140 mmHg. Again, Dr. Poulter stood in favor of more aggressive treatment: “Previously the recommendation was at 130 mmHG, and I think that’s where it should have stayed.” He added that since ACCORD, more recent studies have found highly significant benefits of lower systolic blood pressure on macrovascular risk reduction. We appreciated Dr. Poulter’s willingness to share his opinions candidly, and we found his commentary to be quite compelling. We are proponents of tighter A1c control when possible, given the long-term health benefits to patients and the ability for CGM and insulin-independent therapies to keep hypoglycemia risk in check. By similar thinking, we hope guidelines committees and HCPs encourage patients toward lower lipid levels and systolic blood pressure when safe, especially when patients are willing to do so.
Cardiovascular Outcomes Trials: Current Status
Bernard Zinman, MD (University of Toronto, Canada)
Dr. Bernard Zinman (University of Toronto, Canada) told the story of cardiovascular outcomes trials to date, starting with 2008 FDA guidance aimed at ensuring CV safety, covering the major trials for DPP-4 inhibitors, SGLT-2 inhibitors, and GLP-1 agonists, and highlighting the positive results reported in EMPA-REG OUTCOME (for Lilly/BI’s SGLT-2 inhibitor Jardiance [empagliflozin]) and LEADER (for Novo Nordisk’s GLP-1 agonist Victoza [liraglutide]). On the current state of diabetes drugs, Dr. Zinman stated optimistically “we’re in a new era of hypoglycemia therapies with a positive impact on CV outcomes.” He described his ideal drug as an agent that doesn’t cause hypoglycemia, doesn’t cause weight gain, and confers “added value” in the form of beta cell preservation or reduced CV events – we’re nearing this ambition with SGLT-2 inhibitors and GLP-1 agonists, and hopefully upcoming CVOT data will show cardioprotection from even more products. Dr. Zinman was also optimistic about results from CVOTs and other large-scale clinical trials impacting real-world clinical practice. SGLT-2 inhibitors and GLP-1 agonists have been elevated in the AACE 2016 algorithm, he explained, and the dominant message in the field right now supports earlier use of agents in both drug classes. “We’ve always said we should practice evidence-based medicine, and now studies will help us make informed decisions on optimal management of patients with type 2 diabetes.”
Cardiovascular Outcomes Trials: Implications for Clinical Practice
Juris Meier, MD (Ruhr University of Bochum, Germany)
Anchoring this trio of talks on cardiovascular outcomes, Dr. Juris Meier (Ruhr University of Bochum, Germany) advocated for a number of changes to CVOT study design in order to optimize the impact of these trials on diabetes care. He suggested (i) eliminating the glycemic equipoise design; (ii) investigating the CV effects of both established and newer therapies; and (iii) expanding the focus to include primary prevention. We found Dr. Meier’s proposed change to the glycemic equipoise design of CVOTs to be his most controversial suggestion. He argued that this trial design, in which participants in the placebo arm receive higher insulin doses or other treatment intensification to narrow the A1c gap between agent and placebo groups, makes it difficult to discern the true CV effects of the agent in question, as its glycemic effect likely contributes to its CV benefit somewhat. This opinion stands in contrast to the more common support we’ve heard for the glycemic equipoise design, although we believe there are so many issues around CVOT trials in general that it would be great to have an expert session hosted by FDA (as raised in the August 2014 meeting “FDA Public Hearing on the Confidentiality of Interim Results in Cardiovascular Outcome Safety Trials”). Dr. Meier also advocated for multi-agent CVOTs, pointing out that most CVOTs published thus far compare a relatively new diabetes drug vs. placebo and suggested that head-to-head comparisons of the potential CV benefits of new drugs and relatively older agents would be helpful. Data showing the relative CV benefits of different drugs could be tremendously valuable for high-risk patients – this is certainly something we’d like to see in the coming years as CVOTs gain even more traction, though of course the costs of such a trial would be enormous and it’s unclear which stakeholders might have the incentives and means to fund the endeavor. Dr. Meier also emphasized that published CVOTs have largely investigated secondary prevention, enrolling participants with type 2 diabetes and a history of CV disease. That said, he noted that AZ’s DECLARE (for SGLT-2 inhibitor dapagliflozin) and EXSCEL (for GLP-1 agonist exenatide) will each include a cohort of participants without prior CV history. In his view (and ours), these results on primary CV prevention will be very interesting, and positive results could be a major win in two ways: (i) by promoting greater utilization of these agents across a much wider spectrum of the diabetes patient population; and (ii) by providing even more compelling evidence for cardioprotection in a broader population. We’d be thrilled to see cardioprotective medications that address primary and secondary prevention alike, though we acknowledge the massive time and monetary investment behind CVOTs which presents an obstacle to research in lower-risk populations. Ultimately, we were intrigued by Dr. Meier’s perspective on how to make CVOTs more influential in clinical practice – definitely a worthwhile goal and an important topic for discourse.
