Review Article
The Burden of Access to Insulin Analogues among Vulnerable Populations
Chrysanthus Chukwuma Sr*
Corresponding Author: Chrysanthus Chukwuma, Sr. Executive Director, The CTR Future-Oriented Ltd, Abakaliki, Ebonyi State, Nigeria
Received: December 04th/sup>, 2019; Revised: January 02nd, 2020; Accepted: December 31st, 2019 Available Online: January 14, 2020
Citation: Chukwuma C. (2020) The Burden of Access to Insulin Analogues among Vulnerable Populations. Adv Res Endocrinol Metab, 2(1): 68-73.
Copyrights: ©2020 Chukwuma C. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Insulin is presented as the most superior, effective and consistent substance to control blood glucose level in diabetic individuals. Insulin analogues constitute insulin variants which have undergone molecular alterations. The current global acceptance of the transition to analogue insulin has resulted in elevated costs, but with anecdotal proven or clear evidence of the advantages in persons impaired with type 2 diabetes. Pregnancy impacts on both maternal and foetal metabolism in both diabetic and non-diabetic women but with greater severity in diabetic pregnancies; thus, insulin requirements increase at pregnancy due to progressive elevation of insulin resistance. Universal constraints and challenges to insulin access with security of supply to insulin have been registered in low-income, middle-income countries and high-income countries among the vulnerable populations.

 

Keywords: Diabetes, Treatment, Control, Costs

INTRODUCTION

Insulin remains the most effective and efficacious substance for blood glucose level control in diabetes. Neutral Protamine Hagedorn (NPH) has become ubiquitous as the basal insulin in clinical care since 1946 [1]. Analogue insulin comprises a sub-group of human insulin that is laboratory produced but genetically metamorphosed to induce and enhance rapid acting or better standardized acting attribute of the insulin. The production is conducted by the growth of insulin proteins inside Escherichia coli as the amino acid order is altered per recombinant DNA. There is perspicuous absorption variability, though due to the unavoidable requirement for re-suspension and the time-action profile of peak activity of nearly 4-6 h following subcutaneous administration that confers a significant correlation between-meal and nocturnal hypoglycaemia. During the 1980s, recombinant DNA technology modified the insulin molecule leading to the development of soluble long-acting insulin analogues, such as glargine and detemir. They both have relevance in curbing hypoglycaemia risk when compared to NPH with regard to improved time-action profiles and decreased daily glucose variability [1]. Short-acting insulin analogues ostensibly provide more flexible dosing and convenience, while long-acting analogues are related to decreased risk for hyperglycaemia in comparison to synthetic human insulin, but their cost [2] and security of supply [3] pose a gross disadvantage to vulnerable populations. Universal constraints and challenges with respect to insulin access are evident in low-income and middle-income countries [4] as well as high-income countries [5] in vulnerable populations and others.

 

TYPE 1 DIABETES MELLITUS, T1D

There persists a daunting challenge for type 1 diabetes patients to maintain tight glycaemic control for ideal long-run outcomes via the simulation of physiological beta-cell secretion. The treatment and control of type 1 diabetes encompasses exogenous and extraneous functionalities of beta cells for the achievement of blood glucose concentrations which are proximate to the normal range. This modality depicts that glucose sensing has to be replaced and insulin contents must give a semblance of physiologic insulin-action profiles, basal coverage and changes at meals [6]. It means that the training and education available to diabetic patients must provide to achieve adequate glycaemic control by insulin preparations with action profiles and latitude for stable basal insulin coverage and conventional mealtime insulin peaks for desirable quality of life  without  compromising  stringent  glycemic  control  in type 1 diabetes or other insulin analogues of diverse modifications or regimens [6]. It has been reported that long-acting insulin analogues are efficacious in comparison to NPH, with approximations depicting decreased nocturnal episodes of hypoglycaemia [7]. Stringent glucose controls by applying multiple doses of insulin constitutes the standard treatment of type 1 diabetes but elevated hypoglycaemia risk is a constant deterrent. Regular multiple doses of insulin is significant in achieving strict glycaemic control for type 1 diabetes; however, short-acting insulin analogues may provide better reduction of hypoglycaemia and postprandial glucose concentrations [8].

