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Introduction: To compare responses to basal insulin glargine 300 U/ml (IGlar‐300) and 100 U/ml (IGlar‐100) in newly defined subphenotypes of type 2 diabetes. Methods: Insulin‐naive participants (n = 858) from the EDITION 3 trial were assigned to subphenotypes 'Mild Age‐Related Diabetes (MARD)', 'Mild Obesity Diabetes (MOD)', 'Severe Insulin Resistant Diabetes (SIRD)' and 'Severe Insulin Deficient Diabetes (SIDD)'. Key variables were analysed at baseline and 26 weeks. Results: Participants were comprised of MOD 56.1% (n = 481), SIDD 22.1% (n = 190), MARD 18.2% (n = 156) and SIRD 3.0% (n = 26). After 26 weeks a similar decrease in glycated haemoglobin (HbA1c) and fasting plasma glucose (FPG) of 16‐19 mmol/mol and 1.4‐1.7 mmol/L, respectively, occurred in MARD and MOD with both insulins. SIDD had the most elevated HbA1c and FPG (80‐83 mmol/mol/11.1‐11.4 mmol/L) and reduction in both HbA1c and FPG was greater with IGlar‐100 than with IGlar‐300 (−18 vs. −15 mmol/mol and −1.6 vs. −1.3 mmol/L, respectively; each p =.03). In SIDD, despite receiving the highest basal insulin doses, HbA1c decline (57‐60 mmol/mol/7.3‐7.6%) was suboptimal at week 26. In MOD and SIDD lower incidences with IGlar‐300 were found for level 1 nocturnal hypoglycaemia [odds ratio (OR) 0.59, 95% confidence intervals (CI) 0.36‐0.97; OR 0.49, 95% CI 0.24‐0.99]. In addition, fewer level 2 hypoglycaemia episodes occurred at any time with IGlar‐300 in SIDD (OR 0.31, 95% CI 0.13‐0.77). Conclusion: Both insulins produce comparable outcomes in type 2 diabetes subphenotypes, but in SIDD, add‐on treatment to basal insulin is required to achieve glycaemic targets. [ABSTRACT FROM AUTHOR]

During 1921 to 1922, a team effort by Banting, Macleod, Collip and Best isolated and purified insulin and demonstrated its life‐giving properties, giving rise to the birth of insulin therapy. In the early years (1922‐1950), priorities revolved around the manufacture of insulin to meet demand, improving purity to avoid allergic reactions, establishing insulin standards and increasing its duration of action to avoid multiple daily injections. Shortly after the emergence of insulin, Joslin and Allen advocated the need to achieve and maintain good glycaemic control to realize its full potential. Although this view was opposed by some during a dark period in the history of insulin, it was subsequently endorsed some 60 years later endorsed by the Diabetes Control and Complications Trial and United Kingdom Prospective Diabetes Study. Major scientific advances by the Nobel Laureates Sanger, Hodgkin, Yalow and Gilbert and also by Steiner have revolutionized the understanding of diabetes and facilitated major advances in insulin therapy. The more recent advent of recombinant technology over the last 40 years has provided the potential for unlimited source of insulin, and the ability to generate various insulin 'analogues', in an attempt to better replicate normal insulin secretory patterns. The emerging biosimilars now provide the opportunity to improve availability at a lower cost. [ABSTRACT FROM AUTHOR]

The class of rapid‐acting insulin analogues were introduced more than 20 years ago to control postprandial plasma glucose (PPG) excursions better than unmodified regular human insulin. Insulins, lispro, aspart and glulisine all achieved an earlier onset of action, greater peak effect and shorter duration of action resulting in lower PPG levels and a reduced risk of late postprandial hypoglycaemia. However, the subcutaneous absorption rate of these analogues still fails to match the physiological profile of insulin in the systemic circulation following a meal. Recent reformulations of aspart and lispro have generated a second generation of more rapid‐acting insulin analogue candidates, including fast‐acting aspart (faster aspart), ultra‐rapid lispro and BioChaperone Lispro. These modifications have the potential to mimic physiological prandial insulin secretion better with an even earlier onset of action with improved PPG control, shorter duration of effect and reduced risk of hypoglycaemia. Recent phase 3 trials in type 1 and type 2 diabetes show that faster aspart and ultra‐rapid lispro compared with conventional aspart and lispro, achieved fewer PPG excursions with a small increase in post‐meal hypoglycaemia but similar or marginally superior glycated haemoglobin levels, and suggest the need for parallel optimization of basal insulin replacement. Phase 1 trials for BioChaperone Lispro are equally encouraging with phase 3 trials yet to be initiated. Comparative analysis of the clinical and pharmacological evidence for these new prandial insulin candidates in the treatment of type 1 and type 2 diabetes is the main focus of this review. [ABSTRACT FROM AUTHOR]

