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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.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.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.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.

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.

The Diabetes Control and Complications Trial (DCCT) and the UK Prospective Diabetes Study (UKPDS) have given us fundamental insights into the natural history and management of diabetes (1,2). These include strong evidence that 1 ) enhanced glycemic management can limit some of the complications of diabetes, 2 ) there is a dose-response relationship between HbA1c levels and the risk of complications, and 3 ) a treatment target of

Introduction: SoliMix (EudraCT: 2017-003370-13) found better HbA1c, weight benefit, and lower hypoglycemia risk with iGlarLixi vs. premix BIAsp 30 in people with type 2 diabetes (T2D) advancing from basal insulin (BI) + oral antihyperglycemic drugs (OADs) . Methods: Adults with T2D and HbA1c 7.5-10.0 % on BI + 1-2 OADs were randomized to once-daily iGlarLixi or twice-daily BIAsp 30 for 26 weeks. Primary outcomes were non-inferiority in HbA1c change or superiority in body weight change from baseline to Week 26. SoliMix endpoints were assessed here by baseline age ( Results: No differences in treatment effect were observed across subgroups for HbA1c or body weight changes (heterogeneity p>0.05; Table) ; both primary objectives were met in the age, T2D duration, and the eGFR ≥60-0.80) . The advantage of iGlarLixi over BIAsp 30 for Level 2 hypoglycemia was found in all subgroups with no difference in treatment effect (p>0.10) . Conclusions: The primary findings for iGlarLixi vs. BIAsp 30 were unaffected by baseline age, T2D duration, or renal function. Disclosure P.Home: Advisory Panel; Kriya Therapeutics, Consultant; Mundipharma, Sanofi, Other Relationship; AstraZeneca, Sanofi, Research Support; Gan & Lee Pharmaceuticals, Sanofi, Speaker's Bureau; Gan & Lee Pharmaceuticals, Medscape. J.Rosenstock: Consultant; AstraZeneca, Other Relationship; Applied Therapeutics, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Hanmi Pharm. Co., Ltd., Intarcia Therapeutics, Inc., Novo Nordisk, Oramed Pharmaceuticals, Sanofi, Zealand Pharma A/S, Research Support; Genentech, Inc., Merck & Co., Inc., Metacrine, Inc., Novartis Pharmaceuticals Corporation, Pfizer Inc., vTv Therapeutics. F.Giorgino: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk, Consultant; Lilly Diabetes, Sanofi, Research Support; Lilly Diabetes, Roche Diabetes Care, Takeda Pharmaceutical Company Limited. M.Blüher: Consultant; AstraZeneca, Lilly, Novo Nordisk A/S, Pfizer Inc., Sanofi, Speaker's Bureau; Bayer AG, Boehringer Ingelheim International GmbH, Novartis AG. K.Djaballah: Employee; Sanofi. K.Pegelow: Employee; Sanofi-Aventis Deutschland GmbH. L.Melas-melt: None. R.J.Mccrimmon: Advisory Panel; Novo Nordisk, Sanofi, Research Support; Diabetes UK, European Union, MedImmune. Funding Sanofi

Introduction: SoliMix (EudraCT: 2017-003370-13) found better HbA1c, weight benefit, and lower hypoglycemia risk requiring less insulin with once-daily iGlarLixi vs. twice-daily premix BIAsp 30 in people with type 2 diabetes (T2D) advancing from basal insulin (BI) and oral antihyperglycemic drugs (OADs) . Methods: Adults with T2D and HbA1c 7.5-% on BI + 1-2 OADs were randomized to iGlarLixi or BIAsp 30 for 26 weeks. Primary outcomes were non-inferiority in HbA1c change or superiority in body weight change with iGlarLixi vs. BIAsp 30. This post hoc analysis assessed SoliMix endpoints by baseline HbA1c (7.5-8, >8-9, >9-%) , insulin dose ( Results: No differences in treatment effect were seen across subgroups for change in HbA1c or BMI (heterogeneity p>0.10; Table) ; both primary objectives were met in the HbA1c >8-≤9 %, BMI ≥25-0.10) . Level 2 hypoglycemia incidence and rates were unaffected by baseline HbA1c and BMI (p>0.10) , but p Conclusions: Primary SoliMix findings for iGlarLixi vs. BIAsp 30 were consistent across baseline HbA1c and BMI subgroups but inconsistent for baseline insulin dose. Disclosure P.Home: Advisory Panel; Kriya Therapeutics, Consultant; Mundipharma, Sanofi, Other Relationship; AstraZeneca, Sanofi, Research Support; Gan & Lee Pharmaceuticals, Sanofi, Speaker's Bureau; Gan & Lee Pharmaceuticals, Medscape. R.J.Mccrimmon: Advisory Panel; Novo Nordisk, Sanofi, Research Support; Diabetes UK, European Union, MedImmune. J.Rosenstock: Consultant; AstraZeneca, Other Relationship; Applied Therapeutics, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Hanmi Pharm. Co., Ltd., Intarcia Therapeutics, Inc., Novo Nordisk, Oramed Pharmaceuticals, Sanofi, Zealand Pharma A/S, Research Support; Genentech, Inc., Merck & Co., Inc., Metacrine, Inc., Novartis Pharmaceuticals Corporation, Pfizer Inc., vTv Therapeutics. M.Blüher: Consultant; AstraZeneca, Lilly, Novo Nordisk A/S, Pfizer Inc., Sanofi, Speaker's Bureau; Bayer AG, Boehringer Ingelheim International GmbH, Novartis AG. K.Pegelow: Employee; Sanofi-Aventis Deutschland GmbH. L.Melas-melt: None. K.Djaballah: Employee; Sanofi. F.Giorgino: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk, Consultant; Lilly Diabetes, Sanofi, Research Support; Lilly Diabetes, Roche Diabetes Care, Takeda Pharmaceutical Company Limited. Funding Sanofi

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.

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.

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 [

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.

