Patients with type 2 diabetes (T2D) have a two-fold increased risk for coronary heart disease compared to those without diabetes.1 In 2008, the US Food and Drug Administration (FDA) requested cardiovascular outcome trials (CVOTs) on all glucose-lowering medications.2 Their intention was to rule out harmful effects for high-risk patients, following the withdrawal of rosiglitazone from the market because of its association with increased risk of heart failure and myocardial infarction (MI).3 However, the finding that some glucose-lowering agents result in a major reduction in both all-cause and cardiovascular (CV) death among high-risk patients,4, 5 stunned experts. As a result, CVOTs have become the hottest topic in the diabetes world. Updates from the major CVOTs were presented at the American Diabetes Association (ADA) 2017 Scientific Sessions in San Diego, California.
The most eagerly awaited results were from the Canagliflozin Cardiovascular Assessment Study (CANVAS), which investigated cardiovascular outcomes in patients with T2D taking the sodium glucose cotransporter-2 (SGLT2) inhibitor canagliflozin. Since the landmark Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG) trial showed the CV benefits of another SGLT2 inhibitor,4 empagliflozin (Jardiance, Boehringer Ingelheim) debate has persisted about whether the findings were unique to empagliflozin or represented a class effect.
Results of an integrated analysis of the CANVAS and CANVAS-R (Study of the Effects of Canagliflozin on Renal Endpoints), which were simultaneously published in the New England Journal of Medicine, showed that canagliflozin (Invokana, Janssen) significantly reduced the combined risk of CV death, MI, and nonfatal stroke, versus placebo in patients with T2D at risk for or with a history of CV disease.6 A total of 10,142 participants with T2D and high cardiovascular risk were randomized to receive canagliflozin or placebo and were followed for a mean 188.2 weeks. The rate of the combined primary endpoint was 14% lower with canagliflozin than with placebo (26.9 vs. 31.5 participants per 1000 patient-years; hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.75 to 0.97; p<0.001 for noninferiority; p=0.02 for superiority). However, CV death was not significantly reduced in CANVAS, as it was in both EMPA-REG and the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results—A Long Term Evaluation (LEADER) trial of the glucagonlike peptide-1 (GLP-1) agonist liraglutide (Victoza, Novo Nordisk). Although the renal outcomes did not show a statistically significant benefit for canagliflozin, the progression of albuminuria and the composite outcome of a sustained 40% reduction in the estimated glomerular filtration rate, the need for renal-replacement therapy, or death from renal causes, suggested a possible beneficial effect.
Lead investigator, Bruce Neal, M.B., Ch.B., Ph.D., of the University of New South Wales Sydney, said: “The CANVAS results are important because they show clear benefit of canagliflozin over current standard-of-care treatments. Furthermore, the CANVAS Program showed consistent reductions across all components of the primary study outcome – CV death, MI and stroke.”
The CANVAS data provided additional information about safety concerns, including diabetic ketoacidosis, only a small number of events of which were observed with canagliflozin and placebo (0.6 vs. 0.3 participants with an event per 1000 patient-years; HR, 2.33; 95% CI, 0.76 to 7.17). However, in a new finding, the results showed that people taking canagliflozin were twice as likely to need amputations, especially at the toe or metatarsal (6.3 vs. 3.4 cases per 1000 patient-years; HR, 1.97). The highest risk of amputations occurred among patients with a history of amputation or peripheral vascular disease. Bruce Neal commented: “We believe that for most patients with diabetes who are at high risk, there’s going to be a net positive benefit/risk ratio, but there’s going to be a subset of patients who are at very high risk of amputation for whom this is probably not going to be the drug of choice.” –
A post hoc analysis of the LEADER trial was also presented at the ADA sessions. Results showed that treatment with liraglutide resulted in similar reductions in the risk of major CV events in people with T2D at high CV risk, regardless of whether or not they experienced an episode of severe hypoglycaemia during the trial. In the overall study population, participants who experienced a severe hypoglycaemic episode were at a significantly greater risk of major cardiovascular adverse events (CV death, non-fatal heart attack or non-fatal stroke), CV-death or non-CV death. This risk was heightened within 60 days of a severe hypoglycaemic episode occurring. The investigators, however, stressed that people treated with liraglutide experienced significantly fewer episodes of severe hypoglycaemia when compared to placebo, both in addition to standard of care.
Over a median follow-up of 3.8 years, the liraglutide group had a 13% reduced risk of the composite primary endpoint of cardiovascular death, non-fatal myocardial infarction or non-fatal stroke compared with placebo. Liraglutide conferred a 22% reduction in the incidence of cardiovascular death as well as non-significant reductions in non-fatal myocardial infarction and non-fatal stroke.
In summary, positive data from CVOTs continues to strengtheein the case for the more widespread use of SGLT2 inhibitors and the GLP-1 agonist liraglutide. The need for updated guidelines in light of these CVOT data was also discussed at the ADA sessions. According to cardiologist Steve Nissen, MD, of the Cleveland Clinic, Ohio, the past few years have demonstrated “a triumph of evidence-based medicine.” He went on to say: “It’s very important for changes in the guidelines to reflect contemporary knowledge, but we will still have a way to go with that. We’ve got to overcome clinical inertia.”
1. Emerging Risk Factors C, Sarwar N, Gao P, et al., Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies, Lancet, 2010;375:2215-22.
2. FDA, Guidance for Industry. Diabetes Mellitus — Evaluating Cardiovascular Risk in New
Antidiabetic Therapies to Treat Type 2 Diabetes, December 2008, http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm071627.pdf Accessed 6 September 2016, .
3. Singh S, Loke YK, Furberg CD, Long-term risk of cardiovascular events with rosiglitazone: a meta-analysis, JAMA, 2007;298:1189-95.
4. Zinman B, Wanner C, Lachin JM, et al., Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes, N Engl J Med, 2015;373:2117-28.
5. Marso SP, Daniels GH, Brown-Frandsen K, et al., Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes, N Engl J Med, 2016;375:311-22.
6. Neal B, Perkovic V, Mahaffey KW, et al., Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes, N Engl J Med, 2017;.