Insulin biobetters and biosimilars in clinical practice.

Insulin injections have never been an entirely satisfactory therapy, and as a result a continuing 'biobetter' technological cascade has driven changes in purity and manufacture, in structure and excipients, and in administration devices. The resulting deck of insulin preparations has to be matched by health-care teams and users with individual need. This latter is itself a complex ranging from ambulatory care in type 1 and type 2 diabetes, the topic generally addressed by guidelines and funding advice, to in-patient care and the newly diagnosed, plus secondary diabetes with very different effects on insulin need, through to co-morbidities and medications interfering with glucose metabolism. In this article the match of different clinical scenarios to the available insulins is discussed in the context of available evidence, quality guidelines, and diabetes best practice. Additionally the role of biosimilars of the insulin analogues is addressed, their limited but useful price advantage, and the management consequences of substitution for the originator product.

Understanding Biosimilar Insulins - Development, Manufacturing, and Clinical Trials.

BACKGROUND: A wave of expiring patents for first-generation insulin analogues has created opportunities in the global insulin market for highly similar versions of these products, biosimilar insulins. Biologics are generally large, complex molecules produced through biotechnology in a living system, such as a microorganism, plant cell, or animal cell. Since manufacturing processes of biologics vary, biosimilars cannot be exact copies of their reference product but must exhibit a high degree of functional and structural similarity. Biosimilarity is proven by analytical approaches in comparative assessments, preclinical cell-based and animal studies, as well as clinical studies in humans facilitating the accumulation of evidence across all assessments. The approval of biosimilars follows detailed regulatory pathways derived from those of their reference products and established by agencies such as the European Medicines Agency and the US Food and Drug Administration. Regulatory authorities impose requirements to ensure that biosimilars meet high standards of quality, safety, and efficacy and are highly similar to their reference product. PURPOSE: This review aims to aid clinical understanding of the high standards of development, manufacturing, and regulation of biosimilar insulins. METHODS: Recent relevant studies indexed by PubMed and regulatory documents were included. CONCLUSIONS: Driven by price competition, the emergence of biosimilar insulins may help expand global access to current insulin analogues. To maximize the impact of the advantage for falling retail costs of biosimilar insulins compared with that of reference insulins, healthcare professionals and insulin users must gain further awareness and confidence.

Findings for iGlarLixi versus BIAsp 30 confirmed in groups of people with type 2 diabetes with different biomedical characteristics.

AIM: To report prespecified and post hoc analyses of the SoliMix dataset exploring the impact of baseline participant characteristics on the original SoliMix study outcomes, to enable informed treatment choices for people with different biomedical characteristics. METHODS: SoliMix (EudraCT 2017-003370-13) compared once-daily iGlarLixi (a fixed-ratio combination of insulin glargine 100 U/mL and the glucagon-like peptide-1 receptor agonist lixisenatide) with twice-daily BIAsp 30 (30% insulin aspart and 70% insulin aspart protamine). In this analysis, the original primary outcomes of noninferiority of iGlarLixi versus BIAsp 30 in terms of glycated haemoglobin (HbA1c) change and superiority in terms of body weight change, together with change in basal insulin dose and hypoglycaemia outcomes, were investigated by baseline age, duration of diabetes, insulin dose, HbA1c level, body mass index (BMI), and renal function. RESULTS: No evidence of difference in comparative treatment effect was detected across baseline age, duration of diabetes, insulin dose, HbA1c level, BMI and renal function subgroups for any endpoint (all heterogeneity P > 0.05), except American Diabetes Association Level 2 hypoglycaemia event rate when stratified by insulin dose (P = 0.011), which may be a chance difference given multiple testing and the small numbers of Level 2 events. CONCLUSIONS: Treatment effects of iGlarLixi were consistent irrespective of baseline HbA1c, insulin dose, BMI, age, duration of diabetes and renal function, supporting the use of iGlarLixi as an efficacious and well-tolerated treatment option in people with type 2 diabetes with a wide range of biomedical characteristics.