TYPE 2 DIABETES MELLITUS, T2D

Insulin therapy is ultimately pertinent to control blood glucose in numerous type 2 diabetes patients. Type 2 diabetes is a progressive disorder that requires insulin therapy in several instances to ensure continuous and adequate blood glucose control [9]. At the onset, basal insulin is efficacious in several T2D patients for control sustenance, but in certain individuals, post-prandial glucose concentrations are elevated or become exacerbated with the further reduction of endogenous insulin concentrations. Supplementation with a meal-time insulin becomes pertinent for the provision of better post-prandial glucose control. The post-prandial glucose control is pertinent even at high concentrations of bA1c (> 10.0% or 86 mmol/mol) in the absence of optimized basal insulin, with intended supplementation of up to 30% of subsequent cumulative glucose control [10] and supplementation with a meal-time insulin to basal insulin therapy is reasonable utilizing T2D treatment guidelines as a strategy for optimum precise and flexible insulin procedure [11]. Insulin analogues have been formulated for greater physiological pharmacokinetic/pharmacodynamic profiles as compared to normal human insulin [12]. It was shown that conventional unadulterated human insulin has slower onset and longer action duration than rapid-acting insulin analogues; and the analogues precipitate better post-prandial glucose control in randomized controlled trials, RCTs [13,14].

In this regard, the A1chieve sub-group investigated populations starting the analogue insulin as part in combination with basal insulin, with or without oral glucose reducing drugs; insulin aspart added to extant basal insulin, n=519 at various modifications [15]. The findings undergird the utilization of basal in addition to prandial insulin regimens in routine clinical practice in persons presenting with T2D having inadequate glycaemic control as compared or related to other regimens of diabetes treatment and control. Clinically significant improvements were detected in serum lipids alongside quality of life in the populations investigated. Also, the A1chieve sub-group investigated and analysed the clinical safety and effectiveness of biphasic insulin aspart in T2D individuals with switch from biphasic human insulin [16] demonstrated improved glycemic control and decreased hypoglycaemia rates devoid of tolerability or safety concerns. Thus, it is suggested that biphasic insulin regimens provide the latitude to configure the requirements of both basal and prandial glucose reduction, as they make provision of both intermediate and rapid/short-acting insulin ingredients in a sole injection. Therefore, biphasic insulin preparations give the latitude for an easy strategy to handle both fasting plasma glucose, FPG and post-prandial glucose, PPG for the achievement of glycated haemoglobin, HbA1c targets [17,18]. It has been determined that PPG constitutes an independent risk factor for complications of diabetes [19] and, therefore, becomes pertinent to target both FPG and PPG at every HbA1c concentration for the achievement of glycaemic targets, and to mitigate diabetic sequelae [20] as well as improved glycaemic control and decreased hyperglycaemia risk [21] by selecting insulin with respect to individual insulin requirements, jointly or severally, constituting part of routine clinical care [22]. Clinical trials have exhibited that insulin analogues do not provide better benefits more than human insulin products for type 2 diabetes patients [23].

GESTATION AND DIABETES

Insulin is preferable for glycemic control in diabetic pregnancy; and insulin analogues are of interest in this instance, with decreased hypoglycemic risk and enhanced physiologic glycemia profile than standard human insulin in pregnant type 1, type 2 or gestational diabetes. However, there are extant risks of crossing the placental barrier, embryo toxicity, mitogenic stimulations and teratogenicity. Insulin requirements increase at pregnancy due to progressive augmentation of insulin resistance broadly related to weight gain due to reduction in physical activity, with a transient drop in necessary insulin doses in the first trimester, ostensibly resulting from nausea and vomiting [24]. Relevant safety concerns on the employment of insulin analogues in pregnancy are related to pregnancy and coupled with their capacity of being etiologic agents of immunogenicity, mitogenicity, exacerbated risk of teratogenicity and embryo toxicity as well as transplacental passage of the antibody-analogue complex [25-27].

Rapid-acting insulin analogues used in pregnant diabetic patients include insulin lispro [28], insulin aspart, glulisine and detemir [29,30]. The insulin analogues constitute superior benefits in lowering nocturnal hypoglycemia risks and promoting an enhanced physiologic glycemic profile in pregnant women having T1D, T2D or gestational diabetes. The rapid-acting analogues lispro and aspart are ostensibly safe and efficacious in the reduction of postprandial glucose concentrations in comparison to conventional human insulin, and portends decreased hypoglycemia [31]. The long-acting insulin analogues do not present marked peak effect as HPH insulin and are predicted to produce minimal nocturnal hypoglycemia in particular and generally minimal diurnal hypoglycemia [32].

