Biosimilars are regulated differently from small‐molecule generic, chemically derived medicines. The complexity of biological products means that small changes in manufacturing or formulation may ...result in changes in efficacy and safety of the final product. In the face of this complexity, the regulatory landscape for biosimilars continues to evolve, and global harmonization regarding requirements is currently lacking. It is essential that clinicians and patients are reassured that biosimilars are equally safe and effective as their reference product, and this is particularly important when interchangeability, defined as ‘changing one medicine for another one which is expected to achieve the same clinical effect in a given clinical setting in any one patient’, is considered. Although the automatic substitution (i.e. substitution without input from the prescribing healthcare provider) of biosimilars for reference products is currently not permitted by the majority of countries, this may change in the future. In order to demonstrate interchangeability between reference products and a biosimilar, more stringent and specific studies of the safety and efficacy of biosimilars are likely to be needed; however, guidance on the design of and the need for any such studies is currently limited. The present article provides an overview of the current regulatory framework around the demonstration of interchangeability with biosimilars, with a specific focus on biosimilar insulin analogues, and details experiences with other biosimilar products. In addition, designs for studies to evaluate interchangeability with a biosimilar insulin analogue product are proposed and a discussion about the implications of interchangeability in clinical practice is included.
Summary
Diabetes is currently the world's fastest growing chronic disease and it is caused by deficient production of insulin by the endocrine pancreas or by abnormal insulin action in peripheral ...tissues. This results in persistent hyperglycaemia that over time may produce chronic diabetic complications. Determination of glycated haemoglobin level is currently the gold standard method to evaluate and control sustained hyperglycaemia in diabetic people. This measurement is currently made by high‐performance liquid chromatography, which is a complex chemical process that requires the extraction of blood from the antecubital vein. To reduce the complexity of that measurement, we propose a fully‐optical technique that is based in the fact that there are changes in the optical properties of erythrocytes due to the presence of glucose‐derived adducts in the haemoglobin molecule. To evaluate these changes, we propose to perform quantitative phase maps of erythrocytes by using telecentric digital holographic microscopy. Our experiments show that telecentric digital holographic microscopy allows detecting, almost in real time and from a single drop of blood, significant differences between erythrocytes of diabetic patients and healthy patients. Besides, our phase measurements are well correlated with the values of glycated haemoglobin and the blood glucose values.
Lay description
Conventional wide‐field microscopy does not allow the measurement of the phase of transparent objects. Among diverse methodologies to face this task, off‐axis digital holographic microscopy provides phase measurements from a single hologram. In this paper, we propose the use of digital holographic microscopy for the easy and fast discrimination between patients suffering from diabetes mellitus type 1 and healthy donors. Specifically, we show that phase measurements obtained from a drop of blood are strongly correlated with the glycated haemoglobin (HbA1C) values, which are the gold standard measurement. Consequently, digital holographic microscopy can be adopted as new standard method for diabetes screening.
Long‐acting insulin analogues have been developed to mimic the physiology of basal insulin secretion more closely than human insulin formulations (Neutral Protamine Hagedorn, NPH). However, the ...clinical evidence in favour of analogues is still controversial. Although their major benefit as compared with NPH is a reduction in the hypoglycaemia risk, some cost/effectiveness analyses have not been favourable to analogues, largely because of their higher price. Nevertheless, these new formulations have conquered the insulin market. Human insulin represents currently no more than 20% of market share. Despite (in fact because of) the widespread use of insulin analogues it remains critical to analyse the pharmacodynamics (PD) of basal insulin formulations appropriately to interpret the results of clinical trials correctly. Importantly, these data may help physicians in tailoring insulin therapy to patients' individual needs and, additionally, when clinical evidence is not available, to optimize insulin treatment. For patients at low risk for/from hypoglycaemia, it might be acceptable and also cost‐effective not to use long‐acting insulin analogues as basal insulin replacement. Conversely, in patients with a higher degree of insulin deficiency and increased risk for hypoglycaemia, analogues are the best option due to their more physiological profile, as has been shown in PD and clinical studies. From this perspective optimizing basal insulin treatment, especially in type 2 diabetes patients who are less prone to hypoglycaemia, would be suitable making significant resources available for other relevant aspects of diabetes care.
