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Highlights from the 53rd European Society for the Study of Diabetes (EASD) Annual Meeting

Highlights from the 53rd European Society for the Study of Diabetes (EASD) Annual Meeting
  • Cardiometabolic
  • Diabetes

Author

Ruy Lyra

Resource type

Article

Tags

Diabetes
cardiovascular effects
empagliflozin
exanatide
sotagliflozin

Usage

Practical

Highlights from the 53rd European Society for the Study of Diabetes (EASD) Annual Meeting
Lisbon, Portugal, 11–15 September, 2017

New research and developments were discussed during this meeting. The highlights included the presentation of two studies looking at cardiovascular outcomes of patients with type 2 diabetes (T2D), one studying exenatide, the other empagliflozin. The third study of particular interest looked at sotagliflozin, a new oral inhibitor of sodium–glucose cotransporters (SGLT) 1 and 2, in combination with insulin for patients with type 1 diabetes (T1D).
 


Effects of once-weekly exenatide on cardiovascular outcomes in T2D

Results of this worldwide, multicenter study, presented by Dr Rury Holman (Diabetes Trials Unit, Oxford Centre for Diabetes, Endocrinology, and Metabolism, UK) were much anticipated, following on from other GLP-1 receptor agonist trials (LEADER; liraglutide1 and SUSTAIN 6; semaglutide2). Much was expected with respect to safety and cardiovascular benefit with exenatide.3

Patients with T2D, with or without previous cardiovascular disease, were randomly assigned to receive subcutaneous injections of either 2 mg extended-release exenatide or matching placebo, once weekly. The primary composite outcome was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction or nonfatal stroke. The coprimary hypotheses were that exenatide, administered once weekly, would be noninferior to placebo with respect to safety and superior to placebo with respect to efficacy.

All 14,752 enrolled patients (of whom 10,782 [73.1%] had previous cardiovascular disease) were followed for a median of 3.2 years. A primary composite outcome event occurred in 839 of 7356 patients (11.4%; 3.7 events per 100 person-years) in the exenatide group and in 905 of 7396 patients (12.2%; 4.0 events per 100 person-years) in the placebo group (hazard ratio, 0.91; 95% confidence interval [CI], 0.83 to 1.00), with the intent-to-treat analysis indicating that exenatide, administered once weekly, was noninferior to placebo with respect to safety (P<0.001 for noninferiority) but was not superior to placebo with respect to efficacy (P=0.06 for superiority).

The rates of death from cardiovascular causes, fatal or nonfatal myocardial infarction, fatal or nonfatal stroke, hospitalization for heart failure or for acute coronary syndrome, and the incidence of acute pancreatitis, pancreatic cancer, medullary thyroid carcinoma and serious adverse events did not differ significantly between the two groups. The authors concluded that among patients with T2D with or without previous cardiovascular disease, the incidence of major adverse cardiovascular events did not differ significantly between patients who received exenatide and those who received placebo.

Effect of sodium-glucose co-transporter-2 inhibitors on impaired ventricular repolarization in people with T2D

Results from the EMPA-REG OUTCOME trial showed that empagliflozin, a SGLT2 inhibitor, dramatically reduced cardiovascular death and heart failure in people with T2D who were at high risk of cardiovascular disease.4 However, the mechanism by which empagliflozin reduced cardiovascular events remains unknown.5 Increased ventricular repolarization heterogeneity is associated with the risk of fatal arrhythmias and sudden cardiac death, not only in groups with pathological conditions, such as heart failure and T2D, but also in the general population.6,7 SGLT2 inhibitors also have pleiotropic effects, including blood pressure reduction and body weight loss,4,5 and as reductions in blood pressure and body weight have been reported to improve abnormal ventricular repolarization,8,9 the authors hypothesized that treatment with an SGLT2 inhibitor may reverse ventricular repolarization heterogeneity in people with T2D.

