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Congress Report: 17th American Diabetes Association (ADA) meeting

Congress Report: 17th American Diabetes Association (ADA) meeting
  • Cardiometabolic
  • Diabetes

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Article

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International meeting
type 1 diabetes
Type 2 diabetes
cardiovascular disease

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Practical

Highlights from the 17th American Diabetes Association (ADA) meeting, San Diego, USA, 9–13 June, 2017

One of the highlights of the American Diabetes Association (ADA) conference 2017 was the presentation of results from several studies of diabetes medications including the insulin degludec DEVOTE study,1 canagliflozin in the CANVAS program,2 sodium-glucose co-transporter-2 (SGLT2)-inhibitors in the CVD REAL study3 and metformin in the REMOVAL study.4


The DEVOTE study, comparing the cardiovascular (CV) safety of insulins degludec and glargine in patients with type 2 diabetes (T2D) at high risk of cardiovascular events, were reported by a number of investigators and were simultaneously published in the New England Journal of Medicine.1

In the trial, 7637 patients with T2D were randomized to receive either degludec (n=3818) or glargine U100 (n=3819) once daily between dinner and bedtime in a double-blind, treat-to-target fashion. Of the patients in DEVOTE, 85.2% had established CV disease, chronic kidney disease, or both. Mean age was 65 years, the mean duration of diabetes was 16.4 years, and mean HbA1c was 8.4%. The primary composite outcome was the first occurrence of an adjudicated major CV event (death from CV causes, nonfatal myocardial infarction or nonfatal stroke). Severe hypoglycaemia, as defined by the ADA, was the prespecified secondary outcome. 

The primary outcome occurred in 325 patients (8.5%) in the degludec group and in 356 (9.3%) in the glargine group (hazard ratio, 0.91; 95% CI: 0.78, 1.06; P<0.001 for noninferiority). At 2 years, the mean HbA1c was 7.5% in each group, but the mean fasting plasma glucose level was significantly lower in the degludec group than in the glargine group (128 vs 136 mg/dL; P<0.001). Severe hypoglycaemia occurred in 187 patients (4.9%) in the degludec group and in 252 (6.6%) in the glargine group, for an absolute difference of 1.7 percentage points (rate ratio 0.60; P<0.001 for superiority). Rates of adverse events did not differ between the two groups. 

Commentators on the trial at ADA included Elizabeth R Seaquist, MD, (Minnesota, USA), who said there remained some unanswered questions from the DEVOTE trial. For example, "data on moderate hypoglycaemia were not collected, so the impact on the most common type of hypoglycaemia experienced by patients cannot be addressed," and data were not collated on events when blood glucose was 54 mg/dL (3 mmol/L) or lower, so the impact on the development of impaired awareness of hypoglycaemia could not be assessed. Investigators in DEVOTE could modify the titration process based on clinical judgment, but "it isn't clear if this modification process was applied equally in both arms." Any differential application of this process could have affected the hypoglycaemia outcomes.

Combined results from the Canagliflozin Cardiovascular Assessment Study (CANVAS) and the CANVAS renal-end-points trial (CANVAS-R) were presented by a number of investigators and were simultaneously published in the New England Journal of Medicine.2 The CANVAS program combined data from both trials, CANVAS and CANVAS-R, involving a total of 10,142 patients with T2D and high CV risk. The CANVAS patients were randomized 1:1:1 to canagliflozin 300 mg or 100 mg or placebo, and the CANVAS-R patients to 100 mg (with option to increase to 300 mg after week 13) or placebo. Mean follow-up was 188 weeks (median, 126.1 weeks). Unlike Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG) and Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results—A Long Term Evaluation (LEADER), in which all subjects had established CV disease, in CANVAS only two-thirds of patients had established CV disease.

The lead investigator, Professor Bruce Neal (Sydney, Australia) presented an analysis indicating that use of canagliflozin reduced the risk of major CV adverse events (MACE) per 1000 patients over 5 years by 23, risk of hospitalization for heart failure by 17 per 1000, and renal events by 16 per 1000. These data represent the second time CV benefits have been demonstrated in a US Food and Drug Administration (FDA)-mandated CV outcomes trial for an SGLT2-inhibitor, with the first being the landmark EMPA-REG OUTCOME, which demonstrated a major reduction in both all-cause and CV death among high-risk patients taking empagliflozin.

However, the CANVAS data also revealed a significant doubling in the risk for amputations, primarily of the toe or metatarsal (6.3 vs 3.4 cases per 1000 patient years; hazard ratio, 1.97). That risk, already identified, led to a boxed warning for canagliflozin from the FDA, and a warning on the labels of all SGLT2-inhibitors by the European Medicines Agency. In addition, CV death was not significantly reduced in CANVAS, as it was in both EMPA-REG and the LEADER trial of the glucagon-like peptide-1 (GLP-1) agonist, liraglutide.