Aims To compare the efficacy and safety of once‐weekly taspoglutide with insulin glargine in patients with advanced Type 2 diabetes failing metformin and sulphonylurea combination therapy.
Methods ...This open‐label, parallel‐group, multi‐centre trial randomized 1049 patients continuing metformin 1:1:1 to taspoglutide 10 mg once weekly, taspoglutide 20 mg once weekly or insulin glargine once daily with forced titration to fasting plasma glucose ≤ 6.1 mmol/l. Sulphonylureas were discontinued before randomization. The primary endpoint was change in HbA1c after 24 weeks.
Results After 24 weeks, least‐square mean changes from baseline in HbA1c in patients receiving taspoglutide 10 mg −8 mmol/mol (se 1) −0.77% (se 0.05) or taspoglutide 20 mg −11 mmol/mol (se 1) −0.98% (se 0.05) were non‐inferior to insulin glargine −9 mmol/mol (se 1) −0.84% (se 0.05); treatment difference of 0.07% (95% CI −0.06 to 0.21) and −0.14% (95% CI −0.28 to −0.01), for taspoglutide 10 and 20 mg, respectively, vs. insulin glargine. Taspoglutide was associated with more adverse events (mainly gastrointestinal) and significantly less hypoglycaemia than insulin glargine.
Conclusions Compared with insulin glargine, taspoglutide provided non‐inferior HbA1c reductions associated with less hypoglycaemia, but more gastrointestinal adverse events.
To achieve appropriate glycaemic control, postprandial and baseline hyperglycaemia should be reduced. Various epidemiological studies have suggested an association between fluctuations in ...postprandial blood glucose and cardiovascular risk. However, studies of interventions performed to date have not shown that selective control of postprandial hyperglycaemia is associated with cardiovascular benefits. Accordingly, an appropriate combination of drugs that control both baseline and postprandial hyperglycaemia (individually based on each patient's characteristics) is the best strategy for achieving good glycaemic control. This review seeks to impart to clinicians the concept of postprandial hyperglycaemia, analysing its causes, how to measure it, its prevalence, its consequences and, ultimately, the available therapeutic strategies for the preferential control of the postprandial hyperglycaemia along with baseline hyperglycaemia.
To determine whether baseline characteristics had an impact on clinical outcomes in the LixiLan‐O trial (N = 1170), we compared the efficacy and safety of iGlarLixi, a titratable fixed‐ratio ...combination of insulin glargine 100 U (iGlar) and lixisenatide (Lixi) with iGlar or Lixi alone in patients with uncontrolled type 2 diabetes mellitus (T2DM) on oral therapy. Subgroups according to baseline glycated haemoglobin (HbA1c; <8% or ≥8% <64 or ≥64 mmol/mol), T2DM disease duration (<7 or ≥7 years) and body mass index (BMI; <30 or ≥30 kg/m2) were investigated. In all subpopulations, iGlarLixi was consistently statistically superior to iGlar and Lixi alone in reducing HbA1c from baseline to week 30; higher proportions of patients achieved HbA1c <7% (<53 mmol/mol) with iGlarLixi vs iGlar and Lixi alone. Compared with iGlar, iGlarLixi resulted in a substantial decrease in 2‐hour postprandial plasma glucose levels, and mitigation of weight gain, with no differences among subpopulations in incidence of symptomatic hypoglycaemia. iGlarLixi consistently improved glycaemic control compared with iGlar and Lixi alone, without weight gain or increase in hypoglycaemic risk compared with iGlar in the subpopulations tested, regardless of baseline HbA1c, disease duration and BMI.
