Is Degludec the Insulin of Tomorrow?

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1 5 : 6 Nihal Thomas, Ron Thomas Varghese, Vellore Abstract In an effort to develop better basal insulin with a profile that may cause less hypoglycaemia, ludec an analogue with a decanoic acid side chain involved. Like Detemir and Liraglutide it binds to albumin in the subcutaneous tissue and blood. It forms multimers which break down slowly, thereby leading to a gradual release. ludec is more long acting than the current long acting insulins that are present in the market and therefore from phase 2 and phase 3 trials appear to have a better 24 hour profile with a hypoglycemic profile which is comparable. In combination with short acting insulin, ludec plus (IAsp) can be used on a once daily basis at night to control sugars reasonably well with better control of postprandial sugars when compared to Glargine arm in phase 2 studies. Introduction The advent of Insulin was a landmark in the treatment of Diabetes Mellitus. The change in therapeutic policy from Porcine and Bovine insulin to Human Insulin, through the process of genetic engineering, was able to tackle many adverse effects of animal related insulin which included including hypersensitivity and lipoatrophy. Research advances in this field had seen the entry of intermediate and long acting insulins into the market. The human body secretes basal insulin and bouts of bolus insulin after each meal. The intermediate and long acting insulins were used as an attempt to mimic this physiologic basal-bolus regimen. However they have not been able to achieve this effect with a similar impact in a number of patients. The reason for this is that most of the longer acting exogenous insulins have a peak effect in contrast to the peak-less action of endogenous basal insulin.in addition, many of them precipitated hypoglycemia due to their delayed peak effect. Drugs initially used in an attempt to maximize the basal impact including Ultralente were also unable to withstand the test of time and have been withdrawn from the market, since hypoglycaemia was a major problem. Glargine was initially thought to be a peak less insulin; however some recent studies seem to suggest that this is not entirely the case. With this backdrop we like to discuss the possibility of Insulin ludec as a long acting insulin analogue. Factors that warrant better long acting insulin The benefits for the patient on ideal long acting insulin include the ability to achieve a more physiological control of blood glucose and thereby achieve fewer side effects which include hypoglycemia. Many patients and physicians are often reluctant to start or intensify insulin therapy because of a perceived fear of painful injections, hypoglycemia, weight gain, impairment of quality of life, complexity of insulin regimens, and drug costs. 1 Studies have also suggested that hypoglycemia is more common with insulin when compared to sulphonylureas especially in those subjects with a prolonged duration of diabetes (Figure 1). Therefore, a thrice weekly regimen is more likely to improve the compliance and improve the control with better HbA1c levels, subsequently preventing micro vascular complications on the long run. Studies have shown that satisfaction with the appropriate treatment modality would improve the quality of life amongst diabetes patients. 2,3 Hypoglycemia and fear of hypoglycemia are considered to be the major barriers to achieving good 258

2 Increasing risk of hypoglycaemia with progression of type 2 diabetes Proportion experiencing at least one episode of severe hypoglycaemia over 9-12 months n 13 p=.2* n 85. Treated Type 2 with sulphonylureas <2 yrs Insulin treated patients Type 2 >5 yrs UK Hypoglycaemia Study Group. Diabetologia 27;5:114-7 Type 1 <5 yrs Type 1 >15 yrs Fig. 1 : Hypoglycemia risk increases with the duration of Diabetes glycaemic control by patients and clinicians. 4 Amongst the insulins in the market, Glargine is the one with the smallest peak, but is still not peakless. Given the benefit Glargine has in reducing hypoglycemia s, the flat time action profile action of long acting insulins like ludec may reduce the incidence of hypoglycemia s even further. Lesser inter-subject variability of insulin is helpful in titrating the insulin dosage correctly. It is well known that Glargine has a better profile than NPH insulin in this regard. However the potential still exists for longer acting insulins with an even lower inter-subject variability. By and large neither Glargine nor Detemir have been successfully used on a once daily basis and are able to reliably provide a 24 hour basal insulin replacement in Type 1 Diabetes. Studies have shown that a twice daily regimen of Glargine is required in some patients to reduce the number of hypoglycemic attacks as compared to once daily usage, 5 There is thus a need for a truly reliable 24 hour acting insulin warranting only once daily usage. Most insulins cause weight gain. However Detemir has been found to have a statistically significant weight loss of 1 kg as compared to NPH and Glargine. 6 Given that most treatment intensive regimens cause weight gain attempts are required to develop insulin that does not cause weight gain. Observational studies had suggested that Glargine may have a dose related increase in cancer compared to Human Insulin; however by and large this is probably not a significant problem on careful assessment of the data. 7 However, it would be preferable that any newer insulin should have a low affinity for the IGF-1 receptor to avoid concerns in connection with potential carcinogenicity. n 75 n 5 n 5 ludec Insulin backbone Side chain: fatty acid + linker Allows formation of multi-hexamers Confers albumin binding De glu dec Fig. 2: Structure of ludec ludec Insulin Studies have shown ludec to be equally effective when compared to glargine, in reducing the HBA1c Levels in both Type 1 and Type 2 patients, but with a thrice weekly regimen as compared to the daily administration of Glargine when used in treating Type 1 diabetes. The molecular structure of ludec retains the human insulin amino acid sequence, but for the deletion of Threonine in the B3 position of the chain, and the addition of a 16-carbon fatty diacid attached to Lysine in the B29 position via a glutamic acid spacer. (Figure 2) Insulin ludec forms a soluble multihexamer at the injection site and is slowly released as insulin monomers, thus prolonging the duration of action. 7 It also binds to albumin thereby causing a slow and stable release of monomers. 8 (Figure 3) Studies on Insulin ludec Clinical pharmacology The clinical pharmacology, in particular the pharmacokinetics are usually studied using a hyperinsulinemic euglycemic pancreatic clamp. The principle of the clamp is to clamp the endogenous production of hormones from the pancreas and supplement hormones from outside so as to ascertain the level of glucose needed to achieve euglycemic state during steady state. The glucose infusion thus needed for maintaining euglycemia, after administering fixed levels of the extrinsic insulin, would be then used to ascertain the levels of the extrinsic insulin during various time periods of the study (Figure 4). ludec, On account of a smooth and stable pharmacokinetic profile at a steady state, 9 causes less within-subject variability. As discussed earlier a drug that shows a longer duration of action and lower inter-subject variation is the need of the 259

