Comparative risk of serious hypoglycemia with oral antidiabetic monotherapy: A retrospective cohort study

Pharmacoepidemiol Drug Saf. 2018 Jan;27(1):9-18. doi: 10.1002/pds.4337. Epub 2017 Nov 6.


Purpose: To examine and compare risks of serious hypoglycemia among antidiabetic monotherapy-treated adults receiving metformin, a sulfonylurea, a meglitinide, or a thiazolidinedione.

Methods: We performed a retrospective cohort study of apparently new users of monotherapy with metformin, glimepiride, glipizide, glyburide, pioglitazone, rosiglitazone, nateglinide, or repaglinide within a dataset of Medicaid beneficiaries from California, Florida, New York, Ohio, and Pennsylvania. We did not include users of dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 agonists, or sodium-glucose co-transporter 2 inhibitors. We identified serious hypoglycemia outcomes within 180 days following new use using a validated, diagnosis-based algorithm. We calculated age- and sex-standardized outcome occurrence rates for each drug and generated propensity score-adjusted hazard ratios vs metformin using Cox proportional hazards regression.

Results: The ranking of standardized occurrence rates of serious hypoglycemia was glyburide > glimepiride > glipizide > repaglinide > nateglinide > rosiglitazone > pioglitazone > metformin. Rates were increased for all study drugs at higher average daily doses. Adjusted hazard ratios (95% confidence intervals) vs metformin were 3.95 (3.66-4.26) for glyburide, 3.28 (2.98-3.62) for glimepiride, 2.57 (2.38-2.78) for glipizide, 2.03 (1.64-2.52) for repaglinide, 1.21 (0.89-1.66) for nateglinide, 0.90 (0.75-1.07) for rosiglitazone, and 0.80 (0.68-0.93) for pioglitazone.

Conclusions: Sulfonylureas were associated with the highest rates of serious hypoglycemia. Among all study drugs, the highest rate was seen with glyburide. Pioglitazone was associated with a lower adjusted hazard for serious hypoglycemia vs metformin, while rosiglitazone and nateglinide had hazards similar to that of metformin.

Keywords: hypoglycemia; meglitinide; metformin; pharmacoepidemiology; sulfonylurea compounds; thiazolidinedione.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Administration, Oral
  • Adult
  • Aged
  • Blood Glucose / analysis
  • Blood Glucose / drug effects
  • Datasets as Topic
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Female
  • Follow-Up Studies
  • Humans
  • Hypoglycemia / blood
  • Hypoglycemia / chemically induced
  • Hypoglycemia / diagnosis
  • Hypoglycemia / epidemiology*
  • Hypoglycemic Agents / administration & dosage
  • Hypoglycemic Agents / adverse effects*
  • Incidence
  • Male
  • Medicaid / statistics & numerical data
  • Middle Aged
  • Retrospective Studies
  • Risk Assessment
  • Severity of Illness Index
  • United States / epidemiology


  • Blood Glucose
  • Hypoglycemic Agents