Incretin hormone includes glucagon-like peptide-1 (GLP-1) from L-cells and glucose-dependent insulinotrophic polypeptide from K-cells of the small intestine. GLP-1 stimulates glucose-dependent insulin release, inhibits glucagon release, delays gastric emptying, and suppresses the appetite through GLP-1 receptor binding. However, GLP-1 has a short half-life of 1 to 2 minutes due to degradation by didpeptidyl peptidase-4 (DPP-4), which has been a limitation for its use as an anti-hyperglycemic agent. GLP-1 receptor agonists (GLP-1RAs) are synthetic analogues that are resistant to DPP-4 degradation and have more stable pharmacodynamic profiles [1,2]. The GLP-1RAs are effective in improving glycemic control with reduction in body weight and a low risk of hypoglycemia. Recently, there have been many clinical trials and systematic reviews to determine the efficacy, safety, and cardiovascular effects of GLP-1RAs [3,4,5,6,7,8,9,10].

In the position statement of the Korean Diabetes Association (KDA) 2017 for pharmacological therapy in non-pregnant adult patients with type 2 diabetes mellitus (T2DM), the Committee of Clinical Practice Guidelines of KDA updated the previous recommendations published in 2015 after extensive review of the scientific evidence. In particular, GLP-1RAs were recommended as a monotherapy or combination therapy with oral hypoglycemic agents or basal insulin, which was unlike the previous guideline that recommended them only as a combination therapy.

In this article, we will review the glycemic and metabolic effects and cardiovascular outcome trials and provide the rationale for the recommendation of GLP-1RAs in the position statement of the KDA 2017.

GLP-1RAs reduce fasting glucose concentrations, by up to 50 mg/dL, and glycosylated hemoglobin (HbA1c) by 0.5% to 1.3% with a lower risk of hypoglycemia due to a glucose-dependent mechanism of modulating insulin and glucagon secretion (Table 1) [3,4,5,6,11]. The short-acting GLP-1RAs have more pronounced effects on gastric emptying time and a greater effect on postprandial glucose, whereas the longer-acting agents result in greater effect on fasting glucose and HbA1c concentrations [3,4,5,6]. The risk of hypoglycemia with GLP-1RAs is low due to the glucose-dependent mechanism. In addition to their effects on HbA1c, the GLP-1RAs are associated with the reduction of appetite and food intake resulting in weight loss of between 2 and 4 kg on average [3,4,5,6,12,13]. In clinical trials, increased concentration of high-density lipoprotein cholesterol by 0.01 to 0.02 mmol/L and decreased concentration of triglyceride by 0.15 to 0.7 mmol/L were shown after treatment with GLP-1RAs [5]. The other characteristics, side effects and caution, were introduced in Table 1.

The cardiovascular safety of GLP-1RAs has been assessed in several randomized clinical trials (RCTs) and systematic reviews [4,5,6,7,8,9,10]. In the ELIXA (Evaluation of Lixisenatide in Acute Coronary Syndrome) trial, 6,068 patients with T2DM who had experienced a myocardial infarction or who had been hospitalized for unstable angina in the past 180 days were randomized and assigned to a lixisenatide group or placebo group. There was no reduction in overall cardiovascular risk and no difference in heart failure or serious adverse events between the two groups [7]. In contrast, the long-acting liraglutide and semaglutide reduced the cardiovascular events. In the LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) trial, 9,340 patients with T2DM and high cardiovascular risk were randomized and assigned to either a liraglutide or placebo group, which was added to standard care. Liraglutide reduced the risk for the combined primary outcome of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke by 13%, versus 14.9% in the placebo group (hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.78 to 0.97). The rates of nonfatal myocardial infarction, nonfatal stroke, and hospitalization for heart failure were not significantly lower in the liraglutide group than in the placebo group [8]. The Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in patients with T2DM (SUSTAIN-6) (semaglutide is not currently marketed in Korea) was designed as a noninferiority safety study and randomized 3,297 patients with T2DM who were at high risk of cardiovascular disease. The primary composite outcome (the first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) occurred in fewer patients in the semaglutide group, 6.6% versus 8.9% in the placebo group (HR, 0.74; 95% CI, 0.58 to 0.95) [9]. The difference of results in cardiovascular outcome trials may be related to the pharmacokinetics and potency of the glucose-lowering effect of the respective agents. Differences in study design including duration, patient risk profile, and study size may also influence the results of trials. However, the cardiovascular safety trials have been performed in very high risk populations aiming at captureing cardiovascular safety issue, and the study duration is relatively short. There are few data on cardiovascular disease safety or benefits in lower-risk patients. Several systematic reviews and meta-analyses summarizing the effect of GLP-1RAs did not show an increased risk for hospitalization for heart failure. This was unlike administration of DPP-4 inhibitors, the other incretin-based therapy [4,5,10].

GLP-1RAs have benefits as antihyperglycemic agents which can achieve reduction of glucose levels and body weight with a low risk of hypoglycemia. In the position statement of the KDA 2017, GLP-1RAs were recommended as a monotherapy or combination therapy with oral hypoglycemic agents or basal insulin based on sufficient clinical evidence. Table 2 shows compounds and dosing of currently available GLP-1 RAs in Korea [37]. We can choose a GLP-1 RA according to the patient's status, for example, level and pattern of hyperglycemia and life style.

Cardiovascular disease is the major cause of mortality and morbidity in patients with T2DM [38,39] and reduction of cardiovascular risk is one of the treatment goals in management of T2DM. Each therapeutic agent's capacity to modify cardiovascular risk has been investigated and is one of the important considerations for choice of an antihyperglycemic agent. Therefore, recent reports of cardiovascular outcome trials of GLP-1RAs yield informative data. We should consider the limitation; however, that these trials were performed in very high risk populations. Hypoglycemia is a major barrier to achieving good glycemic control in patients with T2DM, and the risk of hypoglycemia is an important factor for the choice of antihyperglycemic agents [40]. The percentage of those who are obese has increased among Korean patients with diabetes, and nearly half of all patients with diabetes are obese according to a Diabetes Fact Sheet in Korea [41,42]. Weight control is one of the important factors in obese diabetes. Therefore, GLP-1RA may be a choice of therapy when weight control and avoidance of hypoglycemia are important and in patients with high risk of cardiovascular disease. In addition, further studies about cardiovascular disease safety or benefits in lower-risk patients and concerning efficacy and safety in Korean patients are needed.