Effect of Gemigliptin Versus Glimepiride on Cardiac Diastolic Function in Patients With Type 2 Diabetes

Among DPP-4 inhibitors, gemigliptin is a relatively recently developed drug, and many clinical studies have shown results that are equivalent to or superior to existing DPP-4 inhibitors such as sitagliptin. However, studies on the safety of gemigliptin in cardiovascular disease have not been conducted, and studies on its effect on cardiac function are lacking. Considering the increase in hospitalizations due to heart failure found in some DPP-4 inhibitor studies, investigation of directly effect of gemigliptin on heart function would be clinically important.

Many international guidelines including the American Diabetes Association and Korean diabetes association recommend metformin as an initial hypoglycemic agent. They also suggest early active treatment for patients with type 2 diabetes (T2D) when it is difficult to reach the target blood sugar with metformin monotherapy alone. This is a strategy to minimize the period of exposure to hyperglycemia. However, when choosing the second agent, both efficacy and safety should be considered.

The American Diabetes Association guidelines recommend to using glucagon-like peptide 1 receptor agonist (GLP-1 RAs) for patients with T2D at high atherosclerotic cardiovascular disease and sodium-glucose cotransporter-2 inhibitor for T2D patients at high risk of heart failure or chronic kidney disease. However, people at this condition are not majority in many countries.

Sulfonylurea is an oral hypoglycemic agent that was first developed in the 1950s and has been widely used for a long time. Since these sulfonylureas are complementary to metformin in their mechanism of action, sulfonylureas and metformin are one of the suitable combination therapies. In fact, in a phase 3 clinical study conducted on Koreans, compared to increasing the dose of metformin, combined administration of glimepiride and metformin proved superior in the hypoglycemic effect. However, when glimepiride and metformin were combined, hypoglycemia occurred more frequently than metformin monotherapy, and there was a side effect of weight gain. Therefore, although sulfonylurea and metformin combination therapy is an effective combination in terms of lowering blood sugar, there are doubts as to whether it is the optimal combination therapy due to side effects such as hypoglycemia and weight gain, which are disadvantages of sulfonylurea itself.

Dipeptidyl peptidase-4 (DPP-4) inhibitors are an incretin-based therapy that have proven their hypoglycemic effect in both monotherapy and metformin combination therapy. According to the incretin-based mechanism of action, the risk of hypoglycemia is low, and the weight is neutral with DPP-4 inhibitors. In addition, it can be used without serious adverse events. On the contrary to most GLP-1 RAs, DPP-4 inhibitors are oral antidiabetic agents, which are convenient for physicians to prescribe as well as for patients to take. Of note, this class has been known to be more beneficial in Asian ethnic groups. Thus, DPP-4 inhibitors have been widely used in this region.

Like sulfonylurea, when used in combination with initial metformin, it has a superior blood sugar lowering effect compared to metformin alone. However, when metformin is combined with a DPP-4 inhibitor, the risk of hypoglycemia does not increase unlike when sulfonylurea is combined. Therefore, considering the safety related to the occurrence of hypoglycemia, the DPP-4 inhibitor and metformin combination therapy may be the preferred choice over the sulfonylurea and metformin combination therapy. In several phase 3 studies and registry studies in patients with T2D who failed metformin monotherapy, the addition of a DPP-4 inhibitor to metformin was proven to be safe in hypoglycemia compared to the addition of a sulfonylurea.

Among DPP-4 inhibitors, gemigliptin is a relatively recently developed drug, and many clinical studies have shown results that are equivalent to or superior to existing DPP-4 inhibitors such as sitagliptin. However, studies on the safety of gemigliptin in cardiovascular disease have not been conducted, and studies on its effect on cardiac function are lacking. Considering the increase in hospitalizations due to heart failure found in some DPP-4 inhibitor studies, investigation of directly effect of gemigliptin on heart function would be clinically important.

Eligibility Criteria:
Inclusion Criteria:

* Individuals with type 2 diabetes were eligible if they were aged \>20 years, had received metformin (500 mg - 2550 mg) alone for more than 6 weeks and have a glycated hemoglobin of 7%-9.5%.

Exclusion Criteria:

* if they had type 1 diabetes, were pregnant or lactating, or had New York Heart Association class III or IV heart failure. Other exclusion criteria were thyroid stimulating hormone \> 10.0 IU/ml, severe infection, chronic kidney disease with eGFR \< 30, AST/ALT exceeding 3 times the upper limit of the normal range, use of anti-obesity drugs within 12 weeks of the study, primary coronary intervention for acute coronary syndrome or myocardial infarction within 6 months prior to the study