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 Table of Contents  
REVIEW ARTICLE
Year : 2020  |  Volume : 4  |  Issue : 4  |  Page : 164-168

Insulin analogs versus human insulins for the management of diabetes: An evidence-based review


Department of Medicine, Hamad Medical Corporation; Department of Medicine, Weill Cornell Medicine - Qatar, Doha, Qatar

Date of Submission19-Nov-2020
Date of Acceptance23-Nov-2020
Date of Web Publication28-Dec-2020

Correspondence Address:
Dr. Mohsen S Eledrisi
Department of Medicine, Hamad Medical Corporation, P.O. Box 3050, Doha
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/LJMS.LJMS_96_20

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  Abstract 


Insulin analogs are preferred by many physicians over human insulins in the management of Type 1 diabetes and in patients with Type 2 diabetes who require insulin. Insulin analogs have a pharmacological profile that is close to the normal physiological action of insulin. There is a notion among some clinicians that insulin analogs offer advantages over human insulins, including better glucose control, less hypoglycemia, and flexibility. A large number of clinical studies, along with systematic reviews, have compared insulin analogs to human insulins in regard to glucose control, rates of hypoglycemia, quality of life, and cost-effectiveness. For Type 1 diabetes, rapid-acting insulin analogs offer better glucose control and less rates of hypoglycemia compared to regular human insulin. Long-acting basal insulins result in less nocturnal hypoglycemia compared to neutral protamine Hagedorn (NPH) insulin but no difference in glucose control in patients with Type 1 diabetes. For patients with Type 2 diabetes, rapid-acting insulins offer no advantage for glucose control or rates of hypoglycemia when compared to regular insulin. There was only a reduction in rates of nocturnal hypoglycemia with no difference in glucose control with the use of basal insulin analogs compared to NPH insulin in Type 2 diabetes. The cost of insulin analogs is considerably higher than human insulins and favorable cost-effectiveness was only demonstrated with rapid-acting insulin analogs in Type 1 diabetes. The available evidence does not support the routine use of insulin analogs over human insulins. There are only few situations where insulin analogs have shown clear benefit over human insulin. In a large percentage of patients cost consideration and lack of better glucose control would favor the use of human insulins.

Keywords: Diabetes mellitus, human insulins, insulin analogs


How to cite this article:
Eledrisi MS. Insulin analogs versus human insulins for the management of diabetes: An evidence-based review. Libyan J Med Sci 2020;4:164-8

How to cite this URL:
Eledrisi MS. Insulin analogs versus human insulins for the management of diabetes: An evidence-based review. Libyan J Med Sci [serial online] 2020 [cited 2021 Feb 25];4:164-8. Available from: https://www.ljmsonline.com/text.asp?2020/4/4/164/305248




  Introduction Top


The discovery of insulin in 1921 is considered one of the greatest achievements in the history of medicine. Before the availability of insulin, patients with Type 1 diabetes would deteriorate and succumb to diabetic ketoacidosis and early death. The commercial availability of insulin in 1922 was truly a miracle that completely changed the lives of patients with Type 1 diabetes. This was obvious from mortality rates from diabetic ketoacidosis, the main manifestation of uncontrolled glucose, in patients with Type 1 diabetes and can occur in Type 2 diabetes as well. Mortality rates from diabetic ketoacidosis dropped from >90% before the discovery of insulin[1] to 60% in 1923, just a year after the availability of insulin.[2] Current death rates from DKA in developed countries are <1% and may reach up to 2.6% in the elderly.[3] The initially discovered insulin had a short-acting action profile and therefore, required multiple daily injections. It was not until 1950 when neutral protamine Hagedorn (NPH) became the first available intermediate-acting insulin and started to be used with the short-acting regular insulin. Insulin preparations were initially obtained from animal sources until 1982 when the technology of genetic engineering using recombinant DNA technology allowed the commercial production of human insulin. The next step in the development of insulin was the production of insulin analogs where the chemical structure of insulin was altered to produce insulins that have actions closer to normal physiology. The first insulin analog that became available was the rapid-acting insulin lispro in 1996. Several forms of insulins analogs followed including more types of rapid-acting insulins such as aspart and glulisine as well as basal insulins such as glargine, detemir and degludec. In addition, several types of premixed insulin analogs have been developed including aspart 70/30, aspart 50/50, lispro 75/25, and lispro 50/50; these were compared to the existing premixed human insulins: NPH/regular 70/30 and NPH/regular 50/50. [Table 1] contains the different types of human insulins and insulin analogs.
Table 1: Types of insulins

