Accurate diagnosis of diabetes mellitus and new paradigms of classification

A cluster analysis of five independent Swedish cohorts of people with diabetes mellitus has identified five clusters of classification based on age at diagnosis, BMI, HbA1c autoantibodies and markers of insulin resistance. Patients in each of the clusters have specific disease characteristics and unique risk profiles for complications from diabetes mellitus

Cardiovascular outcome trials of glucose-lowering therapies

Introduction: Early initiated and long-term sustained intensive glucose control is associated with a significantly decreased risk of cardiovascular events and all-cause mortality, over and above the well-established decline in the risk of microvascular disease. Based on the recent cardiovascular outcome trial (CVOT) data, this review focuses on the various benefits of the newer medications with their positioning in the treatment algorithm and explores the place of the older medications in the management of type 2 diabetes mellitus (T2DM).Areas covered: We searched the literature for glucose lowering therapies for patients with T2DM. We included CVOTs conducted for newer sulphonylureas, thiazolidinediones, insulin degludec, DPP-4 inhibitors, SGLT2 inhibitors, and GLP-1 receptor agonists.Expert opinion: Selection of glucose-lowering therapy in the management of T2DM should be individualized and based on patient characteristics, associated comorbidities, patient preference, affordability and adherence to treatment. In view of the benefits seen in the CVOTs with SGLT2 inhibitors and GLP-1 receptor agonists, these newer classes should be the preferred choice in patients with/without established atherosclerotic cardiovascular disease and chronic kidney disease.</p

Use of incretin-based medications: what do current international recommendations suggest with respect to GLP-1 receptor agonists and DPP-4 inhibitors?

In recent years guidelines for the treatment of type 2 diabetes (T2DM) have evolved substantially. Initially limited to a few glucose lowering agents, early guidelines predicated strict glycemic control as a main goal in the attempt to reduce the risk of long-term diabetic complications. Nowadays, guidelines are not limited to such a goal but include cardiovascular (and renal) protection. This rapid evolution was made possible by the introduction of new glucose lowering agents, which have been extensively tested in randomized clinical studies including large cardiovascular outcome trials (CVOTs). In this review we will specifically consider the use of incretin-based medications in T2DM as recommended in the recent ADA/EASD consensus, and other international guidelines, with special consideration of their glucose-lowering efficacy, their cardiovascular (and renal) benefit, their effect on body weight and risk of hypoglycemia, as well as the economic implications for their use.</p

First line treatment for type 2 diabetes: Is it too early to abandon Metformin?

With the sulphonylurea gliclazide and insulin, metformin is part of the triad of antihyperglycaemic agents on the 2019 World Health Organization list of essential medications. In most international guidelines on the management of hyperglycaemia, metformin is the recommended first-line glucose-lowering agent in subjects with type 2 diabetes. The evidence underpinning these recommendations is mainly based on the efficacy results in a small subgroup of the UK Prospective Diabetes Study participants, which showed a reduction in macro- and micro-vascular complications in overweight subjects with newly diagnosed type 2 diabetes randomised to metformin or non-pharmacological (diet) intervention. However, uncertainty persist about its cardiovascular benefits, as confirmed in a recent Cochrane systematic review

Draft FDA guidance for assessing the safety of glucose lowering therapies: a missed opportunity?

In 2008, the US Food and Drug Administration (FDA) issued guidance to the pharmaceutical industry to show the cardiovascular safety in new drug applications for treatments of type 2 diabetes. 1 Since then, a plethora of cardiovascular outcome trials have taken place, with some showing cardiovascular benefits, but also unexpected findings such as benefits for heart failure hospitalisation and renal outcomes. These trials have informed evidence-based guidelines and consensus recommendations that have substantially improved patient outcomes. However, these trials are fairly short and are event-driven studies recruiting high–risk populations who are unrepresentative of the general population who are prescribed these agents. [Taken from opening paragraph

Cost-effectiveness of intensive interventions compared to standard care in individuals with type 2 diabetes: A systematic review and critical appraisal of decision-analytic models.

