Find out what you know about which diabetes drugs in which classes show CV protective properties and results of the trials that support their use.
In December 2018, in recognition of the reality that many patients cared for by CV clinicians have known T2DM and ASCVD, the American College of Cardiology published its expert consensus decision pathway on novel therapies for cardiovascular risk reduction in patients with type 2 diabetes and atherosclerotic cardiovascular disease. The document summarizes key elements of published cardiovascular outcome trials and provides guidance on use of sodium glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1RA) in the prevention of CV morbidity and mortality in patients with T2DM. The 8 questions in the slides above are based on this document.
Question 1. Large randomized clinical trials of SGLT2 inhibitors conducted in patients with T2DM, most with established ASCVD, have demonstrated that which 2 drugs in the class reduce MACE and HF hospitalization?
Answer B. Empagliflozin and canagliflozin. In patients randomized to empagliflozin in the EMPA-REG OUTCOME trial there was a 14% relative risk reduction in the primary composite endpoint of CV death, MI, or stroke vs placebo. The reduction in primary outcome was driven primarily by a 38% reduction in CV death. HF hospitalization, a secondary endpoint, was reduced by 35%.
Question 2. Which of the above is a SGLT2 inhibitor with a labeled indication to reduce the risk of CV death in adults with T2DM and diabetes?
Question 3. Which of the above is a proposed mechanism by which SGLT2 inhibition decreases CV events?
Answer: G. All of the above. Diuresis and natriuresis reduce filling pressures and preload and afterload; reduction in sympathetic tone helps reduce blood pressure and the potential for arrhythmia; sodium-hydrogen transporter blockade can reduce renal and myocardial injury. These are among a number of other potential protective mechanisms.
Question 4. True or false? The GLP-1RAs liraglutide, exenatide QW, and semaglutide have all been demonstrated to significantly reduce CV events.
Answer: B. False. Only liraglutide has been definitively shown to reduce CV events and is approved by the FDA to reduce the risk of MACE in adults with T2DM and established CVD. In the LEADER trial, the 3-point MACE composite was reduced by 13% with liraglutide vs placebo; all-cause mortality was reduced by 15%, driven by reduction in CV death. Although the SUSTAIN-6 trial with semaglutide was not powered for superiority, the GLP-1RA reduced 3-point MACE by 26%; magnitude and direction of effect was consistent for nonfatal MI and nonfatal stroke. In the EXSCEL trial, 3-point MACE was directionally lower for exenatide QW vs placebo but the difference did not reach statisitical significance.
Answer: A. HDL-C increase. Although the mechanisms underlying the reduction of CV events by GLP-1RA are not fully understood, they have been shown to lower systolic blood pressure by 1 to 6 mm Hg and to reduce LDL-C by as much as 16%. The benefit may also be related to the weight loss that can be seen with GLP-1RA therapy. Even when taken together, however, these effects are not sufficient to account for the observed benefit.
Question 6. SGLT2 inhibitors confer cardioprotection (reduction in MACE, HF) but are also associated with increased risk of which of the above?
Answer: F. All of the above. The increased risk for genital mycotic infections has been seen in men (balantitis) and women (candida vaginitis) but the infections are not usually serious and resolve with a course of antifungal therapy. Canagliflozin has been associated with an increased risk of lower limb amputation and the FDA required addition of a black box warning to the canagliflozin label in May 2017. It is not clear if amputation risk represents a class effect but caution is advised in patients with amputation history, PAD, and diabetic neuropathy or foot ulcers.
Question 7. When initiating a GLP-1RA with a demonstrated CV benefit, which one of the above is not an appropriate measure?
Answer: B. Reduce basal insulin by 50% (not appropriate). In patients whose A1C is well controlled at baseline or who have a history of frequent hypoglycemic events, it is recommended that basal insulin dose be reduced by 20% when initiating a GLP-1RA for CVD reduction.
Question 8. True or false? Evidence for CV benefit of SGLT2 inhibitors and GLP-1RA in patients with well-controlled A1C is limited at this point.
Answer: A. True. In CV outcome trials of SGLT2 inhibitors and GLP-1RA, the majority of the patients with T2DM and ASCVD had A1C ≥7%. There is evidence from secondary analyses, however, that suggests baseline A1C does not modify CV benefits.
Reference: Das SR, Everett BM, Birtcher KK, et al. 2018 ACC expert consensus decision pathway on novel therapies for cardiovascular risk reduction in patients with type 2 diabetes and atherosclerotic cardiovascular disease: a report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways. J Am Coll Cardiol. 2018;72:3200–3223.