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The results of many registration trials and postmarketing studies showed a great enthusiasm for insulin analogs. Rapid-acting insulin analogs have a pharmacological action profile that is close to normal physiology where a rapid increase followed by a rapid fall in insulin levels are achieved after subcutaneous injection compared to regular insulin. It was suggested that better levels of postprandial glucose and lower rates of hypoglycemia were demonstrated with rapid-acting insulins.[4] Basal insulin analogs were shown to be associated with longer duration of action, less variability, less hypoglycemia and less weight gain-specifically with insulin detemir-compared to human insulins.[4] Premixed insulin analogs were shown in some studies to be associated with less hypoglycemia, better control of postprandial glucose, and improved adherence and quality of life. On the other side, a major constraint with insulin analogs is their considerably higher cost compared to human insulins. This led to evaluation of cost-effectiveness of insulin analogs therapy in comparison to human insulins and it was suggested that insulin analogs are worth the high cost by enhancing satisfaction and adherence to therapy, improving quality of life and possibility reducing rates of diabetes complications.[4] This article will discuss evidence-based characteristics and preferential differences between insulin analogs and human (or conventional) insulins including advantages, drawbacks and cost considerations and provide recommendations on their use in patients with Type 1 diabetes and those with Type 2 diabetes. The subject will be discussed according to the type of insulin.


  Basal Insulin Top


Some, but not all, clinical studies have shown that basal insulin analogs (glargine and detemir) were associated with a reduction in rates of hypoglycemia when compared to NPH insulin in patients with Type 1 diabetes[5],[6],[7],[8],[9] as well as patients with Type 2 diabetes.[10],[11],[12],[13] Basal insulin analogs were associated with small improvements in HbA1c levels (mean reduction of 0.01%–0.08%), which are considered clinically not significant.[14] Systematic reviews and meta-analysis have shown that in patients with Type 1 diabetes, basal insulin analogs resulted in minimal improvement in HbA1c levels and a reduction in rates of nocturnal hypoglycemia but not general hypoglycemia when compared to NPH insulin.[15],[16],[17],[18],[19] There were inconsistencies in the rates of severe hypoglycemia, with the latest systematic review showing no difference among patients on basal insulin analogs compared to those on NPH insulin.[15] The results were even less impressive in patients with Type 2 diabetes where basal insulin analogs only reduced rates of symptomatic nocturnal hypoglycemia with no difference in overall hypoglycemia and glucose control.[17],[20],[21] In addition, a large observational study that included more than 25,000 patients with Type 2 diabetes showed no difference in the rates of hypoglycemia leading to emergency department visits or hospital admissions and no difference in glucose control when comparing basal insulin analogs to NPH insulin.[22] One advantage that was shown with insulin detemir is less weight gain (average 0.6–1.6 kg) compared to NPH insulin;[6],[7] this small amount of weight gain is likely not clinically significant.