Pregnancy impacts on both maternal and foetal metabolism in both diabetic and non-diabetic women. Circa 2% to 14% of pregnant women develop gestational diabetes. Women with T2D on oral hypoglycaemic agents are required to change to insulin therapy, while those having pre-existing T1D need to commence intensive glycaemic control. It is pertinent to evaluate the use of generic basal insulin analogues in pregnancy for safety and efficacy [33]. Thus, the application of insulin analogues may be safe and effective but needs to be evaluated in broader clinical trials [34].

INFORMATION-BASE AND DETERMINANTS

In essence, on a global scale, one out of two persons requiring insulin lack access, and insufficient availability are major constraints and challenges to poor insulin access [35]. Regarding status and income as facilitator as well as ingrained constraints and challenges, it is pertinent that public health and national economy modify the allocation of healthcare expenditures to presenting social programmes [36]. As much as 30% of USA medical expenditure does not enhance individual or population health. To an expansive magnitude, the available excess expenditure emanates from elevated costs or prices and consequent administrative wastage or dissipation of resources. In the public domain with particular emphasis on the state level with concomitant diverse budget constraints and reluctance to increase taxes, this concurrent expenditure overwhelms educational, public and social health ventures. In the long term, healthcare expenditure rises, while expenditure on sustainable enhancement to health social determinants is obliterated. Simultaneous reallocating of ineffectual healthcare spending to determined and cost-effective public health and social programmes tend to be difficult, but potential cognizance provided to improve public health while saving taxpayers enormous amount of pecuniary needs is liable to provide political platform to those likely to be involved in full and proper administrative all-encompassing reform.

It has been determined that Latinos are susceptible to increased risk for type 2 diabetes, T2D, as properly designed information technology, IT interventions have exhibited efficacious improved diabetes self-management, with a paucity of published IT intervention studies concerning Latinos, though. There are few studies on the most feasible approach to strategize on the discrete and unique sociocultural linguistic features which are liable to optimize adoption, utilization and benefit between Latinos. Sustainable e-health programmes associated with frequency in communication, bi-directionality or feedback and multimodal delivery of the intervention provide successful approach to the strategy. The utilization of community health workers, CHWs has consistently improved T2D outcomes in Latinos. The inclusion of CHWs in e-health interventions facilitates to mitigate the barriers associated with the difficulty in technology awareness and literacy with concomitant improvement in patient activation, satisfaction, adherence and compliance. Also, purposeful directed approach or tailoring to suit their needs in these interventions tend to be highly successful for improving patient activation. It is crucial to realize that tailoring is not merely linguistic translation, but involves intervention to the Latinos populace with optimum need to focus on educational language, literacy and acculturation contents simultaneously with discrete and unique illness beliefs, customs and attitudinal disposition concerning T2D in the Latino socio-medical concept in the community. Interventions ought to be expansive as to reach beyond solitary participants by inculcating shared decision-making models of friends, family and others in the community [37].

Although, the USA presents an increased level of medical care expenditure, the population has extant shorter life expectancy and poorer health indices than available in several OECD countries [38]. The current USA health disadvantage may be associated with certain cross-country disparities, however, price differentials and administrative lapses are expansive contributory factors in exacerbating costs in the USA healthcare system which are invariably controlled by policy objectives resulting in significant discordant and incongruent costs for standard medical care services in the USA as opposed to certain high-income nations. Interventions in education, public health, early childhood development, housing, transportation, diet and nutrition, as well as curbing smoking and other inimical behaviours are liable to enhance financial returns. These sustainable programmes may generate high tax revenues from increased earnings and decreased spending in law enforcement which overwhelms the programme costs [39].