3 Medicine Update 212 Vol I.57 U/kg IGlar.6 U/kg Blood glucose level (mg/dl) ludec ligand carboxy group binds to Zn in hexamer Blood glucose (mmol/l) IV glucose infusion rate Fig. 3 : Hexamer formation in ludec due to linker Insulin injection The side chain (linker) forms an accurate fit between ludec hexamers to form multihexamers Time (min) Fig. 4 : Principle of Clamp study 81 Blood glucose (mg/dl) hour. ludec seems to score better than Glargine on this front. (Figure 5) TYPE 1 Diabetes A study, to compare efficacy of ludec and Glargine (1) was conducted amongst 177 Type 1 diabetic subjects, by regimens of either ludec or Glargine and both in combination with aspart. Those subjects between the age of 18 and 75, having Type 1 diabetes for at least 12 months and on continuous treatment with insulin (any regimen) for at least 6 months were included. They were to have an HbA1c between 7% and 11%, and daily insulin dose was to be below 12 IU for inclusion in the study. No restriction was placed on the BMI for inclusion in the study. These subjects were divided into 2 groups: Insulin ludec and one group was receiving Glargine. The primary objective of the study was to assess glucose control with respect to HbA1c after 16 weeks of treatment Secondary objectives were to compare efficacy and safety after 16 weeks of treatment in terms of frequency of hypoglycaemic episodes and body weight (Figure 6). The study showed that ludec was safe and well tolerated Time since trial drug adminstration (h) dose Source: NN , PK/PD MD study in T1D Time since trial drug adminstration (h) dose Fig. 5 : Graph showing 24 hour action of ludec There was a difference in rate of Hypoglycemia (RR=.72), in particular with regards to confirmed nocturnal hypoglycemic attacks (RR=.42) in the two groups in favor of ludec. However there was no difference in HBA1c, FPG or mean daily dose of insulin seen in the two groups, implying that ludec was as efficacious as Glargine with regard to these parameters. The body weight was also maintained over the 16 week period. Type 2 Diabetes A multicentric trial 7 among Type 2 Diabetes Mellitus patients was done to compare once daily Glargine with once daily or thrice weekly ludec. 236 subjects in between 18 and 75 years of age, having at least 3 months duration of Type 2 Diabetes Mellitus were included in the study. Only those who were on up to two oral antidiabetic drugs for at least 2 months were included in the study. Those who were on thiazolidines or insulins were excluded from the study. Only those with BMI between 23 and 42 and HbA1c between 7 % and 11 % were included in the study. The subjects were divided into 3 groups with 2 groups on once daily 1 U ludec, one group on thrice weekly 2 U ludec insulin (1U =9 nmol), and the third group on once daily 1 U Glargine concentrations (1U=6 nmol) They were then followed up for a period of 6 weeks and HbA1c, hypoglycemic attacks, body weight and BMI over this period and the data was compared amongst the groups (Figure 7). The study found no significant differences in the rate of confirmed hypoglycemic events, amongst once daily or thrice weekly ludec as compared to glargine. The efficacy outcome measures, including mean weekly insulin dose was similar across all the groups. Thus it is thought that with half the injections weekly, similar glucose control and lesser hypoglycemias could be obtained with ludec as compared to Glargine. ludec plus ludec plus (IAsp) is a combination of ludec and 26

