What next after metformin? A retrospective evaluation of the outcome of second-line, glucose-lowering therapies in people with type 2 diabetes

J Clin Endocrinol Metab. 2012 Dec;97(12):4605-12. doi: 10.1210/jc.2012-3034. Epub 2012 Oct 17.


Context: After failure of metformin monotherapy, many second-line, glucose-lowering therapies are available to treat people with type 2 diabetes.

Objective: The objective of the study was to compare clinical outcomes using common alternative regimens.

Design and setting: This was a retrospective cohort study using data from the U.K.-based General Practice Research Database.

Patients: These were primary care patients with type 2 diabetes who had metformin monotherapy as their first treatment and who then initiated on relevant second-line, glucose-lowering regimens during the study period 2000-2010. A total of 27,457 patients were prescribed a second-line therapy, of whom 26,278 (95.7%) were prescribed a regimen with 1,000 or more observations.

Main outcome measures: All-cause mortality, major adverse cardiovascular events (MACE), cancer, and a combined end point of any of these were measured. Secondary end points were change in glycosylated hemoglobin between baseline and 12 months. Time to clinical end points was compared using Cox proportional hazards models.

Results: Sulfonylurea monotherapy had significantly higher hazard ratios (HRs) for all-cause mortality (HR 1.459, 1.207-1.763); MACE (HR 1.578, 1.187-2.099); stroke (HR 1.444, 1.050-1.987); and the combined end point (HR 1.381, 1.194-1.597). Metformin plus pioglitazone had significantly lower adjusted HRs for all-cause mortality (HR 0.707, 0.515-0.970) and the combined end point (HR 0.747, 0.612-0.911). Mean glycosylated hemoglobin improved between baseline and 12 months for all regimens other than sulfonylurea monotherapy.

Conclusion: The combination of metformin plus pioglitazone appears to provide superior clinical outcomes compared with the most commonly used regimen, metformin plus sulfonylurea. Sulfonylurea monotherapy resulted in worse outcome.

Publication types

  • Evaluation Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Blood Glucose / drug effects
  • Chemotherapy, Adjuvant
  • Cohort Studies
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / epidemiology
  • Drug Administration Schedule
  • Drug Substitution / statistics & numerical data
  • Female
  • Humans
  • Hypoglycemic Agents / administration & dosage
  • Male
  • Metformin / administration & dosage*
  • Middle Aged
  • Retrospective Studies
  • Treatment Outcome
  • United Kingdom / epidemiology


  • Blood Glucose
  • Hypoglycemic Agents
  • Metformin