Metformin (Glucophage®) versus Insulin

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

	Metformin	Insulin
Brand name/Year of initial approval	Glucophage®, 1995	Humalog®, NovoLog®, NovoRapid®, Lantus®
Formulations	Oral tablets, Extended-release tablets	Subcutaneous injection
Drug class	Antidiabetic agent
	Biguanide	Human insulin analog
FDA-approved Indications	• Adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus	• Type 1 diabetes mellitus • 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	• Regulates glucose metabolism: stimulates peripheral glucose uptake by skeletal muscle and fat, and inhibits hepatic glucose production.
Oral bioavailability	50-60%	55-77%
Metabolism, Elimination	Metformin is not metabolized and is excreted unchanged by the kidneys	Identical to regular human insulin
Contraindications	• Hypersensitivity to metformin • Metabolic acidosis • Renal dysfunction (serum creatinine levels ≥ 1.4 mg/dL or abnormal creatinine clearance)	• Hypersensitivity to insulin
Warnings & precautions	• Possible risk of lactic acidosis • Kidney injury, hepatic dysfunction, conditions associated with hypoxia are risk factors for lactic acidosis	• Hypoglycemia - the most common adverse reaction, may be life-threatening • Severe, life-threatening hypersensitivity reactions can occur • Risk of hypokalemia
Side effects	• Gastrointestinal side effects: diarrhea, nausea, flatulence, abdominal discomfort • Decreased absorption of Vitamin B 12 and folic acid	• Hypoglycemia • Weight gain • Lipodystrophy at the site of repeated injections • Edema
Hypoglycemia	Very low risk of hypoglycemia	Hypoglycemia (particularly nocturnal) is a major side effect of insulin therapy 3
Effect on body weight	No weight gain May promote weight loss	Weight gain
Drug interactions	• Concomitant use with radiocontrast agents can result in lactic acidosis • Alcohol can potentiate metformin effect on lactate metabolism	• Thiazolidinediones can fluid retention when used in combination with insulin.
Food	Should be taken with meals	Short-acting insulins should be administrated within 15 minutes before a meal or immediately after a meal
Pregnancy category	B
Cost	Inexpensive	Inexpensive

Results of randomized, controlled trial of metformin vs insulin in women with type 2 diabetes mellitus during pregnancy 2	Metformin	Insulin
Glycemic control, HgbA1c	5.96 ± 5.88	6.34 ± 0.92%
Rates of cesarean delivery, birth weights, neonatal intensive care unit admissions, respiratory distress syndrome, and neonatal dextrose	similar

Metformin provides comparable to insulin glycemic control with lower mean glucose levels throughout the day, less weight gain, and a lower risk of neonatal hypoglycemia6. Also, metformin is more effective than insulin in lowering 2-hour post-prandial blood glucose.

Results of randomized clinical trial comparing metformin versus insulin for pre-gestational diabetes mellitus in pregnancy and gestational diabetes mellitus5	Metformin	Insulin
Two hour post-prandial blood glucose	significantly lower in the metformin group than the insulin group

Results of randomized open study of metformin versus insulin for gestational diabetes 1	Metformin	Insulin
The rate of the primary composite outcome (neonatal hypoglycemia, respiratory distress, need for phototherapy, birth trauma, 5-minute Apgar score less than 7, or prematurity)	32.0%	32.2%
46.3% received supplemental insulin
The women preferred metformin to insulin

Results of randomized controlled trial compared metformin with insulin for gestational diabetes mellitus 4	Metformin	Insulin
Fasting blood sugar and postprandial measures	comparable
Maternal weight gain	reduced
Neonatal and obstetric complications	comparable
In metformin group 14% of women needed supplemental insulin.

• Metformin (Glucophage®) facts
• Metformin vs Sitagliptin

• 1. Rowan JA, Hague WM, Gao W, Battin MR, Moore MP; MiG Trial Investigators. Metformin versus insulin for the treatment of gestational diabetes. N Engl J Med. 2008 May 8;358(19):2003-15. PubMed
• 2. Refuerzo JS, Gowen R, Pedroza C, Hutchinson M, Blackwell SC, Ramin S. A pilot randomized, controlled trial of metformin versus insulin in women with type 2 diabetes mellitus during pregnancy. Am J Perinatol. 2015 Feb;30(2):163-70. PubMed
• 3. Rosenstock J, Dailey G, Massi-Benedetti M, Fritsche A, Lin Z, Salzman A. Reduced hypoglycemia risk with insulin glargine: a meta-analysis comparing insulin glargine with human NPH insulin in type 2 diabetes. Diabetes Care. 2005 Apr;28(4):950-5. PubMed
• 4. Niromanesh S, Alavi A, Sharbaf FR, Amjadi N, Moosavi S, Akbari S. Metformin compared with insulin in the management of gestational diabetes mellitus: a randomized clinical trial. Diabetes Res Clin Pract. 2012 Dec;98(3):422-9 PubMed
• 5. Beyuo T, Obed SA, Adjepong-Yamoah KK, Bugyei KA, Oppong SA, Marfoh K. Metformin versus Insulin in the Management of Pre-Gestational Diabetes Mellitus in Pregnancy and Gestational Diabetes Mellitus at the Korle Bu Teaching Hospital: A Randomized Clinical Trial. PLoS One. 2015 May 6;10(5):e0125712. PubMed
• 6. Spaulonci CP, Bernardes LS, Trindade TC, Zugaib M, Francisco RP. Randomized trial of metformin vs insulin in the management of gestational diabetes. Am J Obstet Gynecol. 2013 Jul;209(1):34.e1-7. PubMed

Published: May 14, 2016
Last updated: May 26, 2017