SGLT2 inhibitors: providing cardiovascular protection in type 2 diabetes?

Abstract

New glucose-lowering agents for type 2 diabetes are expensive compared with older drugs, so it is important for patients, those treating them, and payers that information used to guide treatment decisions is based on a clear analysis of the benefits and risks of each drug. Although the benefit of glucose lowering to reduce microvascular complications was established in the UKPDS trial, 1 UK Prospective Diabetes Study (UKPDS) GroupIntensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998; 352: 837-853 Summary Full Text Full Text PDF PubMed Scopus (18982) Google Scholar uncertainty remains in relation to the risk of cardiovascular disease, as highlighted by the controversy about thiazolidinediones, particularly rosiglitazone, and the adverse effects on cardiovascular death seen in the ACCORD trial of intensive glucose lowering in patients with longstanding diabetes. 2 Ferrannini E DeFronzo RA Impact of glucose-lowering drugs on cardiovascular disease in type 2 diabetes. Eur Heart J. 2015; 36: 2288-2296 Crossref PubMed Scopus (191) Google Scholar As a result, regulators such as the US Food and Drug Administration now require evidence (based on adjudicated outcomes from phase 3 trials) that the risk of cardiovascular harm is low for all new glucose-lowering therapies before a drug is made available and usually also require a post-marketing cardiovascular safety trial. 3 US Department of Health and Human ServicesGuidance for industry. Diabetes mellitus—evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm071627.pdfDate: December, 2008 Google Scholar The results of published cardiovascular outcome trials with the dipeptidyl peptidase 4 inhibitor class of drugs 4 White WB Cannon CP Heller SR et al. for the EXAMINE InvestigatorsAlogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med. 2013; 369: 1327-1335 Crossref PubMed Scopus (2047) Google Scholar , 5 Green JB Bethel MA Armstrong PW et al. for the TECOS Study GroupEffect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015; 373: 232-242 Crossref PubMed Scopus (1965) Google Scholar and of one trial with a glucagon-like peptide 1 receptor agonist 6 Pfeffer MA Claggett B Diaz R et al. for the ELIXA InvestigatorsLixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med. 2015; 373: 2247-2257 Crossref PubMed Scopus (1604) Google Scholar have largely substantiated the safety of these treatments—with the exception of a signal for increased admission to hospital for heart failure with saxagliptin 7 Scirica BM Bhatt DL Braunwald E et al. for the SAVOR-TIMI 53 Steering Committee and InvestigatorsSaxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013; 369: 1317-1326 Crossref PubMed Scopus (2734) Google Scholar —but have not shown cardiovascular benefit, although a press release from the LEADER (NCT01179048) trial with liraglutide suggests that this GLP-1 analogue does reduce major cardiovascular events. 8 Novo NordiskCompany announcement. https://www.novonordisk.com/bin/getPDF.1991879.pdf Google Scholar Effects of sodium-glucose cotransporter-2 inhibitors on cardiovascular events, death, and major safety outcomes in adults with type 2 diabetes: a systematic review and meta-analysisThese data suggest net protection of SGLT2 inhibitors against cardiovascular outcomes and death. The efficacy results were driven by findings for empagliflozin (the only SGLT2 inhibitor for which data from a dedicated long-term cardiovascular safety trial have been reported), although results for the other drugs in the class were not clearly different. Adverse events were more difficult to quantify than was efficacy, with the effects of individual drugs in the class seeming to differ for some safety outcomes. Full-Text PDF