4 HbA1c - Improvement in glycaemic control Baseline adjusted change in HbA1c (%) ( (Gla [95 % CI] FPG - Mean change over time Change from baseline (mmol/l) Change from baseline (mg/dl) Gla [ 95% CT] Confirmed hypoglycemias - Cumulative mean Major and minor - Mean No Glar RR.72 [.52,.99] Body weight (kg) Body weight - Mean over time Glar Change from baseline in body weight (kg) Body weight - Mean change over time Fig. 6 : Results of Type 1 study: Comparison of HbA1c, Fasting Plasma Glucose, Hypoglycemia, and weight gain in the 2 groups. FPG - Mean Change Over Time HbA 1c - Mean Change Over Time ludec 3TW No of Hypoglycemias 9 ludec OD 34 IGlar OD 76 J OD J 3TW J Gla Fig. 7 : Results of Type 2 study: Comparison of HbA1c, Fasting Plasma Glucose, Hypoglycemia, among the groups - Aspart in a 7:3 formulation. Studies have been done to compare ludec plus and other alternative formulations (AF) of ludec Aspart (55:45) with Glargine (IGlar) in Type 2 Diabetes Mellitus, all in combination with Metformin. 11 Insulin was administered before the evening meal and dosetitrated to a fasting plasma glucose (FPG) target of mmol/l. After 16 weeks, mean A1C decreased in all groups to comparable levels. Mean 2-h post dinner plasma glucose increase was lower for IAsp and AF than IGlar, whereas mean Fasting Plasma Glucose was similar. Hypoglycemia rates were lower for IAsp and IGlar than AF. Nocturnal hypoglycemic events occurred rarely for IAsp and IGlar compared with AF. Thus no significant difference in HbA1c and fasting blood glucose seen between the three groups.however those on IAsp had a mean decrease in post prandial sugar of 27 mg/ dl as compared to those on Glargine. The daily mean insulin dose was also lesser by 7 u/kg in the former as compared to the latter Conclusion ludec gives a comparable glycemic control with Glargine 261

5 Medicine Update 212 Vol. 22 at a similar molar and unit dose in both Type 1 and Type 2 Diabetes. There was lower rate of hypoglycemic events in those patients on once daily ludec compared to those on once daily glargine in type 2 Diabetes. In type 1 Diabetes, the rate of hypoglycemia was significantly lower in those on ludec once daily when compared to Glargine once daily. The longer 24 hour action of ludec may also pave the way for a flexible once daily dosing of insulin at any time of the day. Phase 3 trials are in progress and preliminary reports show that a thrice weekly administration of ludec appeared promising. Once daily dosage of ludec resulted in significantly lower plasma glucose, and a reduction in hypoglycemic episodes, in 52 week trials in type 2 diabetes when ludec was compared with once daily glargine. Amongst type 1 diabetes a lower risk of nocturnal Hypoglycemia was seen with once daily ludec as against Glargine on a daily basis. References 1. Kunt T, Snoek FJ. Barriers to insulin initiation and intensification and how to overcome them. Int J Clin Pract Suppl 29;164: Vijayakumar K, Varghese RT. Quality of life among diabetic subjects - Indian perspectives. Preedy & Watson edn. Handbook of Disease Burdens and Quality of Life Measures. Germany, 21, Springer-Verlag Publishers, Part 3,3.1, Varghese RT, Rekha S, Pradeep A, Reeshma KK, Vijayakumar K. Determinants of the Quality of life among Diabetic subjects in Kerala, India. Diabetes & Metabolic syndrome: Clinical research and reviews, 27;1: Cryer PE. Hypoglycaemia: the limiting factor in the glycaemic management of Type I and Type II diabetes. Diabetologia 22;45: Ashwell SG, Gebbie J, Home PD. Twice-daily compared with once-daily insulin glargine in people with Type 1 diabetes using meal-time insulin aspart. Diabet Med 26;23: Hermansen K, Davies M: Does insulin detemir have a role in reducing risk of insulin-associated weight gain? Diabetes Obes Metab 27;9: Zinman B, Fulcher GR, Rao PV, Thomas N, Endhal L, Johansen T, Lewin A, Rosenstock J, Pinget M, Mathieu C, Insulin degludec, a new generation ultra-long acting insulin, used once daily or 3-times weekly in people with type 2 diabetes: comparison to insulin glargine. The Lancet 211;377: Heise T, Hermanski L, Nosek L, et al. Insulin degludec: less pharmacodynamic variability than insulin glargine under steady state conditions. Diabetologia 21;53(Suppl. 1):S Jonassen I, Havelund S, Ribel U, et al. Insulin degludec is a new generation ultra-long acting basal insulin with a unique mechanism of protraction based on multihexamer formation. Diabetes 21;59(Suppl. 1):A11 1. Kåre I. Birkeland, Philip D. Home, Ulrich Wendisch, et al. Insulin ludec in Type 1 DiabetesA randomized controlled trial of a new-generation ultra-long-acting insulin compared with insulin glargine. Diabetes Care 211,34: Heise T, Tack CJ, Cuddihy R, et al. A new-generation ultra-longacting basal insulin with a bolus boost compared with insulin glargine in insulin-naive people with type 2 diabetes: a randomized, controlled trial. Diabetes Care 211;34: