Insulin degludec reduces rate of hypoglycaemic episodes

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Treatment with the insulin degludec compared to glargine U100 for 32 weeks resulted in a reduced rate of hypoglycaemic (low blood sugar) episodes among patients with type 1 or 2 diabetes and at least one risk factor for hypoglycaemia, according to two studies.

In one study, Dr Wendy Lane, of Mountain Diabetes and Endocrine Centre, Asheville, North Carolina, and colleagues randomly assigned 501 adults with type 1 diabetes and at least one hypoglycemia risk factor to receive once-daily insulin degludec followed by insulin glargine U100 (n = 249) or to receive insulin glargine U100 followed by insulin degludec (n = 252) for two 32-week treatment periods. The patients were randomised to morning or evening dosing within each treatment sequence.

Hypoglycemia, common in patients with type 1 diabetes, is a major barrier to achieving good glycemic control. Severe hypoglycemia can lead to coma or death.

Of the patients randomised, 395 (79%) completed the trial. The researchers found that insulin degludec compared with insulin glargine U100 resulted in lower rates of overall symptomatic hypoglycemic episodes and nocturnal symptomatic hypoglycemia in the 16-week maintenance period and a lower proportion experienced severe hypoglycemia during the maintenance period (10% vs 17%). The findings were consistent when analyzed over the full 32-week treatment period.

A limitation of the study, the higher-than-expected withdrawal rate, may have been a result of the demanding nature of the trial, including its 64-week duration, two different treatments, and the use of a vial and syringe.

In another study, Dr Carol Wysham, of the University of Washington School of Medicine, Spokane, and colleagues randomly assigned 721 adults with type 2 diabetes and at least one hypoglycemia risk factor who were previously treated with basal insulin with or without oral antidiabetic drugs to receive once-daily insulin degludec followed by insulin glargine U100 (n = 361) or to receive insulin glargine U100 followed by insulin degludec (n = 360), and were randomized to morning or evening dosing within each treatment sequence. The trial included two 32-week treatment periods. Hypoglycemia is a serious risk for insulin-treated patients with type 2 diabetes.

Of the randomised patients, 580 (80%) completed the trial. The researchers found that treatment with insulin degludec compared with insulin glargine U100 resulted in a statistically significant and clinically meaningful reduction in the rate of overall symptomatic hypoglycemia and nocturnal symptomatic hypoglycemia during the 16-week maintenance period. The hypoglycemia findings were consistent when analyzed over the full treatment period, and they showed a significantly lower rate of severe hypoglycemia with insulin degludec. The proportion of patients experiencing severe hypoglycemia during the maintenance period were 1.6 percent for insulin degludec vs 2.4 percent for insulin glargine U100.

Limitations of the study are noted in the article.

Abstract 1
Importance: Hypoglycemia, common in patients with type 1 diabetes, is a major barrier to achieving good glycemic control. Severe hypoglycemia can lead to coma or death.
Objective: To determine whether insulin degludec is noninferior or superior to insulin glargine U100 in reducing the rate of symptomatic hypoglycemic episodes.
Design, Setting, and Participants: Double-blind, randomized, crossover noninferiority trial involving 501 adults with at least 1 hypoglycemia risk factor treated at 84 US and 6 Polish centers (January 2014-January 12, 2016) for two 32-week treatment periods, each with a 16-week titration and a 16-week maintenance period.
Interventions: Patients were randomized 1:1 to receive once-daily insulin degludec followed by insulin glargine U100 (n = 249) or to receive insulin glargine U100 followed by insulin degludec (n = 252) and randomized 1:1 to morning or evening dosing within each treatment sequence.
Main Outcomes and Measures: The primary end point was the rate of overall severe or blood glucose-confirmed ( Results: Of the 501 patients randomized (mean age, 45.9 years; 53.7% men), 395 (78.8%) completed the trial. During the maintenance period, the rates of overall symptomatic hypoglycemia were 2200.9 episodes per 100 person-years’ exposure (PYE) in the insulin degludec group vs 2462.7 episodes per 100 PYE in the insulin glargine U100 group for a rate ratio (RR) of 0.89 (95% CI, 0.85-0.94; P < .001 for noninferiority; P < .001 for superiority; rate difference, −130.31 episodes per 100 PYE; 95% CI, −193.5 to −67.16). The rates of nocturnal symptomatic hypoglycemia were 277.1 per 100 PYE in the insulin degludec group vs 428.6 episodes per 100 PYE in the insulin glargine U100 group, for an RR of 0.64 (95% CI, 0.56-0.73; P < .001 for noninferiority; P < .001 for superiority; rate difference, −61.94 episodes per 100 PYE; 95% CI, −83.85 to −40.03). A lower proportion of patients in the insulin degludec than in the insulin glargine U100 group experienced severe hypoglycemia during the maintenance period (10.3%, 95% CI, 7.3%-13.3% vs 17.1%, 95% CI, 13.4%-20.8%, respectively; McNemar P = .002; risk difference, −6.8%; 95% CI, −10.8% to −2.7%).
Conclusions and Relevance: Among patients with type 1 diabetes and at least 1 risk factor for hypoglycemia, 32 weeks’ treatment with insulin degludec vs insulin glargine U100 resulted in a reduced rate of overall symptomatic hypoglycemic episodes.

