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Editorial comment by Dr. Vivian Fonseca: Comparing effects of insulin analogues and human insulin on nocturnal glycaemia
Since the development of insulin analogues there has been controversy about their value. One reason for this is that, in most trials comparing analogues with human insulin, the dose of insulin is titrated by the clinician and/or the patient to reach a glucose goal – in the case of long/intermediate-acting insulin the goal is fasting glucose. Due to titration, the fasting glucose is similar for human insulin and insulin analogues; consequently, the HbA1c does …
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Comparing effects of insulin analogues and human insulin on nocturnal glycaemia in hypoglycaemia-prone people with Type 1 diabetes
Kristensen PL, Tarnow L, Bay C, Nørgaard K, Jensen T, Parving HH, Perrild H, Beck-Nielsen H, Christiansen JS, Thorsteinsson B, Pedersen-Bjergaard UDiabet Med. 2017 May; 34(5): 625-631. doi: 10.1111/dme.13317. Epub 2017 Feb 14.
Editorial comment by Dr. Vivian Fonseca
Since the development of insulin analogues there has been controversy about their value. One reason for this is that, in most trials comparing analogues with human insulin, the dose of insulin is titrated by the clinician and/or the patient to reach a glucose goal – in the case of long/intermediate-acting insulin the goal is fasting glucose. Due to titration, the fasting glucose is similar for human insulin and insulin analogues; consequently, the HbA1c does also not differ. However, in almost all trials hypoglycemia occurs less frequently with analogues – mainly due to their pharmacokinetic profiles which lead to more consistent action profiles. From a patient’s perspective, less nocturnal hypoglycemia is particularly important for many reasons. However, the study design does usually not detect such differences as it is difficult and expensive to monitor night-time glucose. This sub-study of a carefully performed clinical trial comparing NPH with the analogue detemir shows less hypoglycemia during the night. While this study required venous blood testing for proof of concept, it is now possible in clinical practice to use continuous glucose monitoring in order to demonstrate less hypoglycemia in the real-life setting. Such studies should put the above mentioned controversy to rest.
Rawshani A, Rawshani A, Franzén S et al.N Engl J Med 2017; 376: 1407-18
Editorial comment by Professor Kamlesh Khunti
The Swedish National Diabetes Register was set up in 1996; it has improved the care of people with diabetes and led to some very high-quality publications. The registry covers over 90% of the population with diabetes. The most recent paper from this registry determined long-term trends in mortality and cardiovascular outcomes in people with both type 1 (T1DM) and type 2 diabetes (T2DM) and compared the excess outcomes with the general population. The cohort included all patients registered from 1998 to 2012 and followed them up to 2014. For each patient, controls were selected from the general population matched for age, sex, and county.
Overall, 36,869 patients with T1DM and 457,473 with T2DM as well as their matched controls were included in the analysis. The mean age was 35.3 years and 65.2 years for people with T1DM and T2DM, respectively. Mean HbA1c was 8.2% (66.0 mmol/mol) and 7.1% (54.5 mmol/mol) for patients with T1DM and T2DM, respectively. Mean duration of diabetes was 20 years and 5.7 years. Over a median of 15 years follow-up, the absolute changes in all-cause mortality per 10,000 person years were as follows:
• Death from any cause: −31.4 (95% confidence interval [CI], −56.1 to −6.7)
• Death from cardiovascular disease: −26.0 (95% CI, −42.6 to −9.4)
• Death from coronary heart disease: −21.7 (95% CI, −37.1 to −6.4)
• Hospitalisation for cardiovascular disease: −45.7 (95% CI, −71.4 to −20.1).
• Death from any cause: −69.6 (95% CI, −95.9 to −43.2)
• Death from cardiovascular disease: −110.0 (95% CI, −128.9 to −91.1)
• Death from coronary heart disease: −91.9 (95% CI, −108.9 to −75.0)
• Hospitalisation for cardiovascular disease: −203.6 (95% CI, −230.9 to −176.3).
Overall, people with T1DM had a 40% greater reduction in cardiovascular outcomes than controls, and patients with T2DM had approximately 20% greater reduction than controls. Patients with T2DM had smaller reductions for fatal outcomes compared to controls. Despite improvements in care for people with diabetes, there are still large differences in fatal and nonfatal outcomes in people with diabetes compared to the general population.
Impact of postprandial glucose control on diabetes-related complications: How is the evidence evolving?
Sten MadsbadJournal of Diabetes and its Complications, Volume 30, Issue 2, March 2016, Pages 374–385
Editorial comment by Sarah Cvach
Postprandial glucose (PPG) control needs to be considered when managing Diabetes.
Cardiovascular disease (CVD) is known to be one of the major complications of both type 1 and type 2 diabetes and the leading cause of mortality in this patient population.
Microvascular complications of Diabetes, including retinopathy, nephropathy and neuropathy are likewise playing a significant role in morbidity and mortality.
To avoid, minimize or prevent complications of Diabetes is a challenging task of the management of the disease. Landmark studies such as the United Kingdom Prospective Diabetes Study (UKPDS) have shown the association between HbA1c and microvascular complications. Strategies to lower HbA1c have led to reduction of cardiovascular risk. While in the past fasting plasma glucose (FPG) levels were in the focus, attention moved to the role of postprandial hyperglycaemia. Postprandial glucose (PPG) is a key contributor to overall glucose control as well as a predictor of microvascular and macrovascular events.
