Initial Combination Therapy With Sitagliptin, a Dipeptidyl Peptidase-4 Inhibitor, and Metformin for Patients With Type 2 Diabetes Mellitus

Tina Vilsbøll


Expert Rev Endocrinol Metab. 2008;3(1):13-19. 

In This Article

Clinical Efficacy

In the USA, patients with T2DM are treated with sitagliptin as monotherapy as an adjunct to diet and exercise, or in combination with metformin or TZD. Recently, the US FDA approved Janumet as initial combination therapy as a supplement to diet and exercise to improve glycemic control in adult patients with T2DM.

The efficacy of sitagliptin (100 mg or 200 mg once daily) as monotherapy compared with placebo was evaluated in patients with inadequately controlled diabetes (baseline glycosylated hemoglobin [HbA1c] of 8.1% [per protocol analysis]) for 18 weeks, and demonstrated placebo-corrected reductions of 0.60 and 0.48%, respectively.[32] Similar placebo-subtracted reductions in HbA1c of -0.79 and -0.94 %, respectively, were obtained after 24 weeks of treatment with sitagliptin (100 or 200 mg) once daily as monotherapy in more than 700 patients with T2DM (baseline HbA1c of 8.0%).[33] Sustained and similar efficacy throughout the 24-week period was seen with both doses of sitagliptin. Patients with the highest baseline HbA1c (>9%) experienced the greatest improvements, with decreases in HbA1c averaging 1.52%. On average, fasting plasma glucose and postprandial plasma glucose decreased up to 1.2 and 3.0 mM, respectively, in the sitagliptin groups when compared with placebo.[33] Throughout the monotherapy studies, bodyweight was reported to be unchanged. Markers of ß-cell function (proinsulin:insulin ratio and homeostasis model assessment of ß-cell function [HOMA-ß]) improved significantly in both studies with both doses of sitagliptin when compared with placebo.[32,33]

Evaluation of sitagliptin 100-mg once-daily treatment as add-on to ongoing metformin therapy in patients with T2DM (n = 701; baseline HbA1c of 8.0%) demonstrated a placebo-subtracted reduction of HbA1c from baseline of 0.65% after 24 weeks.[34] The proportion of patients reaching the American Diabetes Association (ADA) goal for acceptable control (HbA1c < 7%[8] ) was 47%, and 17% reached HbA1c less than 6.5% (compared with 18 and 5%, respectively, of patients in the placebo arm).[34] Recently, at the Annual Scientific Session of the ADA in Chicago (IL, USA), similar sustained efficacy was demonstrated over 54 weeks, with addition of once-daily sitagliptin to metformin, which produced clinically meaningful and durable improvements in glycemic control, and the combination treatment was well tolerated.[35] In order to compare the efficacy and safety of sitagliptin versus glipizide in patients with T2DM with inadequate glycemic control on metformin monotherapy, a total of 1172 patients were randomized to the addition of sitagliptin (100 mg once daily) or glipizide (5-20 mg/day).[36] From a mean baseline of 7.5% HbA1c, similar changes from baseline were obtained (0.67% in both groups), demonstrating noninferiority. Notably, the proportion of patients experiencing hypoglycemic episodes was markedly higher in the glipizide group compared with the sitagliptin group (32 vs 5%). Furthermore, a difference in bodyweight of 2.5 kg in favor of sitagliptin was reported.[36] However, more patients in the sitagliptin group discontinued treatment compared with those in the glipizide group (mainly because of lack of efficacy), which might bias the results in the favor of sitagliptin. Throughout the studies, and as shown previously with other OADs, patients with T2DM and more severe baseline hyperglycemia (i.e., HbA1c ≥ 9%) had the most pronounced response to sitagliptin. Furthermore, in patients with T2DM and uncontrolled diabetes on metformin (n = 190; baseline HbA1c of 9.3%), a sustained effect of sitagliptin administered once daily (100 mg/day) during 18 weeks was recently demonstrated. After an 18-week treatment period, a placebo-corrected decrease of 1% in HbA1c was observed, with a 1.8% reduction in the patient subgroup with the highest HbA1c (baseline HbA1c 10.5%) [Data on file, MSD, Merck & Co Inc., Whitehouse Station, NJ, USA].