AIMS:The objective of this systematic review is to identify and assess the quality of published decision-analytic models evaluating the long-term cost-effectiveness of target-driven intensive interventions for single and multifactorial risk factor control compared to standard care in people with type 2 diabetes. METHODS:We searched the electronic databases MEDLINE, the National Health Service Economic Evaluation Database, Web of Science and the Cochrane Library from inception to October 31, 2019. Articles were eligible for inclusion if the studies had used a decision-analytic model evaluating both the long-term costs and benefits associated with intensive interventions for risk factor control compared to standard care in people with type 2 diabetes. Data were extracted using a standardised form, while quality was assessed using the decision-analytic model-specific Philips-criteria. RESULTS:Overall, nine articles (11 models) were identified, four models evaluated intensive glycaemic control, three evaluated intensive blood pressure control, two evaluated intensive lipid control, and two evaluated intensive multifactorial interventions. Six reported using discrete-time simulations modelling approach, whereas five reported using a Markov modelling framework. The majority, seven studies, reported that the intensive interventions were dominant or cost-effective, given the assumptions and analytical perspective taken. The methodological and reporting quality of the studies was generally weak, with only four studies fulfilling more than 50% of their applicable Philips-criteria. CONCLUSIONS:This is the first systematic review of decision-analytic models of target-driven intensive interventions for single and multifactorial risk factor control in individuals with type 2 diabetes. Identified shortcomings are lack of transparency in data identification and evidence synthesis as well as for the selection of the modelling approaches. Future models should aim to include greater evaluation of the quality of the data sources used and the assessment of uncertainty in the model

Cardiovascular effects of sodium-glucose co-transporter-2 inhibitors and glucagon-like peptide-1 receptor agonists: The P value and beyond

Despite growing awareness of the dangers of a dichotomous interpretation of trial results based on the ‘statistical significance’ of a treatment effect, the uptake of new approaches has been slow in diabetes medicine. We showcase a number of ways to interpret the evidence for a treatment effect applied to the cardiovascular outcome trials of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose co-transporter-2 inhibitors (SGLT-2is): the P value function (or confidence curves), which depicts the treatment effect across the whole spectrum of confidence levels; the counternull value, which is the hazard ratio (i.e. treatment effect size) supported by the same amount of evidence as the null value (i.e. no treatment effect); and the S value, which quantifies the strength of the evidence against the null hypothesis in terms of the number of coin tosses yielding the same side. We show how this approach identifies potential treatment effects, highlights similarities among trials straddling the threshold of statistical significance, and quantifies differences in the strength of the evidence from trials reporting statistically significant results. For example, while REWIND, CANVAS and CREDENCE failed to reach statistical significance at the .05 level for all-cause mortality, their counternull values indicate that reduced death rates by 19%, 24% and 31%, respectively, are supported by the same amount of evidence as that indicating no treatment effect. Moreover, similarities among results emerge in trials of GLP-1RAs (REWIND, EXSCEL and LEADER) lying closely around the threshold of ‘statistical significance’. Lastly, several S values, such as for the primary outcome in HARMONY Outcomes (S value 10.9) and all-cause death in EMPAREG-OUTCOME (S value 15.0), stand out compared with values for other outcomes and other trials, suggesting much larger differences in the evidence between these studies and several others that cluster around the .05 significance threshold. P value functions, counternull values and S values should complement the standard reporting of the treatment effect to help interpret clinical trials and make decisions among competing glucose-lowering medications

Association and relative importance of multiple risk factor control on cardiovascular disease, end-stage renal disease and mortality in people with type 2 diabetes: A population-based retrospective cohort study

