Use of GLP-1 RAs in Cardiovascular Disease Prevention: A Practical Guide

Although many cardiologists have not routinely prescribed antihyperglycemic agents, the results of cardiovascular outcome trials with sodium-glucose transport protein 2 (SGLT2) inhibitors and glucagon-like protein-1 receptor agonists (GLP-1 RAs), demonstrating significant reductions in cardiovascular events and mortality, make it imperative that cardiologists become more familiar with these agents. As part of a comprehensive cardiovascular risk reduction strategy, cardiologists can prescribe these agents or provide the recommendation to the healthcare team. In either case, involving the entire healthcare team, including the primary care provider and diabetologist/endocrinologist, ensures a team approach to manage potential patient concerns, side effects, and concomitant glucose-lowering medications. This article provides practical facts and tips to aid in the appropriate prescription of liraglutide, the first GLP-1 RA with a cardiovascular indication.

Four cardiovascular outcomes studies evaluating GLP-1 RAs have been reported to date,¹ of which only one² showed unequivocally a superior cardiovascular outcome. The LEADER trial² randomized 9340 patients with type 2 diabetes mellitus and high cardiovascular risk to liraglutide 1.8 mg or placebo in addition to standard of care. After a median follow-up of 3.8 years, participants in the liraglutide group experienced a significantly reduced risk (13.0% versus 14.9%; hazard ratio, 0.87; P=0.01) versus placebo for the primary composite outcome (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke).² All individual components of the composite primary outcome favored liraglutide, with cardiovascular death (4.7% versus 6.0%; hazard ratio, 0.78; P=0.007) and all-cause death (8.2% versus 9.6%; hazard ratio, 0.85; P=0.02) both reduced significantly. Based on the results of this study, liraglutide is now approved to reduce the risk of major cardiovascular events in adults with type 2 diabetes mellitus and established cardiovascular disease and is recommended by the American Diabetes Association guidelines as a second-line agent, after metformin, for patients with known atherosclerotic cardiovascular disease.³

Liraglutide lowers glucose by stimulating insulin and decreasing glucagon secretion. It is interesting to note that the observed cardiovascular benefits appear to be above and beyond the effects on glycemia and are likely because of the beneficial effects on various risk factors (including weight, blood pressure, lipid profile, inflammatory markers, and renal disease) as well as direct effects on the heart and vasculature.⁴

The most common side effects associated with these agents are gastrointestinal in nature, including nausea, vomiting, diarrhea, and abdominal discomfort. These are thought be because of their central actions, which promote satiety and fullness and delayed gastric emptying. Gastrointestinal adverse events can occur in ≤50% to 60% of patients but are generally transient and mild to moderate in intensity. Although no evidence-based recommendations exist for the prevention or treatment of these side effects, we recommend decreasing food intake at the time of drug initiation, eating smaller, more frequent meals, consuming food slower, and stopping before feeling full. Although these measures can prevent or minimize these side effects, they can also jumpstart the weight loss effect, a motivator for continuing treatment. Furthermore, a slow-dose titration schedule is recommended to minimize these effects. The initial dose is 0.6 mg daily for ≥1 week, then increase to 1.2 mg daily for ≥1 week, and then increase again to 1.8 mg daily. In patients with gastrointestinal side effects, an even slower titration or capping at a lower dose are additional options. Patients should be reassured of the transient and benign nature of these symptoms.

GLP-1 RA-induced hypoglycemia is rare given the glucose-dependent mechanism of action where at lower glucose levels insulin stimulation ceases. The only exception is when used in conjunction with either insulin or sulfonylureas, both of which increase insulin levels in a glucose-independent manner. To prevent hypoglycemia in this setting, we recommend a preemptive 30% to 50% decrease in the dose of insulin and sulfonylurea upon initiation of liraglutide, especially when glucose levels are close to normal.

Several serious side effects, including pancreatitis, pancreatic cancer, and medullary thyroid cancer, have been potential concerns, but none was increased in any of the completed large trials. Liraglutide should not be prescribed in patients with a family or personal history of medullary thyroid cancer or multiple endocrine neoplasia type 2 syndrome.

GLP-1 RAs are easy to administer despite that they are injectables. Liraglutide is administered using a prefilled pen device with a thin (≤32-gauge) and short needle, and thus the injection is virtually painless. Fear of injections can be readily overcome with an office demo injection. Patients will invariably note that the discomfort associated with the injection is much less compared with that of glucose self-monitoring, which they are accustomed to and accepting of. Correct injection technique (ie, new needles for every injection, clean skin, and a steady hand) will further minimize any discomfort. Liraglutide is administered once a day, any time, irrespective of meals or other medications (including insulin). Liraglutide does not require dose adjustment for any stage of renal disease. It is important to note that the European and Canadian labels do not recommend liraglutide in patients with end-stage renal disease because of limited experience in this population. GLP-1 RAs exert complementary mechanisms of action with other glucose-lowering agents and thus can be safely used in any combination. A summary of the practical considerations regarding treatment with liraglutide is presented in the Table.

Several important unanswered clinical questions remain. Liraglutide and empagliflozin now both carry a formal cardiovascular indication, yet it is not known whether combining the two would confer additional benefit or negate each other’s beneficial effect. Furthermore, their cardiovascular benefit has only been proven in patients with diabetes mellitus and prevalent atherosclerotic cardiovascular disease, and it is unknown whether similar benefits would be observed if used in patients who have a lower risk or those without diabetes mellitus. Lastly, neither drug is recommended as first-line therapy for diabetes mellitus, even in patients with established cardiovascular disease, but rather as a preferred second-line option after metformin.

In conclusion, in patients with diabetes mellitus and atherosclerotic cardiovascular disease, liraglutide reduces the occurrence of major cardiovascular events and should be considered an intrinsic part of a multifactorial risk reduction plan, including a healthy lifestyle; glycemic, lipid, and blood pressure control; and statin and aspirin.