So-called 'real-world' studies seem increasingly popular in diabetes care, as are the economic evaluations in secondary literature based upon them. The term is usually used for pharmacoepidemiological uncontrolled observational studies of different designs. Interpretation of the study findings is, however, badly undermined by the very reasons that the randomised controlled blinded study was invented – namely, non-medication study effects and biases in investigator selection and behaviour. In diabetes studies, glucose control seems particularly susceptible to such effects, perhaps through changes in patient motivation and education. Further, insulin studies are heavily influenced by baseline factors such as the site of starting insulin, the health circumstances of the patient at the time and the clinician involved. It is rare to see these issues adequately addressed or attempts made to understand their influence. In this article an attempt is made to discuss some of the issues further.

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.

Introduction: Therapeutic approaches to advancing treatment from basal insulin in T2D require assessment of the benefits and risks of any chosen intervention. Methods: SoliMix was a 26-week, open-label, multicenter study in which adults (N=887) with T2D and HbA1c ≥7.5-≤10.0 % (≥58-≤86 mmol/mol) using basal insulin + metformin ± sodium-glucose co-transporter-2 inhibitors were randomized to once-daily iGlarLixi (fixed-ratio combination of basal insulin glargine 100 U/mL + lixisenatide) or twice-daily premix insulin 30/70 analog (BiAsp 30). HbA1c improved and bodyweight changes were favorable with iGlarLixi vs. BiAsp 30 (primary outcomes), while hypoglycemia event rates were also lower with iGlarLixi vs. BiAsp 30. This subanalysis assessed estimated hypoglycemia event rates over the whole treatment period as a function of HbA1c at Week 26. Results: Modelled event profiles for clinically significant hypoglycemia (ADA Level 2 [ Conclusion: Lower rates of hypoglycemia with iGlarLixi across a broad range of HbA1c suggests that iGlarLixi facilitates greater HbA1c improvement vs. premix insulin 30/70. Disclosure R. J. Mccrimmon: Advisory Panel; Self; Novo Nordisk Inc., Sanofi-Aventis, Board Member; Self; Novo Nordisk Foundation, Research Support; Self; AstraZeneca. J. Rosenstock: Board Member; Self; Applied Therapeutics, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Intarcia Therapeutics, Inc., Novo Nordisk, Oramed Pharmaceuticals, Inc., Sanofi, Consultant; Self; Applied Therapeutics, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Intarcia Therapeutics, Inc., Novo Nordisk, Oramed Pharmaceuticals, Inc., Sanofi, Research Support; Self; Applied Therapeutics, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Genentech, Inc., Intarcia Therapeutics, Inc., Lexicon Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk, Oramed Pharmaceuticals, Inc., Pfizer Inc., REMD Biotherapeutics, Sanofi. P. Home: Consultant; Self; American Diabetes Association, Kriya Technologies, Sanofi, Other Relationship; Self; Association of British Clinical Diabetologists, AstraZeneca, Novartis Malaysia, Sanofi, Research Support; Self; Sanofi. A. Y. Cheng: Advisory Panel; Self; Abbott, AstraZeneca, Bayer Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, HLS Therapeutics Inc., Janssen Pharmaceuticals, Inc., Medtronic, Merck & Co., Inc., Merck Sharp & Dohme Corp., Novo Nordisk, Sanofi, Research Support; Self; Applied Therapeutics, The Medicine Company, Speaker’s Bureau; Self; Abbott, AstraZeneca, Bausch Health, Canada, Bayer Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, HLS Therapeutics Inc., Janssen Pharmaceuticals, Inc., Medtronic, Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk, Sanofi. F. Giorgino: Consultant; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Novo Nordisk, Roche Diabetes Care, Sanofi, Research Support; Self; Lilly Diabetes, Roche Diabetes Care. V. Fonseca: Consultant; Self; Abbott Diabetes, Asahi Kasei Corporation, Bayer Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Intarcia Therapeutics, Inc., Novo Nordisk, Pfizer Inc., Sanofi-Aventis, Stock/Shareholder; Self; Amgen Inc., Bravo4health, Mellitus Health. E. Souhami: Employee; Self; Sanofi, Stock/Shareholder; Self; Sanofi. A. Alvarez: Employee; Self; Sanofi. A. H. Boss: Employee; Self; Sanofi, Stock/Shareholder; Self; Novo Nordisk A/S. L. Melas-melt: None. Funding Sanofi

Introduction: No head-to-head trials compare iGlarLixi, a fixed-ratio combination of basal insulin (BI) and glucagon-like peptide-1 receptor agonist, with IDegAsp, a co-formulation of BI analog and meal-time insulin. Methods: A systematic literature search of randomized controlled trials (RCTs) of iGlarLixi and IDegAsp vs. comparators was carried out. Studies were compared by an ITC using a Bayesian framework. Results are given for all trials, Japanese trials, and international trials. Results: Eight RCTs (duration 24-30 weeks) were included. Change in HbA1c with iGlarLixi was greater, and bodyweight trajectory was more favorable than with IDegAsp for all analyses (Figure). A greater percentage of people achieved HbA1c target ( Conclusion: iGlarLixi offers clinical benefit in glycemic control and weight change vs. IDegAsp in those requiring both basal plus meal-time insulin interventions. Disclosure P. Home: Consultant; Self; American Diabetes Association, Kriya Technologies, Sanofi, Other Relationship; Self; Association of British Clinical Diabetologists, AstraZeneca, Novartis Malaysia, Sanofi, Research Support; Self; Sanofi. R. Mehta: Advisory Panel; Self; AstraZeneca, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Novo Nordisk, Sanofi, Speaker’s Bureau; Self; Abbott, Amgen Inc., Boehringer Ingelheim Pharmaceuticals, Inc. K. Hafidh: None. O. Gurova: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Novo Nordisk, Sanofi, STADA, Takeda Pharmaceutical Co. A. Alvarez: Employee; Self; Sanofi. P. Serafini: Other Relationship; Self; Sanofi. M. Pourrahmat: Other Relationship; Self; Sanofi. Funding Sanofi

The recent changes to hypoglycemia definitions, as proposed by the International Hypoglycaemia Study Group (IHSG) and widely accepted by some regulators and major diabetes associations, were poorly evidence-based, relying on pathophysiological studies and small clinical studies (1). In this issue of Diabetes Care , Heller et al. (2) attempt to remedy this, and they present some useful information on the effect of choice of level for hypoglycemia on statistical power and effect size when comparing insulins. The definitions are for use in clinical trials, as the IHSG emphasizes, and not for application to individual people with diabetes seen in clinical practice (1). Broadly, using data from the SWITCH 1 (type 1 diabetes [T1D]) and SWITCH 2 (type 2 diabetes [T2D]) studies of insulin degludec versus insulin glargine 100 units/mL (3,4), the difference in event rates declines below the earlier American Diabetes Association (ADA) threshold of

Glycated hemoglobin targets have been given in guidelines for the last three decades, mostly without change at around 6.5–7.0% (47–53 mmol/mol). Personalization of such targets has also long been advocated, but often with little and inappropriate guidance. More recently some have suggested higher targets might be indicated, and more specifically lower targets avoided, even in those in whom they are easily attained without seeming burden or risk. Prospective data from randomized and observational studies, in people with type 2 diabetes and indeed those without diabetes, find cardiovascular and mortality risk are uniformly lowest at lower levels including into the normal range. In some studies with large populations, a high proportion of people are found to attain such levels, and the UK Prospective Diabetes Study (UKPDS) and more recent studies appear to confirm the importance of starting low and continuing long. Studies of cardiovascular events and mortality in people with diabetes will already factor in any effect of hypoglycemia, which therefore should not be double-counted in setting targets. Nevertheless, some factors should lead to modification of target levels, and these will include experience of hypoglycemia where therapy change and glucose monitoring cannot ameliorate it and sometimes prospectively in those at social or occupational risk. The fact that clinical experience will modify targets emphasizes that targets will not be stable over time but will change, for example, with occurrence of adverse events or perceptions of increase/decreased burden of therapy. The evidence suggests that glucose control takes 5 years or more to have any impact on vascular outcomes or mortality, so targets may also be higher in those with shorter life expectancy or higher health burden or simply reflect individual preferences. This article discusses the evidence behind these conclusions.

Three further cardiovascular (CV) outcome studies of glucose-lowering drugs (linagliptin, albiglutide and dapagliflozin) have recently been published, adding to the twelve earlier within-class studies. The linagliptin study (CARMELINA) recruited people with renal disease as well as prior CV events and confirms the overall CV safety (and other safety) of the dipeptidylpeptidase-4 (DPP4) inhibitors, with no heart failure risk associated with this agent. However, taken together with the findings from two previous studies of DPP4 inhibitors (sitagliptin and saxagliptin), the three DPP4 inhibitor CV outcome trials (CVOTs) have highlighted a safety signal regarding risk of pancreatitis. Like CARMELINA, the albiglutide study (Harmony Outcome) had a very high CV event rate. Despite being a short duration study, albiglutide showed strong superiority for reduction in the major adverse CV events (MACE) composite in people with extant cardiovascular disease (CVD), in line with the earlier studies on the GLP-1 receptor agonists (GLP-1RAs) liraglutide and semaglutide. Positive effects can be detected for all these medications from before 12 months and continue for the whole study duration. No new safety issues for albiglutide are identified and the lack of a pancreatitis or a pancreatic cancer signal for this class is now clear. For the sodium-glucose cotransporter-2 (SGLT2) inhibitor class, the DECLARE-TIMI 58 study (of dapagliflozin) clearly indicates strong protection for heart failure in those with CVD, and probably in those with no prior CVD. There is also strong protection against renal decline with dapagliflozin, with similar risk estimates in DECLARE as previously reported for empagliflozin and canagliflozin. However, findings for MACE outcomes with dapagliflozin are not concordant with the empagliflozin and canagliflozin studies, and are not convincingly superior across class and for the longer term. Care is required when prescribing the SGLT2 inhibitor class of medications to people with foot vascular issues or prior amputation, and to insulin users in regard of ketoacidosis. In summary, taking into account the findings from these new studies, it is suggested that a GLP-1RA should be offered to all people with CVD and type 2 diabetes, and SGLT2 inhibitors should be prescribed for those at high risk of heart failure or with progressive decline in eGFR. DPP4 inhibitors are a safe choice within the glucose-lowering stepped algorithm.

AIMS To identify factors associated with achievement of glycated haemoglobin A1c (HbA1c) target at 24 weeks after commencing basal insulin therapy in individuals with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS Post-hoc pooled analysis of 16 randomized, treat-to-target trials involving individuals with T2DM inadequately controlled with oral anti-hyperglycaemic drugs (n = 3415) initiated on once-daily insulin glargine 100 U/mL (Gla-100). Clinical outcomes were assessed by HbA1c response at 24 weeks and individuals were classified as "good responders" with HbA1c

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.

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.

Objective: The principle of replacing prandial insulin lispro with a once-weekly GLP-1 receptor agonist (GLP-1RA) in 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+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, were reduced at week 26 to 6.7±0.8% (49±8 mmol/mol) and 6.6±0.8% (48±8 mmol/mol); respectively (LS difference 0.06% [95% CI, −0.05 to 0.17]; noninferiority P. 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 62U/day (95% CI −65.9 to −57.8; P 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 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 GLP1RA arm. Replacing prandial insulin with a weekly GLP-1RA can simplify basal+prandial insulin treatments and achieve better outcomes in type 2 diabetes.

In people with type 2 diabetes uncontrolled by GLP-1 RAs, fixed-ratio combination (FRC; basal insulin + GLP-1 RA) is a recommended option. A PICO-framework systematic review of RCTs followed by an ITC was performed to compare the efficacy and safety of the FRCs iGlarLixi (insulin glargine 100 U/mL + lixisenatide) and IDegLira (insulin degludec + liraglutide) in this population. A fixed effects model was used on the two eligible RCTs. Outcomes: change from baseline to week 26 in HbA1c, clinic fasting plasma glucose (FPG), self-monitored plasma glucose (SMPG), and body weight; proportion achieving HbA1c Disclosure P. Home: Advisory Panel; Self; Roche Diabetes Care. Consultant; Self; Mundipharma International, Novartis AG, Sanofi. Research Support; Self; GlaxoSmithKline plc., Merck & Co., Inc., Sanofi. Other Relationship; Self; AstraZeneca, Boehringer Ingelheim International GmbH. V.R. Aroda: Consultant; Self; Duke, Novo Nordisk Inc., Sanofi. Employee; Spouse/Partner; Merck & Co., Inc. Research Support; Self; Applied Therapeutics, Fractyl Laboratories, Inc., Novo Nordisk Inc., Sanofi. Other Relationship; Self; IMNE, Medscape. M. Fazeli: None. C. Whittington: Employee; Self; Sanofi US. H. Goswami: None. A. Shaunik: None. M. Pourrahmat: Other Relationship; Self; Sanofi US. L. Blonde: Advisory Panel; Self; AstraZeneca, Gilead Sciences, Inc. Consultant; Self; Merck & Co., Inc., Novo Nordisk A/S, Sanofi. Research Support; Self; Janssen Scientific Affairs, LLC., Novo Nordisk A/S, Sanofi. Speaker’s Bureau; Self; Janssen Pharmaceuticals, Inc., Sanofi. S. Kalra: Advisory Panel; Self; Eli Lilly and Company. Speaker’s Bureau; Self; Novo Nordisk A/S, Sanofi-Aventis. Funding Sanofi

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.

After a century of medical progress, people nowadays live longer with diabetes than ever before. However, current preventative approaches, compounded in part by increased life-expectancy, are failing to reduce the prevalence of diabetes. Cardiovascular sequelae account for many of the four million deaths annually attributable to diabetes. Evidence indicates that certain glucose-lowering medications can improve vascular outcomes in some people with type 2 diabetes, which, together with better understanding of using multiple therapies concurrently, offers opportunities for beneficial personalization of medication regimens. However, further well-designed long-term studies are needed to evaluate cardiovascular benefits and safety of new and older medications, particularly in users typical of everyday diabetes care. Although there are numerous other promising advances in pharmacotherapies and biotechnology, these will probably be unaffordable for most people with diabetes globally. Therefore, effective national public health approaches will be essential to reducing the incidence of diabetes and its associated burdens; these may entail politically controversial measures to change unhealthy lifestyle behaviours. Stakeholders could learn from past failures and emulate successes in other health-care initiatives. Without early action at all levels, we face a future in which approaching one-quarter of humans will have diabetes, with more than half afflicted during their lifetime.

Aim To compare the efficacy and safety of MK-1293 insulin glargine (Mk-Gla; 100 U/mL) with originator insulin glargine, Lantus (Sa-Gla), in people with type 1 diabetes mellitus (T1DM). Materials and methods This phase 3, randomized, active-controlled, open-label, 52-week study (ClinicalTrials.gov NCT02059161) enrolled 508 people with T1DM (HbA1c ≤11.0%; 97 mmol/mol) taking basal and prandial insulin. Participants were randomized 1:1 to once-daily Mk-Gla (n = 245) or Sa-Gla (n = 263). Dose titration of basal insulin was by a pre-breakfast plasma glucose dosing algorithm. The primary efficacy objective was assessment of the non-inferiority of HbA1c change from baseline (margin of 0.40% [4.4 mmol/mol]) for Mk-Gla compared with Sa-Gla over 24 weeks. The primary safety objective was assessment of anti-insulin antibody development over 24 weeks. Results The least squares (LS) mean HbA1c change from baseline at week 24 was -0.62 (95% CI -0.79, -0.45)% (-6.8 [-8.7, -4.9] mmol/mol) and -0.66 (-0.82, -0.50)% (-7.2 [-9.0, -5.4] mmol/mol) for Mk-Gla and Sa-Gla. The LS mean HbA1c difference was 0.04 (-0.11, 0.19)% (0.4 [-1.2, 2.0] mmol/mol) for Mk-Gla minus Sa-Gla, meeting the primary and secondary objective criteria for non-inferiority and equivalence. Week 24 mean insulin glargine dose for Mk-Gla and Sa-Gla was 0.46 and 0.48 U/kg, respectively. Similarity of HbA1c response and basal insulin dose trajectory persisted over the 52 weeks. Safety and tolerability, including anti-insulin antibody responses, hypoglycaemia, adverse events and body weight, were similar between insulins over the 52-week study duration. Conclusions Mk-Gla and Sa-Gla exhibited similar efficacy and safety over 52 weeks in people with T1DM. ClinicalTrials.gov: NCT02059161.

Background: SAR342434 (SAR-Lis) is a biosimilar (follow-on) of insulin lispro (Humalog®; Ly-Lis). Two randomized, controlled, open-label, parallel-group, phase 3 studies were conducted to compare the efficacy and safety of SAR-Lis and Ly-Lis, both in combination with insulin glargine (Lantus®). SORELLA 1 was a 12-month study in 507 people with type 1 diabetes mellitus (T1DM); SORELLA 2 was a 6-month study in 505 people with type 2 diabetes mellitus (T2DM). In this study, the impact of anti-insulin antibodies (AIA) to SAR-Lis and Ly-Lis on safety and glycemic control is reported. Methods: AIA were measured regularly throughout both studies at a centralized laboratory blinded to treatment groups using a drug-specific AIA assay. The AIA status (positive or negative), AIA titers, and cross-reactivity to human insulin, insulin glargine, and insulin glargine metabolite M1 were analyzed. The potential effect of AIA on safety, particularly as related to hypersensitivity reactions, hypoglycemia, and treatment-emergent adverse events, as well as on glycemic control (HbA1c, insulin dose), was evaluated. Results: AIA positive status at baseline was similar for the two insulins, but higher in T1DM than in T2DM. In both studies, the percentage of people newly developing AIA in the two treatment groups, or having a ≥4-fold increase in AIA titers, did not differ. No relationship was observed between maximum individual AIA titers and change in HbA1c or insulin dose, hypoglycemia, or hypersensitivity reactions or between efficacy/safety measures and subgroups by presence or absence of treatment-emergent AIA. Hypersensitivity events and events adjudicated as allergic reactions were few and did not differ between the two groups. Conclusion: Insulin lispro SAR342434 and the originator insulin lispro had a similar immunogenicity profile in people with T1DM or T2DM.

Aims A number of insulin regimens are used in type 2 diabetes. This analysis aims to better understand the evolution of insulin therapy in different regions of Europe. Methods Data from people starting any insulin were collected in eastern Europe (EEur: Croatia, Russia, Ukraine), northern Europe (NEur: Finland, Germany, UK) and southern Europe (SEur: France, Italy, Portugal, Spain). Retrospective data on starting insulin and prospective follow-up data were extracted from clinical records. Results At 4 years, 1699 (76.0%) of 2236 eligible people had data. EEur participants were mostly female, younger and had shorter diabetes duration on starting insulin, yet had highest baseline HbA1c and more micro-/macrovascular disease. A majority (60%–64%) in all regions started on basal insulin alone, declining to 30%–38% at 4 years, with most switching to basal + mealtime insulin regimen (24%–40%). Higher baseline (28%) and 4-year use (34%) of premix insulin was observed in NEur. Change in HbA1c (SD) ranged from −1.2 (2.1)% (−13 [23] mmol/mol) in NEur to −2.4 (2.0)% (−26 [22] mmol/mol) in EEur. Weight change ranged from +1.9 (8.3) kg in NEur to +3.2 (7.0) kg in SEur. Overall documented hypoglycemia ranged from 0.3 (1.3) to 1.3 (4.4) events/person/6-months (NEur vs. EEur, respectively) and was stable with time. Severe hypoglycemia rates remained low. Conclusion When starting insulin, HbA1c and prevalence of complications were higher in EEur. Regional differences exist in choice of insulin regimens in Europe. However, people starting insulin improved and sustained their glycemic control regardless of regional differences or insulin regimens used.

Aims Diabetes therapies that provide durable glycaemic control for people with type 2 diabetes mellitus (T2DM) are needed. We present efficacy results of albiglutide, a glucagon-like peptide-1 receptor agonist, in people with T2DM over a 3-year period. Methods Five of the 8 HARMONY phase 3 trials, comparing albiglutide with other therapies or placebo across a spectrum of clinical care, lasted for a preplanned 3 years. Participants with uncontrolled hyperglycaemia who met predetermined criteria could receive rescue medication. The ability to remain on study medication without needing additional rescue was an efficacy measure. Glycaemic measures and body weight were analysed in 2 populations: those who remained rescue-free and all participants. Results Participants ( n = 3132) were randomised to albiglutide or comparator. A greater proportion of participants who received albiglutide remained rescue-free (55–71%) compared with placebo (35–51%; p p = 0.002). The proportion of rescue-free participants with albiglutide did not differ from glimepiride or insulin glargine, was higher than with sitagliptin ( p = 0.013), and lower than with pioglitazone ( p = 0.045). At 3 years, albiglutide was associated with clinically significant reductions in hyperglycaemia (eg, rescue-free participants: HbA1c −0.52% [SE0.11] to −0.98% [0.12]; −5.7 mmol/mol [1.2] to −10.7 mmol/mol [1.3] and all participants: HbA1c −0.29% [0.11] to − 0.92% [0.13]; −3.2 mmol/mol [1.2] to −10.1 mmol/mol [1.4]). Albiglutide was also associated with modest reductions in body weight vs pioglitazone, glimepiride, and insulin glargine, which were associated with weight gain. Conclusion These 3-year efficacy data support long-term use of albiglutide in the management of people with T2DM. ClinicalTrials.gov NCT00849056 , NCT00849017 , NCT00838903 , NCT00838916 , NCT00839527 .

Aim To explore if efficacy and safety findings for insulin glargine 300U/mL (Gla-300) versus insulin glargine 100U/mL (Gla-100), observed over 6 months in insulin- naive people with type 2 diabetes, are maintained after 12 months. Methods EDITION 3 was a phase 3a, randomized, multicentre, open-label, parallel-group, treat-to-target study of once-daily Gla-300 versus Gla-100 (target fasting self-monitored plasma glucose, 4.4–5.6mmol/L [80–100mg/dL]). Participants completing the initial 6-month treatment phase continued their previously allocated basal insulin. Results Of 878 participants randomized, 337/439 (77%) and 314/439 (72%) assigned to Gla-300 and Gla-100, respectively, completed 12 months of treatment. Improved glycaemic control was sustained until 12 months in both treatment groups, with similar reductions in HbA 1c from baseline to month 12 (difference: −0.08 [95% confidence interval (CI): −0.23 to 0.07] % or −0.9 [−2.5 to 0.8] mmol/mol). Relative risk of experiencing≥1 confirmed (≤3.9mmol/L [≤70mg/dL]) or severe hypoglycaemic event with Gla-300 versus Gla-100 was 0.86 (95% CI: 0.69 to 1.07) at night and 0.92 (0.82 to 1.03) at any time of day. For events with a glycaemic threshold of Conclusion Over 12 months, Gla-300 treatment was as effective as Gla-100 in reducing HbA 1c in insulin- naive people with type 2 diabetes, with lower overall risk of hypoglycaemia at the

Thanks to significant improvements in the precision, accuracy, and usability of continuous glucose monitoring (CGM), its relevance in both ambulatory diabetes care and clinical research is increasing. In this study, we address the latter perspective and derive provisional reporting recommendations. CGM systems have been available since around the year 2000 and used primarily in people with type 1 diabetes. In contrast to self-measured glucose, CGM can provide continuous real-time measurement of glucose levels, alerts for hypoglycemia and hyperglycemia, and a detailed assessment of glycemic variability. Through a broad spectrum of derived glucose data, CGM should be a useful tool for clinical evaluation of new glucose-lowering medications and strategies. It is the only technology that can measure hyperglycemic and hypoglycemic exposure in ambulatory care, or provide data for comprehensive assessment of glucose variability. Other advantages of current CGM systems include the opportunity for improved self-management of glycemic control, with particular relevance to those at higher risk of or from hypoglycemia. We therefore summarize the current status and limitations of CGM from the perspective of clinical trials and derive suggested recommendations for how these should facilitate optimal CGM use and reporting of data in clinical research.