  Meal Insulin Top


Most of the clinical studies found that the use of rapid-acting insulin analogs in patients with Type 1 diabetes has resulted in improvement in HbA1c levels, reduction in rates of hypoglycemia, and decrease in postprandial glucose levels compared to regular insulin.[23],[24],[25],[26],[27] On the other hand, most studies in patients with Type 2 diabetes have shown no difference in rates of hypoglycemia or glucose control between rapid-acting insulin analogs and regular insulin.[28],[29],[30],[31] Systematic reviews and meta-analysis have shown that rapid-acting insulin analogs resulted in a reduction in rates of hypoglycemia, including nocturnal and severe forms, lower postprandial glucose levels, and improvement in HbA1c levels when compared with regular insulin in patients with Type 1 diabetes.[32],[33],[34],[35] However, these benefits were mostly not observed among patients with Type 2 diabetes, where there was no difference in rates of hypoglycemia-including nocturnal and severe forms- and glucose control with only a possible reduction of postprandial glucose levels with rapid-acting insulin analogs.[17],[32],[36] One important advantage of rapid-acting insulins is that their quick onset of action permits their use at the time of meals or after the end of meals, compared with regular insulin, which requires injection generally 30 min before meals. This distinctive feature is particularly important in patients for whom food intake cannot be quantified at the start of meals, and therefore, an adjustment of insulin dose is required according to the amount of consumed carbohydrates.[37] This situation is important in young children where the doses of rapid-acting insulin can be injected immediately after meals and adjusted using carbohydrate counting by a family member or a caretaker. Some clinicians apply the same concept when administering rapid-acting insulin to elderly patients for whom the quantity of consumed food cannot be predicted, and therefore, dose adjustments are employed for those patients; even though this idea is appealing, supportive data for such practice are not available.


  Premixed Insulins Top


Premixed insulins are used only in some patients with Type 2 diabetes, while patients with Type 1 diabetes are always recommended to use a regimen of basal + meal insulin (human or analogs).

A systematic review found that premixed insulin analogs are similar to premixed human insulins in reducing fasting glucose levels, HbA1c levels, and the rates of hypoglycemia but were more efficient in lowering postprandial glucose levels.[38] Another systematic review conducted by the Agency for Healthcare Research and Quality in the United States examined the comparative effectiveness of premixed insulin analogs compared to premixed human insulins and demonstrated no difference in lowering fasting glucose, reducing HbA1c levels or rates of hypoglycemia and weight gain and found only less postprandial glucose levels with premixed insulin analogs.[39] Another review showed no difference between premixed insulin analogs and premixed human insulins on the risk of hypoglycemia and rates of glucose control.[40] A meta-analysis of clinical studies comparing premixed insulin analog aspart 70/30 to premixed NPH/regular 70/30 human insulin found less nocturnal and major hypoglycemia with the analog insulin and less daytime hypoglycemia with the human insulin, but no difference in glucose control as assessed by HbA1c levels.[41]


  Cost and Cost Effectiveness Top


The cost of insulin forms a major part of patients' overall health budget. The increasing cost of insulin has risen as a global health challenge not only in low-income and middle-income countries but also in high-income countries.[42] In the United States it was estimated that, in 2018, the use of insulin costs around $6,000 annually per person and that insulin costs account for about $48 billion (20%) of the direct medical costs of diabetes.[43] The list prices of insulin have increased significantly over the years. As an example, in the United States and between 2005 and 2011, the increase in price was 114% for regular insulin and NPH insulin, 134% for insulin lispro, 116% for insulin glargine, and 117% for insulin aspart.[44] Between 2002 and 2013, the cost of all insulin preparations increased by more than 300%, while the cost of insulin analogs was generally higher than human insulins by more than 200%.[45] A survey conducted by the American Diabetes Association noted that the increase in insulin costs had adversely affected patient care.[46] Because of the high cost of insulin, patients were forced to take less doses than prescribed, had to change to less expensive types or brands, and very alarmingly, had to miss insulin doses. In addition, a significant proportion of patients had to make the choice between buying insulin or paying for other necessities such as other health services, utilities, or transportation.

