The American Diabetes Association (ADA) recommends metformin monotherapy as the initial pharmacologic treatment for type 2 diabetes without contraindications.1 The ADA considers metformin safe because of its low rates of adverse effects. The main side effects of metformin include gastrointestinal intolerance from bloating, abdominal discomfort, nausea, and diarrhea.2-4
Under typical circumstances, patients taking metformin very rarely experience hypoglycemia.5-8 Hypoglycemia is not listed by drug manufacturers as a potential adverse reaction of metformin monotherapy.2-4 However, they advise that concomitant use of metformin with insulin or insulin secretagogues such as sulfonylurea can increase the risk of hypoglycemia. Discontinuing certain medications that tend to produce hyperglycemia (e.g., thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, isoniazid) while using metformin may lead to loss of glycemic control and subsequent hypoglycemia.
Studies have reported on the incidence of hypoglycemia with metformin use, however most do not account for confounders that can make hypoglycemia more likely, such as in the contexts of insufficient caloric intake, large amounts of alcohol, or strenuous exercise that is not supplemented with adequate calories. Even so, hypoglycemia has been very rarely reported at therapeutic doses.
The UK Prospective Diabetes Study (UKPDS) published in 2006 is a frequently cited study regarding the incidence of hypoglycemia in patients with type 2 diabetes receiving various monotherapies over six years.5 The prospective study involved 4,191 individuals with type 2 diabetes who were randomized to diet (949), sulfonylurea (1,687), metformin (336), or insulin (1,219) monotherapies. Hypoglycemia rates were lowest in patients in the diet (0.1%) and metformin (0.3%) arms compared to those on sulfonylurea (1.2%) or insulin (3.8% on basal insulin, 5.3% on basal plus prandial insulin; p<0.0001). Compared to other agents, hypoglycemia is relatively rare with metformin monotherapy.
In a 2008 nested case-control analysis, matched 2,025 case subjects with recorded hypoglycemia to 7,278 control subjects.6 The incidence rate of hypoglycemia for metformin monotherapy was 60 per 100,000 person-years (Odds Ratio [OR] 1.42, 95% Confidence Interval [CI] [1.22-1.64]) compared to 110 per 100,000 person-years for sulfonylurea monotherapy (OR 3.73, 95% CI [3.16-4.42]). Only 73 (3.6%) hypoglycemic episodes were considered severe, defined as resulting in an emergency hospitalization and/or death. Of these 73 cases, 35 patients used insulin (26 insulin only, 9 insulin plus oral antidiabetic agent), 22 used sulfonylureas monotherapy, 11 used sulfonylurea and metformin combination therapy, 3 used metformin monotherapy, and 2 were previous users of antihyperglycemic agents.
A 2016 retrospective cohort study (n=925,185) examined the rates of serious hypoglycemia in individuals taking monotherapies of metformin, a sulfonylurea, a meglitinide, and a thiazolidinedione.7 Sulfonylurea monotherapy was associated with the highest rate of serious hypoglycemia overall (68.0 per 1,000 person-years for glyburide, 52.9 for glimepiride, 49.6 for glipizide for 49.6). Meglitinides (44.4 per 1,000 person=years for repaglinide, 23.2 nateglinide 23.2) and thiazolidinediones (14.6 per 1,000-person years for rosiglitazone, 13.8 for pioglitazone) were second and third highest, respectively. Hypoglycemia occurred the least among those taking metformin monotherapy (11.9 per 1,000 person-years).
While many studies have demonstrated the low occurrence and risk of hypoglycemia when taking metformin, metformin-induced hypoglycemia is still possible. The first case report of a patient who developed symptomatic hypoglycemia while receiving a therapeutic dose of metformin monotherapy was published in 2021.8 It proposed that additional confounding circumstances are necessary for hypoglycemia to manifest while taking metformin, including concomitant use of metformin with other hypoglycemic agents, poor oral intake, heavy alcohol use, strenuous activity that is not supplemented with adequate calories, and cessation of certain medications.
Symptoms of hypoglycemia include dizziness, tachycardia, weakness, sweating, irritability, confusion, and intense hunger.9 Hypoglycemia is a potentially life-threatening sequela; it can lead to coma or seizure and is associated with complications such as myocardial ischemia, dementia, and increased mortality.
References
- 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Care in Diabetes-2024. Diabetes Care. Jan 1 2024;47(Suppl 1):S158-s178. doi:10.2337/dc24-S009
- Glucophage (metformin hydrochloride) tablets, for oral use & Glucophage XR (metformin hydrochloride) extended-release tablets, for oral use. [Package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2018.
- Riomet (metformin hydrochloride) oral solution. [Package insert]. Cranbury, NJ: Sun Pharmaceutical Industries; 2018.
- Riomet ER (metformin hydrochloride for extended-release oral suspension). [Package insert]. Cranbury, NJ: Sun Pharmaceutical Industries; 2019.
- Wright A, Cull C, Macleod K, Holman R. Hypoglycemia in Type 2 diabetic patients randomized to and maintained on monotherapy with diet, sulfonylurea, metformin, or insulin for 6 years from diagnosis: UKPDS73. Journal of Diabetes and Its Complications. Nov-Dec 2006 2006;20(6)doi:10.1016/j.jdiacomp.2005.08.010
- Bodmer M, Meier C, Krähenbühl S, Jick S, Meier C. Metformin, sulfonylureas, or other antidiabetes drugs and the risk of lactic acidosis or hypoglycemia: a nested case-control analysis. Diabetes Care. 2008 Nov 2008;31(11)doi:10.2337/dc08-1171
- Leonard CE, Han X, Brensinger CM, et al. Comparative risk of serious hypoglycemia with oral antidiabetic monotherapy: A retrospective cohort study. Pharmacoepidemiol Drug Saf. Jan 2018;27(1):9-18. doi:10.1002/pds.4337
- Joseph C. Symptomatic Hypoglycemia During Treatment with a Therapeutic Dose of Metformin. The American Journal of Case Reports. 06/02/2021 2021;22doi:10.12659/AJCR.931311
- 6. Glycemic Goals and Hypoglycemia: Standards of Care in Diabetes-2024. Diabetes Care. Jan 1 2024;47(Suppl 1):S111-s125. doi:10.2337/dc24-S006
