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Few trials of glucose-lowering drugs or strategies in people with type 2 diabetes have investigated cardiovascular outcomes, even though most patients die from cardiovascular causes despite the beneficial effects of lipid-reducing and blood pressure-lowering treatments. The evidence-based reduction in risk of microvascular disease with glucose lowering has resulted in guidelines worldwide recommending optimisation of glycosylated haemoglobin, but no trial results have shown unequivocal cardiovascular risk reduction with glucose lowering. However, results of the post-trial follow-up of the UK Prospective Diabetes Study, and of a meta-analysis of the four glucose-lowering outcome trials completed to date, suggest about a 15% cardiovascular relative risk reduction per 1% decrement in HbA1c. The 2008 US Food and Drug Administration industry guidance for licensing of antidiabetic drugs greatly increased the number of cardiovascular outcome trials in diabetes, but most trials opted for non-inferiority designs aiming primarily to show absence of cardiovascular toxicity in the shortest possible time. This unintended consequence of the new regulations has meant that the potential long-term benefits, and the possible risks of new therapies, are not being assessed effectively. Also, essential head-to-head trials of therapies for this complex progressive disease, to answer issues such as how best to achieve and maintain optimum glycaemia without promoting weight gain or hypoglycaemia, are not being undertaken. In this Series paper, we summarise randomised controlled cardiovascular outcome trials in type 2 diabetes, provide an overview of ongoing trials and their limitations, and speculate on how future trials could be made more efficient and effective.

Precision medicine aims to treat an individual based on their clinical characteristics. A differential drug response, critical to using these features for therapy selection, has never been examined directly in type 2 diabetes. In this study, we tested two hypotheses: (1) individuals with body mass index (BMI) > 30 kg/m 2 , compared to BMI ≤ 30 kg/m 2 , have greater glucose lowering with thiazolidinediones than with DPP4 inhibitors, and (2) individuals with estimated glomerular filtration rate (eGFR) 60–90 ml/min/1.73 m 2 , compared to eGFR >90 ml/min/1.73 m 2 , have greater glucose lowering with DPP4 inhibitors than with SGLT2 inhibitors. The primary endpoint for both hypotheses was the achieved HbA1c difference between strata for the two drugs. In total, 525 people with type 2 diabetes participated in this UK-based randomized, double-blind, three-way crossover trial of 16 weeks of treatment with each of sitagliptin 100 mg once daily, canagliflozin 100 mg once daily and pioglitazone 30 mg once daily added to metformin alone or metformin plus sulfonylurea. Overall, the achieved HbA1c was similar for the three drugs: pioglitazone 59.6 mmol/mol, sitagliptin 60.0 mmol/mol and canagliflozin 60.6 mmol/mol ( P  = 0.2). Participants with BMI > 30 kg/m 2 , compared to BMI ≤ 30 kg/m 2 , had a 2.88 mmol/mol (95% confidence interval (CI): 0.98, 4.79) lower HbA1c on pioglitazone than on sitagliptin ( n  = 356, P  = 0.003). Participants with eGFR 60–90 ml/min/1.73 m 2 , compared to eGFR >90 ml/min/1.73 m 2 , had a 2.90 mmol/mol (95% CI: 1.19, 4.61) lower HbA1c on sitagliptin than on canagliflozin ( n  = 342, P  = 0.001). There were 2,201 adverse events reported, and 447/525 (85%) randomized participants experienced an adverse event on at least one of the study drugs. In this precision medicine trial in type 2 diabetes, our findings support the use of simple, routinely available clinical measures to identify the drug class most likely to deliver the greatest glycemic reduction for a given patient. (ClinicalTrials.gov registration: NCT02653209 ; ISRCTN registration: 12039221 .) Using a randomized three-way crossover design and stratification approaches based on obesity and renal function in people with type 2 diabetes, the TriMaster study demonstrated that patients with obesity were more likely to have greater glycemic control with pioglitazone (a thiazolidinedione) than with sitagliptin (a DPP4 inhibitor) and that patients with eGFR 60–90 ml/min/1.73 m 2 were more likely to achieve lower HbA1c levels on sitagliptin than on canagliflozin (an SGLT2 inhibitor).