A new evaluation reported by Matthew Cavender, MD, (North Carolina, USA) of the observational CVD REAL study of patients with T2D starting on SGLT2-inhibitors, analysing outcomes according to the baseline CV disease status of the participants, found benefit on all-cause mortality at 8 months in both patients receiving a SGLT2-inhibitor or another glucose-lowering drug.3 Those with CV disease and taking a SGLT2-inhibitor had a 53% reduced risk of all-cause mortality at 8 months compared with patients who were started on another glucose-lowering drug. Similarly, those without CV disease (87% of the study population) who were initiated on an SGLT2-inhibitor had a 46% lower risk of this outcome. In addition, all the patients who took SGLT2-inhibitors were significantly less likely to be hospitalized for heart failure, again with benefit seen in those without CV disease at baseline. The findings hint at a possible benefit of this drug class in the primary prevention of CV disease in those with T2D.

Invited to comment, Jay H Shubrook, DO (Vallejo, USA), a family physician and diabetologist, agreed that it was "a little surprising to see that much of a difference" in mortality benefit in such a short time, unless there were a difference in baseline characteristics between those taking SGLT2-inhibitors and other glucose-lowering agents.

The REMOVAL trial (Reducing with Metformin Vascular Adverse Lesions) was presented by its lead investigator John R Petrie, MD, PhD (Glasgow, Scotland) and simultaneously published in Lancet Diabetes and Endocrinology.4 

This multicenter trial randomized 428 adults aged ≥40 years with type 1 diabetes and increased CV risk to daily metformin 1000 mg twice daily or placebo as adjuncts to insulin. All patients in REMOVAL had at least three of 10 specified CV disease risk factors, including BMI ≥27 kg/m2, HbA1c >8.0%, strong family history of CV disease, and/or current smoker. Mean patient age was 55.5 years, diabetes duration was 33.8 years, HbA1c was 8.05% and BMI 28.5 kg/m2. About a third were using insulin pumps. Their mean blood pressure was 130/72 mm Hg and LDL cholesterol was 2.2 mmol/L, with 73% and 82%, respectively, on antihypertensives and statins.

After a 3-month optimization phase, patients were randomized to receive 1000 mg of oral metformin or placebo twice daily, in combination with titrated insulin therapy for 36 months. The primary outcome, the difference in mean within-person cIMT slopes (metformin relative to placebo) was -0.005 mm per year, non-significantly in favor of metformin (P=0.167). Prespecified sensitivity analyses showed similar results, but a tertiary outcome, averaged maximal cIMT, did show a slower progression over time with metformin (difference in slope -0.013 mm/year, P=0.0093).

HbA1c levels were significantly reduced by metformin at 3 years (-0.13%, P=0.006), but this was entirely due to a drop within the first 3 months (-0.24%, P<0.0001) and not thereafter. There was no reduction in average insulin dose requirement over the 3 years         (-0.005 units/kg, P=0.5450). However, metformin did significantly reduce body weight (-1.17 kg, P<0.0001) and LDL cholesterol (-0.13 mmol/L, P=0.0117).

There were no differences in the incidence of major or minor hypoglycaemia. Vitamin B12 deficiency was more common with metformin (12% vs 5%, P=0.0094), but there were no cases of lactic acidosis. There were five and two deaths in the metformin and placebo groups, respectively, but none were deemed treatment-related.

In an editorial accompanying the trial report in Lancet Diabetes and Endocrinology, Eberhard Standl (Neuherberg, Germany), stated "The findings from REMOVAL do not necessarily mean removal of metformin from use in type 1 diabetes, but the primary core question of whether metformin has a practically relevant role in the treatment of (specific) patients with type 1 diabetes has yet to be substantiated. Nevertheless, for patients with type 1 diabetes currently being exposed to experimental metformin therapy, it is helpful that REMOVAL did not show an increased risk for minor or major hypoglycaemia, but rather suggested the need for regular monitoring for vitamin B12 deficiency."


References

  1. Marso SP, et al.  Efficacy and safety of degludec versus glargine in type 2 diabetes.  Published on line June 12, 2017 at NEJM.org
  2. Neal B, et al.  Canagliflozin and cardiovascular and renal events in type 2 diabetes.  Published on line June 12, 2017 at NEJM.org
  3. Cavender MA.  Hospitalization for heart failure and death in new users of SGLT2 inhibitors in patients with and without cardiovascular disease: CVD REAL Study.  American Diabetes Association 2017 Scientific Sessions. June 13, 2016; San Diego, California. Abstract 377-OR
  4. Petrie JR, et al.  Cardiovascular and metabolic effects of metformin in patients with type 1 diabetes (REMOVAL): a double-blind, randomized, placebo-controlled trial.  Published online June 11, 2017 at Lancet Diabetes Endocrinol.

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