050P London, UK
Pharmacology 2017

 

 

Network meta-analysis of cardiovascular outcomes in randomised controlled trials of new classes of antidiabetic drugs

B. M. Cheung, Y. Fei, M. F. Tsoi, T. T. Cheung, C. R. Kumana. Department of Medicine, University of Hong Kong, Hong Kong, Hong Kong.

Introduction: The prevalence of cardiovascular disease is high in patients with type 2 diabetes mellitus (T2DM). New antidiabetic drugs are required to demonstrate cardiovascular safety in outcome trials. However, they are rarely compared with each other in such trials. Therefore, we performed a network meta-analysis to compare the cardiovascular outcomes of the new classes of antidiabetic drugs.

Method: We searched for randomised controlled trials involving glucagon-like peptide-1 receptor agonists (GLP-1 RAs), sodium-glucose co-transporter 2 (SGLT-2) inhibitors and dipeptidyl peptidase-4 (DPP-4) inhibitors in T2DM patients with cardiovascular outcomes, namely, major adverse cardiovascular events (MACE) and mortality, as endpoints. Both frequentist approach and Bayesian framework were used for analysis in R.

Results: Nine randomised controlled trials with altogether 72262 T2DM patients were included in our network meta-analysis -8. SGLT-2 inhibitors and GLP-1 RAs reduced MACE (OR 0.86, 95%CI 0.77-0.95 and 0.89, 0.82-0.97, respectively), all-cause mortality (0.78, 0.69-0.88 and 0.89, 0.80-0.99, respectively), and cardiovascular mortality (0.76, 0.65-0.88 and 0.85, 0.73-0.99, respectively) when compared to placebo. Moreover, SGLT-2 inhibitors reduced MACE (0.87, 0.77-0.98), and cardiovascular mortality (0.75, 0.62-0.90) when compared to DPP-4 inhibitors. In contrast, DPP-4 inhibitors were not significantly different from placebo in cardiovascular outcomes but were associated with higher all-cause mortality when compared to SGLT-2 inhibitors (1.31, 1.13-1.53) and GLP-1 RAs (1.16,1.01-1.33).

Conclusions: SGLT-2 inhibitors and GLP-1 RAs reduce MACE and mortality compared to placebo. DPP-4 inhibitors are safe in that they do not worsen cardiovascular outcome, but are inferior to SGLT-2 in terms of MACE and cardiovascular mortality. This network meta-analysis shows clearly that SGLT-2 inhibitors and GLP-1 RAs should be the preferred treatment.

References:

1. Marso SP et al. (2016). N Engl J Med 375: 311-322.

2. Marso SP et al. (2016). N Engl J Med 375: 1834-1844.

3. Pfeffer MA et al. (2015). N Engl J Med 373(23): 2247-57.

4. Zinman B et al. (2015). N Engl J Med373(22): 2117-28.

5. Neal B et al. (2017). N Engl J Med 377(7): 644-657.

6. Scirica BM et al. (2013). N Engl J Med 369(14): 1317-26.

7. Green JB et al. (2015). N Engl J Med 373(3): 232-42.

8. White WB et al. (2013). N Engl J Med369(14): 1327-35.


Trials included in the network meta-analysis

Study Drug Drug class Reference
LEADER Liraglutide GLP-1 RA Marso SP et al. (1)
SUSTAIN-6 Semaglutide GLP-1 RA Marso SP et al. (2)
ELIXA Lixisenatide GLP-1 RA Pfeffer MA et al. (3)
EMPA-REG OUTCOME Empagliflozin SGLT-2 inhibitor Zinman B et al. (4)
CANVAS Canagliflozin SGLT-2 inhibitor Neal B et al. (5)
CANVAS-R Canagliflozin SGLT-2 inhibitor Neal B et al. (5)
SAVOR-TIMI 53 Saxagliptin DPP-4 inhibitor Scirica BM et al. (6)
TECOS Sitagliptin DPP-4 inhibitor Green JB et al. (7)
EXAMINE Alogliptin DPP-4 inhibitor White WB et al. (8)