PracticeUpdate Diabetes Best of 2018

CONFERENCE COVERAGE 26

Diuretics LinkedWith Greater Amputation Risk in Type 2 Diabetes May help explain risk of amputations with SGLT-2 inhibitor in CANVAS. T he use of diuretics among patients with type 2 diabetes is associated with an increased risk of having a lower limb event, particularly one requiring an amputation, according to a presentation made at EASD 2018. “This study was based on the hypothesis that amputation warn- ings found in the CANVAS trial could be driven by the diuretic effect of SGLT-2 inhibitors,” Louis Potier, MD, with Assistance Publique – Hôpitaux de Paris (AP-HP) in France told Elsevier’s PracticeUpdate . “This is, to our knowledge, the first study so far to propose a mechanistic explanation for this unexpected outcome.” For the prospective, observational cohort study known as SURDIAGENE, 1074 patients with type 2 diabetes were enrolled between 2002 and 2012 and followed-up until the onset of lower-limb events, death, or December 31, 2015. The primary outcome measure was the first occurrence of a lower-limb event, defined as a composite of lower-limb ampu- tation and lower-limb revascularization. Patients were divided into those who were using diuretics at baseline and those who were not, with 537 patients in each group. The two groups of patients were matched. The mean age in each group was 65.9 years and 66.3 years, respec- tively. The proportion of males in each group was 57.2% and 57.4%, respectively. During a median follow-up of period of 7.2 years, the incident rate of lower-limb events was 0.81 per 100 patient years among those using diuretics and 0.54 per 100 patient years among non-users. The hazard ratio for lower-limb events in users vs non-users of diuretics was 1.75 (95% CI 1.19–2.58; P = .005). Looking at lower-limb amputation and revasculariation separately revealed that diuretic use was associated with a greater risk of amputations (hazard ratio 2.34; 95% CI 1.35–4.05; P = .003), but not revascularizarions (hazard ratio 1.28; 95% CI 0.82–2.01; P = .28). “In the light of our primary hypothesis of diuretic-induced effect for amputations observed in CANVAS, we assume that volume depletion could lead to hypoperfusion of the dis- tal extremities and then trigger amputations,” said Dr. Potier. “However, this assumption remains speculative; we do not have enough data in our study to support this hypovolemia hypothesis. … Further studies with careful assessment of volemic status are needed to address this question.” He also noted important limitations to the study. Only base- line exposure to diuretics was evaluated without considering duration of therapy or introductions and interruptions of these drugs during the study period. While he recommended that clinical implications be addressed with caution, given the ongoing uncertainty about what drives this observed link, Dr. Potier suggested that, “clinical implica- tions might be to use diuresis-inducing drugs with caution and with careful assessment of the volemia in patients at highest risk of amputations (ie, those with peripheral arterial disease or foot ulcers).” www.practiceupdate.com/c/74331

PIONEER Shows Safety and Efficacy of Oral Formulation GLP-1 Receptor Agonist Investigational drug also stimulates weight loss T he first GLP-1 receptor agonist that can be taken as an oral tablet safely and effectively reduces HbA1c when used as monotherapy in treatment-naïve patients with type 2 diabetes. This is the main finding of the PIONEER 1 trial presented at EASD 2018. Semaglutide is a GLP-1 receptor agonist under late-stage investigation for the treatment of type 2 diabetes. Unlike currently available GLP-1 receptor agonists, it is taken in the form of an oral tablet instead of via subcutaneous injection. For the PIONEER trial, 703 patients with type 2 diabetes that was not controlled with diet and exercise were randomized to 3, 7, or 14 mg of semaglutide taken once daily or a placebo. None of the patients had ever been previously prescribed medication for their diabetes. Baseline characteristics were balanced among the treatment groups, with about 49% of patients female, a mean age of 55 years, and mean duration of diabetes of 3.5 years. The primary endpoint of the trial was a change from baseline in HbA1c at 26 weeks. Effectiveness was evaluated regardless of trial product discontinuation or rescue medication use. The trial was supported by Novo Nordisk, manufacturers of semaglutide. Treatment with oral semaglutide resulted in clinically meaningful reductions in both HbA1c and body weight at all doses at week 26. Reductions in HbA1c (% points ± standard error) from baseline were -0.9 ± 1 on the 3 mg dose, -1.2 ± 0.1 on the 7 mg dose, and 1.4 ± 0.1 on the 14 mg dose, compared with 0.3 ± 0.1 on placebo. Reductions in weight (kg ± standard error) from baseline were -1.5 ±0.3 with the 3 mg dose, -2.3 ± 0.4 with the 7 mg dose, and -3.7 ± 0.3 with the 14 mg dose. Weight loss on placebo was -1.4 ± 0.3. Adverse events occurred in 58% of patients on the 3 mg dose, 53% on the 7 mg dose, and 57% on the 14mg dose. The rate of adverse events in all three groups was similar to the 56% rate of adverse events reported in the placebo group. The most common adverse was transient mild or moderate nausea. The rate of nausea was 5% to 16% among those taking semaglutide and 6% among those on placebo. Presenter Martin Haluzík, MD, PhD, of the Institute for Clinical and Experi- mental Medicine in Prague, CzechRepublic, toldElsevier’s PracticeUpdate that for the patient population used in this trial, metformin would usually be the first treatment choice. “The results suggest that the efficacy and safety of oral semaglutidemay eventually place it on the very early stages of the type 2 diabetes treatment algorithm and confirm its good safety and tolerability. In fact, the magnitude of reduction in HbA1 we have seen with the highest dose of semaglutide in PIONEER 1 (approximately 1.5 %) is something that has, in this patient population, never been reportedwith any other oral antidiabetic agent. “The availability of an oral medication with efficacy and safety com- parable or better than that of most effective injectables can certainly affect current treatment algorithms,” he added. “From the patients´ perspective, taking a pill is always much easier than to inject any med- ication. I would expect better compliance that may translate to better long-term efficacy and possibly the use in the very early stages of diabetes treatment.” Still, pointed out Dr. Haluzík, the study has its limitations. These include a relatively short follow-up period and a lack of an active control arm. “We need a trial directly comparing oral semaglutide with metformin in patients with newly diagnosed type 2 diabetes,” he said. www.practiceupdate.com/c/74335

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