Recently published guidelines recommend initiation of metformin concomitantly with lifestyle changes in newly diagnosed obese patients with T2DM[37] but, as the targets for acceptable glycemic control are lowered, even fewer patients will actually manage to reach the goal described in the guideline with a single OAD. Thus, if an additional treatment is demanded in order to obtain further improvement of glycemic control, sulphonylureas, TZDs or, recently, DPP-4 inhibitors are often being added before initiation of insulin. Furthermore, due to the progressive nature of T2DM, more than one agent is often required over time in order to maintain glycemic control. Since sitagliptin and metformin lower glucose through different mechanisms, initial combination therapy with metformin and sitagliptin is a tempting and interesting approach, offering potential complementary effects. Therefore, the efficacy and safety of combination therapy using co-administration of sitagliptin and metformin, as first-line therapy for patients with T2DM, was investigated over 24 weeks in 1091 patients.[38] Patients with T2DM were randomized to one of six daily treatments: sitagliptin 100 mg/metformin 1000 mg; sitagliptin 100 mg/metformin 2000 mg; metformin 1000 mg; metformin 2000 mg (all as divided doses administered twice daily); sitagliptin 100 mg once daily; or placebo.[38] All active treatments produced statistically significant changes in HbA1c when compared with baseline, although the most pronounced effect was seen in patients receiving initial combination of sitagliptin 100 mg/metformin 2000 mg, with changes in HbA1c of -2.07%. In the same study, patients with a baseline HbA1c greater than 11% were evaluated in an open-label substudy and this group of patients demonstrated within-group mean HbA1c changes from baseline of -2.9%. Overall, the incidence of hypoglycemia was not significantly different in any of the groups when compared with placebo and the incidence of gastrointestinal adverse experiences was similar for co-administration therapies compared to their respective metformin monotherapy.[38] Thus, so far, the combination of metformin and sitagliptin is the only combination therapy that maintains the advantage of having no weight gain and no hypoglycemia. The only other exception to this is metformin and an α-glucosidase inhibitor, which, however, is not used very often worldwide (due to gastrointestinal side effects).

At the ADA in June 2007, the study by Goldstein et al.[38] was continued in a 30-week, double-blind active-controlled phase.[39] In the all-patients-treated analysis, mean HbA1c from baseline in the highest dose group (sitagliptin 100 mg plus metformin 2000 mg) was -1.8 %, indicating that the initial combination therapy provides durable and sustained glycemic improvement and is well tolerated over 54 weeks in patients with T2DM.

To further elucidate the mechanism of action behind the effective combination of sitagliptin and metformin, a randomized, placebo-controlled, double-blind, four-period, crossover study in 16 healthy adults was recently presented at the ADA in June 2007.[40] The study design included administration of sitagliptin or metformin as monotherapy, co-administration of sitagliptin and metformin compared with treatment with placebo.[40] Blood samples for active and total GLP-1 and GIP were collected during meal ingestion. The study indicated that metformin increased total GLP-1 secretion (recently suggested to be caused by an increase in proglucagon mRNA in the L-cell). When combining metformin and sitagliptin, complementary (more than additive) effects are seen in respect to active GLP-1 concentrations, probably due to increased secretion combined with decreased degradation, respectively, of the secreted GLP-1.[40] This effect may provide a unique benefit of combination therapy in patients with T2DM through substantial enhancement of the incretin axis and does make initial combination with the two drugs extremely interesting in patients with T2DM.

Sitagliptin, both as monotherapy and in combination with metformin, is generally well tolerated. Recently, the safety and tolerability of sitagliptin was assessed by pooling data from nine completed clinical trials, including a total of more than 5000 patients, of which 2786 were treated with sitagliptin.[41] The studies were up to 2 years in duration. In respect to clinical adverse events (AEs), the overall incidence of AEs, serious AEs and discontinuation due to AEs, similar incidences were seen in the sitagliptin and nonexposed groups.[41] The overall gastrointestinal AE rates were also similar for both groups and no meaningful differences in laboratory AEs were observed.[41] Sitagliptin has been on the market in the USA since October 2006 and in Europe since April 2007, is now used widely and, presently, only very few additional adverse reactions have been identified during postapproval use of the drug. These are hypersensitivity reactions, including anaphylaxis, angioedema, rash and urticaria. However, because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.


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