This trial was conducted to determine whether the reduction in microvascular risk and improved glycemic control that had been observed with medical therapy, as compared with conventional dietary treatment, in patients with newly diagnosed type 2 diabetes was sustained during 10 years of follow-up. Despite an early loss of glycemic differences, continued microvascular risk reduction and emergent risk reductions for myocardial infarction and death from any cause were observed. Despite an early loss of glycemic differences, continued microvascular risk reduction and emergent risk reductions for myocardial infarction and death from any cause were observed. The United Kingdom Prospective Diabetes Study (UKPDS), a randomized, prospective, multicenter trial, showed that intensive glucose therapy in patients with newly diagnosed type 2 diabetes mellitus was associated with a reduced risk of clinically evident microvascular complications and a nonsignificant reduction of 16% in the relative risk of myocardial infarction (P=0.052). 1 In patients whose body weight was more than 120% of their ideal weight 2 and who primarily received metformin, reductions in the risk of myocardial infarction of 39% (P=0.01) and of death from any cause of 36% (P=0.01) were observed. The results of the UKPDS, which were published in 1998, . . .

Dipeptidyl peptidase-4 (DPP4) modulates inflammation by enzymatic cleavage of immunoregulatory peptides and through its soluble form (sDPP4) that directly engages immune cells. Here we examine whether reduction of DPP4 activity alters inflammation. Prolonged DPP4 inhibition increases plasma levels of sDPP4, and induces sDPP4 expression in lymphocyte-enriched organs in mice. Bone marrow transplantation experiments identify hematopoietic cells as the predominant source of plasma sDPP4 following catalytic DPP4 inhibition. Surprisingly, systemic DPP4 inhibition increases plasma levels of inflammatory markers in regular chow-fed but not in high fat-fed mice. Plasma levels of sDPP4 and biomarkers of inflammation are lower in metformin-treated subjects with type 2 diabetes (T2D) and cardiovascular disease, yet exhibit considerable inter-individual variation. Sitagliptin therapy for 12 months reduces DPP4 activity yet does not increase markers of inflammation or levels of sDPP4. Collectively our findings dissociate levels of DPP4 enzyme activity, sDPP4 and biomarkers of inflammation in mice and humans. DPP4 inhibitors are used for the treatment of diabetes, but the impact of DPP4 activity and soluble DPP4 on development of diabetes-associated inflammation remains uncertain. Here the authors study whether DPP4 inhibition controls sDPP4 and inflammatory biomarkers, and demonstrate that DPP4 inhibition is dissociated from changes in inflammation in mice and humans.

A post-trial monitoring study involving follow-up of patients with type 2 diabetes who had been assigned to tight or less-tight blood-pressure control revealed that benefits of previously improved control were not sustained when between-group blood-pressure differences equalized. Early improved blood-pressure control in patients with type 2 diabetes and hypertension was associated with a reduced risk of complications, but it must continue for benefits to be sustained. Follow-up of patients with type 2 diabetes who had been assigned to tight or less-tight blood-pressure control revealed that benefits of previously improved control were not sustained when between-group blood-pressure differences equalized. The United Kingdom Prospective Diabetes Study (UKPDS) was a randomized, prospective, multicenter trial that indicated that improved glucose control in patients with newly diagnosed type 2 diabetes mellitus reduces the risk of clinically evident microvascular complications, with a relative risk reduction for myocardial infarction of 16% (P=0.052). 1 From 1987 to 1991, UKPDS patients with hypertension were, in addition, randomly assigned in a factorial manner to a tight blood-pressure control regimen involving an angiotensin-converting–enzyme (ACE) inhibitor or a beta-blocker or to a less-tight blood-pressure control strategy that excluded these agents. 2 For tight as compared with the less-tight control of blood pressure, . . .

