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 Table of Contents  
EDITORIAL
Year : 2019  |  Volume : 24  |  Issue : 1  |  Page : 4-6

Coventional insulin versus insulin analogs


1 Consultant Diabetologist, Gomber Medicare, Delhi, India
2 Department of Pathology, RML Hospital, New Delhi, India

Date of Web Publication14-Mar-2019

Correspondence Address:
Dr. Anil Gomber
Gomber Medicare, Delhi 9
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jmgims.jmgims_5_19

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How to cite this article:
Gomber A, Gomber A. Coventional insulin versus insulin analogs. J Mahatma Gandhi Inst Med Sci 2019;24:4-6

How to cite this URL:
Gomber A, Gomber A. Coventional insulin versus insulin analogs. J Mahatma Gandhi Inst Med Sci [serial online] 2019 [cited 2019 Dec 9];24:4-6. Available from: http://www.jmgims.co.in/text.asp?2019/24/1/4/254133



One of the greatest medical discoveries is only a few years away from the centenary of the first use of insulin by Banting in 1921. We have come a long way in the journey of insulin. Insulins are now available in a wide range of time-action profiles, onset, peak, and duration of action with different delivery systems, but the quest for normal physiological actions for insulin release patterns always looms on.[1],[2],[3]

Over the past two decades since the release of Diabetes Control and Complications Trial results, doctors worldwide have recognized and accepted the value of normalizing glycemia.[4],[5] To achieve this goal, innovations for physiological patterns of insulin with different regimens and with different conventional insulin and insulin analogs remain a fundamental component of diabetes management today.

Insulin molecules consist of 51 amino acids (AAs) arranged in two chains (A chain [21 AAs] and B chain [30 AAs] are linked by two disulfide bonds). With the availability of human insulin by recombinant DNA technology in 1980, the use of animal insulin declined rapidly. Beef insulin, pork insulin, and beef–pork insulin are no longer commercially available. Now currently, insulins used are either human insulin or analogs of human insulin.[6]

The recombinant DNA technique for human insulin involves the insertion of human proinsulin gene into Saccharomyces Cerevisiae (Baker's yeast) or nonpathogenic laboratory strains of  Escherichia More Details coli which serves as production organism. Human insulin is then isolated and purified.

Recombinant DNA technology has allowed for the development and production of analogs to human insulin where modifications of insulin molecule structure are to alter in pharmacokinetics, as the absorption of insulin gets different from the subcutaneous tissue. Insulin analogs are modified human insulin and insulin-like growth factor-1 receptor binding affinities. Comparing these insulins in clinical practice is dependent on well-conducted clinical trials. Second more important is the balance between opinion and evidence.

I have, therefore, attempted to present balanced information with an occasional personal view.

Commercially available insulins are categorized as rapid-acting, short-acting, intermediate–acting, and long-acting insulins.

Since the introduction of insulin analogs in 1996, these “designer” insulin therapy options get widened. The new insulin analogs including rapid-acting analogs (aspart, lispro, and glulisine), long-acting basal analogs (glargine and detemir), and premixed insulin analogs formulations as 75% neutral protamine lispro, 25% lispro, 70% protamine aspart, and 30% aspart have been formulated to have a closer to physiological effects of normal endogenous insulin profile. While long-acting analogs have a smooth relatively flat 24-h basal supply with less variability profile as compared to insulin neutral protamine Hagedorn (NPH). Rapid-acting insulin analogs have the advantage of being able to mimic the mealtime insulin response more closely than can injection of unmodified human insulin.[6],[7],[8],[9]

With advancements and new research, a designer insulin-ultra fast-acting mealtime insulin is launched known as Fiasp (fast-acting insulin aspart).[10],[11] This insulin aspart in an innovative formulation with two excipients added: Vitamin B3 (niacinamide) to increase the speed of absorption and naturally occurring AA (L-arginine) for stability. The result is a mealtime insulin that is more closely mimics the natural physiological insulin response of a person without diabetes after a meal compared with conventional insulin aspart.

Regular insulin forms hexamers after injection into subcutaneous tissue slowing its absorption. These hexamers further dissociate into dimers and monomers. Rapid-acting analogs result from changes of AAs structure of human insulin which leads to decreases in hexameric insulin formation after injection into subcutaneous tissue. This leads to more rapid dissolution to monomers so more rapid absorption with shorter duration of action. While on molar basis rapid-acting insulin analogs have identical in vivo potency as compared to regular human insulins, higher peak concentrations are achieved. For this reason when converting from regular insulin to rapid-acting insulin analogs, the dose of insulin may need to be reduced.