Background After 98 years of insulin therapy, issues of safety remain of concern. Areas of uncertainty Uncertainty has been expressed variously in regard of arterial cell wall proliferation, promotion of proliferative retinopathy, promotion of tumor growth, and for pregnancy. Immunological issues have been little studied since the advent of highly purified insulins in the 1970s. A specific topic is whether hypoglycemia, severe or otherwise, might promote cardiac thrombotic or dysrhythmic events. Data sources A literature review in these areas is difficult because nearly all clinical trials with insulin refer to adverse events. However, the specific topics aforementioned allow for some informed literature searching supplemented by finger-searching of published articles, notably in connection with the insulin analogues. Therapeutic understandings Safety data for pregnancy are weak because of power problems, but there are no signals for added maternal or fetal risk. Clinical-outcome trials that assess insulin against other glucose-lowering therapies or with significantly different insulin preparations in different arms are few and are sometimes conducted at modest dosage but fail to suggest promotion of arterial disease. Concern over growth-promoting activity of insulin glargine turned out to be ill-founded when the circulating moiety after injection was noted to have a lower IGF-1:insulin activity than human insulin, and a direct study of retinopathy progression or meta-analysis of malignancy incidence failed to show signals of concern. It does seem that severe hypoglycemia can cause death in some people with type 1 diabetes, although the tissue mechanism is unknown, but reducing severe hypoglycemia in type 2 diabetes does not protect against arterial events. Both symptomatic and severe hypoglycemia can however be reduced by use of more recently marketed insulin analogues, and this improves tolerability if not safety. Conclusions In conclusion, although insulin therapy clearly gives health benefits, the evidence for long-term harm is absent or weak.

AIMS/HYPOTHESIS: Observational studies suggest that metformin may reduce cancer risk by approximately one-third. We examined cancer outcomes and all-cause mortality in published randomised controlled trials (RCTs). METHODS: RCTs comparing metformin with active glucose-lowering therapy or placebo/usual care, with minimum 500 participants and 1-year follow-up, were identified by systematic review. Data on cancer incidence and all-cause mortality were obtained from publications or by contacting investigators. For two trials, cancer incidence data were not available; cancer mortality was used as a surrogate. Summary RRs, 95% CIs and I (2)statistics for heterogeneity were calculated by fixed effects meta-analysis. RESULTS: Of 4,039 abstracts identified, 94 publications described 14 eligible studies. RRs for cancer were available from 11 RCTs with 398 cancers during 51,681 person-years. RRs for all-cause mortality were available from 13 RCTs with 552 deaths during 66,447 person-years. Summary RRs for cancer outcomes in people randomised to metformin compared with any comparator were 1.02 (95% CI 0.82, 1.26) across all trials, 0.98 (95% CI 0.77, 1.23) in a subgroup analysis of active-comparator trials and 1.36 (95% CI 0.74, 2.49) in a subgroup analysis of placebo/usual care comparator trials. The summary RR for all-cause mortality was 0.94 (95% CI 0.79, 1.12) across all trials. CONCLUSIONS/INTERPRETATION: Meta-analysis of currently available RCT data does not support the hypothesis that metformin lowers cancer risk by one-third. Eligible trials also showed no significant effect of metformin on all-cause mortality. However, limitations include heterogeneous comparator types, absent cancer data from two trials, and short follow-up, especially for mortality.

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.

AIMS: To examine the relationships between glycated haemoglobin (HbA1c) and cardiovascular (CV) events in people beginning insulin in routine clinical practice in Europe, North America and Asia in a non-interventional study, the Cardiovascular Risk Evaluation in people with Type 2 Diabetes on Insulin Therapy (CREDIT) study. METHODS: Data on 2999 people were collected prospectively over 4 years from physician reports. The primary outcome was the composite of stroke or myocardial infarction (MI) or CV-specific death. Events were blindly adjudicated. The relative hazards of CV events were described from Cox proportional hazards models incorporating patient risk factors, with updated average HbA1c as a time-dependent covariate. The relationship of severe and symptomatic hypoglycaemia (collected during the 6 months before yearly ascertainment) with CV and all-cause mortality was examined. RESULTS: A total of 147 primary events were accrued during up to 54 months of follow-up. In all, 60 CV-specific deaths, 44 non-fatal MIs and 57 non-fatal strokes occurred, totalling 161 events. There was a significant positive relationship between updated mean HbA1c and primary outcome: hazard ratio (HR) 1.25 [95% confidence interval (CI) 1.12-1.40; p

The co-formulation insulin degludec/insulin aspart (IDegAsp) contains insulin degludec (IDeg), a basal insulin, and the rapid-acting insulin aspart (IAsp). Its unique pharmacodynamic profile provides a stable basal insulin action over a 24-h period due to the flat, ultra-long effect of IDeg, combined with prandial control from IAsp, which is unaffected by the basal component. IDegAsp provides a distinct mealtime insulin peak effect and reduces the likelihood of postprandial glucose excursions. The phase 2 and 3 clinical trial program demonstrates that IDegAsp provides effective glycemic control with lower rates of hypoglycemia compared with the current standard of care for insulins. Compared with premixed insulin formulations, IDegAsp allows mealtime flexibility, enabling the time of injection to be adjusted to a different meal(s) on a daily basis to suit changing needs, and has the potential to improve adherence rates. IDegAsp offers a promising new insulin strategy for the treatment of type 2 diabetes.