In this 3-year multicenter trial, patients with suboptimal glycated hemoglobin levels while receiving metformin and sulfonylurea therapy were randomly assigned to add biphasic, prandial, or basal insulin. During the first year, sulfonylurea therapy was replaced by additional insulin for unacceptable hyperglycemia or subsequently for a glycated hemoglobin level of more than 6.5%. Basal- or prandial-based insulin regimens more often achieved glycated hemoglobin targets. Fewer hypoglycemic episodes and less weight gain occurred with regimens initiated with basal insulin. Basal- or prandial-based insulin regimens more often achieved glycated hemoglobin targets. Fewer hypoglycemic episodes and less weight gain occurred with regimens initiated with basal insulin. Most patients with type 2 diabetes require insulin therapy when oral antidiabetic agents provide suboptimal glycemic control, since long-term glycemic improvement reduces the risks of both microvascular 1 and macrovascular 1 , 2 complications. However, different insulin regimens have varying effects on glycemic control, weight gain, and the risk of hypoglycemia. 3 In the first phase of the Treating to Target in Type 2 Diabetes (4-T) study, we evaluated patients with type 2 diabetes who had suboptimal glycemic control despite maximally tolerated doses of metformin and sulfonylurea to see whether the randomized addition of a biphasic, prandial, or basal analogue insulin would lead to . . .

No clinical trials have assessed the effects or cost-effectiveness of sequential screening strategies to detect new cases of type 2 diabetes. We used a mathematical model to estimate the cost-effectiveness of several screening strategies. We used person-specific data from a representative sample of the US population to create a simulated population of 325 000 people aged 30 years without diabetes. We used the Archimedes model to compare eight simulated screening strategies for type 2 diabetes with a no-screening control strategy. Strategies differed in terms of age at initiation and frequency of screening. Once diagnosed, diabetes treatment was simulated in a standard manner. We calculated the effects of each strategy on the incidence of type 2 diabetes, myocardial infarction, stroke, and microvascular complications in addition to quality of life, costs, and cost per quality-adjusted life-year (QALY). Compared with no screening, all simulated screening strategies reduced the incidence of myocardial infarction (3–9 events prevented per 1000 people screened) and diabetes-related microvascular complications (3–9 events prevented per 1000 people), and increased the number of QALYs (93–194 undiscounted QALYs) added over 50 years. Most strategies prevented a significant number of simulated deaths (2–5 events per 1000 people). There was little or no effect of screening on incidence of stroke (0–1 event prevented per 1000 people). Five screening strategies had costs per QALY of about US$10 500 or less, whereas costs were much higher for screening started at 45 years of age and repeated every year ($15 509), screening started at 60 years of age and repeated every 3 years ($25 738), or a maximum screening strategy (screening started at 30 years of age and repeated every 6 months; $40 778). Several strategies differed substantially in the number of QALYs gained. Costs per QALY were sensitive to the disutility assigned to the state of having diabetes diagnosed with or without symptoms. In the US population, screening for type 2 diabetes is cost effective when started between the ages of 30 years and 45 years, with screening repeated every 3–5 years. Novo Nordisk, Bayer HealthCare, and Pfizer.

Current state of affairs : The potential for hypoglycaemia is a 100-year-long challenge that can complicate blood glucose lowering therapy in people with type 2 diabetes. This omnipresent imminent risk continues to the present day, particularly with insulin or sulfonylurea treatment. Specific objective : This clinical perspective seeks to synthesize new insights and tools to help reduce the hypoglycaemic burden related to type 2 diabetes pharmacotherapy by suggesting a synergistic triad approach: Guidance using an innovative approach based on comprehensive network analyses evaluating differential risk of diabetes medications for severe hypoglycaemic events (SHEs) observed in randomized controlled trials. These show an estimated background risk of 60 SHEs per 1000 patients over five years in the trial control populations allocated to standard treatments. Adopting this approach, the data indicate that the highest risk (~ fivefold higher) relates to therapy with sulfonylureas or with basal-bolus insulin regimens, whereas novel therapies with sodium-glucose transport protein 2 inhibitors (SGLT2is) or glucagon-like peptide-1 receptor agonists (GLP1-RAs) have minimal risk of SHEs, with the non-steroidal mineralocorticoid receptor antagonist finerenone showing a potential risk reduction. Recognition of these insights and translating them into treatment guidance should underpin the approach to minimizing the risk of hypoglycaemia, as they likely reflect drug related hypoglycaemia risk more broadly across all degrees of hypoglycaemia. Following this approach would be particularly helpful in those either with specific risk factors for hypoglycaemia (Fig. 1) or with the recently established frail phenotype at dual risk of SHEs and cardiovascular (CV) events in the context of multiple co-morbidities including heart failure, frailty or cancer and a high Charlson Co-Morbidity Index. Also the acute CV risk related to arrhythmias and mortality must not be ignored. Continuous glucose monitoring (CGM) for people with type 2 diabetes is advisable given it has been shown convincingly to provide a powerful new tool in those at dual risk of hypoglycaemia and CV events by reducing related hospitalization emergencies by ~ 50%. Conclusion : Each of these new insights and tools comprise an important step forward in their own right. Used together in a synergistic manner they, for the first time in over one hundred years, appear to provide the capacity to mitigate the threats of hypoglycaemia related to type 2 diabetes pharmacotherapy. Graphical abstract