Aim: To examine the relationship between baseline fasting C‐peptide (FCP) and outcomes in insulin‐naïve people with type 2 diabetes initiating basal insulin glargine 100 U/mL (Gla‐100). Materials and methods: Post hoc pooled analysis of nine randomized, treat‐to‐target trials in patients with type 2 diabetes inadequately controlled on oral antihyperglycaemic drugs initiating once‐daily Gla‐100. Participants (n = 2165) were stratified at baseline according to FCP (≤0.40, >0.40–1.20, >1.20–2.00, >2.00 nmol/L). Glycaemic control, body weight, insulin dose and hypoglycaemia were determined at 24 weeks. Results: At baseline low FCP levels were associated with longer known diabetes duration, lower body mass index and higher fasting plasma glucose (FPG). Following Gla‐100 introduction, the mean HbA1c reduction at week 24 was similar in all four FCP groups, albeit fewer people in the lowest FCP group achieved HbA1c <7.0% versus FCP groups >0.40 nmol/L. By contrast, FPG reduction and proportion reaching FPG ≤5.6 mmol/L were greatest in the lowest FCP group, diminishing at higher FCP levels. Gla‐100 dose at week 24 was lowest in the ≤0.40 nmol/L FCP group and highest in the >1.20 nmol/L FCP group. Incidence and event rate of overall, nocturnal and severe hypoglycaemia were higher at week 24 in groups with lower FCP levels. In multivariable regression analysis baseline FCP, concomitant sulphonylurea use and endpoint HbA1c were strong predictors of hypoglycaemia. Conclusions: FCP levels identified patients with type 2 diabetes experiencing different responses to basal insulin Gla‐100. A low FCP identifies a markedly insulin‐deficient, insulin‐sensitive subgroup/phenotype with an enhanced risk of hypoglycaemia, which requires a low initial basal insulin dose, cautious titration and earlier addition of prandial glucose‐lowering therapy. [ABSTRACT FROM AUTHOR]

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 <7.0% (<53 mmol/mol) or as "poor responders" with HbA1c ≥7.0% (≥53 mmol/mol). Univariable and multivariable stepwise logistic regression analyses were performed to identify predictive factors for attaining HbA1c <7.0%. Results: Lower levels of baseline HbA1c, fasting plasma glucose (FPG) and post‐prandial plasma glucose (PPG), higher body mass index (BMI), shorter diabetes duration and male sex were associated with a good glycaemic response, but not age or baseline C‐peptide levels. Gla‐100 dose (U/kg) was highest in the poor‐responder group, which had the fewest hypoglycaemia episodes. Univariable analysis for achievement of HbA1c <7.0% confirmed these observations. Multivariable analysis retained baseline HbA1c, body weight, BMI, sex, 2‐hours PPG and diabetes duration as predictors of a good response. Continued use of sulfonylureas, hypoglycaemia and change in body weight were indicative of poor response. Conclusions: Baseline HbA1c was the strongest determinant for achieving target HbA1c <7.0% by supplementary Gla‐100 therapy, while sex and BMI were also useful indicators. However, age and C‐peptide levels at baseline did not predict glycaemic response to the introduction of basal insulin. [ABSTRACT FROM AUTHOR]

Patient characteristics associated with hypoglycaemia frequency during insulin glargine 100 U/mL (Gla‐100) titration and clinical outcomes at Week 24 were examined using participant‐level data from 16 treat‐to‐target trials involving individuals with type 2 diabetes mellitus who were inadequately controlled with oral antidiabetes drugs and were initiating Gla‐100 (n = 3549). Hypoglycaemia (plasma glucose <3.9 mmol/L or severe) during the first 8 weeks of titration was stratified by number of events (0, 1‐3 and ≥4), resulting in 72.5%, 20.6% and 6.9% of participants in each group, respectively. Changes in glycaemia, body weight and insulin dose from baseline to Weeks 12 and 24 were analysed. Hypoglycaemia was more common in participants with lower BMI and fasting C‐peptide, and in those undergoing sulfonylurea treatment. Glycaemic outcomes at Week 24 were similar in each hypoglycaemia group, despite the fact that the Week 24 mean daily dose and dose increase for Gla‐100 were highest in participants without hypoglycaemia and were lowest in those experiencing ≥4 events. The risk of hypoglycaemia during Gla‐100 titration depends mainly on patient characteristics and on sulfonylurea use and may delay dose titration, which apparently has little effect on short‐term glycaemic control in a clinical trial setting. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus ( T2DM) is an independent risk factor for cardiovascular ( CV) comorbidities, with CV disease being the most common cause of death in adults with T2DM. Although glucocentric therapies may improve glycaemic control (as determined by glycated haemoglobin levels), evidence suggests that this approach alone has limited beneficial effects on CV outcomes relative to improvements in lipid and blood pressure control. This may be explained in part by the fact that current antidiabetic treatment regimens primarily address overall glycaemia and/or fasting plasma glucose, but not the postprandial plasma glucose ( PPG) excursions that have a fundamental causative role in increasing CV risk. This literature review evaluates the relationship between PPG and the risk of CV disease, discusses the treatment of T2DM with glucagon-like peptide-1 receptor agonists ( GLP-1 RAs) and examines the associated CV outcomes. The literature analysis suggests that exaggerated PPG excursions are a risk factor for CV disease because of their adverse pathophysiologic effects on the vasculature, resulting in increased all-cause and CV-related mortality. Although GLP-1 RAs are well established in the current T2DM treatment paradigm, a subgroup of these compounds has a particularly pronounced, persistent and short-lived effect on gastric emptying and, hence, lower PPG substantially. However, current long-term data on CV outcomes with GLP-1 RAs are contradictory, with both beneficial and adverse effects having been reported. This review explores the opportunity to direct treatment towards controlling PPG excursions, thereby improving not only overall glycaemic control but also CV outcomes. [ABSTRACT FROM AUTHOR]

