Sitagliptin as combination therapy in the treatment of type 2 diabetes mellitus

Figures & data

Figure 1 The role of glucagon-like peptide (GLP-1) in glucose homeostasis. Reprinted with permission from Weber A. Dipeptidyl peptidase IV inhibitors for the treatment of diabetes. J Med Chem. 2004;47:4135–4141.² Copyright © American Chemical Society.

Table 1 Pivotal combination studies with sitagliptin

Variable	Study 1	Study 2	Study 3	Study 4	Study 5	Study 6
Author	Brazg^Citation9	Goldstein^Citation10	Charbonnel^Citation11	Nauck^Citation13	Hermansen^Citation14	Rosenstock^Citation15
Baseline data
No. of patientsa	28	1091	701	1172	441	353
Design	R, DB, PC, CO	R, DB, PC, PG	R, DB, PC, PG	R, DB, AC, PG	R, DB, PG	R, DB, PC, PG
Concomitant treatment for T2DMb	Met ≥ 1500 mg/d	Met 1000 mg + Sit Met 2000 mg + Sit Met 1000 mg Met 2000 mg	Met ≥ 1500 mg/d	Met ≥ 1500 mg/d	Glim ± Met	Pioglitazone
Sitagliptin dose or comparator	50 mg bid or PBO	100 mg daily or pbo 100 mg or pbo	100 mg daily or pbo	Sit 100 mg Glip 5 mg/d	100 mg daily or pbo	100 mg daily or pbo
Findings
Change from placebo A1c (%)	Not evaluated	Met 1000 mg + Sit −1.57c Met 2000 mg + Sit −2.07c Met 1000 mg −0.99c Met 2000 mg −1.30c Sit alone −0.83c	−0.65 (p < 0.001)	−0.67% (both groups)	Sit −0.74 (p < 0.001) Sit + Glim + Met −0.89e Sit + Glim −0.57e	0.7 (p < 0.001)
FPG (mg/dL)	−20.3 (p < 0.001)	Met 1000 mg + Sit −52.9c Met 2000 mg + Sit −69.7c Met 1000 mg alone −33.1c Met 2000 mg alone −35.1c Sit alone −23.3c	−25.4 (p < 0.001)	Sit −10.0 Glip −7.5	Sit −20.1 (p < 0.001) Sit + Glim + Met −19.3 (p < 0.05) Sit + Glim −20.7 (p < 0.05)	−17.7 (p < 0.001)
Others	−32.8 mg/dL WMG (p < 0.001)			Weight gain Glip +1.1 kg; weight loss Sit −1.5 kg
Adverse events
Hypoglycemia	None	0.5%–2% active 0.6% pbo	1.3% active 2.1% pbo	5% Sit 32% Glip	12% Sit 1.8% pbo	1.1% active 0% in pbo
Increased incidence of Gi?	No	No	Yesd 11.9% active 10.5% pbo	Yesd Nausea (1.1% vs 0%) Diarrhea (1.7% vs 1.1%)	No	Yesd Nausea (1.1% vs 0%) Diarrhea (1.7% vs 1.1%)

a Number of patients randomized.

b Type 2 diabetes mellitus.

c p < 0.001 for the between-group difference relative to placebo.

d Determined not to be statistically significant.

e p value not reported.

Abbreviations: R, randomized; DB, double-blind; PC, placebo-controlled; CO, crossover; bid, twice daily; pbo, placebo; PG, parallel group; AC, active controlled; Met, metformin; Sit, sitagliptin; Glip, glipizide; Glim, glimepiride A1c, hemoglobin A1c; FPG, fasting plasma glucose; GI, gastrointestinal; WMG, 24-hour weighted mean glucose.

Table 2 Comparison of approved antidiabetic medications in the United States^7,16,23

Medication	Class	Dosage form	A1c reduction (%)	Adverse effects
metformin	Biguanides	Oral	1.5	Gastrointestinal effects, rare lactic acidosisa
glipizide, glimepiride, glyburide	Sulfonylureas	Oral	1.5	Hypoglycemia, weight gain
rosiglitazone, pioglitazone	Thiazolidinediones	Oral	0.8–1.0	Weight gain, exacerbation of heart failure
nateglinide, repaglinide	Meglitinides	Oral	1–1.5	Hypoglycemia, weight gain
acarbose, miglitol	α-glucosidase inhibitors	Oral	0.5–0.8	Gastrointestinal effects
Various trade names	Insulin	Parenteral	≥2.5	Hypoglycemia, weight gain
pramlintide	Amylinomimetics	Parenteral	0.6	Gastrointestinal effects, hypoglycemiab
exenatide	GLP-I analog	Parenteral	0.5–1.0	Gastrointestinal effects
sitagliptin	DPP-IV inhibitors	Oral	0.5–0.9	Nasopharyngitis, URI, headache

a Incidence in 0.03 cases per 1000 patient years.

b Black-box warning for severe insulin-induced hypoglycemia if administered within 3 hours of insulin.

Abbreviations: A1c, glycosylated hemoglobin; DPP-IV, dipeptidyl peptidase IV; GLP, glucagon-like peptide; URI, upper respiratory tract infection.

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