Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of morbidity and mortality in patients with diabetes.1,2 In fact, patients with type 2 diabetes are at least two times more likely to die from cardiovascular causes than the general population.3 This disparity underscores the importance of considering therapy impact on cardiovascular morbidity and mortality in patients with type 2 diabetes. In 2008 the Food and Drug Administration (FDA) published a guidance document proposing that all sponsors of antihyperglycemic drugs should conduct cardiovascular outcome trials (CVOTs) to demonstrate that the new drug does not result in an unacceptable increase in cardiovascular risk.4 More recently, the American Diabetes Association (ADA) addressed emerging evidence concerning cardiovascular outcomes by adding a recommendation in their 2018 guideline publication. This recommendation suggests that in patients with established ASCVD, an agent with proven reductions in major adverse cardiovascular events and/or cardiovascular mortality should be incorporated after metformin and lifestyle modifications have failed.5 Of the medications that have come to market since the 2008 FDA guidance document, a class of antidiabetic medications called sodium-glucose co-transporter 2 (SGLT2) inhibitors have demonstrated promising cardiovascular effects.
SGLT2 inhibitors are a class of oral antihyperglycemic medications that include empagliflozin, canagliflozin, and dapagliflozin. When used as add-on therapy to metformin, they provide an intermediate A1c lowering of around 0.5-1.0%.6 Apart from favorable effects on A1c and glucose control, SGLT2 inhibitors produce desirable metabolic effects, such as improved blood pressure and body weight (average reduction of 2 kg).7,8 Additionally, these agents have a low risk of hypoglycemia and may confer renal-protective properties.7,9
The EMPA-REG OUTCOME study was the first CVOT published for the SGLT2 inhibitor class.10 Published in September 2015, this large randomized controlled trial studied the cardiovascular safety of empagliflozin. Nearly two years later in June 2017, the CANVAS Program was published which analyzed cardiovascular safety data pooled from two sister trials comparing canagliflozin to placebo.11 Overall, EMPA-REG and CANVAS were similar in study design. Both trials were multicenter, international, double-blind, non-inferiority to superiority, placebo-controlled, randomized trials. However, only patients with established cardiovascular disease were included in EMPA-REG, while approximately a third of the study subjects in CANVAS did not have a history of cardiovascular disease. The primary outcome studied was the same for both trials and was a composite of death from cardiovascular causes, nonfatal myocardial infarction, and nonfatal stroke. [See Table 1 for comparison of trials]
The results of EMPA-REG and CANVAS were also comparable, with both trials demonstrating a 14% decrease in the primary composite endpoint [empagliflozin: (HR 0.86; 95.02% confidence interval, 0.74 to 0.99; P=0.04 for superiority), canagliflozin: (HR 0.86; 95% confidence interval, 0.75 to 0.97; P=0.02 for superiority)]. However, the individual components of the composite outcome were not necessarily lower. Empagliflozin was found to cause a statistically significant decrease in death from cardiovascular causes (HR 0.62; 95% CI, 0.49 to 0.77), but not in nonfatal myocardial infarction or nonfatal stroke event rates. On the other hand, canagliflozin did not achieve statistical significance for any individual component of the primary composite outcome. Interestingly, subgroup analyses of each of the trials revealed ethnic variations in cardiovascular benefits. These analyses revealed that Asian subjects had more desirable outcomes in the EMPA-REG study, while black patients had more desirable outcomes in the CANVAS Program.12 Although differences in study design prevent the direct comparison of results between these two trials, overall lower rates of adverse cardiovascular events were shown with empagliflozin and canagliflozin compared to placebo. Adding to CVOT data for this class of medications, another trial by the acronym of DECLARE-TIMI 58 evaluating the effects of dapagliflozin on cardiovascular events is anticipated for publication in 2019.13
In addition to the cardiovascular outcomes data garnered from SGLT2 inhibitor CVOT trials, both expected and unexpected adverse events were observed. In line with previously reported adverse events, patients receiving an SGLT2 inhibitor were more likely to experience a genital infection, most often mycotic in nature. Volume depletion was observed at a somewhat increased incidence also in line with previous findings. Euglycemic diabetic ketoacidosis, an extremely rare adverse event for which there is a class warning, was observed at a slightly increased incidence, but at an expected rate of less than 1% of patients taking the interventional drug.14 Furthermore, two unexpected adverse effects were observed in the CANVAS Program that were not observed with SGLT2 inhibitors previously or in the EMPA-REG trial. The first of these was a 23% increased risk of low-trauma fracture (HR 1.23; 95% CI, 0.99 to 1.52). The second unexpected adverse effect was a nearly two-fold increase in lower extremity amputations (6.3 v. 3.4 amputations per 1,000 patient-years; HR 1.97; 95% CI, 1.41 to 2.75) with the majority of the amputations occurring at the toe or metatarsal. Although increased fracture and amputation risk was not observed in the EMPA-REG trial, rates of these complications were not systematically collected.12 Additionally, neither EMPA-REG nor CANVAS were adequately powered to detect a significant difference in fracture and amputation risks. The negative safety data of these agents, combined with the current average monthly cost of about $430, can make SGLT2 inhibitors less ideal for some patients.15
All things considered, the results of the EMPA-REG OUTCOME study and CANVAS Program have changed the overall clinical picture of how SGLT2 inhibitors fit into therapy. As previously mentioned, advantages of SGLT2 inhibitors include weight loss, blood pressure reduction, renal-protective properties and a low hypoglycemia risk profile. Although the increase in low-trauma fracture and lower-extremity amputations observed in the CANVAS Program cannot be confirmed without further research, many practitioners are hesitant to utilize SGLT2 inhibitors because of these risks. Given current knowledge, whether or not the benefits of SGLT2 inhibitors outweigh the risks is not entirely clear. However, the positive cardiovascular outcomes data observed in the EMPA-REG OUTCOME study and CANVAS Program provide a larger picture of how SGLT2 inhibitors may be beneficial in patients with high cardiovascular risk.
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13. AstraZeneca. Bristol-Myers Squibb. The TIMI Study Group. Hadassah Medical Organization. ClinicalTrials.gov [Internet] Bethesda, MD: National Library of Medicine (US); 2000. [Accessed December 15, 2017]. Multicenter trial to evaluate the effect of dapagliflozin on the incidence of cardiovascular events (DECLARE-TIMI58). Available from: https://clinicaltrials.gov/ct2/show/NCT01730534
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