Cardiovascular Outcomes of Glycemia Reduction in Type 2 Diabetes: Key Points

Nathan DM, Lachin JM, Bebu I, et al., on behalf of the GRADE Study Research Group.
Glycemia Reduction in Type 2 Diabetes — Microvascular and Cardiovascular Outcomes. N Engl J Med 2022;387:1075-1088.

The following are key points to remember from this review of a novel, long-awaited, and important clinical trial in type 2 diabetes (T2D):

  1. This is the second publication of the GRADE (Glycemia Reduction Approaches in Type 2 Diabetes: A Comparative Effectiveness) study. The first article in the same issue (N Engl J Med 2022;387:1067-74), titled “Glycemia Reduction in Type 2 Diabetes — Glycemic Outcomes,” assessed the comparative effectiveness of four commonly used glucose-lowering medications, added to metformin, in achieving and maintaining a glycated hemoglobin (HbA1c) level of <7.0% in participants with T2D.
  2. This study evaluated the microvascular and cardiovascular (CV) outcomes in the same subjects. Randomization began in July 2013 and was concluded in August 2017 with follow-up until April 2021. For any CV disease (CVD), it was estimated that a rate of 0.01 per year would provide 72% power to detect a 50% difference among the groups. The observed rate was higher (0.018 per year), resulting in 99% power to detect a 50% difference.
  3. Patients were ≥30 years old with T2D within the past 10 years and treated with ≥500 mg/day of metformin with a baseline HbA1c of 6.8-8.5%. Exclusion criteria included a history of a major CV event (CVE) in the year before randomization, New York Heart Association functional classification of III or higher, and an estimated glomerular filtration rate (eGFR) of <30 ml/min/1.73 m2 of body surface area (BSA). The participants were evaluated every 3 months.
  4. Prior to randomization, metformin dose was increased to ≥1000 mg/day with target maximal dose 2000 mg/day. The randomly assigned therapies were insulin glargine U-100 (glargine beginning at up to 20 U), glimepiride (sulfonylurea 1-8 mg), liraglutide (glucagon-like peptide-1 [GLP-1] receptor agonist subQ max 1.8 mg/day), and sitagliptin (dipeptidyl peptidase-4 [DPP-4] inhibitor 100 mg adjusted for renal function).
  5. The sodium-glucose cotransporter-2 (SGLT2) inhibitors were not available at the time of the study. During the trial, updated consensus recommendations on the choice of glucose-lowering medications in participants with prevalent CVD or kidney disease were issued by the American Diabetes Association and the European Association for the Study of Diabetes. These recommendations were communicated to participants and health care providers who were free to use other agents. The participants’ own health care providers were responsible for all medications other than the glucose-lowering medications specified in the trial protocol.
  6. Prespecified secondary outcomes with respect to microvascular disease and CVD included hypertension and dyslipidemia, moderately or severely increased albuminuria or an eGFR of <60 ml/min/1.73 m2 of BSA, diabetic peripheral neuropathy, CVE (major adverse cardiovascular events [MACE], hospitalization for heart failure, or an aggregate outcome of any CVE), and death. Hazard ratios are presented with 95% confidence interval (CI) not adjusted for multiple comparisons.
  7. Mean age was 57.2 (10) years, 41.5% were at ≥60 years old, 64% were men, 66% White, 20% Black, 6% other; ethnicity 19% Hispanic or Latinx. The mean body mass index (BMI) was 34.3 ± 6.8 kg/m2, and the mean glycated hemoglobin level was 7.5 ± 0.5%. At baseline, the prevalence of hypertension and dyslipidemia, largely indicated by the use of medications, was 77% and 96%, respectively. The prevalence of diabetic peripheral neuropathy was 42%, only 6% had a history of myocardial infarction or stroke, and none during year prior to randomization.
  8. During a mean 5.0 years of follow-up in 5,047 participants, there were no material differences among the interventions with respect to the development of hypertension or dyslipidemia most likely because primary physicians treated each. When added to metformin, glargine and liraglutide were more effective than glimepiride (0.2%) and sitagliptin (0.1%) for glycemic targets. Liraglutide had a relative benefit for blood pressure, while glargine had greater incident hypertension (insulin increases renal sodium reabsorption).
  9. There was no difference in 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 absence of differences by hypoglycemic agent was thought related to the very small separation in glycemia.
  10. The study was not powered to detect differences among treatment groups for CVE or death and CVE rate was low overall, likely because CV risk factors were well controlled. The trial wide rate of the aggregate of any CVE was 1.79 events per 100 participant-years, with the incidence reaching 10-15% among the treatment groups by the end of the trial. Treatment groups did not differ with respect to MACE (overall rate, 1.0), hospitalization for heart failure (0.4), death from CV causes (0.3), or all deaths (0.6). There were small differences with respect to rates of any CVD, 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 CVD were 1.1 (95% CI, 0.9-1.3) in the glargine group, 1.1 (95% CI, 0.9-1.4) in the glimepiride group, 0.7 (95% CI, 0.6-0.9) in the liraglutide group, and 1.2 (95% CI, 1.0-1.5) in the sitagliptin group. Previous studies showing a significant benefit of GLP-1 receptor agonists that included liraglutide had a higher CV risk at baseline than in this trial.
  11. Use of nonstudy medication by subjects’ physician totaled 14%. Order of most often needed was sulfonylurea, sitagliptin, glargine, and liraglutide. The most common added were 6.7% sulfonylurea, 4.8% SGLT2 inhibitors, 4.3% GLP1 agonists, and 3.8% glargine insulin.
  12. In participants with T2D, 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 CVD. In a recent systematic review and network meta-analysis comparison of the effects of SGLT2 inhibitors and GLP-1 receptor agonists in T2M with/without albuminuria, SGLT2 inhibitors may be superior to GLP-1 receptor agonists for renal outcomes with/without albuminuria, although there was no difference in the risk of MACE (Diabetes Res Clin Pract 2022;183:109146).

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Heart Failure and Cardiomyopathies, Prevention, Acute Heart Failure, Hypertension

Keywords: Albuminuria, Cardiovascular Diseases, Diabetes Mellitus, Type 2, Diabetic Neuropathies, Dipeptidyl-Peptidase IV Inhibitors, Dyslipidemias, Glomerular Filtration Rate, Glucagon-Like Peptide-1 Receptor, Glucose, Glycated Hemoglobin A, Health Personnel, Heart Failure, Hypertension, Insulin Glargine, Kidney Diseases, Liraglutide, Metformin, Primary Prevention, Risk Factors, Sodium-Glucose Transporter 2 Inhibitors, Stroke

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