The extent to which change in physical activity can modify the risk of cardiovascular disease in individuals at high cardiovascular risk is uncertain. We investigated whether baseline and change in objectively-assessed ambulatory activity is associated with the risk of a cardiovascular event in individuals at high cardiovascular risk with impaired glucose tolerance. We assessed prospective data from the NAVIGATOR trial involving 9306 individuals with impaired glucose tolerance who were recruited in 40 countries between January, 2002, and January, 2004. Participants also either had existing cardiovascular disease (if age ≥50 years) or at least one additional cardiovascular risk factor (if age ≥55 years). Participants were followed-up for cardiovascular events (defined as cardiovascular mortality, non-fatal stroke, or myocardial infarction) for 6 years on average and had ambulatory activity assessed by pedometer at baseline and 12 months. Adjusted Cox proportional hazard models quantified the association of baseline and change in ambulatory activity (from baseline to 12 months) with the risk of a subsequent cardiovascular event, after adjustment for each other and potential confounding variables. This study is registered with ClinicalTrials.govNCT00097786. During 45 211 person-years follow-up, 531 cardiovascular events occurred. Baseline ambulatory activity (hazard ratio [HR] per 2000 steps per day 0·90, 95% CI 0·84–0·96) and change in ambulatory activity (0·92, 0·86–0·99) were inversely associated with the risk of a cardiovascular event. Results for change in ambulatory activity were unaffected when also adjusted for changes in body-mass index and other potential confounding variables at 12 months. In individuals at high cardiovascular risk with impaired glucose tolerance, both baseline levels of daily ambulatory activity and change in ambulatory activity display a graded inverse association with the subsequent risk of a cardiovascular event. Novartis Pharmaceuticals.

Background Glucagon-like peptide-1 receptor agonists are a viable option for the prevention of Alzheimer’s disease (AD) but the mechanisms of this potential disease modifying action are unclear. We investigated the effects of once-weekly exenatide (EQW) on AD associated proteomic clusters. Methods The Exenatide Study of Cardiovascular Event Lowering study compared the cardiovascular effects of EQW 2 mg with placebo in 13,752 people with type 2 diabetes mellitus. 4,979 proteins were measured (Somascan V0.4) on baseline and 1-year plasma samples of 3,973 participants. C-reactive protein (CRP), ficolin-2 (FCN2), plasminogen activator inhibitor 1 (PAI-1), soluble vascular cell adhesion protein 1 (sVCAM1) and 4 protein clusters were tested in multivariable mixed models. Results EQW affected FCN2 (Cohen’s d -0.019), PAI-1 (Cohen’s d -0.033), sVCAM-1 (Cohen’s d 0.035) and a cytokine-cytokine cluster (Cohen’s d 0.037) significantly compared with placebo. These effects were sustained in individuals over the age of 65 but not in those under 65. Conclusions EQW treatment was associated with significant change in inflammatory proteins associated with AD. Trial Registration EXSCEL is registered on ClinicalTrials.gov: NCT01144338 on 10th of June 2010.