Author + information
- Caroline K. Kramer, MD, PhD,
- Chang Ye, MSc and
- Ravi Retnakaran, MD∗ ()
- ↵∗University of Toronto, Leadership Sinai Centre for Diabetes, Mount Sinai Hospital, 60 Murray Street, Suite L5-025, Mailbox-21, Toronto, Ontario M5T 3L9, Canada
We thank Drs. Zheng and Roddick for their interest in our recent network meta-analysis of placebo-controlled, randomized clinical trials of new glucose-lowering drugs in type 2 diabetes, in which we compared the effects of glucagon-like peptide (GLP)-1 agonists, dipeptidyl peptidase (DPP)-4 inhibitors, and sodium glucose co-transporter (SGLT)-2 inhibitors on the risk of hospitalization for heart failure (HF) (1). This network meta-analysis involved 9 cardiovascular outcome/safety trials that have been conducted since the U.S. Food and Drug Administration issued a Guidance for Industry in 2008 mandating the demonstration of cardiovascular safety for any new glucose-lowering drugs. Our analysis showed that SGLT-2 inhibitors yielded the greatest risk reduction for HF hospitalization as compared to placebo (risk ratio [RR]: 0.56; 95% credibility interval [CrI]: 0.43 to 0.72) and were associated with significant risk reduction in pairwise comparisons with both GLP-1 agonists (RR: 0.59; 95% CrI: 0.43 to 0.79) and DPP-4 inhibitors (RR: 0.50; 95% CrI: 0.36 to 0.70). Ranking of the classes revealed 99.6% probability of SGLT-2 inhibitors being the optimal treatment for reducing the risk of this outcome, followed by GLP-1 agonists (0.27%) and DPP-4 inhibitors (0.1%).
As 2 of the 9 trials (EXAMINE [Examination of Cardiovascular Outcomes with Alogliptin Versus Standard of Care Trial]  and the ELIXA [Evaluation of Lixisenatide in Acute Coronary Syndrome Trial] ) enrolled participants after a recent acute coronary event, we fully concur with Zheng and Roddick that their respective patient populations may be inherently different from those of the other 7 trials. As such, we have conducted a sensitivity analysis in which the network meta-analysis was repeated with the exclusion of these 2 trials. This analysis revealed that the findings remained unchanged. Specifically, SGLT-2 inhibitors again yielded the greatest risk reduction for HF hospitalization as compared to placebo (RR: 0.57; 95% CrI: 0.38 to 0.82) and were associated with significant risk reduction in pairwise comparisons with both GLP-1 agonists (RR: 0.62; 95% CrI: 0.36 to 0.95) and DPP-4 inhibitors (RR: 0.56; 95% CrI: 0.30 to 0.85). Moreover, on ranking of the classes, there was again 97.3% probability of SGLT-2 inhibitors being the optimal treatment for reducing the risk of hospitalization for HF, followed by GLP-1 agonists (1.59%) and DPP-4 inhibitors (0.93%). These data thus continue to strongly favor the choice of SGLT-2 inhibitors over either GLP-1 agonists or DPP-4 inhibitors for reducing the risk of HF hospitalization in patients with type 2 diabetes.
Please note: Dr. Kramer has received grants from Boehringer Ingelheim, outside the submitted work; and a Canadian Diabetes Association Clinician-Scientist award. Dr. Retnakaran has received grants from Novo Nordisk, Boehringer Ingelheim, and Merck; personal fees from Novo Nordisk, Eli Lilly, Takeda, Sanofi, Merck, outside the submitted work, and the Boehringer Ingelheim Chair in Beta-cell Preservation, Function and Regeneration at Mount Sinai Hospital. Ms. Ye has reported that she has no relationships relevant to the contents of this paper to disclose.
- 2018 American College of Cardiology Foundation