Hypoglycaemia events with iGlarLixi versus premix biphasic insulin aspart 30 (BIAsp 30) in people with type 2 diabetes advancing from basal insulin: An analysis of the SoliMix trial.

AIMS: To explore details of the incidence and rates of daytime and nocturnal hypoglycaemia, levels of hypoglycaemia, and relationship to glycated haemoglobin (HbA1c), when comparing iGlarLixi versus premixed biphasic insulin aspart 30 (BIAsp 30) in the SoliMix randomized controlled trial. MATERIALS AND METHODS: This exploratory analysis of SoliMix used logistic regression and negative binomial regression analyses to assess between-treatment differences in the incidence and rates of hypoglycaemia by time of day. A negative binomial model was used to derive estimated annualized hypoglycaemia rates as a function of HbA1c. RESULTS: iGlarLixi was associated with lower incidence and rates of American Diabetes Association Level 2 (<54 mg/dL [<3.0 mmol/L]) hypoglycaemia during both night and day versus BIAsp 30. Incidence and rates of Level 1 (<70 to ≥54 mg/dL [<3.9 to ≥3.0 mmol/L]) hypoglycaemia were also mostly shown to be reduced with iGlarLixi versus BIAsp 30. Severe (Level 3) events were too few for analysis (n = 3). iGlarLixi was associated with lower modelled event rates of Level 2 and Level 1 hypoglycaemia over a wide range of HbA1c levels versus BIAsp 30. CONCLUSIONS: These results show that the lower HbA1c levels and weight benefit seen with iGlarLixi versus premixed BIAsp 30 in people with type 2 diabetes advancing their basal insulin therapy in the SoliMix trial are also accompanied by a lower risk of hypoglycaemia at any time of day and across a broad range of HbA1c levels.

Future directions in insulin therapy.

Insulin therapy has a long history at the cutting edge of technological development through purification, extended-action, molecular chemistry, and devices, and in support technologies including self-measurement and patient education. But unmet needs remain large. Today's therapy cannot deliver minute-to-minute control of glucose levels, and cannot imitate the reflex/incretin driven physiological insulin delivery at mealtimes. Further it depends on a raft of devices for administration several times a day, devices liked for their functionality, but disliked as an intrusive reminder of the condition, several times a day. Approaches to overcoming these barriers include closed-loop systems and further modification of insulin formulations, but are limited by fundamental underlying difficulties. While clinical studies of oral insulin are in progress, the barriers to success look daunting. Development of small-molecule approaches (insulin-mimetic tablets) appears to have stalled, while concepts for glucose-responsive insulin as yet fail to deliver the necessary insulin-to-glucose gradient. Gene therapy, feasible in animals in preliminary studies, is not capable of providing feedback control. Transplantation of cultured islets and islet B-cells from stem cells thus looks to the be the best long-term prospect for insulin delivery in terms of overcoming the above barriers, but is a true biotechnological tour-de-force which will take time to mature.

Insulin therapy development beyond 100 years.

The first insulin preparation capable of consistently lowering blood glucose was developed in 1921. But 100 years later, blood glucose control with insulin in people with diabetes is nearly universally suboptimal, with essentially the same molecule still delivered by the same inappropriate subcutaneous injection route. Bypassing this route with oral administration appears to have become technologically feasible, accelerating over the past 50 years, either with packaged insulin peptides or by chemical insulin mimetics. Some of the problems of prospective unregulated absorption of insulin into the circulation from subcutaneous depots might be overcome with glucose-responsive insulins. Approaches to these problems could be modification of the peptide by adducts, or the use of nanoparticles or insulin patches, which deliver insulin according to glucose concentration. Some attention has been paid to targeting insulin preferentially to different organs, either by molecular engineering of insulin, or with adducts. But all these approaches still have problems in even beginning to match the responsiveness of physiological insulin delivery to metabolic requirements, both prandially and basally. As would be expected, for all these technically complex approaches, many examples of abandoned development can be found. Meanwhile, it is becoming possible to change the duration of action of subcutaneous injected insulin analogues to act even more rapidly for meals, and towards weekly insulin for basal administration. The state of the art of all these approaches, and the barriers to success, are reviewed here.

