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Reply to Qayyum et al.
Submit responseA reply by Novo Nordisk:
We would like to congratulate the authors of the recent systematic review entitled ‘Comparative Effectiveness, Safety, and Indications of Insulin Analogues in Premixed Formulations for Adults With Type 2 Diabetes' published in Annals of Internal Medicine. As a company with an interest in improving the treatment of patients with diabetes, Novo Nordisk welcomes systematic reviews that will equip physicians with the important information needed to best treat their patients. We would like to draw readers’ attention, however, to one of the conclusions of the review regarding premixed insulin analogues: “Premixed insulin analogues (insulin aspart 70/30, insulin lispro 75/25, and insulin lispro 50/50) were similar to premixed human insulin preparations in terms of the incidence of hypoglycemia.” Whilst this statement is correct regarding minor hypoglycaemia, this conclusion is inaccurate with regard to the incidence of major and nocturnal hypoglycaemia. Therefore, we would like comment briefly on this point, and in doing so will focus on biphasic insulin aspart 70/30 (BIAsp 30) as we are fully conversant with the clinical data concerning this product. We acknowledge that many of the principles apply equally to insulin lispro mix 75/25.
Hypoglycaemia is a key barrier to treatment success (Murata, 2004), with major and nocturnal hypoglycaemia especially important due to the potential dangers they represent. Hence, it is essential to distinguish any treatment differences or advantages that emerge between treatments with premixed insulin analogues and premixed human insulins (BHI). The improved safety profile of BIAsp 30 has been consistently shown in the literature and is illustrated in the study by Boehm et al. (2004) included in the systematic review in question. The authors reported that although the proportion of patients experiencing major hypoglycaemia was similar during the first year of the study, it was significantly lower with BIAsp 30 than with BHI 30 during the second year, in fact no episodes of major hypoglycaemia were reported during BIAsp 30 therapy (BIAsp 30, 0%; BHI 30, 10%; p=0.04). Furthermore, in the first 3 months of the study (Boehm et al., 2002), half as many episodes of major hypoglycaemia were reported with BIAsp 30 than with BHI 30.
In addition, it has been shown by continuous glucose monitoring that rates of interstitial glucose (IG; related to blood glucose levels) below 3.5 and 2.5 mmol/l at night may be double those during the day in patients with type 2 diabetes treated with BIAsp 30 or BHI 30 (McNally et al. 2007). This finding is contrary to the general perception, based on self-reported data, that nocturnal hypoglycaemia is uncommon in patients with type 2 diabetes. Furthermore, McNally et al. (2007) showed that patients using BIAsp 30 experienced significantly fewer nocturnal episodes of IG <3.5 mmol/l than patients using BHI 30 (1.18 vs. 1.62, p=0.011). Also, the percentage of time patients spent with IG <3.5 mmol/l at night was significantly lower for the BIAsp 30 group (6.4 vs. 7.9%, p=0.018), as was self-reported, symptomatic, nocturnal hypoglycaemia.
Further evidence of the improved safety profile of BIAsp 30 over BHI comes from a meta-analysis of nine randomised controlled trials comparing the risk of hypoglycaemia associated with BIAsp 30 and BHI 30 (Davidson et al., 2008). BIAsp 30 was associated with a significantly lower risk of major and nocturnal hypoglycaemia when compared with BHI 30 (major OR, 0.45 [0.22; 0.93], p<0.05; nocturnal RR, 0.50, 95% CI [0.38; 0.67], p<0.01) without compromising HbA1c.
From the evidence outlined above, it is apparent that BIAsp 30 offers a significantly reduced risk of major and nocturnal hypoglycaemia compared with BHI 30, without compromising overall glycaemic control. We feel strongly that the statements regarding hypoglycaemia associated with premixed insulins in the review by Qayyum et al. (2008) are too general and do not reflect the published data highlighted above.
References
1. Boehm B, Home P, Behrend C, Kamp N, Lindholm A. Premixed insulin aspart 30 versus premixed human insulin 30/70 twice daily: a randomized trial in type 1 and type 2 diabetic patients. Diabet Med 2002;19(5):393–399.
2. Boehm BO, Vaz JA, Brøndsted L, Home PD. Long-term efficacy and safety of biphasic insulin aspart 30 in type 2 diabetes. Eur J Intern Med 2004;15(8):496–502.
3. Davidson J, Christiansen JS, Brown P, Gylvin T, Kawamori R. Biphasic insulin aspart has a lower risk of hypoglycemia than biphasic human insulin without compromising glycemic control: a meta-analysis of randomized controlled trials. Diabetes 2008; 57 (Suppl. 1):A590–A591 (2138 -PO).
4. McNally P, Dean J, Morris A, Wilkinson P, Compion G, Heller S. Using continuous glucose monitoring to measure the frequency of low glucose values when using biphasic insulin aspart 30 compared with biphasic human insulin 30: a double-blind crossover study in individuals with type 2 diabetes. Diabetes Care 2007;30(5):1044–1048.
5. Murata GH, Duckworth WC, Hoffman RM, Wendel CS, Mohler MJ, Shah JH. Hypoglycemia in type 2 diabetes: a critical review. Biomed Pharmacother 2004;58(10):551–559.
Conflict of Interest:
The authors are employed by Novo Nordisk.