The glycemic efficacy of weekly Albi 50 mg to replace prandial insulin lispro (Lis) was evaluated in T2DM inadequately controlled on a multiple daily insulin regimen (≥3 injections/day). Basal/bolus insulin was optimized during a 4 week run-in phase before randomization to: 1) Albi + optimized insulin glargine (Gla), with prandial Lis subsequently discontinued by week 4 (n = 402) or 2) optimized Lis + optimized Gla (n = 412). At 26 week, the LS mean ± SE change from baseline in HbA1c was −1.04 ± 0.04 vs. −1.10 ± 0.04% (treatment difference 0.[95% CI, −0.05, 0.17]%; non-inferiority p In conclusion, Albi meaningfully improved glucose control; prandial insulin was stopped in 54% of participants, allowing substantial reductions in insulin dose and number of injections, less hypoglycemia, and body weight loss. Disclosure J. Rosenstock: Advisory Panel; Self; Eli Lilly and Company. Consultant; Self; Eli Lilly and Company. Research Support; Self; Novo Nordisk Inc.. Consultant; Self; Novo Nordisk Inc.. Advisory Panel; Self; Sanofi. Consultant; Self; Sanofi. Advisory Panel; Self; Janssen Pharmaceuticals, Inc.. Consultant; Self; Janssen Pharmaceuticals, Inc.. Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Advisory Panel; Self; Intarcia Therapeutics, Inc.. Consultant; Self; Intarcia Therapeutics, Inc.. Research Support; Self; Merck & Co., Inc., Pfizer Inc., Sanofi, Novo Nordisk Inc., Bristol-Myers Squibb Company, Eli Lilly and Company, Intarcia Therapeutics, Inc., Genentech, Inc. A.J. Nino: Employee; Self; GlaxoSmithKline plc.. Stock/Shareholder; Self; GlaxoSmithKline plc. J. Soffer: Employee; Self; GlaxoSmithKline plc.. Other Relationship; Self; GlaxoSmithKline plc.. J.M. Mallory: None. L.M. Erskine: Employee; Self; GlaxoSmithKline plc.. Stock/Shareholder; Self; GlaxoSmithKline plc. A. Acusta: Employee; Self; GlaxoSmithKline plc. J.F. Dole: Employee; Self; GlaxoSmithKline plc. M. Carr: Employee; Self; GlaxoSmithKline plc. P. Home: Consultant; Self; AstraZeneca. Other Relationship; Self; Biocon, Boehringer Ingelheim GmbH. Research Support; Self; GlaxoSmithKline plc.. Consultant; Self; Hanmi Pharmaceutical. Other Relationship; Self; Janssen Research & Development. Consultant; Self; Janssen Research & Development, Merck & Co., Inc.. Other Relationship; Self; Merck & Co., Inc.. Research Support; Self; Merck & Co., Inc.. Other Relationship; Self; Novo Nordisk A/S. Consultant; Self; AntriaBio, Inc., Earlysign, Roche Diabetes Care Health and Digital Solutions. Research Support; Self; Sanofi. Consultant; Self; Sanofi.

Pooled participant-level data from 16 RCTs (≥ 24 weeks) were used to explore the association of demographic and clinical markers with different levels of HbA1c achieved at Week 24 in insulin-naive people with T2DM on oral agents after starting insulin glargine 100 U/mL (Gla-100). A stepwise logistic regression analysis was performed to identify potential predictive and exploratory factors for attaining an HbA1c < 7.0%. In total, 46%, 37%, and 17% of 3,415 participants (53% male) included in the analysis achieved Week 24 HbA1c < 7.0%, 7.0-8.0%, and > 8.0%, respectively. Key clinical findings and multivariate analysis results are shown in the Table. Sex, diabetes duration, baseline BMI, HbA1c, FPG, and overall 2h-PPG were significant predictors of attaining HbA1c < 7.0% at Week 24, whereas change in FPG or 2h-PPG were not. FPG and 2h-PPG levels in the HbA1c > 8.0% group remained highest despite a higher Gla-100 dose (0.52 U/kg) and lower overall hypoglycaemia (PG < 3.9 mmol/L) rate at Week 24. In people with T2DM, high baseline HbA1c, FPG, and PPG levels are important predictors of failure of basal insulin/OAD therapy to achieve desired glycaemic goals. A more active treatment strategy targeting both fasting and postprandial hyperglycaemia appears to be indicated for people with poor glycaemic control after starting basal insulin therapy. Disclosure D.R. Owens: Consultant; Self; Boehringer Ingelheim GmbH, Roche Diagnostics Corporation, Eli Lilly and Company, Sanofi, Takeda Development Centre Europe Ltd.. Speaker's Bureau; Self; Boehringer Ingelheim GmbH, Roche Diagnostics Corporation, Eli Lilly and Company, Sanofi, Takeda Development Centre Europe Ltd. W. Landgraf: Employee; Self; Sanofi-Aventis Deutschland GmbH. Stock/Shareholder; Self; Sanofi. M. Zhang: Employee; Self; Sanofi US. Stock/Shareholder; Self; Sanofi US. B.M. Frier: Advisory Panel; Self; Novo Nordisk A/S, Eli Lilly and Company. Consultant; Self; Locemia Solutions, Zucara Therapeutics. Speaker's Bureau; Self; Novo Nordisk A/S, Eli Lilly and Company, Roche Pharma, AstraZeneca. L. Meneghini: Advisory Panel; Self; Novo Nordisk Inc., Sanofi US. Consultant; Self; Sanofi US, Novo Nordisk Inc.. Advisory Panel; Self; Intarcia Therapeutics, Inc.. Other Relationship; Self; American Diabetes Association. P. Home: Consultant; Self; AstraZeneca. Other Relationship; Self; Biocon, Boehringer Ingelheim GmbH. Research Support; Self; GlaxoSmithKline plc.. Consultant; Self; Hanmi Pharmaceutical. Other Relationship; Self; Janssen Research & Development. Consultant; Self; Janssen Research & Development, Merck & Co., Inc.. Other Relationship; Self; Merck & Co., Inc.. Research Support; Self; Merck & Co., Inc.. Other Relationship; Self; Novo Nordisk A/S. Consultant; Self; AntriaBio, Inc., Earlysign, Roche Diabetes Care Health and Digital Solutions. Research Support; Self; Sanofi. Consultant; Self; Sanofi. G.B. Bolli: Speaker's Bureau; Self; Menarini Group, Sanofi. Research Support; Self; Sanofi.

