PracticeUpdate: Endocrinology

CONFERENCE COVERAGE

EASD 2016

6

Insulin degludec reduces severe or blood glucose-confirmed hypoglycaemia and is noninferior to insulin glargine in reducing HbA1c in types 1 and 2 diabetes

In the SWITCH 1 and 2 trials, despite similar reductions in haemoglobin A1c, insulin degludec reduced severe or blood glucose-confirmed symptomatic hypoglycaemia compared to insulin glargine in both type 1 and 2 diabetes. These outcomes of the randomised, double- blind, 2 x 32 week, treat-to-target, crossover SWITCH 1 and 2 trials, were reported at the EASD 2016 meeting. SWITCH 1, in type 1 diabetes

glucose-confirmed symptomatic overall and nocturnal hypoglycaemia versus insulin glargine. SWITCH 2, in type 2 diabetes Carol Wysham, MD, of the Rock- wood Center for Diabetes and En- docrinology, Spokane, Washington, explained that SWITCH 2 compared the same parameters as SWITCH 1. Aside from the patient population, SWITCH 2 differed from SWITCH 1 inasmuch as both insulin degludec U100 and insulin glargine U100 were given in combination with pretrial oral antidiabetic drugs. She said, “The study was per- formed to compare the relative risk of hypoglycaemia with insulin degludec versus insulin glargine in a population of patients with type 2 diabetes who were at high risk of hypoglycaemia. This is a popula- tion that would have been largely excluded from previous studies.” A total of 721 adults with type 2 diabetes and at least one factor associated with increased risk of hypoglycaemia received once-daily insulin degludec or insulin glargine followed by crossover to insulin degludec or insulin glargine for 32 weeks (a 16-week titration and a 16-week maintenance period). Pa- tients had been treated with basal insulin with or without oral antidia- betic drugs excluding sulphonylurea/ meglitinides. The primary endpoint was the number of severe or blood

glucose-confirmed (<3.1 mmoL/L) symptomatic hypoglycaemic episodes during the maintenance periods. Treatment with insulin degludec resulted in significantly lower rates of severe or blood glucose-confirmed symptomatic hypoglycaemia and severe or blood glucose-confirmed symptomatic nocturnal hypogly- caemia (00:01–05:59) than insulin glargine in the maintenance and total treatment periods. The proportion of patients experi- encing severe hypoglycaemia in the maintenance periods was 1.6% for insulin degludec vs 2.4% for insulin glargine (difference not significant). The rate of severe hypoglycaemia was significantly lower with insulin degludec than with insulin glargine in the total treatment period. Insulin degludec was noninferior to insulin glargine in haemoglobin A reduction. Adverse event rates were similar with the two agents. Dr Wysham concluded that, com- pared with insulin glargine, insulin degludec resulted in a consistent re- duction in hypoglycaemia in patients with type 2 diabetes at increased risk of hypoglycaemia and was shown to be noninferior to insulin glargine in haemoglobin A reduction. She added, “In clinical practice, the results give us direction in how to treat this population at high risk of morbidity and mortality from hy- poglycaemia”.

both with mealtime insulin aspart, for 32 weeks (a 16-week titration period and a 16-week maintenance period), followed by crossover to insulin degludec or insulin glargine. The primary objective was to con- firm noninferiority in terms of the number of severe or blood glucose- confirmed (<3.1 mmoL/L) symp- tomatic hypoglycaemic episodes during the maintenance periods. Treatment with insulin degludec resulted in an 11%, significantly lower rate of severe or blood glu- cose-confirmed symptomatic hy- poglycaemia than insulin glargine in the maintenance period. Severe

or blood glucose-confirmed symp- tomatic nocturnal hypoglycaemia (00:01–05:59) was also significantly reduced by 36% for insulin degludec versus insulin glargine. Severe hypoglycaemia was signifi- cantly reduced, by 35%more with in- sulin degludec versus insulin glargine. Significant reductions for all three hypoglycaemia categories were also seen for the total treatment periods. In addition, a significantly lower proportion of patients taking insulin degludec experienced severe hypo- glycaemia during both the mainte- nance and total treatment periods than those taking insulin glargine (P = 0.0016). Noninferior reduction in hae- moglobin A1c between insulin de- gludec versus insulin glargine was confirmed in both treatment periods (week 32: 6.95 vs 6.92%; week 64: 6.95 vs 6.97%). The rates of adverse events were similar for insulin deglu- dec and insulin glargine. Dr Lane concluded that in patients with type 1 diabetes at increased risk of experiencing severe hypoglycae- mia, insulin degludec was noninferior in terms of haemoglobinA reduction and significantly reduced the rates and proportions of severe hypogly- caemia and rates of severe or blood