Neil Poulter, MD (Hammersmith Hospital and Imperial College, London, UK); Bernard Zinman, MD (University of Toronto, Canada); Juris Meier, MD (Ruhr University of Bochum, Germany)
Q: What’s the single trial that has had the biggest impact for you and your patients?
Dr. Zinman: For type 1 diabetes, it would be the DCCT, obviously. For type 2 diabetes patients, EMPA-REG OUTCOME provided a lot of good data (although I am a little biased). It was the first clear evidence we’ve seen that a diabetes therapy can have added value, reducing CV events. CV death is a big issue, as is heart failure in type 2 diabetes.
Dr. Poulter: EMPA-REG OUTCOME.
Dr. Meier: I think the UKPDS was very important, and the follow-up to that was very interesting because it showed a mortality benefit from tighter glycemic control.
Dr. Poulter: Can I say, the FDA voting of 12-11 was extraordinary for Jardiance, when you have such a fantastic benefit. Excuses were “we’re not quite sure about mechanism” – who cares?! – and “maybe it’s chance” – very, very unlikely. While I applaud conservatism, I’m with the Canadian guidelines, and I think it’s time to take action.
Dr. Zinman: Health Canada is usually behind, but we already have an approved indication on the label for empagliflozin for the prevention of cardiovascular death.
Dr. Meier: It’s extremely difficult to understand these trials because of the multiplicity of effects. 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.
Dr. Zinman: To interfere with atherosclerosis by glucose lowering, an agent has to be introduced early. A glucose lowering strategy initiated late in diabetes doesn’t do much for atherosclerosis. SGLT-2 inhibitors, I think, are very good diabetes drugs even independent of their CV benefit, and they could be used early on just like any other oral agent. They lead to weight loss, they lower blood pressure, they’re good for glucose control. Will they be helpful in prediabetes? Perhaps, by reducing hyperglycemia and also helping to preserve beta cell function.
Q: Can you talk about the mechanism of cardioprotection seen in EMPA-REG OUTCOME, and also in LEADER?
Dr. Zinman: Several things might be going on. With empagliflozin, there was probably a volume effect. An increase in hematocrit is a measure of volume reduction, and we think that clearly plays an important role. Notably, the differences in CV death with empagliflozin vs. placebo spread very early, which is different from LEADER, where you see it takes more time and is likely an atherosclerotic effect. There’s been a metabolic effect postulated for EMPA-REG OUTCOME related to ketones as an energy source. We’re looking. It will be unraveled.
Dr. Meier: I can speculate, as all of us can. Empagliflozin’s cardioprotection probably has something to with a combined effect on various risk factors, including glucose, weight loss, lipids, and blood pressure. There’s also a hypothesis in the mix that GLP-1 agonists may exert CV benefits independent of glucose-lowering. We have plenty of evidence for this in rodents, and with the unexpectedly positive results from LEADER, I wouldn’t be surprised to find out about liraglutide’s independent, direct cardioprotective effects.