Aim To compare the efficacy and safety of MK-1293 insulin glargine (Mk-Gla) and Lantus (Sa-Gla) in people with type 2 diabetes mellitus (T2DM). Materials and methods This Phase 3, randomized, active-controlled, open-label, 24-week clinical trial (ClinicalTrials.gov number NCT02059187) enrolled 531 participants with T2DM (HbA1c ≤11.0%) either eligible for or currently taking basal insulin (≥10 U/day). Participants were randomized 1:1 to once-daily Mk-Gla (n = 263) or Sa-Gla (n = 263). Titration of insulin was guided by a fasting plasma glucose (FPG)-based dosing algorithm. The primary efficacy objective was to demonstrate the non-inferiority of change from baseline in HbA1c (margin of 0.40% [4.4 mmol/mol]) with Mk-Gla versus Sa-Gla after 24 weeks. The primary safety objective was anti-insulin antibody development after 24 weeks. Results For Mk-Gla and Sa-Gla, the least squares (LS) mean HbA1c change from baseline (95% CI) was -1.28 (-1.41, -1.15)% (-14.0 [-15.4, -12.6] mmol/mol) and -1.30 (-1.43, -1.18)% (-14.2 [-15.6, -12.8] mmol/mol). The LS mean HbA1c difference (Mk-Gla minus Sa-Gla) was 0.03 (-0.12, 0.18)% (0.3 [-1.4, 1.9] mmol/mol), meeting non-inferiority and equivalence (secondary objective) criteria. Insulin doses, FPG, and seven-point plasma glucose profiles were similar between groups. Safety and tolerability, including anti-insulin antibody responses, hypoglycaemia, adverse events and body weight, were similar between insulins. The efficacy and safety of Mk-Gla and Sa-Gla were similar both in participants who were insulin-treated or insulin-naive at baseline. Conclusions Mk-Gla and Sa-Gla demonstrated similar efficacy and safety over 24 weeks of treatment in people with T2DM.

Many people with diabetes rely on insulin therapy to achieve optimal blood glucose control. A fundamental aim of such therapy is to mimic the pattern of ‘normal’ physiological insulin secretion, thereby controlling basal and meal‐time plasma glucose and fatty acid turnover. In people without diabetes, insulin release is modulated on a time base of 3–10 min, something that is impossible to replicate without intravascular glucose sensing and insulin delivery. Overnight physiological insulin delivery by islet β cells is unchanging, in contrast to requirements once any degree of hyperglycaemia occurs, when diurnal influences are evident. Subcutaneous pumped insulin or injected insulin analogues can approach the physiological profile, but there remains the challenge of responding to day‐to‐day changes in insulin sensitivity. Physiologically, meal‐time insulin release begins rapidly in response to reflex activity and incretins, continuing with the rise in glucose and amino acid concentrations. This rapid response reflects the need to fill the insulin space with maximum concentration as early as 30 min after starting the meal. Current meal‐time insulins, by contrast, are associated with a delay after injection before absorption begins, and a delay to peak because of tissue diffusion. While decay from peak for monomeric analogues is not dissimilar to average physiological needs, changes in meal type and, again, in day‐to‐day insulin sensitivity, are difficult to match. Recent and current developments in insulin depot technology are moving towards establishing flatter basal and closer‐to‐average physiological meal‐time plasma insulin profiles. The present article discusses the ideal physiological insulin profile, how this can be met by available and future insulin therapies and devices, and the challenges faced by healthcare professionals and people with diabetes in trying to achieve an optimum plasma insulin profile.

As obesity rates increase, so too do the risks of type 2 diabetes, cardiovascular disease, and numerous other detrimental conditions. The prevalence of obesity in U.S. adults more than doubled between 1980 and 2010, from 15.0 to 36.1%. Although this trend may be leveling off, obesity and its individual, societal, and economic costs remain of grave concern. In June 2014, a Diabetes Care Editors’ Expert Forum convened to review the state of obesity research and discuss the latest prevention initiatives and behavioral, medical, and surgical therapies. This article, an outgrowth of the forum, offers an expansive view of the obesity epidemic, beginning with a discussion of its root causes. Recent insights into the genetic and physiological factors that influence body weight are reviewed, as are the pathophysiology of obesity-related metabolic dysfunction and the concept of metabolically healthy obesity. The authors address the crucial question of how much weight loss is necessary to yield meaningful benefits. They describe the challenges of behavioral modification and predictors of its success. The effects of diabetes pharmacotherapies on body weight are reviewed, including potential weight-neutral combination therapies. The authors also summarize the evidence for safety and efficacy of pharmacotherapeutic and surgical obesity treatments. The article concludes with an impassioned call for researchers, clinicians, governmental agencies, health policymakers, and health-related industries to collectively embrace the urgent mandate to improve prevention and treatment and for society at large to acknowledge and manage obesity as a serious disease.

Biosimilar insulins are approved copies of insulins outside patent protection. Advantages may include greater market competition and potential cost reduction, but clinicians and users lack a clear perspective on 'biosimilarity' for insulins. The manufacturing processes for biosimilar insulins are manufacturer-specific and, although these are reviewed by regulators there are few public data available to allow independent assessment or review of issues such as intrinsic quality or batch-to-batch variation. Preclinical measures used to assess biosimilarity, such as tissue and cellular studies of metabolic activity, physico-chemical stability and animal studies of pharmacodynamics, pharmacokinetics and immunogenicity may be insufficiently sensitive to differences, and are often not formally published. Pharmacokinetic and pharmacodynamic studies (glucose clamps) with humans, although core assessments, have problems of precision which are relevant for accurate insulin dosing. Studies that assess clinical efficacy and safety and device compatibility are limited by current outcome measures, such as glycated haemoblobin levels and hypoglycaemia, which are insensitive to differences between insulins. To address these issues, we suggest that all comparative data are put in the public domain, and that systematic clinical studies are performed to address batch-to-batch variability, delivery devices, interchangeability in practice and long-term efficacy and safety. Despite these challenges biosimilar insulins are a welcome addition to diabetes therapy and, with a transparent approach, should provide useful benefit to insulin users.