When compared to regular insulin, the rapid-acting insulin analogs lead to less late postprandial hypoglycemia. Solubilization of insulin crystals is an important factor contributing to the poor reproducibility of NPH and Lente effects.[7],[8],[10]

The shorter interval for insulin injection premeal (10–15 min) is more convenient and better adherence is noted. All rapid-acting insulin analogs are recommended for an insulin pump.

Many randomized control trials of comparing these insulins in Type 1 diabetes show less severe nocturnal hypoglycemia events with insulin analogs as compared with human insulin, which is attributable to a pronounced difference in the nocturnal pharmacodynamic profile.[6],[7],[8],[9],[10],[11]

HypoAna Trial obtained in Type 1 diabetes during their hospital stays showed that treatment with insulin analogs such as detemir and aspart was associated with a significant 66% relative risk reduction of nocturnal hypoglycemia compared with human insulin, which is attributable difference in the nocturnal pharmacodynamic profile.

Nocturnal hypoglycemia is lower in Type 2 diabetes than Type 1 diabetes when patients were matched for similar A1c level in many studies,[10],[12],[13],[14] although there are statistically significant reported differences in hypoglycemia between analogs and human insulin.

Overall hypoglycemia was evaluated in 62 studies in comparison, wherein 17 of them, hypoglycemia was significantly less with analog insulin, whereas in 3, it was significantly increased. In none of the 60 studies, there was a bedtime snack recommendation.[14]

Only 15 of 64 (23%) showed a significant increase in the lowering of A1c levels with analogs. The weighted mean difference in hemoglobin A1c (HbA1c) levels between regular and analogs insulin is hardly of clinical importance.

Premixed insulin analogs are having an edge over premixed human insulin in improving postprandial glycemia. Premixed human insulin appears to have more intraday excursions of hypo–hyper glycemia with glucose variability episodes. Overall premixed insulin cannot be closer to physiological endogenous insulin as a result in mismatch requirement and availability. It can only be seen having better performance with just two meals a day with proper timing adherence. With proportions of mixed insulin which are having less physiologic action, so there is an increased risk of hypoglycemia when compared with basal-bolus regimens.

Studies show regular and insulin analogs (glulisine) are equally effective during acute treatment of diabetic ketoacidosis (DKA). Recent studies and previous reports indicate the treatment with intravenous glulisine and regular insulin are equally safe and efficacious in acute management of DKA.[7],[14] A transition to subcutaneous glargine and glulisine after the resolution of DKA resulted in similar glycemic control but in a lower rate of hypoglycemia than with NPH and regular insulin. Hence, a basal-bolus regimen is preferred over NPH and regular insulin after DKA.[15]

The intensification of insulin therapy to lower HbA1c (<7%) is not easy. However, fasting plasma glucose, glucose variability, and nocturnal hypoglycemia always hover in the minds of doctors. Effects of insulin analogs (long and short acting) on HbA1c have been studied in two recent Cochrane Reviews in favor of analogs in patients with T1 diabetes.[16],[17] Patients of T2 diabetes showed no difference in HbA1c between rapid-acting analogs and regular human insulin. In a similar review of eight studies when compared to each other, the short-acting insulin analogs appear to have relatively similar pharmacokinetic characteristics. Traditionally, long-acting insulin products have a high rate of pharmacokinetic and pharmacodynamic variabilities.

Analogs of insulins have shown to improve treatment adherence and treatment satisfaction due to fewer injections, flexibility of timings of basal analogs, less fear of dose adjustments, mealtime administration of prandial analogs as well as user-friendly injection devices. Pharmacoeconomics are also highlighted with analogs mainly due to a reduction in hypoglycemia-related claims and lower in patient cost. Analogs of long-acting and short-acting insulins improve treatment satisfaction which reduce the negative impact of diabetes on quality of life in comparisons with unmodified human insulin with NPH.

Cost of analogs is a deterrent in adherence; nevertheless, the improvement in satisfaction is highly statistically significant and appears difficult to ignore. Patient's quality of life should be assigned its own price tag when the cost of insulin is being considered. Different studies on insulin analogs have shown increase in quality-adjusted life expectancy.[13],[18],[19]

To provide in-depth understanding of cost-effective regimens of both sides (regular vs. analogs), we need to have a much more global assessment of all these issues which are hard to measure with this complex diabetes disease. General conclusions from various studies suggest that total health-care costs may be relatively similar and may be associated with increases in quality-adjusted life expectancy.

Despite advances in insulin therapy over the past decade, significant proportions of subjects are not achieving adequate glycemic control even with many regimens. Individualization is the success with these insulins and on patients' acceptance and adherence to the treatment protocol. Other factors such as variability, hypoglycemic risk, weight issues, and other comorbid conditions also impact on diabetes and quality of life.