There are published studies that evaluated cost-effectiveness of insulin analogs compared to human insulins. These studies were based on models that analyzed the proposed advantages of insulin analogs such as flexibility, convenience, satisfaction, improvement in HbA1c levels-which is expected to lower rates of diabetes complications-, costs for hypoglycemia (emergency department visits or/and hospitalization), and fear of hypoglycemia. Many of these studies were based on computer models and projected costs based on the presumed decreased incidence of long-term diabetes complications and improved quality-adjusted life expectancy. The mean difference in HbA1c levels between analog and human insulins was 0.01%–0.23%,[44] a change that is considered not clinically significant.[14] This was supported by a large cohort study that included 127,600 patients with Type 2 diabetes and found no difference in major cardiovascular events, cardiovascular mortality, and overall mortality when comparing insulin analogs to human insulins.[47] A systematic review found that insulin analogs are cost-effective in patients with Type 1 diabetes but not for those with Type 2 diabetes.[48] Another systematic review found that only rapid-acting insulin analogs in patients with Type 1 diabetes are cost-effective and that the routine use of insulin analogs, especially long-acting analogs in Type 2 diabetes, is unlikely to be associated with efficient use of health care resources.[49] Switching insulin analogs to human insulins in a large cohort of patients with Type 2 diabetes resulted in a minimal increase in HbA1c levels (by 0.14%), no difference in serious hypoglycemic or hyperglycemic events and a substantial estimated savings to the health care system.[50]

The importance of making the choice between insulin analogs and human insulins led several professional organizations to issue recommendations on this subject. In Germany, the Independent Institute for Quality and Efficiency in Health Care (Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen) concluded that there is no convincing evidence of superiority of rapid-acting insulin analogs compared to human regular insulin in patients with Type 2 diabetes and that rapid-acting insulin analogs have not been sufficiently investigated with regard to their potential long term beneficial and harmful effects.[51] The World Health Organization issued recommendations on the use of insulin for patients with Type 1 as well as those with Type 2 diabetes in low resource settings in both low- and high-income countries.[52] The organization gives a strong recommendation on the use of human insulins (regular and NPH insulins) in patients with Type 1 diabetes and for patients with Type 2 diabetes for whom insulin is indicated. Long-acting insulin analogs are given a weak recommendation for use in adults with Type 1 or Type 2 diabetes who encounter frequent severe hypoglycemia with human insulins. The American Diabetes Association recommends the use of rapid-acting insulin analogs and suggests the use of long-acting insulin analogs over NPH to reduce the risk of hypoglycemia for patients with Type 1 diabetes.[53] For patients with Type 2 diabetes, the association notes that the advantages of long-acting analogs over NPH are modest and may not persist and highlights the importance of cost consideration while it emphasizes that there are no differences between rapid-acting analogs and human insulin.

Despite the marginal advantage of basal insulin analogs over NPH insulin, the lack of clinical evidence of rapid-acting insulins over regular insulin for patients with Type 2 diabetes and the considerably higher cost,[54],[55],[56] there has been increasing use of insulin analogs compared with human insulins over the recent past leading to the dominance of insulin analogs particularly in developed and high-income countries.[43] Heavy promotion of insulin analogs by pharmaceutical companies is an important contributing factor.


  The Verdict Top


When choosing between insulin analogs and human insulins, it is important to consider patient's profile, including the type of diabetes, risk and occurrence of hypoglycemia and the cost of insulin therapy. For patients with Type 1 diabetes, rapid-acting insulin analogs have clear advantages over human insulins, including better glucose control and less hypoglycemia and are cost-effective; therefore, their use is highly recommended, particularly in children younger than 6 years of age where they can be administered immediately after meals which offer the advantage of adjusting insulin doses according to the carbohydrate content of the consumed meal. Long-acting basal insulins cause less nocturnal hypoglycemia compared to NPH insulin; their use is preferred in patients with Type 1 diabetes when possible. For patients with Type 2 diabetes, long-acting basal analogs are only suggested in the setting of hypoglycemia-particularly nocturnal- and putting into consideration their higher cost compared to NPH insulin. Rapid-acting insulin analogs over no clear clinical advantages in patients with Type 2 diabetes and a serious attention to the cost difference compared to human insulin should be considered before implementing their routine use. Convenience remains better for patients as rapid-acting insulin analogs can be injected just before meals, but this should be weighed against their considerable higher cost.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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  In this article
Abstract
Introduction
Basal Insulin
Meal Insulin
Premixed Insulins
Cost and Cost Ef...
The Verdict
References
Article Tables

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