Authors
Wendy Lane, Timothy S. Bailey, Gregg Gerety, Janusz Gumprecht, Athena Philis-Tsimikas, Charlotte Thim Hansen, Thor S. S. Nielsen, Mark Warren

Abstract 2
Importance: Hypoglycemia, a serious risk for insulin-treated patients with type 2 diabetes, negatively affects glycemic control.
Objective: To test whether treatment with basal insulin degludec is associated with a lower rate of hypoglycemia compared with insulin glargine U100 in patients with type 2 diabetes.
Design, Setting, and Participants: Randomized, double-blind, treat-to-target crossover trial including two 32-week treatment periods, each with a 16-week titration period and a 16-week maintenance period. The trial was conducted at 152 US centers between January 2014 and December 2015 in 721 adults with type 2 diabetes and at least 1 hypoglycemia risk factor who were previously treated with basal insulin with or without oral antidiabetic drugs.
Interventions: Patients were randomized 1:1 to receive once-daily insulin degludec followed by insulin glargine U100 (n = 361) or to receive insulin glargine U100 followed by insulin degludec (n = 360) and randomized 1:1 to morning or evening dosing within each treatment sequence.
Main Outcomes and Measures: The primary end point was the rate of overall symptomatic hypoglycemic episodes (severe or blood glucose confirmed [ Results: Of the 721 patients randomized (mean [SD] age, 61.4 [10.5] years; 53.1% male), 580 (80.4%) completed the trial. During the maintenance period, the rates of overall symptomatic hypoglycemia for insulin degludec vs insulin glargine U100 were 185.6 vs 265.4 episodes per 100 patient-years of exposure (PYE) (rate ratio = 0.70 [95% CI, 0.61-0.80]; P < .001; difference, −23.66 episodes/100 PYE [95% CI, −33.98 to −13.33]), and the proportions of patients with hypoglycemic episodes were 22.5% vs 31.6% (difference, −9.1% [95% CI, −13.1% to −5.0%]). The rates of nocturnal symptomatic hypoglycemia with insulin degludec vs insulin glargine U100 were 55.2 vs 93.6 episodes/100 PYE (rate ratio = 0.58 [95% CI, 0.46-0.74]; P < .001; difference, −7.41 episodes/100 PYE [95% CI, −11.98 to −2.85]), and the proportions of patients with hypoglycemic episodes were 9.7% vs 14.7% (difference, −5.1% [95% CI, −8.1% to −2.0%]). The proportions of patients experiencing severe hypoglycemia during the maintenance period were 1.6% (95% CI, 0.6%-2.7%) for insulin degludec vs 2.4% (95% CI, 1.1%-3.7%) for insulin glargine U100 (McNemar P = .35; risk difference, −0.8% [95% CI, −2.2% to 0.5%]). Statistically significant reductions in overall and nocturnal symptomatic hypoglycemia for insulin degludec vs insulin glargine U100 were also seen for the full treatment period.
Conclusions and Relevance: Among patients with type 2 diabetes treated with insulin and with at least 1 hypoglycemia risk factor, 32 weeks’ treatment with insulin degludec vs insulin glargine U100 resulted in a reduced rate of overall symptomatic hypoglycemia.

Authors
Carol Wysham, Anuj Bhargava, Louis Chaykin, Raymond de la Rosa, Yehuda Handelsman, Lone N. Troelsen, Kajsa Kvist, Paul Norwood

JAMA material
JAMA abstract
JAMA abstract 2


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