Efficacy and safety of iGlarLixi versus IDegAsp: Results of a systematic literature review and indirect treatment comparison.

AIM: To assess the efficacy and safety of iGlarLixi, a fixed-ratio combination of basal insulin glargine 100 U/mL and lixisenatide (glucagon-like peptide-1 receptor agonist) versus IDegAsp, a co-formulation of basal insulin degludec 100 U/mL with rapid-acting insulin aspart. MATERIALS AND METHODS: A systematic literature search of randomized controlled trials (RCTs) was performed. Outcomes from eligible RCTs were compared by an indirect treatment comparison using a Bayesian framework. Subanalyses of Japanese and international trials were performed. RESULTS: Eight RCTs (duration 26-30 weeks) were included. Mean difference in HbA1c change with iGlarLixi exceeded that for IDegAsp: -0.64 (95% credible interval -1.01, -0.28) %-units (-7.0 [-11.0, -3.1] mmol/mol) for all trials, -0.39 (-0.55, -0.23) %-units (-4.3 [-6.0, -2.5] mmol/mol) for international, and -0.88 (-1.11, -0.64) %-units (-9.6 [-12.1, -7.0] mmol/mol) for Japanese trials. HbA1c target achievement (<7.0%-units [<53 mmol/mol]) was greater for iGlarLixi in all trials (odds ratio 2.50 [1.06, 5.56]) and Japanese trials (2.17 [1.27, 3.70]), but not in international trials (2.17 [0.42, 11.11]). Analyses suggesting differences in mean postmeal self-measured plasma glucose were significantly lower by 1.0-2.0 mmol/L (18-36 mg/dL) with iGlarLixi in all analyses. Bodyweight change was more favourable (1-2 kg) for iGlarLixi versus IDegAsp for all analyses (P < 0.05). Comparisons of hypoglycaemia were inconclusive owing to differences in definitions between studies. Adverse events were more frequent with iGlarLixi because of gastrointestinal intolerance. CONCLUSIONS: iGlarLixi appears to offer clinical benefit in glucose control and bodyweight change in people needing both basal and meal-time intervention.

Heart failure management; a perspective from diabetes care.

People with type 2 diabetes (T2DM) are recognized as having a 2-4 times increased risk of heart failure (HF). Ambulatory diabetes care has long concentrated on the prevention of microvascular and arterial disease, and surveillance for manageable problems such as with the feet and retinae. Accordingly, management of heart failure has never been a specific focus, although the preventative management of cardiac and kidney disease through glucose-lowering, blood pressure (BP) control, and blood lipid control, have had a positive impact on its incidence. Indeed, the very complexity of routine diabetes care, and its enormous prevalence, has generally excluded the management of any of the advanced late complications, whether cardiac, arterial, retinal, renal, or neurodegenerative. Furthermore, advances in HF management itself, in diagnostics, medications, and technology, has carried it deeper into the remit of specialist cardiological care. More recently and in addition to medications already routinely used in diabetes care such as renin-angiotensin system (RAS) blockers, some glucose-lowering therapies such as sodium glucose transporter inhibitors 2 (SGLT-2 inhibitors), have been found to have very positive effects on hospitalization for HF, indeed even in people who do not have T2DM. Here, from the perspective of the diabetologist, we review the clinical scenario of ambulatory diabetes care, in regard of how HF prevention and management should fit in to clinical practice.

The evolution of insulin therapy.

Evolution in medicine is generally driven by clinical need, hand in hand with opportunities generated by novel chemical and mechanical engineering technologies. Since 1921 that has been a continuing paradigm for insulin therapy, some advances being a continual process, and others arising from external scientific or engineering developments. Purification of insulin preparations was an early issue, resolved in the 1970s, then challenged by the switch to manufacture in microorganisms. The nature of insulin was established serially, in 1928 as a polypeptide, in 1955 by amino acid sequence, and later by 3-dimensional structure (1969), laying foundations for understandings on routes of administration, and later the engineering of novel insulins. Insulin was the first, and remains the predominant, pharmaceutical therapy to benefit from scientific advances underlying the genetic code, and thus recombinant DNA technology. Advances in mechanical and chemical engineering have contributed to important changes in insulin delivery devices. Biological science, including both cellular mechanisms and whole organism physiology, has led to considerable understandings of clinical defects in insulin action, but currently has been disappointing in its applicability to the insulins available for clinical practice, something perhaps now changing. The pathways of these changes are reviewed here.

