Annual Meeting, ICM Messe München, Munich, Germany
12–16 September 2016
Three studies stand out within the research and developments discussed at EASD 2016 – liraglutide add on therapy for type 1 diabetes, semaglutide for cardiovascular outcomes and canaglifozin for renal function preservation, both in type 2 diabetes
Efficacy and safety of liraglutide added to insulin treatment in type 1 diabetes
This study investigated whether adjunct treatment with liraglutide, a glucagon-like peptide-1 (GLP-1) analogue, improves glycaemic control and reduces insulin requirement and body weight in patients with type 1 diabetes (T1D).1 The study was a 52-week, double-blind, multinational, treat-to-target trial in adults with T1D and suboptimal glycaemic control (HbA1c 7–10%). There were 1398 enrolled patients randomised 3:1 to receive once-daily subcutaneous injections of liraglutide (1.8 mg, 1.2 mg or 0.6 mg) or placebo in addition to insulin. The primary endpoints were the change in HbA1c, fasting body weight and total insulin dose. A secondary endpoint was the number of symptomatic hypoglycaemic episodes.
The reduction in HbA1c was significantly greater for liraglutide 1.8 mg and 1.2 mg compared with placebo (estimated treatment difference: 1.8 mg: -0.20% [-0.32, -0.07], 1.2 mg: -0.15% [-0.27, -0.03], 0.6 mg: -0.09% [-0.21, 0.03]). Reductions in body weight were significantly larger for all liraglutide groups compared with placebo (1.8 mg: -4.9 kg [-5.7, -4.2], 1.2 mg: -3.6 kg [-4.3, -2.8], 0.6 mg: -2.2 kg [-2.9, -1.5]); reductions in total insulin dose were significantly larger for liraglutide 1.8 mg and 1.2 mg compared with placebo (estimated treatment ratios: 1.8 mg: 0.92 [0.88, 0.96], 1.2 mg: 0.95 [0.91, 0.99], 0.6 mg: 1.00 [0.96, 1.04]). However, significantly more symptomatic hypoglycaemic episodes were seen in those receiving 1.8 mg liraglutide (77) than for placebo (37), but not for either of the other 2 doses of liraglutide: 1.2 mg (44) or 0.6 mg (54). There were 8 diabetic ketoacidosis episodes (1.8 mg , 1.2 mg , 0.6 mg , placebo ). The most frequently reported adverse events with liraglutide were nausea and vomiting. The authors concluded that liraglutide 1.8 mg and 1.2 mg, as adjunctive therapy to insulin, led to greater reductions in HbA1c, body weight and total insulin dose compared with placebo, but with higher rates of symptomatic hypoglycaemia.
Semaglutide and cardiovascular outcomes in patients with type 2 diabetes
The presentation of this study was one of the highlights of EASD. After publication of study results with liraglutide,2 much was expected of other GLP-1 receptor agonists, particularly with regards to safety and eventual cardiovascular benefit with semaglutide,3 a GLP-1 analogue with an extended half-life of approximately 1 week. The authors randomly assigned 3297 patients with type 2 diabetes (T2D) and on a standard-care regimen to receive either once-weekly semaglutide (0.5 mg or 1.0 mg) or placebo for 104 weeks. The primary composite outcome was the first occurrence of cardiovascular death, nonfatal myocardial infarction or nonfatal stroke. They hypothesized that those treated with semaglutide would not be more likely to reach the primary outcome than those receiving placebo (showing noninferiority). At baseline, 2735 of the patients (83.0%) had established cardiovascular disease, chronic kidney disease, or both.
The primary outcome occurred in 108 of 1648 semaglutide group patients (6.6%) and in 146 of 1649 placebo group patients (8.9%; hazard ratio, 0.74; [0.58, 0.95]; P<0.001 for noninferiority). Nonfatal myocardial infarction occurred less often in patients receiving semaglutide than placebo (2.9% versus 3.9%; hazard ratio, 0.74; [0.51, 1.08]) but this difference was not significant. Nonfatal stroke occurred in 1.6% and 2.7%, respectively (hazard ratio, 0.61; [0.38, 0.99]; P=0.04). Rates of death from cardiovascular causes were similar in the two groups. Rates of new or worsening nephropathy were lower in the semaglutide group, but rates of retinopathy complications (vitreous haemorrhage, blindness, or conditions requiring treatment with an intravitreal agent or photocoagulation) were significantly higher. Although more patients discontinued treatment because of adverse events (mainly gastrointestinal) with semaglutide, fewer serious adverse events occurred compared with placebo. The authors concluded that the rate of cardiovascular death, nonfatal myocardial infarction or nonfatal stroke was significantly lower among patients receiving semaglutide than among those receiving placebo in patients with T2D who were at high cardiovascular risk.
The effect of canagliflozin on renal function decline
The use of sodium-glucose cotransporter 2 (SGLT2) inhibitors for the treatment of patients with T2D is gaining popularity after the results of the EMPA-REG OUTCOME study, which showed a significant reduction in fatal cardiovascular events4 and benefits to renal function with empaglifozin.5 Results on renal function with another SGLT2 inhibitor, canaglifozin, were presented at EASD 2016. Canaglifozin has been shown to decrease HbA1c, body weight, blood pressure and albuminuria, implying that it is renoprotective.6 The aim of this analysis was to determine whether canaglifozin could decrease the urine albumin-to-creatinine ratio (UACR) and slow the estimated glomerular filtration rate (eGFR) decline independently of its glycaemic effects. This was a post-hoc analysis of a phase 3 clinical trial in 1450 patients with T2D, receiving metformin, and randomly assigned to canaglifozin 100 or 300 mg or glimepiride (GLIM) 6 to 8 mg. Patients were followed for 2 years, and study endpoints were the annual change in eGFR and UACR.
The annual eGFR decline was 3.3 ml/min/1.73 m2 [2.8, 3.8] with GLIM, 0.5 ml/min/1.73 m2 [0.0, 1.0] with canaglifozin 100 mg and 0.9 ml/min/1.73 m2 [0.4, 1.4] with canaglifozin 300 mg – a significant difference in annual eGFR decline between treatment with GLIM compared with treatment with either dose of canaglifozin (P<0.01).
In a subgroup of patients with urinary albumin-to-creatinine ratios ≥30 mg/g, there was significantly greater decrease in the ratio with both doses of canaglifozin than with GLIM. Reductions in HbA1c with GLIM, canaglifozin 100 and 300 mg were 0.81%, 0.82% and 0.93% at 1 year and 0.55%, 0.65% and 0.74% at 2 years, respectively. The authors concluded that canaglifozin 100 or 300 mg/day slowed the progression of renal disease compared with GLIM over 2 years. The beneficial effects of canaglifozin appear to be independent of the differences in HbA1c, and suggest that canaglifozin may offer renoprotection in addition to its glycaemic effects.
- Mathieu C, et al. Efficacy and safety of liraglutide added to insulin treatment in type 1 diabetes: The ADJUNCT ONE treat-to-target randomized trial. Diabetes Care. 2016;39:1702–10.
- Marso SP, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375:311–22.
- Marso SP, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016 Sep 15. [Epub ahead of print].
- Zinman B, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117-28.
- Wanner C, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med. 2016;375:323–34.
- Heerspink HJ, et al. Canagliflozin slows progression of renal function decline independently of glycemic effects. J Am Soc Nephrol. 2016 Aug 18. Pii:ASN.2016030278. [Epub ahead of print]