Discussion
In this prospective observational study with drug-naïve patients with high HbA1c, initial triple combination therapy of metformin, sitagliptin, and lobeglitazone showed better efficacy and safety profiles than the conventional stepwise approach with glimepiride and metformin. HbA1c was maintained at <7.0% at 12 months by 69.8% of participants receiving triple therapy and 52.4% of participants receiving conventional therapy, which was significantly different. This difference became more obvious for the stricter target goal of HbA1c<6.5% (58.1% vs 36.9%, p<0.05).
After 12 months of treatment, significant improvement in surrogated markers related to insulin sensitivity and β-cell function was observed only in patients who received initial triple therapy. This result suggests that a proactive approach targeting pathophysiological defects of T2D using DPP4 inhibitor and TZD on top of metformin is a good option for management of T2D particularly in those with high HbA1c level at diagnosis.
In the conventional group treated with metformin and sulfonylurea, the QUICKI and Matsuda index scores increased significantly, which may indicate improvements in insulin sensitivity. By contrast, β-cell function estimated by HOMA-β increased non-significantly in in this group. Considering that the HOMA-IR score was 5.7 and C-peptide level at baseline was 2.6 ng/mL in the conventional group, the study subjects seemed to have exhibited greater insulin resistance than a β-cell defect. This might be the reason for the lack of significant improvement in HOMA-β in this group despite the significant decrease in HbA1c level. Metformin is known to decrease insulin resistance, but not to act on β-cells. Sulfonylurea is an insulin secretagogue, but it is not a drug that can improve β-cell function fundamentally.
A pathophysiological approach aiming to alleviate insulin resistance and hyperglucagonemia or to improve β-cell function has shown long-term benefit in T2D management, compared with simple insulin secretagogues.28–30 Here, both treatments showed substantial and comparable reductions in HbA1c levels during the first 5 months. However, hypoglycemia was reported in only one patient in the initial triple group, while 11 patients in the conventional group experienced hypoglycemia. Among them, one patient in the initial triple group and five in the conventional group discontinued the study because of hypoglycemia. High numbers of hypoglycemic events in the conventional therapy arm can be attributed to the uptitration of glimepiride or insulin, which was added as a rescue therapy.
The HbA1c levels in both groups were decreased significantly at the 2 and 5-month visits (>2.0% and another >1.0%, respectively). The participants receiving initial triple combination therapy were able to maintain a target HbA1c goal of <7.0% over 12 months (69.8%). By contrast, the HbA1c level rebounded after 5 months using the stepwise approach. Only 52.4% of patients maintained the HbA1c target <7.0% over 12 months. These results support the use of initial triple combination therapy with DPP4 inhibitor, metformin, and TZD for greater durability in glucose control than the stepwise therapy with metformin and sulfonylurea.
The 0.2% increasing tendency in HbA1c level after 5 months in our stepwise approach is consistent with data from previous studies with metformin, sulfonylurea, or insulin.12 13 31 It should be noted that the progressive increase in HbA1c levels was paralleled by a progressive decline in β-cell function.11
At 12 months, 141 mg/dL of fasting plasma glucose (FPG) in the conventional group seemed not to be satisfactory but the metformin dose was not escalated to the maximum possible level; instead, 1425 mg of metformin was used. High-dose metformin therapy is not generally prescribed in Asian countries because it tends to increase the incidence of adverse side effects, such as gastrointestinal discomfort, without affecting its glucose-lowering efficacy.32 Furthermore, high doses of metformin are also not recommended for elderly people because of their attenuated renal function. In our study, about 30% of the subjects were aged >60 years. For these reasons, a moderate dose of metformin (up to ~1500 mg) was used in the conventional therapy group.
Theoretically, the combination of incretin-based therapy and TZD appears more ideal than either treatment alone, considering complementary mechanisms of action. To confirm this hypothesis, sitagliptin and lobeglitazone, a TZD, on top of metformin were chosen for a triple combination in the present study. In humans, initial combination treatment of sitagliptin and metformin showed larger improvements in glucose homeostasis and improvements in β-cell function than individual monotherapies for up to 2 years.33 We demonstrated that drug-naïve patients with T2D benefited the most from early initial combination therapy of sitagliptin and metformin.34 35
In the present study, lobeglitazone was used as a TZD, which was developed aiming at a highly effective TZD with reduced side effects. Docking analysis for structural characteristics of TZD-bound PPAR-γ suggested that lobeglitazone displays 12 times higher affinity to PPAR-γ than rosiglitazone or pioglitazone.36
The results of the present study are consistent with previous work showing that metformin, pioglitazone, and exenatide triple combination therapy achieved an HbA1c target more successfully than in those receiving conventional therapy.17 However, it should be noted that adverse events related with exenatide injection were not negligible. The dropout rate in our triple group was much less than that observed in most studies with GLP1R agonists including exenatide37 and liraglutide.38 Recently, SGLT2 inhibitors have proven cardiovascular and renal benefits in large cardiovascular outcome trials.39–41 Because SGLT2 inhibitors decrease body weight and blood pressure as well as glucose concentration, they might be another good agent for early combination.
In this study, the initial triple treatment involving a DPP4 inhibitor and a TZD decreased triglyceride and increased HDL-cholesterol levels. It alleviated albuminuria significantly, and improved liver enzyme activities compared with conventional treatment with metformin and sulfonylurea. These are additional advantages supporting an initial triple regimen for sulfonylurea-based regimens.
Recent evidence has shown that hypoglycemia might be associated with higher mortality,42 and the American Diabetes Association and European Association for the Study of Diabetes have recommended less aggressive glucose control in individuals at high cardiovascular risk.6 In the present study, despite greater glucose lowering, the risk of hypoglycemia in the patients receiving initial triple therapy was one-fifth that in those receiving conventional therapy but is to be expected as conventional therapy included use of sulfonylureas known to significantly increase the risk of hypoglycemia. Drug compliance was higher in participants in the triple group than in those in conventional group, may be as a result of less hypoglycemia. Thus, initiation of a combination therapy with metformin, sitagliptin, and lobeglitazone produced greater and more durable HbA1c reductions and was safer with respect to hypoglycemia and other adverse events compared with a conventional stepwise approach with sulfonylureas and metformin.
The present study has several limitations. First, we did not use the same drugs and same drug number in the comparison, which prohibited complete blinding of the study. However, we wanted to compare the efficacy, safety, and durability of initial triple therapy including TZD and a DPP4 inhibitor, which might be an ideal combination, with those of conventional dose escalation approach with metformin and sulfonylurea. Second, because of the relatively small sample size and short duration, long-term outcome data were not available.