Insulin glargine/lixisenatide fixed-ratio combination (iGlarLixi) compared with premix or addition of meal-time insulin to basal insulin in people with type 2 diabetes: A systematic review and Bayesian network meta-analysis.

AIM: To assess the efficacy and safety of iGlarLixi, a fixed-ratio combination of insulin glargine 100 U/mL and lixisenatide, relative to premix insulin and other insulin options through network meta-analysis. METHODS: A systematic literature search identified randomized controlled trials (RCTs) comparing iGlarLixi, premix insulin or basal insulin (BI) in combination with meal-time insulin, in people inadequately controlled with BI. Eligible RCTs were compared using Bayesian network meta-analysis. RESULTS: Eight RCTs, some open-label, involving 3538 participants, with a study duration of 24-30 weeks were included. The estimated difference in HbA1c reduction with iGlarLixi compared with premix insulin was -0.50%-units (95% credible interval: -0.93 to -0.06) with 98% probability of iGlarLixi being superior to premix. Estimates for iGlarLixi versus meal-time + BI (thrice-daily meal-time insulin + basal) and basal-plus (once-daily meal-time insulin + BI) were -0.35 (-0.89 to +0.13)%-units and -0.68 (-1.18 to -0.17)%-units with probabilities of real difference of 94% and 99%, respectively. Safety outcome analysis suggested that iGlarLixi had lower rates of both confirmed and documented symptomatic hypoglycaemia compared with premix insulin (probabilities of 85% and 93%, respectively) and lower weight gain (probability 98%). CONCLUSIONS: iGlarLixi showed similar or improved efficacy and safety versus other intensification choices from BI included in this study, providing a clinically relevant treatment option in people with type 2 diabetes not well controlled on BI.

Impact of a Weekly Glucagon-Like Peptide 1 Receptor Agonist, Albiglutide, on Glycemic Control and on Reducing Prandial Insulin Use in Type 2 Diabetes Inadequately Controlled on Multiple Insulin Therapy: A Randomized Trial.

OBJECTIVE: The principle of replacing prandial insulin lispro with a once-weekly glucagon-like peptide 1 receptor agonist (GLP-1RA) for type 2 diabetes inadequately controlled on a multiple daily insulin injections regimen was tested with albiglutide. RESEARCH DESIGN AND METHODS: In this treat-to-target study, basal plus prandial insulin was optimized over 4 weeks before participants were randomized (1:1) to albiglutide plus optimized basal insulin glargine and lispro (dose reduced by 50% at randomization; subsequently, lispro injections were fully discontinued 4 weeks later) (n = 402) or to continued optimized lispro plus optimized glargine (n = 412). RESULTS: Mean ± SD HbA1c at baseline, 7.8 ± 0.6% (61 ± 7 mmol/mol) in the albiglutide + glargine group and 7.7 ± 0.6% (60 ± 7 mmol/mol) in the lispro + glargine group, was reduced at week 26 to 6.7 ± 0.8% (49 ± 8 mmol/mol) and 6.6 ± 0.8% (48 ± 8 mmol/mol), respectively (least squares [LS] difference 0.06% [95% CI -0.05 to 0.17]; noninferiority P < 0.0001). In the albiglutide + glargine group, 218 participants (54%) replaced all prandial insulin without reintroducing lispro up to week 26. Total daily prandial insulin dose was similar at baseline but was lower by 62 units/day (95% CI -65.9 to -57.8; P < 0.0001) at week 26 in the albiglutide + glargine group, and the total number of weekly injections was also reduced from 29 to 13 per week. Less severe/documented symptomatic hypoglycemia (57.2% vs. 75.0%) occurred in the albiglutide + glargine group with meaningful weight differences (LS mean ± SE -2.0 ± 0.2 vs. +2.4 ± 0.2 kg; P < 0.0001) vs. lispro + glargine. Gastrointestinal adverse events were higher with albiglutide + glargine (26% vs. 13%). CONCLUSIONS: A once-weekly GLP-1RA was able to substitute for prandial insulin in 54% of people, substantially reducing the number of prandial insulin injections; glycemic control improved, with the added benefits of weight loss and less hypoglycemia in the GLP-1RA arm. Replacing prandial insulin with a weekly GLP-1RA can simplify basal plus prandial insulin treatments and achieve better outcomes in type 2 diabetes.