Aims To compare the efficacy and safety of once-weekly taspoglutide with insulin glargine in patients with advanced Type2 diabetes failing metformin and sulphonylurea combination therapy. Methods ...This open-label, parallel-group, multi-centre trial randomized 1049 patients continuing metformin 1:1:1 to taspoglutide 10mg once weekly, taspoglutide 20mg once weekly or insulin glargine once daily with forced titration to fasting plasma glucose ≤6.1mmol/l. Sulphonylureas were discontinued before randomization. The primary endpoint was change in HbA1c after 24weeks. Results After 24weeks, least-square mean changes from baseline in HbA1c in patients receiving taspoglutide 10mg -8mmol/mol (se1) -0.77% (se0.05) or taspoglutide 20mg -11mmol/mol (se1) -0.98% (se0.05) were non-inferior to insulin glargine -9mmol/mol (se1) -0.84% (se0.05); treatment difference of 0.07% (95%CI -0.06 to 0.21) and -0.14% (95%CI -0.28 to -0.01), for taspoglutide 10 and 20mg, respectively, vs. insulin glargine. Taspoglutide was associated with more adverse events (mainly gastrointestinal) and significantly less hypoglycaemia than insulin glargine. Conclusions Compared with insulin glargine, taspoglutide provided non-inferior HbA1c reductions associated with less hypoglycaemia, but more gastrointestinal adverse events. PUBLICATION ABSTRACT
Aim
To conduct two exploratory analyses to compare indirectly the efficacy and safety of simultaneous administration of insulin glargine 100 U (iGlar) and the glucagon‐like peptide‐1 receptor agonist ...(GLP‐1RA) lixisenatide (Lixi) as a single‐pen, titratable, fixed‐ratio combination (iGlarLixi LixiLan trials) vs sequential administration of iGlar + Lixi (GetGoal Duo trials) in people with type 2 diabetes (T2D).
Materials and Methods
Propensity‐score matching based on baseline covariates was used to compare simultaneous iGlarLixi vs sequential combination of iGlar + Lixi with the addition of Lixi in patients who did not reach the glycated haemoglobin (HbA1c) goal of <53 mmol/mol (<7%) after short‐term use of iGlar alone (LixiLan‐O vs GetGoal Duo‐1 comparison) and vs sequential addition of Lixi in uncontrolled patients after long‐term use of iGlar alone (LixiLan‐L vs GetGoal Duo‐2 comparison).
Results
In both analyses, compared with sequential iGlar + Lixi, iGlarLixi led to significantly greater HbA1c reductions with associated weight loss and significantly more patients reaching target HbA1c <53 mmol/mol despite lower insulin doses. Symptomatic hypoglycaemia rates were similar, despite greater HbA1c reductions with iGlarLixi. Lower rates of gastrointestinal adverse events were observed with iGlarLixi, probably as a result of the more gradual titration of Lixi with iGlarLixi.
Conclusions
Indirect propensity‐score‐matched exploratory comparisons suggest that early treatment with a simultaneous, titratable, fixed‐ratio combination of basal insulin and a GLP‐1RA (iGlarLixi) may be more effective and possess better gastrointestinal tolerability than a sequential approach of adding a GLP‐1RA in patients with uncontrolled T2D initiating or intensifying basal insulin therapy.
The recently published cardiovascular outcomes data for the first sodium-glucose cotransporter 2 (SGLT2) inhibitor, empagliflozin, have shown cardiovascular safety and additional benefits in patients ...with type 2 diabetes and established cardiovascular disease. Empagliflozin showed lower rates of death from cardiovascular causes or from any causes and lower hospitalization rates from heart failure compared with placebo, both in addition to standard care. This commentary discusses the existence of a possible class effect considering the available evidence described for other SGLT2 inhibitors.
Empagliflozin, dapagliflozin and canagliflozin share the same mechanism of action, and it is a plausible hypothesis that some of the benefits of empagliflozin treatment could also be expected from other SGLT2 inhibitors. However, the rapid and persistent occurrence of cardiovascular benefits observed with empagliflozin and the different results shown by the three inhibitors in meta-analyses of some of their respective Phase II and III trials might suggest another possible mechanism of action, perhaps related to the different selectivity to inhibit SGLT-2 and other SGLT family members that these compounds present.
There is still lack of evidence to answer whether the cardiovascular benefits observed with empagliflozin in the EMPA-REG OUTCOME study could be seen as a "class effect", which is also attributable to dapagliflozin and canagliflozin.
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