Metformin (Glucophage®) versus Sitagliptin (Januvia®)

Based on "Harrison's Endocrinology"
written by J. Larry Jameson, MD, PhD

Difference between Metformin and Sitagliptin

The mechanism of action of metformin is completely different from that of sitagliptin. So these antidiabetic drugs work in different ways and have different safety and side effect profiles.

Brand name/Year of initial approval Glucophage®, 1995 Januvia®, 2006
Formulations Oral tablets,
Extended-release tablets
Oral tablets
Drug class Antidiabetic agent
Biguanide Dipeptidyl peptidase-4 (DPP-4) inhibitor
Insulin secretagogue
FDA-approved Indications Adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus
Off-label uses • Gestational diabetes
• Prediabetes
• Type I diabetes
Mechanism of action • Decreases hepatic glucose production
• Improves insulin sensitivity (increases peripheral glucose uptake and utilization)
• Reduce absorption of glucose in the gut
• Inhibits DPP-4 enzyme (the primary enzyme degrading the incretin hormones) resulting in prolonged active incretin levels, which regulate glucose homeostasis by increasing insulin synthesis and release from pancreatic beta - cells and decreasing glucagon secretion from pancreatic alpha-cells.
Sitagliptin monotherapy requires intact ß-cells, it may be best used in people with early-stage diabetes.
Metformin and sitagliptin differently influence on metabolism of glycolipids after different diets5
Half-life 6.2 hours 12.4 hours
Oral bioavailability 50-60% 87%
Metabolism, Elimination Metformin is not metabolized and is excreted unchanged by the kidneys 79% excreted unchanged in urine, minor metabolism
Contraindications • Hypersensitivity to metformin
• Metabolic acidosis
• Renal dysfunction (serum creatinine levels ≥ 1.4 mg/dL or abnormal creatinine clearance)
• Hypersensitivity to sitagliptin
Warnings & precautions • Possible risk of lactic acidosis
• Renal impairment, hepatic insufficiency, conditions associated with hypoxia are risk factors for lactic acidosis
• Renal impairment: postmarketing reports of worsening renal function
• Pancreatitis: postmarketing reports of acute pancreatitis
• Musculoskeletal complaints 2
• Urticaria, angioedema
• Use with caution in moderate-severe renal impairment
Side effects • Gastrointestinal side effects: diarrhea, nausea, flatulence, abdominal discomfort
• Decreased absorption of Vitamin B 12 and folic acid
• Nasopharynitis (stuffy or runny nose)
• Headache
• Cold-like symptoms
• Respiratory tract infections
Anti-osteoporotic effects 3 • No osteogenic effects
• No anti-osteoporotic effects
• Can reduce bone loss and increase bone strength
Effect on body weight No weight gain
May promote weight loss
No weight gain
Drug interactions • Concomitant use with radiocontrast agents can result in lactic acidosis
• Alcohol can potentiate metformin effect on lactate metabolism
Increased serum levels of dioxin, insulin, glyburide, glipizide, and glimepiride
Food Should be taken with meals Requires to be taken with food to work
Pregnancy category B
Extra health benefits • Reduction in cardiovascular events and mortality
• Decrease in LDL cholesterol and triglycerides
Cost Very inexpensive Expensive


Monotherapy for type 2 diabetes
Results of double-blind study of efficacy and safety of sitagliptin compared with metformin for type 2 diabetes 1 Metformin Sitagliptin
Regimen 1.000 mg twice daily for 24 weeks 100 mg once daily for 24 weeks
HbA(1c) change from baseline at week 24. -0.57% -0.43%
The proportions of patients at week 24 with HbA(1c) values at the goals of <7 or <6.5% 76%, 39% 69%, 34%
Fasting plasma glucose changes from baseline -19.4 mg/dL
(-1.1 mmol/l)
-11.5 mg/dL
(-0.6 mmol/l)
Incidence of hypoglycaemia 3.3% 1.7%
Gastrointestinal adverse effects 20.7% 11.6%
Body weight loss -1.9 kg -0.6 kg

Effectiveness: In terms of lowering HbA1c sitagliptin is inferior to metformin4.


Further reading


    • 1. Aschner P, Katzeff HL, Guo H, Sunga S, Williams-Herman D, Kaufman KD, Goldstein BJ; Sitagliptin Study 049 Group. Efficacy and safety of monotherapy of sitagliptin compared with metformin in patients with type 2 diabetes. Diabetes Obes Metab. 2010 Mar;12(3):252-61. PubMed
    • 2. Tarapués M, Cereza G, Figueras A. Association of musculoskeletal complaints and gliptin use: review of spontaneous reports. Pharmacoepidemiol Drug Saf. 2013 Oct;22(10):1115-8. PubMed
    • 3. Hegazy SK. Evaluation of the anti-osteoporotic effects of metformin and sitagliptin in postmenopausal diabetic women. J Bone Miner Metab. 2015 Mar;33(2):207-12. PubMed
    • 4. Dean L. Comparing newer drugs for diabetes, including combination drugs. May 16, 2011
    • 5. Yang J, Ba T, Chen L,et al. Effects of metformin and sitagliptin on glycolipid metabolism in type 2 diabetic rats on different diets. Arch Med Sci. 2016 Apr 1;12(2):233-42 PubMed

Published: May 12, 2016
Last updated: July 10, 2016


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