Efficacy and safety of iGlarLixi versus IDegLira in adults with type 2 diabetes inadequately controlled by glucagon-like peptide-1 receptor agonists: a systematic literature review and indirect treatment comparison.

AIMS: To estimate the relative treatment effect between the fixed-ratio combinations iGlarLixi and IDegLira (glucagon-like peptide 1 receptor agonist with basal insulin) in people with type 2 diabetes inadequately controlled on a glucagon-like peptide 1 receptor agonist. MATERIALS AND METHODS: A systematic literature review of randomized controlled trials followed by an indirect treatment comparison was performed to compare the efficacy and safety of the available fixed-ratio combinations. Main outcomes were glycated haemoglobin (HbA1c) change and target achievement [<6.5% and <7.0% (<48 and <53 mmol/mol)], fasting plasma glucose, self-monitored plasma glucose, body weight, and incidence and rate of hypoglycaemia. RESULTS: From 4850 abstracts screened, 78 qualified for full-text article review and two randomized controlled trials were included. Baseline characteristics were similar in the two studies. The mean difference at 26 weeks between IDegLira and iGlarLixi was -0.36 (95% credible intervals -0.58, -0.14) % [-3.9 (-6.3, -1.5) mmol/mol] for HbA1c and -1.0 (-1.6, -0.4) mmol/L for fasting plasma glucose. No significant differences were found in HbA1c target attainment, preprandial or postprandial self-monitored plasma glucose, or body weight change. Formal comparisons of hypoglycaemia were limited by differences in definitions between the studies: in non-sulphonylurea users, incidence was 28% for IDegLira ('confirmed' at ≤3.1 mmol/L); for iGlarLixi, incidence was 9% ('documented symptomatic' at <3.0 mmol/L). CONCLUSIONS: Results of this indirect treatment comparison using two studies suggest iGlarLixi and IDegLira appear to offer similar benefits for HbA1c target achievement. However, the findings suggest differences in other glycaemia results and hypoglycaemia, which may reflect differences in study design and titration approaches.

Hypoglycaemia risk with insulin glargine 300 U/mL compared with glargine 100 U/mL across different baseline fasting C-peptide levels in insulin-naïve people with type 2 diabetes: A post hoc analysis of the EDITION 3 trial.

The relationship between baseline fasting C-peptide (FCP) and glucose control was examined in insulin-naïve people with type 2 diabetes inadequately controlled with oral antihyperglycaemic drugs commencing basal insulin glargine 300 U/mL (Gla-300) or 100 U/mL (Gla-100) in the absence of sulfonylurea/glinides. Participants with FCP measurement from the EDITION 3 trial (n = 867) were stratified according to baseline FCP (≤0.40, >0.40-1.20, >1.20 nmol/L); 11.0%, 70.9% and 18.1% contributed to each group. Glycaemic control, body weight, insulin dose and hypoglycaemia were determined at 26 weeks. Glycaemic control (HbA1c, FPG) at 26 weeks was similar in each FCP group between insulins. However, end-of-study insulin dose was greater with higher FCP for both insulins. More people with lower baseline FCP experienced hypoglycaemia with both insulins, but with numerically lower incidence for Gla-300 versus Gla-100 across all FCP groups for all definitions (time periods and levels) of hypoglycaemia. This suggests that Gla-300 might be particularly advantageous for people who are at higher risk of hypoglycaemia.