Glycemia Reduction in Type 2 Diabetes - Microvascular and Cardiovascular Outcomes

The GRADE Study Research Group

Research output: Contribution to journalArticlepeer-review

41 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1075-1088
Number of pages14
JournalNew England Journal of Medicine
Issue number12
StatePublished - Sep 22 2022

Bibliographical note

Publisher Copyright:
Copyright © 2022 Massachusetts Medical Society.


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

PubMed: MeSH publication types

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


Dive into the research topics of 'Glycemia Reduction in Type 2 Diabetes - Microvascular and Cardiovascular Outcomes'. Together they form a unique fingerprint.

Cite this