Glycemia Reduction in Type 2 Diabetes - Microvascular and Cardiovascular Outcomes

N Engl J Med. 2022 Sep 22;387(12):1075-1088. doi: 10.1056/NEJMoa2200436.


Background: Data are lacking on the comparative effectiveness of commonly used glucose-lowering medications, when added to metformin, with respect to microvascular and cardiovascular disease outcomes in persons with type 2 diabetes.

Methods: We assessed the comparative effectiveness of four commonly used glucose-lowering medications, added to metformin, in achieving and maintaining a glycated hemoglobin level of less than 7.0% in participants with type 2 diabetes. The randomly assigned therapies were insulin glargine U-100 (hereafter, glargine), glimepiride, liraglutide, and sitagliptin. Prespecified secondary outcomes with respect to microvascular and cardiovascular disease included hypertension and dyslipidemia, confirmed moderately or severely increased albuminuria or an estimated glomerular filtration rate of less than 60 ml per minute per 1.73 m2 of body-surface area, diabetic peripheral neuropathy assessed with the Michigan Neuropathy Screening Instrument, cardiovascular events (major adverse cardiovascular events [MACE], hospitalization for heart failure, or an aggregate outcome of any cardiovascular event), and death. Hazard ratios are presented with 95% confidence limits that are not adjusted for multiple comparisons.

Results: During a mean 5.0 years of follow-up in 5047 participants, there were no material differences among the interventions with respect to the development of hypertension or dyslipidemia or with respect to microvascular outcomes; the mean overall rate (i.e., events per 100 participant-years) of moderately increased albuminuria levels was 2.6, of severely increased albuminuria levels 1.1, of renal impairment 2.9, and of diabetic peripheral neuropathy 16.7. The treatment groups did not differ with respect to MACE (overall rate, 1.0), hospitalization for heart failure (0.4), death from cardiovascular causes (0.3), or all deaths (0.6). There were small differences with respect to rates of any cardiovascular disease, with 1.9, 1.9, 1.4, and 2.0 in the glargine, glimepiride, liraglutide, and sitagliptin groups, respectively. When one treatment was compared with the combined results of the other three treatments, the hazard ratios for any cardiovascular disease were 1.1 (95% confidence interval [CI], 0.9 to 1.3) in the glargine group, 1.1 (95% CI, 0.9 to 1.4) in the glimepiride group, 0.7 (95% CI, 0.6 to 0.9) in the liraglutide group, and 1.2 (95% CI, 1.0 to 1.5) in the sitagliptin group.

Conclusions: In participants with type 2 diabetes, the incidences of microvascular complications and death were not materially different among the four treatment groups. The findings indicated possible differences among the groups in the incidence of any cardiovascular disease. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; GRADE number, NCT01794143.).

Publication types

  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Albuminuria / etiology
  • Albuminuria / prevention & control
  • Blood Glucose / analysis
  • Cardiovascular Diseases* / etiology
  • Cardiovascular Diseases* / prevention & control
  • Comparative Effectiveness Research
  • Diabetes Complications* / etiology
  • Diabetes Complications* / prevention & control
  • Diabetes Mellitus, Type 2* / complications
  • Diabetes Mellitus, Type 2* / drug therapy
  • Diabetic Neuropathies / diagnosis
  • Diabetic Neuropathies / etiology
  • Diabetic Neuropathies / prevention & control
  • Drug Therapy, Combination
  • Dyslipidemias / etiology
  • Dyslipidemias / prevention & control
  • Glomerular Filtration Rate
  • Glycated Hemoglobin* / analysis
  • Heart Failure / etiology
  • Heart Failure / prevention & control
  • Humans
  • Hypertension / etiology
  • Hypertension / prevention & control
  • Hypoglycemic Agents* / adverse effects
  • Hypoglycemic Agents* / therapeutic use
  • Insulin Glargine / adverse effects
  • Insulin Glargine / therapeutic use
  • Liraglutide / adverse effects
  • Liraglutide / therapeutic use
  • Metformin* / adverse effects
  • Metformin* / therapeutic use
  • Microvessels / drug effects
  • Sitagliptin Phosphate / adverse effects
  • Sitagliptin Phosphate / therapeutic use
  • Sulfonylurea Compounds / adverse effects
  • Sulfonylurea Compounds / therapeutic use


  • Blood Glucose
  • Glycated Hemoglobin A
  • Hypoglycemic Agents
  • Sulfonylurea Compounds
  • Insulin Glargine
  • glimepiride
  • Liraglutide
  • Metformin
  • Sitagliptin Phosphate

Associated data