Wendy Lane, MD, of Mountain Diabetes and Endocrine Center, Asheville, North Carolina, explained that SWITCH 1 compared the num- ber of severe or blood glucose-con- firmed, symptomatic hypoglycaemic episodes in patients with type 1 dia- betes treated with insulin degludec U100 versus insulin glargine U100, both in combination with mealtime insulin aspart. Five-hundred one adults with type 1 diabetes and at least one fac- tor associated with increased risk of hypoglycaemia received once-daily insulin degludec or insulin glargine,

Courtesy of EASD 2016

Even in a clinical trial setting, keeping HbA1c at goal for 3 years is difficult Maintaining haemoglobin A1c to goal over 3 years in patients with type 2 diabetes has been shown to be a challenge, even in a clinical trial setting. Reduced haemoglobin A1c and fasting glucose values after 26 weeks of treatment increases a patient’s likelihood of sustaining a haemoglobin A1c <53 mmol/mol (<7%) over 3 years

antibodies, and sulfonylurea use, were not related to sustained response. Dr Trautmann concluded that the analysis demonstrated the difficulty of maintaining haemoglobin A1c to goal over 3 years, even in a clinical trial setting, and suggested that lower haemoglobin A1c and fasting glucose values after 26 weeks of treatment raise a patient’s likelihood of sustaining haemoglobin A1c <53 mmol/mol (<7%) over 3 years with minimal medication changes. Weekly fixed-dose exenatide supported long-term glycaemic control to a greater extent than titrated insulin glargine, though sustained success was achieved with both therapies. Greater response to weekly ex- enatide treatment after 26 weeks raises the likelihood of sustaining glycaemic control over 3 years.

with minimal medication changes. T his conclusion, based on a retrospec- tive analysis of DURATION-3, a 3-year, randomised, open-label trial of exena- tide versus insulin glargine in type 2 diabetes, was presented at the EASD 2016 meeting. M.E. Trautmann, MD, of Diabetes Re- search, Hamburg, Germany, explained that long-term haemoglobin A1c control with minimal medication change is a reasonable goal for patients with type 2 diabetes. Dr Trau- tmann and colleagues analysed 3-year data from the DURATION-3 study retrospectively to characterise patients who sustained a hae- moglobin A1c response to goal (<53 mmol/ mol [7%]) over 3 years. Type 2 diabetic patients taking metformin ± sulfonylurea were randomised to 2 mg sub- cutaneous exenatide once weekly or insulin glargine titrated to a fasting glucose level of 4.0–5.5 mmoL/L). Patients with a sustained response to ther- apy were defined as achieving haemoglobin A1c <53 mmol/mol (<7%) at 26 weeks and maintaining haemoglobinA1c <53 mmol/mol (<7%) for 80% of remaining visits, includ- ing one of two visits in the last 6 months.

Thirty-two potential model parameters were tested iteratively and included if related to sustained success (P < 0.05). The intent-to-treat population was com- posed of 456 patients, of whom 287 (63%) completed 3 years. Of the 287 completers, 175 (61%) had a haemoglobin A1c level <53 mmol/mol (<7%) at 26 weeks. Of completers who reached the haemoglobin A1c goal, 84 (48%) demon- strated sustained control for ≥ 80% of visits over 3 years. Responders with a sustained haemoglobin A1c response were a mean age of 57.7 years, baseline body mass index was 32.2 kg/m 2 . Fifty-percent were males and 81% were white. Their mean baseline and week 26 haemoglo- bin A1c levels were 62 mmol/mol (7.8%) and 44 mmol/mol (6.2%), respectively. Patients unable to sustain goal response were a mean age of 58.6 years and had a baseline body mass index of 32.3 kg/m 2 . Fifty-three percent were male and 92% were white. Their mean baseline and week 26 haemoglobin A1c were 65 mmol/mol (8.1%) and 48 mmol/mol (6.5%), respectively. Among

patients achieving haemoglobinA1c goal con- sistently, significantly more were treated with weekly exenatide (n = 53) than with insulin glargine (n = 31; P = 0.03). Other factors related to sustained treat- ment success included haemoglobin A1c and fasting glucose at 26 weeks. The major- ity of evaluated factors, including age, weight loss, waist-to-hip ratio, titre of anti-exenatide

Courtesy of EASD 2016

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