 
  References Top

1.
Müller N, Frank T, Kloos C, Lehmann T, Wolf G, Müller UA, et al. Randomized crossover study to examine the necessity of an injection-to-meal interval in patients with type 2 diabetes and human insulin. Diabetes Care 2013;36:1865-9.  Back to cited text no. 1
    
2.
Speight J, Bradley C. DAFNE: Improved Quality of Life as a Result of Intensified Treatment is Counter-Intuitive to Many Clinicians; 2002. Available from: http://www.bmj.com/cgi/eletters/325/7367/746#26769. [Last accessed on 2019 Jan 22].  Back to cited text no. 2
    
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Howorka K. Preface. In: Functional Insulin Treatment. 2nd ed. Berlin: Springer Verlag; 1996.  Back to cited text no. 3
    
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Nathan DM; DCCT/EDIC Research Group. The diabetes control and complications trial/epidemiology of diabetes interventions and complications study at 30 years: Overview. Diabetes Care 2014;37:9-16.  Back to cited text no. 4
    
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Hypoglycemia in the diabetes control and complications trial. The Diabetes Control and Complications Trial Research Group. Diabetes 1997;46:271-86.  Back to cited text no. 5
    
6.
Ceriello A, Kilpatrick ES. Glycemic variability: Both sides of the story. Diabetes Care 2013;36 Suppl 2:S272-5.  Back to cited text no. 6
    
7.
Umpierrez GE, Jones S, Smiley D, Mulligan P, Keyler T, Temponi A, et al. Insulin analogs versus human insulin in the treatment of patients with diabetic ketoacidosis: A randomized controlled trial. Diabetes Care 2009;32:1164-9.  Back to cited text no. 7
    
8.
Bolli GB, Songini M, Trovati M, Del Prato S, Ghirlanda G, Cordera R, et al. Lower fasting blood glucose, glucose variability and nocturnal hypoglycaemia with glargine vs. NPH basal insulin in subjects with type 1 diabetes. Nutr Metab Cardiovasc Dis 2009;19:571-9.  Back to cited text no. 8
    
9.
Hartman I. Insulin analogs: Impact on treatment success, satisfaction, quality of life, and adherence. Clin Med Res 2008;6:54-67.  Back to cited text no. 9
    
10.
Heise T, Hövelmann U, Brøndsted L, Adrian CL, Nosek L, Haahr H, et al. Faster-acting insulin aspart: Earlier onset of appearance and greater early pharmacokinetic and pharmacodynamic effects than insulin aspart. Diabetes Obes Metab 2015;17:682-8.  Back to cited text no. 10
    
11.
Bode BW, Johnson JA, Hyveled L, Tamer SC, Demissie M. Improved postprandial glycemic control with faster-acting insulin aspart in patients with type 1 diabetes using continuous subcutaneous insulin infusion. Diabetes Technol Ther 2017;19:25-33.  Back to cited text no. 11
    
12.
Laranjeira FO, de Andrade KR, Figueiredo AC, Silva EN, Pereira MG. Long-acting insulin analogues for type 1 diabetes: An overview of systematic reviews and meta-analysis of randomized controlled trials. PLoS One 2018;13:e0194801.  Back to cited text no. 12
    
13.
Grunberger G. Insulin analogs-are they worth it? Yes! Diabetes Care 2014;37:1767-70.  Back to cited text no. 13
    
14.
McCall AL. Insulin therapy and hypoglycemia. Endocrinol Metab Clin North Am 2012;41:57-87.  Back to cited text no. 14
    
15.
Rossetti P, Pampanelli S, Fanelli C, Porcellati F, Costa E, Torlone E, et al. Intensive replacement of basal insulin in patients with type 1 diabetes given rapid-acting insulin analog at mealtime: A 3-month comparison between administration of NPH insulin four times daily and glargine insulin at dinner or bedtime. Diabetes Care 2003;26:1490-6.  Back to cited text no. 15
    
16.
Horvath K, Jeitler K, Berghold A, Ebrahim SH, Gratzer TW, Plank J, et al. Long-acting insulin analogues versus NPH insulin (human isophane insulin) for type 2 diabetes mellitus. Cochrane Database Syst Rev 2007;CD005613.  Back to cited text no. 16
    
17.
Becker LA, Oxman AD. Overviews of reviews. In: Higgins JP, Green S, editors. Cochrane: Handbook for Systematic Reviews of Interventions. Ch. 22. 2011. Available from: http://www.cochrane-handbook.org. [Last accessed on 2019 Jan 15].  Back to cited text no. 17
    
18.
Warren E, Weatherley-Jones E, Chilcott J, Beverley C. Systematic review and economic evaluation of a long-acting insulin analogue, insulin glargine. Health Technol Assess 2004;8:iii, 1-57.  Back to cited text no. 18
    
19.
Holden E, Currie J. Do the benefits of analog insulins justify their costs? Diabetes Manage 2012;2:173-5.  Back to cited text no. 19
    




 

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