BACKGROUND AND PURPOSE:

• The metabolic results of the GRADE trial were recently published, with researchers finding that glargine and liraglutide were more effective than glimepiride and sitagliptin in maintaining glycemic targets when combined with metformin for type 2 diabetes
• The GRADE Study Research Group (NEJM, 2022) presents the effects of these therapies on prespecified secondary outcomes, including microvascular complications and cardiovascular events

METHODS:

• Multicenter, parallel-group, comparative-effectiveness clinical trial
• Participants
  • Adults with type 2 diabetes receiving metformin
• Interventions
  • Insulin glargine U-100 (referred to as glargine)
  • Glimepiride (a sulfonylurea)
  • Liraglutide (a glucagon-like peptide-1 receptor agonist)
  • Sitagliptin (a dipeptidyl peptidase 4 inhibitor)
• Study design
  • Hazard ratios (HR) are presented with 95% confidence limits that are not adjusted for multiple comparisons
• Secondary outcomes
  • Hypertension and dyslipidemia
  • Renal: 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 | Aggregate outcome of any cardiovascular event
  • Death

RESULTS:

• 5047 participants
  • Mean follow-up: 5.0 years
• There were no material differences among the interventions with respect to
  • The development of hypertension or dyslipidemia
  • Microvascular outcomes
• Mean overall rates of renal outcomes
  • Moderately increased albuminuria levels: 2.6 events per 100 participant-years
  • Severely increased albuminuria levels: 1.1 events per 100 participant-years
  • Renal impairment: 2.9 events per 100 participant-years
  • Diabetic peripheral neuropathy: 16.7 events per 100 participant-years
• The treatment groups did not differ in
  • MACE
    • Overall rate 1.0 events per 100 participant-years
  • Hospitalization for heart failure
    • Overall rate 0.4 events per 100 participant-years
  • Death from cardiovascular causes
    • Overall rate: 0.3 events per 100 participant-years
  • All deaths
    • Overall rate 0.6 events per 100 participant-years
• There were small differences in the rates of any cardiovascular disease
  • Glargine: 1.9 events per 100 participant-years
  • Glimepiride: 1.9 events per 100 participant-years
  • Liraglutide: 1.4 events per 100 participant-years
  • Sitagliptin: 2.0 events per 100 participant-years
• When one treatment was compared with the combined results of the other three treatments, the HRs for any cardiovascular disease were
  • Glargine: HR 1.1 (95% CI, 0.9 to 1.3)
  • Glimepiride: HR 1.1 (95% CI, 0.9 to 1.4)
  • Liraglutide: HR 0.7 (95% CI, 0.6 to 0.9)
  • Sitagliptin: HR 1.2 (95% CI, 1.0 to 1.5)
• Comparing liraglutide vs the other 3 groups combined demonstrated a reduced risk of any cardiovascular disease
  • HR 0.71 (95% CI, 0.56 to 0.90)

CONCLUSION:

• There were no major differences in microvascular complications and death among the groups receiving the four secondary diabetes treatment medications
• There may have been some small difference in the incidence of any cardiovascular disease between the groups
• The authors state

The absence of the expected effect of lower glycemia on microvascular complications has been noted in some trials, including studies of diabetes prevention, and this absence has been ascribed to inadequate separation of glycemic levels over time, insufficient trial duration, threshold effects, or inadequate power

Any or all of these factors, including the small separation in glycemia might have been operative in our trial

Learn More – Primary Sources:

Glycemia Reduction in Type 2 Diabetes — Microvascular and Cardiovascular Outcomes