Comment

Severe hypoglycaemia is feared by many patients with type 1 diabetes, and is a major obstacle in the achievement of good glycaemic control.1,2 Accordingly, any measure that decreases the rate of severe hypoglycaemia has the potential to improve the quality of life in patients at risk for such episodes. In The Lancet Diabetes & Endocrinology, Ulrik Pedersen-Bjergaard and colleagues report the outcomes of the HypoAna trial,3 which aimed to test whether insulin analogues reduce the frequency of severe hypoglycaemia when compared with human insulin in patients with a history of recurrent hypoglycaemia.3 The 2-year study was an investigator-initiated, multicentre, prospective, randomised, open-label, blinded-endpoint trial with a crossover design. Current strategies for management of patients with recurrent hypoglycaemia are based on structured patient education, use of insulin pumps, and continuous glucose monitoring;4 the role of insulin analogues in the management of hypoglycaemia has remained controversial. A 2006 meta-analysis5 concluded that the overall frequency of hypoglycaemia in patients receiving short-acting analogues was no different to that in patients receiving regular human insulin. That analysis reported a reduction of 52% in the incidence of severe hypoglycaemia with short-acting insulin analogues compared with human insulin; however, that outcome was heavily based on the inclusion of one study6 with a very short duration. Results of earlier trials7,8 suggest that the use of insulin detemir as the basal insulin in patients receiving several daily insulin injections reduces the rate of nocturnal hypoglycaemia. Furthermore, a 2009 meta-analysis9 provided evidence that the use of long-acting insulin analogues decreases the rate of severe hypoglycaemia and nocturnal hypoglycaemia in patients with type 1 diabetes, when compared with neutral protamine Hagedorn insulin. A British study10 also showed that the combination of insulin glargine and insulin lispro reduced the rate of nocturnal hypoglycaemia by 44% when compared with unmodified human insulin in a trial with a similar crossover design to the HypoAna trial.3 A common drawback in most previous trials has been that the rate of severe hypoglycaemia has been low, and therefore the studies have been underpowered to

address the effect of the intervention on the frequency of severe hypoglycaemia. The HypoAna trial3 tried to avoid that pitfall by recruiting only patients with recurrent severe hypoglycaemia. The sample size estimate in the study protocol was 370 patients, assuming a 15% reduction in the rate of severe hypoglycaemia in the analogue group, a power of 80%, a confidence level of 95%, and a drop-out rate of 15%. However, the steering committee decided to terminate recruitment after the initially planned recruitment period had been exceeded by 18 months. At that time, the investigators had enrolled only 159 eligible patients despite an extensive recruitment effort that included mailing a questionnaire to more than 6000 patients with type 1 diabetes, which shows that recruitment of patients with recurrent severe hypoglycaemia is a real challenge. The HypoAna trial3 showed that treatment with insulin analogues resulted in an absolute rate reduction of 0·51 episodes (95% CI 0·19–0·84) per patient-year and a relative rate reduction of 29% (95% CI 11–48; p=0·010) in the intention-to-treat population, which is a statistically significant and clinically meaningful reduction. The discrepancy in the frequency of severe hypoglycaemic episodes between the two treatments seemed to be greater during the night (2300–0700 h). Additionally, a slight improvement in glycaemic control in patients receiving analogue treatment was reported during the maintenance periods, with a decrease in HbA1c of 0·13% (95% CI 0·02–0·24; p=0·020) compared with human insulin. The number needed to treat with insulin analogues to avoid one episode of severe hypoglycaemia was two patients in 1 year. The randomly assigned patients had a mean of 5·8 episodes (SD 6·5) of severe hypoglycaemia during the year preceding the study, whereas the rate was reduced to 1·6 episodes (SD 2·1) per patient-year during the study period. This result implies a strong study effect, and includes the effect of increased attention and more frequent self-monitoring. Some issues have not yet been addressed—eg, the investigators do not discuss why, and by which mechanisms, treatment with insulin analogues decreases the frequency of severe hypoglycaemic episodes. Similarly, they do not comment on why patients receiving insulin analogues seemed to have a higher number of

www.thelancet.com/diabetes-endocrinology Published online May 2, 2014 http://dx.doi.org/10.1016/S2213-8587(14)70105-6