Aims: To evaluate the risk of cardiovascular disease (CVD), end-stage renal disease (ESRD), and mortality, when implementing a multifactorial optimal control approach in primary care in the United Kingdom (UK), in individuals with newly diagnosed type 2 diabetes. Materials and methods: A retrospective cohort of 53 942 patients were stratified into 1 of the 8 groups according to whether glycated haemoglobin (HbA1c), blood pressure (BP) and total cholesterol (TC) target values were achieved or not from baseline to the date of last follow-up. Those with single or combinations of risk factor control targets achieved, were compared to those who achieved no targets in any of the risk factor. Hazard ratios from the Cox proportional hazards models were estimated against patients who achieved no targets. Results: Of 53 942 patients with newly diagnosed type 2 diabetes, 28%, 55%, and 68% were at target levels for HbA1c <48 mmol/mol (<6.5%), BP < 140/85 mm Hg, and TC < 5 mmol/L respectively, 36%, 40%, and 12% were at target levels for any one, two, or all three risk factors respectively. Being at HbA1c, BP, and TC targets was associated with an overall 47%, 25%, 42%, 55% and 42% reduction in the risk of ischemic heart disease, cerebrovascular disease, ESRD, cardiovascular-mortality, and all-cause-mortality respectively. Among all subgroups, the risk reduction of study outcome events was greater in the subgroups of patients with microalbuminuria, males, smokers, and patients with BMI ≥ 30 kg/m2. Conclusions: Optimal levels of HbA1c, BP, and TC occurring together in patients with newly diagnosed type 2 diabetes are uncommon. Achieving multiple risk factor control targets could substantially reduce the risk of CVD, ESRD and mortality

Body mass index and risk of COVID-19 across ethnic groups: analysis of UK Biobank study

Coronavirus disease-2019 (COVID-19), an infectious disease caused by the SARS-CoV-2 virus, has devastated global economies and put unprecedented strain on clinical services. Emerging evidence has suggested that black and minority ethnic (BME) groups, particularly South Asian (SA) and black African or Caribbean (BAC) populations, are at an increased risk of COVID-19 and resulting complications1. Obesity is also associated with a higher risk of testing positive for, and dying from,COVID-191,2. However, the interaction between ethnicity and obesity on the risk of COVID-19 has not been tested. As ethnicity is known to modify the association between BMI and cardiometabolic health3,4, we hypothesise that BMI also acts to modify the relative risk of COVID-19 across ethnic groups. [Opening paragraph]</div

Walking pace improves all-cause and cardiovascular mortality risk prediction: A UK Biobank prognostic study

Aims: The purpose of this study was to quantify and rank the prognostic relevance of dietary, physical activity and physical function factors in predicting all-cause and cardiovascular mortality in comparison with the established risk factors included in the European Society of Cardiology Systematic COronary Risk Evaluation (SCORE). Methods: We examined the predictive discrimination of lifestyle measures using C-index and R2 in sex-stratified analyses adjusted for: model 1, age; model 2, SCORE variables (age, smoking status, systolic blood pressure, total and high-density lipoprotein cholesterol). Results: The sample comprised 298,829 adults (median age, 57 years; 53.5% women) from the UK Biobank free from cancer and cardiovascular disease at baseline. Over a median follow-up of 6.9 years, there were 2174 and 3522 all–cause and 286 and 796 cardiovascular deaths in women and men, respectively. When added to model 1, self-reported walking pace improved C-index in women and men by 0.013 (99% CI: 0.007–0.020) and 0.022 (0.017–0.028) respectively for all-cause mortality; and by 0.023 (0.005–0.042) and 0.034 (0.020–0.048) respectively for cardiovascular mortality. When added to model 2, corresponding values for women and men were: 0.008 (0.003–0.012) and 0.013 (0.009–0.017) for all-cause mortality; and 0.012 (–0.001–0.025) and 0.024 (0.013–0.035) for cardiovascular mortality. Other lifestyle factors did not consistently improve discrimination across models and outcomes. The pattern of results for R2 mirrored those for C-index. Conclusion: A simple self-reported measure of walking pace was the only lifestyle variable found to improve risk prediction for all-cause and cardiovascular mortality when added to established risk factors.</div