This article highlights the role of postprandial hyperglycaemia and its management. Faster insulin absorption of modern analogues and advances in insulin delivery modes might mimic more closely insulin secretory response to meals and may contribute in lowering PPG. Current evidence supports PPG control as an important factor to consider when managing Diabetes.
Pharmacological properties of faster-acting insulin aspart vs insulin aspart in patients with type 1 diabetes receiving continuous subcutaneous insulin infusion: Randomized, double-blind, crossover trial
Tim Heise, Eric Zijlstra, Leszek Nosek, Tord Rikte, Hanne HaahrDiabetes, Obesity and Metabolism 2017; 19(2):208–215
Editorial Comment by Professor Thomas Pieber
Ultra-Fast insulin analogues demonstrate improved pharmacokinetic and pharmacodynamic profiles in continuous subcutaneous insulin infusion (CSII)
Since the first attempts in the 1960’s delivery systems for continuous subcutaneous insulin infusion (CSII) have become compact, reliable, and wearable. The Diabetes Control and Complications Trial (DCCT, 1983-1993) shed light on the importance of tight control of blood glucose levels to limit microvascular complications. In turn, DCCT stimulated the development of the CSII pump as a means of delivering basal and prandial insulin; and CSII is increasingly used in patients with diabetes. Despite the introduction of short-acting insulin analogues postprandial glucose control remains a challenge, which prompted the quest of more physiologic insulin profiles for coverage of the prandial insulin need in patients with diabetes. Faster-acting insulin aspart (FIAsp) is insulin aspart in a new formulation with two added excipients, niacinamide and L-arginine. Both compounds, approved by the Food and Drug Administration (FDA) for injection, result in a faster onset of action that is twice as fast and leads to a twofold higher insulin exposure in the first 30 minutes after single injection, however, so far no data on CSII are available. In this randomized, double-blind, crossover trial Heise and colleagues evaluated the pharmacokinetic and pharmacodynamic profiles of FIAsp in patients with type 1 diabetes. All patients were on CSII and received a bolus of 0.15 U/kg of either FIAsp or insulin aspart on top of a basal rate of 0.02 U/kg body weight. Early insulin exposure in the first 30 minutes was 3fold higher with FIAsp, and glucose lowering effect was 2fold higher with FIAsp. The improved pharmacokinetic profile led to left shift of the curve, with a higher peak concentration (Cmax) and a 35 minutes earlier disappearance of insulin. Overall, this improved pharmacokinetic profile should lead to a substantial improvement of postprandial glycaemic control, currently under investigation in a phase 3 trial. Furthermore, the pharmacokinetic properties of this new formulation will open great opportunities in attempts to “close the loop” and will spur the development of the artificial pancreas, the long-term goal of modern CSII systems.
A Comparison of Pharmacokinetic and Pharmacodynamic Properties Between Faster-Acting Insulin Aspart and Insulin Aspart in Elderly Subjects Type 1 Diabetes Mellitus
Tim Heise, Ulrike Hövelmann, Eric Zijlstra, Kirstine Stender-Petersen, Jacob Bonde Jacobsen, Hanne HaahrDrugs Aging (2017) 34: 29. doi:10.1007/s40266-016-0418-6
Editorial comment by Professor Thomas Pieber
Improved pharmacokinetic and pharmacodynamic profiles of a new ultra-fast insulin analogue in an elderly population.
Management of diabetes mellitus in elderly subjects is complex, as this heterogeneous patient population includes individuals with diabetes who have additional chronic disorders, differing degrees of diabetes-related co-morbidities, cognitive impairment, and frailty. Treatment of elderly subjects with diabetes is further confounded by the limited clinical data currently available in this subject population regarding new insulin analogues. In this study, the pharmacokinetic and pharmacodynamic profiles of FIAsp, a new ultra-fast insulin analogue were investigated in elderly subjects. Faster insulin aspart is actually the molecule of insulin aspart prepared in a new formulation containing two well characterized excipients, niacinamide and L-arginine. The excipients, both approved by the FDA, result in a stable formulation and faster initial absorption after subcutaneous injection. In clinical trials in subjects with type 1 diabetes, FIAsp had a faster onset of appearance compared with insulin aspart (5 vs 11 min) and leads to a twofold higher insulin exposure in the first 30 minutes after single injection. In the current randomised, double-blind crossover trial 30 subjects with type 1 diabetes above 65 years have been compared against 37 younger type 1 diabetic subjects below 35 years of age. After injection of a single dose of either faster insulin aspart or insulin aspart (0.2 U/kg) pharmacokinetic and pharmacodynamic profile were assessed in a euglycaemic clamp. Onset of appearance was twice as fast, early insulin exposure, and early glucose lowering effects were greater for faster insulin aspart than for insulin aspart. The ultra-fast pharmacokinetic and pharmacodynamic properties of faster insulin aspart observed in younger adults are preserved in the elderly. These data suggest that faster aspart also has the potential to improve postprandial glucose control over current rapid-acting insulin analogues in elderly patients with diabetes.