Regarding the shift from social expenditure and public health, it is suggestive that health outcomes have deteriorated relative to the expectancy as envisaged. Evidence demonstrates that in addition to lagging behind other high-income countries in life expectancy, irrespective of higher endowment of national wealth and resources, that enhancement in life expectancy in the USA has been both retarded and incongruent in recent decades [40]. There is extant perspicuous uncertainty regarding the potential savings in healthcare and effectiveness of the educational and public health programme in the instant case. It is pertinent to consider a point estimate of the trade-offs of elevated healthcare expenditure with that associated with social and public health. As is evident in medical care, it is not all expenditures on social services which result in intended benefits and impacts with resultant cost effectiveness. Studies have elucidated the potential and practical advantages of shifting expenditures based on comparative advantage, such as from low-value ventures to high-value activities. It is suggested that high-value interventions are amenable in public health, early childhood education, development and other sectors, without encouraging categorical expenditure shifts from a sector to another in the absence of evidence on the associated effectiveness and programme costs [41]. Medical care prices could be genuinely decreased by circa 15% in the long term as progress needs proper latitude in conjunction with political will and fundamental reduction in wastage, dissipation of pecuniary resources and unwarranted increase in the USA healthcare system [41]. Enhancing insulin availability and affordability must be addressed in all ramifications, such as usage of biosimilars and improved distribution conduits [35].

DISCUSSION

Diabetes without adequate supply of insulin is presently expanding globally with debilitating impact in low- and middle-income countries, LMICs with special effect in certain conurbation [35,42]. One major constraint is that a vast majority of the data on the epidemiology of the interface between diabetes and insulin usage with undergirding socioeconomic factors emerge from developed countries, whereas the population at risk are in low- and middle-income countries, LMICs. Research, preventive, new-fangled therapeutic strategies are required in a global scale, particularly in LMICs where there is vast emergence of the greatest risk coupled with least availability of detection, treatment and control. The adverse sequelae of diabetes without appropriate insulin treatment and control may present deranging impacts on the global burden of diseases. The basal insulin agents currently in the market do not optimally have a semblance of endogenous insulin secretion. These unmet criteria have created the lacunae with need to fill them via the production of new-fangled basal insulin analogues to enhance their pharmokinetics/pharmacodynamics profile [43]. Degludec is prolonged-acting insulin that constitutes elongated subcutaneous multi-hexamers with resultant absorption procrastination. Phase trials in T1D and T2D exhibit the non-inferiority of degludec to comparators, such as glargine with a less albeit inconsistent decrease in total hyperglycaemia and a slight absolute disparity in nocturnal hypoglycemia. Other developmental analogues include LY2605541 that comprises insulin lispro coupled with polyethylene glycol, culminating in elevated hydrodynamic size and retarded absorption via the subcutaneous tissue. Another agent is glargine U300 that is formulated from glargine with resultant flatter and more elongated time-action profile in excess of its predecessor [44]. Globally, as insulin analogues substitute regular human insulin, the relative prices will increasingly become of significance. It was revealed that total costs of long-acting insulin analogues are not essentially disparate from prices of intermediate-acting human insulin and oral ant diabetic supplies [45,46]. These findings may be important for formulary decision making for diabetic patients in a price-constrained ambient [47-50].

 

CONCLUSION

This paper addresses issues and opportunities which are significant for decision-makers and healthcare providers. The novel insulin analogues must be stringently monitored for adverse signals irrespective of their advantages of inter alia increased molecular hydrodynamic size, reduction in absorption and clearance after subcutaneous administration, formation of compact subcutaneous depot and smaller surface area to form gradual and prolonged release. Future research is mandatory inter alia to develop insulin’s which are in compliance with physiologic insulin profiles at pregnancy and other diabetic conditions. In essence ‘diabetes mellitus is a disorder of metabolic dysregulation inextricably linked as anomalous glucose metabolism and long-term sequelae. In the absence of efficacious pharmaceutical agent, it becomes imperative to seek insulin or insulin analogues as the perspicuous remedy to achieve optimal glucose control. Glucose-lowering interventions of minimal costs among vulnerable populations are necessary for to abate or obviate susceptibility to further risk for appropriate risk reductions and complications, such as nephropathy, neuropathy and retinopathy.

On this score, the introduction and development of new-fangled strategies and contemporary revelations on diabetes may elucidate the channels for new modalities in insulin access for diabetic subjects. The development of action research programmes is likely to optimise diabetes treatment and control in resource-limited settings, such as vulnerable populations with the issue of access to insulin/insulin analogues.

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