Two-Year Therapeutic Efficacy and Safety of Initial Triple Combination of Metformin, Sitagliptin, and Empagliflozin in Drug-Naïve Type 2 Diabetes Mellitus Patients

Abstract

Backgruound: We investigated the long-term efficacy and safety of initial triple therapy using metformin, a dipeptidyl peptidase-4 inhibitor, and a sodium-glucose cotransporter-2 inhibitor, in patients with type 2 diabetes mellitus.

Methods: We enrolled 170 drug-naïve patients with glycosylated hemoglobin (HbA1c) level >7.5% who had started triple therapy (metformin, sitagliptin, and empagliflozin). Glycemic, metabolic, and urinary parameters were measured for 24 months.

Results: After 24 months, HbA1c level decreased significantly from 11.0%±1.8% to 7.0%±1.7%. At 12 and 24 months, the rates of achievement of the glycemic target goal (HbA1c <7.0%) were 72.5% and 61.7%, respectively, and homeostasis model assessment of β-cell function and insulin resistance indices improved. Whole-body fat percentage decreased by 1.08%, and whole-body muscle percentage increased by 0.97% after 24 months. Fatty liver indices and albuminuria improved significantly. The concentration of ketone bodies was elevated at the baseline but decreased after 24 months. There were no serious adverse events, including ketoacidosis.

Conclusion: Initial triple combination therapy with metformin, sitagliptin, and empagliflozin led to achievement of the glycemic target goal, which was maintained for 24 months without severe hypoglycemia but with improved metabolic function and albuminuria. This combination therapy may be a good strategy for drug-naïve patients with type 2 diabetes mellitus.

Keywords: Dipeptidyl-peptidase IV inhibitors; Glycated hemoglobin; Sodium-glucose transporter 2 inhibitors.

Fig. 1.

Parameters related to glycemic control over the 24 months. Values are presented as mean±standard deviation. (A) Glycosylated hemoglobin (HbA1c) level. (B) Fasting plasma glucose concentration. (C) Postload 2-hour glucose levels. (D) Fasting insulin levels. (E) Homeostasis model assessment of insulin resistance (HOMA-IR). (F) Homeostasis model assessment of β-cell function (HOMA-β). ^aP<0.05: paired t-test between the baseline and after treatment.

Fig. 2.

Body weight, body mass index (BMI), muscle mass, fat mass, and muscle and fat percentages over the 24 months. Values are presented as mean±standard deviation. (A) Body weight. (B) BMI. (C) Total muscle and fat mass. (E) Total muscle and fat percentages. ^aP<0.05: paired t-test between the values recorded at the baseline and after treatment.

Fig. 3.

Changes in the concentrations of ketone bodies, glucagon, and free fatty acids over the 24 months. Values are presented as mean±standard deviation. Logarithmically transformed values were used for comparisons of the concentrations of fasting glucagon, total ketone bodies, β-hydroxybutyrate, and acetoacetate. (A) Total ketone bodies. (B) β-Hydroxybutyrate. (C) Acetoacetate. (D) Glucagon. (E) Free fatty acids. ^aP<0.05: paired t-test between the values recorded at the baseline and after treatment.

Fig. 4.

Renal and liver functional indexes over the 24 months. Values are presented as mean±standard deviation. (A) Serum creatinine (Cr) concentration. (B) Estimated glomerular filtration rate by Chronic Kidney Disease Epidemiology Collaboration equation (eGFR-CKD-EPI). (C) Urinary protein/Cr and urinary albumin/Cr ratios at 0, 12, and 24 months. (D) Aspartate aminotransferase (AST). (E) Alanine aminotransferase (ALT). (F) Prevalence of nonalcoholic fatty liver disease (NAFLD) based on the NAFLD fatty liver score at 0, 12, and 24 months. ^aP<0.05: paired t-test between the values recorded at the baseline and after treatment.