Entering the market in 2013, sodium-glucose cotransporter 2 (SGLT2) inhibitors are a new class of antidiabetic medications for type 2 diabetes (DM2). These SGLT2 inhibitors were approved by the FDA for use as second-line therapy and endorsed by the American Diabetes Association (ADA) and the American Association of Clinical Endocrinologists (AACE).1,2
They are shown to lower HbA1c by 0.4-1.1% and lower glucose through insulin independent mechanisms, thereby offering a promising new mechanism of action.3 In keeping with FDA guidance,4 cardiovascular safety trials with SGLT2 inhibitors are now in progress. The only cardiovasular (CV) outcomes data available to date come from the Cardiovascular Outcome Event (EMPA-REG OUTCOME) Trial with empagliflozin (Jardiance), which was published at the end of 2015 in the New England Journal of Medicine.5,6
(See Table 1)
The EMPA-REG OUTCOME trial was a randomized, double-blind, placebo-controlled trial that investigated cardiovascular outcomes in patients with T2DM at high risk of cardiovascular disease (CVD) who were treated with empagliflozin added to standard of care.5 A group of 7020 patients were randomized to receive empagliflozin (10mg or 25mg doses) vs. placebo, with continuation of standard of care treatment for both diabetes and comorbid conditions, including optimization of cardiac risk factors. Patients enrolled in the trial were required to be on a stable diabetes treatment regimen for 12 weeks following the initiation of randomized treatment and be at elevated risk for CVD. After 12 weeks, adjustment of treatment regimen was permitted at the discretion of the treating provider.
The primary composite outcome of the EMPA-REG OUTCOME trial was a 3-point MACE including death from cardiovascular causes, nonfatal myocardial infarction, and nonfatal stroke. This study was powered as a non-inferiority trial but also to evaluate superiority of empaglifozin compared to placebo for both primary (3-point MACE) and secondary outcomes (4-point MACE, primary composite outcome plus hospitalization for unstable angina).5
The primary outcome occurred in a significantly lower percentage of patients treated with empagliflozin than those receiving placebo (10.5% vs. 12.1%, respectively; hazard ratio [HR] 0.86; 95% confidence interval [CI], 0.74 to 0.99; P<0.001 for non-inferiority and P = 0.04 for superiority). However, when each component of the 3-point MACE was evaluated, patients treated with empagliflozin had a significantly lower risk (38%) of death from cardiovascular causes, but the risk of non-fatal MI and non-fatal stroke remained similar between groups.
The secondary outcome investigating hospitalizations for unstable angina in addition to the primary outcome (4-point MACE) did not reveal significant differences between the two groups; 12.8% in the empagliflozin group versus 14.3% in the placebo group (HR 0.89; 95% CI 0.78 to 1.01; P<0.001 for non-inferiority and P = 0.08 for superiority).
A follow-up study looking at renal outcomes indicated that patients with type 2 diabetes (DM2) and chronic kidney disease experienced a decreased progression of renal disease.7 A pre-specified secondary objective of the EMPA-REG OUTCOME trial was to investigate its effect on composite microvascular outcomes, including first occurrence of: initiation of retinal photocoagulation, vitreous hemorrhage, diabetes-related blindness, or incident or worsening nephropathy.
The study findings revealed a significant relative risk reduction in composite microvascular outcomes in the empagliflozin group, with most of the observed risk reduction related to renal outcomes. Patients in the empagliflozin group had significantly lower risk of progression to microalbuminuria (11.2% vs. 16.2% in the placebo group; HR 0.62; 95% CI 0.54–0.72, P<0.001), doubling of the serum creatinine (1.5% vs. 2.6%; HR 0.56; 95% CI 0.39–0.79, P<0.001), and initiation of renal-replacement therapy (0.3% vs 0.6%; HR 0.45; 95% CI 0.21–0.97, P=0.04).7
The reason for improved cardiovascular and renal outcomes is unclear. Overall, patients treated with empagliflozin plus standard of care had lower HbA1c levels, though not necessarily meeting target values.7 Patients in the empagliflozin cohort also showed a reduction in weight and lower blood pressure, but also had increased levels of both LDL and HLD cholesterol.6 It is possible that weight loss could have contributed to the improved cardiovascular and renal outcomes. However, the reduction in CV risk factors, such as blood pressure (BP) and body weight, while statistically significant, were minimal and the differences observed within 2-4 months make it unlikely that the improved CV outcomes were due solely to modification of the CV risk factors.
Another possible explanation for the findings may be that SGLT2 inhibitors may provide alternate fuel for the heart through a shift in carbohydrate utilization to fatty acid substrates.8 The question remains as to whether this improvement is a class effect or an outcome specific to empagliflozin.
Studies with the SGLT2 inhibitors, canagliflozin (CANVAS and CANVAS-R trials),9 and dapagliflozin (DECLARE-TIMI 58 trial) are in progress, which should help to answer these questions. In addition, the important outcomes from the results of these studies have clinical applications. For example, would initiating a SGLT2 inhibitor work in primary prevention of cardiac and renal disease?
Future research is needed to investigate if these drugs have an effect on CV prevention.
1. American Diabetes Association: Approaches to glycemic treatment. Diabetes Care. 2015;38(Suppl):S41-48.
2. Handelsman Y, Bloomgarden ZT, Grunberger G, et al. American association of clinical endocrinologists and american college of endocrinology - clinical practice guidelines for developing a diabetes mellitus comprehensive care plan - 2015. Endocr Pract. 2015;21(Suppl 1):1-87.
3. Monica Reddy RP, Inzucchi SE. SGLT2 inhibitors in the management of type 2 diabetes. Endocrine. 2016;53(2):364-372.
4. Guidance for Industry. Diabetes Mellitus--Evaluating cardiovascular risk in new antibiabetic therapies to treat type 2 diabetes. Available at: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm071627.pdf. Accessed October 17, 2016.
5. Zinman B, Inzucchi SE, Lachin JM, et al. Rationale, design, and baseline characteristics of a randomized, placebo-controlled cardiovascular outcome trial of empagliflozin (EMPA-REG OUTCOME). Cardiovasc Diabetol. 2014;13:102.
6. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015;373(22):2117-2128.
7. Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes. N Engl J Med. 2016;375(4):323-334.
8. Ferrannini E, Baldi S, Frascerra S, et al. Shift to Fatty Substrate Utilization in Response to Sodium-Glucose Cotransporter 2 Inhibition in Subjects Without Diabetes and Patients With Type 2 Diabetes. Diabetes. May 2016;65(5):1190-1195.
9. Neal B, Perkovic V, de Zeeuw D, et al. Rationale, design, and baseline characteristics of the Canagliflozin Cardiovascular Assessment Study (CANVAS)--a randomized placebo-controlled trial. Am Heart J. 2013;166(2):217-223 e211.