Oral Presentations: SGLT-2 Inhibitors: Metabolic Effects
canagliflozin Slows Progression of Renal Function Decline Independent of Glycemic Effects
Hiddo Heerspink, MD (University Medical Center Groningen, the Netherlands)
Dr. Hiddo Heerspink (University Medical Center Groningen, Groningen, the Netherlands) presented a compelling new post-hoc analysis of CANTATA-SU to support a glucose-independent, renal-protective benefit for the SGLT-2 inhibitor canagliflozin (Janssen’s Invokana). The analysis was published recently in the Journal of the American Society of Nephrology. CANTATA-SU was a phase 3, double-blind, head-to-head study of canagliflozin (100 or 300 mg/day) vs. sulfonylurea glimepiride (titrated to 6-8 mg/day) over 24 months in patients with type 2 diabetes (n=1,450) on metformin monotherapy. In the post-hoc analysis, eGFR declines throughout the trial were smaller with both doses of canagliflozin compared to glimepiride (declining 0.5 ml/min in the canagliflozin 100 mg group [p=0.01] and 0.9 ml/min in the canagliflozin 300 mg group [p=0.01], compared to a 3.3 ml/min reduction in the glimepiride group. The results suggest that canagliflozin, compared with glimepiride, slows the progression of renal disease in type 2 diabetes patients over two years. Canagliflozin furthermore produced reductions in urinary albumin:creatinine ratio (UACR) compared to glimepiride (5.7% reduction with the 100 mg dose and 11.2% reduction with the 300 mg dose, p=0.01). This was especially pronounced in the subgroup of patients with baseline UACR above 30 mg/g, who experienced a 31.7% (p=0.01) decline in this ratio with canagliflozin 100 mg and a 49.3% (p=0.01) decline in this ratio on the 300 mg canagliflozin dose compared to glimepiride treatment. Further post-hoc analysis revealed that the treatment effect of canagliflozin on albuminuria persisted even after statistically controlling for the differences in A1c reduction, systolic blood pressure, body weight, or the combined changes in all three of these factors between the canagliflozin and glimepiride arms. This suggests that canagliflozin’s effect on albuminuria occurs independently of its glycemic effects – wow! We’re intrigued by the suggestion of renal-protection for canagliflozin demonstrated by these analyses and our curiosity is piqued regarding the mechanism by which SGLT-2 inhibitors achieve this renal-protective effect. Lilly/BI’s SGLT-2 inhibitor Jardiance (empagliflozin) recently demonstrated impressive renal-protective benefits in EMPA-REG OUTCOME and we’re certainly looking forward to more renal outcomes data from other products in the class – as well as for GLP-1 compounds. Diabetic nephropathy is an extremely costly complication of diabetes, both in human and economic terms, and the availability of glucose-lowering drugs with additional renal-protective benefits is a major win for patients. We look forward to hearing more on renal impact of diabetes drugs in the coming days at EASD.
- An astute comment during the ensuing Q&A session pointed out that this study lacks a sufficient control group. Thus it is impossible to tell whether the renal benefits of canagliflozin over glimiperide are due to canagliflozin being beneficial or glimiperide being harmful. To resolve this issue, we would love to see similarly-designed trials in the future that includes a third, placebo-controlled arm. Also, just in general, we’d love to see SFUs used in more outcomes trials. Though it may make more patients not want to participate in the trials, we think that more data is needed to show the negativity of SFUs – so many patients are forced to be on SFUs still and there is not enough data for patient advocates to try to push back for these patients. For some group of course, lower-dose SFUs may be fine, but we think the combination of weight gain and hypoglycemia and fracture risk and beta cell burnout is quite negative for most.
- The CREDENCE trial is underway to assess the effects of canagliflozin (100 mg/day) on renal endpoints in patients with diabetic kidney disease. With nearly 4,000 subjects enrolled, Dr. Heerspink explained that the CREDENCE trial will be powered to definitively show whether canagliflozin has renal-protective effects. According to ClinicalTrials.gov, this trial is estimated to complete in January 2020.
-- by Abigail Dove, Helen Gao, Brian Levine, Payal Marathe, and Kelly Close