Aims To analyse the effects of patient characteristics and different oral antidiabetes drug (OAD) use on standardised clinical outcomes in type 2 diabetes patients initiating insulin glargine 100 U/mL ( Gla-100). Materials and methods Patient-level data from 16 randomized, treat-to-target clinical trials that added Gla-100 to existing metformin ( MET), sulfonylurea ( SU) or metformin plus sulfonylurea ( MET+ SU) treatment in insulin-naïve patients inadequately controlled by oral therapy were analysed and patients were followed for ≥24 weeks. Change in glycated haemoglobin A1c ( HbA1c) from baseline to week 24, other glycaemic endpoints and incidence of hypoglycaemia (overall, nocturnal, and severe) were analysed by age (<65 vs ≥65 years), gender (male vs female), body mass index ( BMI; <25 vs ≥25 to <30 vs >30 kg/m2) and concomitant OAD ( MET vs SU vs MET+ SU). Results At baseline, the overall population ( N = 3188) had a mean age of 57.7 years, BMI of 30.5 kg/m2, HbA1c of 8.7%, fasting plasma glucose of 192 mg/dL, and 52.7% were male. Younger and older patients had similar HbA1c reductions with Gla-100 and a similar risk of hypoglycaemia. Females and patients with BMI <25 kg/m2 were less likely to achieve HbA1c targets and more likely to experience hypoglycaemia, regardless of concomitant OAD. Adding Gla-100 to SU therapy (alone or in combination with MET) increased hypoglycaemia risk across all analyses. Conclusions Our data suggest that female patients with type 2 diabetes and normal-weight patients treated with Gla-100 and MET ± SU are less likely to achieve glycaemic targets and, therefore, may require more clinical attention. Addition of Gla-100 to SU regimens may increase hypoglycaemia risk irrespective of age, gender, or BMI. [ABSTRACT FROM AUTHOR]

Examines the concept of prandial glucose regulation in the management of type two diabetes in Great Britain. Clinical efficacy of glucose regulation; Factors in the development of diabetic complications; Value of combination therapy.

Most algorithms for type 2 diabetes mellitus ( T2DM) do not recommend treatment escalation until glycated haemoglobin ( HbA1c) fails to reach the recommended target of 7% (53 mmol/mol) within approximately 3 months on any treatment regimen ('treat to failure'). Clinical inertia and/or poor adherence to therapy contribute to patients not reaching glycaemic targets when managed according to this paradigm. Clinical inertia exists across the entire spectrum of anti-diabetes therapies, although it is most pronounced when initiating and optimizing insulin therapy. Possible reasons include needle aversion, fear of hypoglycaemia, excessive weight gain and/or the need for increased self-monitoring of blood glucose. Studies have suggested, however, that early intensive insulin therapy in newly diagnosed, symptomatic patients with T2DM with HbA1c >9% (75 mmol/mol) can preserve beta-cell function, thereby modulating the disease process. Furthermore, postprandial plasma glucose is a key component of residual dysglycaemia, evident especially when HbA1c remains above target despite fasting normoglycaemia. Therefore, to achieve near normoglycaemia, additional treatment with prandial insulin or a glucagon-like peptide-1 receptor agonist ( GLP-1 RA) is often required. Long- or short-acting GLP-1 RAs offer effective alternatives to basal or prandial insulin in patients inadequately controlled with other therapies or basal insulin alone, respectively. This review highlights the limitations of current algorithms, and proposes an alternative based on the early introduction of insulin therapy and the rationale for the sequential or fixed combination of GLP-1 RAs with insulin ('treat-to-success' paradigm). [ABSTRACT FROM AUTHOR]