Jolyot, BSIP/Science Photo Library

Insulin analogues for recurrent severe hypoglycaemia

Lancet Diabetes Endocrinol 2014 Published Online May 2, 2014 http://dx.doi.org/10.1016/ S2213-8587(14)70105-6 See Online/Articles http://dx.doi.org/10.1016/ S2213-8587(14)70073-7

1

Comment

severe hypoglycaemic episodes during the evening (1900–2300 h) than did those receiving human insulin. No information is provided about possible changes in weight or BMI during the treatments. The results of the HypoAna trial3 show that treatment with insulin analogues decreases the rate of severe hypoglycaemic episodes in patients with type 1 diabetes who are prone to such episodes. However, the effect is individual, because although nearly 40% of the patients seemed to benefit from treatment with insulin analogues, around 20% seemed to have fewer severe hypoglycaemic events while receiving human insulin, and the rate of events seemed to be similar with either insulin treatment in the remaining patients. These findings provide further evidence for the inclusion of insulin analogues as one of several therapeutic options for managing patients with type 1 diabetes and recurrent severe hypoglycaemia.

I declare no competing interests. 1

2 3

4 5

6

7

8

9

Mikael Knip Children’s Hospital and Diabetes and Obesity Research Program, University of Helsinki and Helsinki University Hospital, Helsinki, Finland mikael.knip@helsinki.fi

2

10

Banck-Petersen P, Larsen T, Pedersen-Bjergaard U, Bie-Olsen L, Høi-Hansen T, Thorsteinsson B. Concerns about hypoglycaemia and late complications in patients with insulin-treated diabetes. Eur Diabetes Nurs 2007; 4: 113–18. Cryer PE. Hypoglycemia is the limiting factor in the management of diabetes. Diabetes Metab Res Rev 1999; 15: 42–46. Pedersen-Bjergaard U, Kristensen PL, Beck-Nielsen H, et al. Effect of insulin analogues on risk of severe hypoglycaemia in patients with type 1 diabetes prone to recurrent severe hypoglycaemia (HypoAna trial): a prospective, randomised, open-label, blinded-endpoint crossover trial. Lancet Diabetes Endocrinol 2014; published online May 2. http://dx.doi. org/10.1016/S2213-8587(14)70073-7. Choudhary P, Amiel SA. Hypoglycaemia: current management and controversies. Postgrad Med J 2011; 87: 298–306. Siebenhofer A, Plank J, Berghold A, et al. Short acting insulin analogues versus regular human insulin in patients with diabetes mellitus. Cochrane Database Syst Rev 2006; 2: CD003287. Home PD, Lindholm A, Hylleberg B, Round P. Improved glycemic control with insulin aspart: a multicenter randomized double-blind crossover trial in type 1 diabetic patients. Diabetes Care 1998; 21: 1904–09. Home P, Bartley P, Russell-Jones D, et al. Insulin detemir offers improved glycemic control compared with NPH insulin in people with type 1 diabetes: a randomized clinical trial. Diabetes Care 2004; 27: 1081–87. De Leeuw I, Vague P, Selam JL, et al. Insulin detemir used in basal-bolus therapy in people with type 1 diabetes is associated with a lower risk of nocturnal hypoglycaemia and less weight gain over 12 months in comparison to NPH insulin. Diabetes Obes Metab 2005; 7: 73–82. Ashwell SG, Amiel SA, Bilous RW, et al. Improved glycaemic control with insulin glargine plus insulin lispro: a multicentre, randomized, cross-over trial in people with type 1 diabetes. Diabet Med 2006; 23: 285–92. Monami M, Marchionni N, Mannucci E. Long-acting insulin analogues vs. NPH human insulin in type 1 diabetes: a meta-analysis. Diabetes Obes Metab 2009; 11: 372–78.

www.thelancet.com/diabetes-endocrinology Published online May 2, 2014 http://dx.doi.org/10.1016/S2213-8587(14)70105-6

Insulin analogues for recurrent severe hypoglycaemia.

Insulin analogues for recurrent severe hypoglycaemia. - PDF Download Free
129KB Sizes 0 Downloads 3 Views