Given this scenario, Tatsuya Sato (Sapporo Medical University School of Medicine, Sapporo, Japan) and colleagues tested the hypothesis that treatment with a SGLT2 inhibitor would reverse ventricular repolarization heterogeneity, a predictor of cardiovascular mortality, in people with T2D.10 They retrospectively analyzed changes in indices of ventricular repolarization before and after treatment with a SGLT2 inhibitor in 46 people with T2D. They found that SGLT2 inhibitor treatment reduced HbA1c concentration (62±13 mmol/mol [7.7±1.2%] versus 59±16 mmol/mol [7.5±1.4%]), body weight (77.8±13.9 versus 74.7±12.5 kg) and systolic blood pressure (133±18 versus 126±12 mmHg) in the study participants. Heart rate and QTc interval were not changed by SGLT2 inhibitor treatment, but QTc dispersion was significantly reduced (median, 48.8 versus 44.2 ms). SGLT2 inhibitor treatment was more effective at reversing QTc dispersion in participants with larger pretreatment QTc dispersion. Changes in systolic blood pressure (Spearman’s q= 0.319; P=0.031), but not in HbA1c concentration, were correlated with changes in QTc dispersion after SGLT2 inhibitor treatment. These results suggest that SGLT2 inhibitor treatment reverses ventricular repolarization heterogeneity in people with T2D independently of its effect on glycaemic control. The favourable effect on ventricular repolarization heterogeneity could be the mechanism by which empaglifozin reduced cardiovascular events in the EMPA-REG OUTCOME trial.

Effects of sotagliflozin added to insulin in patients with T1D 

This multicenter study, conducted by Satish Garg (University of Colorado Denver, USA), was designed to evaluated the safety and efficacy of sotagliflozin, a new oral inhibitor of SGLT 1 and 2, in combination with insulin treatment in patients with T1D.11 In this phase 3, double-blind trial conducted at 133 centers worldwide, 1402 patients with T1D, who were receiving treatment with any insulin therapy (pump or injections), were randomly assigned to receive sotagliflozin (400 mg per day) or placebo for 24 weeks. The primary end point was a HbA1c level lower than 7.0% at week 24, with no episodes of severe hypoglycaemia or diabetic ketoacidosis after randomization. Secondary end points included the change from baseline in HbA1c level, weight, systolic blood pressure and mean daily bolus dose of insulin.

A significantly larger proportion of patients in the sotagliflozin group than in the placebo group achieved the primary end point (200 of 699 patients [28.6%] versus 107 of 703 [15.2%], P<0.001). The least-squares mean change from baseline was significantly greater in the sotagliflozin group than in the placebo group for HbA1c (difference, −0.46 percentage points), weight (−2.98 kg), systolic blood pressure (−3.5 mm Hg), and mean daily bolus dose of insulin (−2.8 units per day), P≤0.002 for all comparisons. The rate of severe hypoglycaemia was similar in the sotagliflozin group and the placebo group (3.0% [21 patients] and 2.4% [17 patients], respectively). The rate of documented hypoglycaemia with a blood glucose level of 55 mg per deciliter (3.1 mmol per liter) or below was significantly lower in the sotagliflozin group than in the placebo group. The rate of diabetic ketoacidosis was higher in the sotagliflozin group than in the placebo group (3.0% [21 patients] and 0.6% [4 patients], respectively). The authors concluded that among patients with T1D who were receiving insulin, the proportion of patients who achieved a HbA1c level lower than 7.0% with no severe hypoglycaemia or diabetic ketoacidosis was larger in the group that received sotagliflozin than in the placebo group. However, the rate of diabetic ketoacidosis was higher in the sotagliflozin group.


References

  1. Marso SP, et al. Liraglutide and cardiovascularo in type 2 diabetes. N Engl J Med 2016;375(4):311-22.
  2. Marso SP, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2016;375(19):1834-844.
  3. Holman RR, et al. Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes. N Engl J Med 2017;377:1228-39.
  4. Zinman B, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117-28. 
  5. Sattar N, et al. SGLT2 inhibition and cardiovascular events: why did EMPA-REG Outcomes surprise and what were the likely mechanisms? Diabetologia 2016;59: 1333-9. 
  6. Malik M, Batchvarov VN. Measurement, interpretation and clinical potential of QT dispersion. J Am Coll Cardiol 2000;36:1749-66. 
  7. Veglio M, et al. QT interval, cardiovascular risk factors and risk of death in diabetes. J Endocrinol Invest 2004;27:175-81. 
  8. Klimas J, et al. Modulation of the QT interval duration in hypertension with antihypertensive treatment. Hypertens Res 2015;38:447-54.
  9. Omran J, et al. Effect of obesity and weight loss on ventricular repolarization: a systematic review and meta-analysis. Obes Rev 2016;17:520-30.
  10. Sato T, et al. Effect of sodium-glucose co-transporter-2 inhibitors on impaired ventricular repolarization in people with type 2 diabetes. Diabet Med 2017;34(10):1367-71.
  11. Garg SK, et al. Effects of sotagliflozin added to insulin in patients with type 1 diabetes. N Engl J Med Sept 13 2017. http://www.nejm.org/doi/full/10.1056/NEJMoa1708337#t=article

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