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Evidence‐based guidelines provide the premise for the delivery of quality care to preserve health and prevent disabilities and premature death. The systematic gathering of observational, mechanistic and experimental data contributes to the hierarchy of evidence used to guide clinical practice. In the field of diabetes, metformin was discovered more than 100 years ago, and with 60 years of clinical use, it has stood the test of time regarding its value in the prevention and management of type 2 diabetes. Although some guidelines have challenged the role of metformin as the first‐line glucose‐lowering drug, it is important to point out that the cardiovascular‐renal protective effects of sodium‐glucose co‐transporter‐2 inhibitors and glucagon‐like peptide‐1 receptor agonists were gathered from patients with type 2 diabetes, the majority of whom were treated with metformin. Most national, regional and international guidelines recommend metformin as a foundation therapy with emphasis on avoidance of therapeutic inertia and early attainment of multiple treatment goals. Moreover, real‐world evidence has confirmed the glucose‐lowering and cardiovascular‐renal benefits of metformin accompanied by an extremely low risk of lactic acidosis. In patients with type 2 diabetes and advanced chronic kidney disease (estimated glomerular filtration rate 15‐30 mL/min/1.73m2), metformin discontinuation was associated with an increased risk of cardiovascular‐renal events compared with metformin persistence. Meanwhile, it is understood that microbiota, nutrients and metformin can interact through the gut‐brain‐kidney axis to modulate homeostasis of bioactive molecules, systemic inflammation and energy metabolism. While these biological changes contribute to the multisystem effects of metformin, they may also explain the gastrointestinal side effects and vitamin B12 deficiency associated with metformin intolerance. By understanding the interactions between metformin, foods and microbiota, healthcare professionals are in a better position to optimize the use of metformin and mitigate potential side effects. The United Kingdom Prospective Diabetes Study and the Da Qing Diabetes Prevention Program commenced 40 years ago provided the first evidence that type 2 diabetes is preventable and treatable. To drive real‐world impact from this evidence, payors, practitioners and planners need to co‐design and implement an integrated, data‐driven, metformin‐based programme to detect people with undiagnosed diabetes and prediabetes (intermediate hyperglycaemia), notably impaired glucose tolerance, for early intervention. The systematic data collection will create real‐world evidence to bring out the best of metformin and make healthcare sustainable, affordable and accessible. [ABSTRACT FROM AUTHOR]

Aim: The use of vitamin K antagonists (VKAs) may increase the risk of peripheral arterial disease (PAD) because vitamin K is a strong inhibitor of medial arterial calcification. Type 2 diabetes (T2D) exposes patients to an increased risk of PAD. We examined how the use of VKAs modulates the risk of incident PAD in people with T2D. Materials and Methods: SURDIAGENE is a French cohort including 1468 patients with T2D with a prospective follow‐up from 2002 to 2015. The primary outcome of the current analysis was the first occurrence of PAD, a composite of lower‐limb amputation (LLA) or lower‐limb revascularization. LLA and lower‐limb revascularization were considered individually as secondary outcomes. Results: During a 7‐year median follow‐up, PAD occurred in 147 (10%) of the 1468 participants. The use of VKAs was not significantly associated with the risk of PAD [multivariable adjusted hazard ratio (HR) 1.42, 95% confidence interval (CI), 0.88‐2.31]. During the study period, LLA and lower‐limb revascularization occurred in 82 (6%) and 105 (7%) participants, respectively. The use of VKAs was significantly associated with increased risk of LLA [multivariable adjusted HR 1.90 (95% CI, 1.04‐3.47)], but not lower‐limb revascularization [multivariable adjusted HR 1.08 (95% CI, 0.59‐1.97)]. Conclusions: In this prospective study, we did not observe any excess risk of PAD requiring lower‐limb revascularization in people with type 2 diabetes using VKAs. However, our data suggest a high risk of LLA in VKA users. Further studies are required to confirm this observation. [ABSTRACT FROM AUTHOR]

Aims: To develop and externally validate the LIFE‐T1D model for the estimation of lifetime and 10‐year risk of cardiovascular disease (CVD) in individuals with type 1 diabetes. Materials and Methods: A sex‐specific competing risk‐adjusted Cox proportional hazards model was derived in individuals with type 1 diabetes without prior CVD from the Swedish National Diabetes Register (NDR), using age as the time axis. Predictors included age at diabetes onset, smoking status, body mass index, systolic blood pressure, glycated haemoglobin level, estimated glomerular filtration rate, non‐high‐density lipoprotein cholesterol, albuminuria and retinopathy. The model was externally validated in the Danish Funen Diabetes Database (FDDB) and the UK Biobank. Results: During a median follow‐up of 11.8 years (interquartile interval 6.1–17.1 years), 4608 CVD events and 1316 non‐CVD deaths were observed in the NDR (n = 39 756). The internal validation c‐statistic was 0.85 (95% confidence interval [CI] 0.84–0.85) and the external validation c‐statistics were 0.77 (95% CI 0.74–0.81) for the FDDB (n = 2709) and 0.73 (95% CI 0.70–0.77) for the UK Biobank (n = 1022). Predicted risks were consistent with the observed incidence in the derivation and both validation cohorts. Conclusions: The LIFE‐T1D model can estimate lifetime risk of CVD and CVD‐free life expectancy in individuals with type 1 diabetes without previous CVD. This model can facilitate individualized CVD prevention among individuals with type 1 diabetes. Validation in additional cohorts will improve future clinical implementation. [ABSTRACT FROM AUTHOR]

Aim: Despite the increasing use of combination treatment with sodium‐glucose cotransporter 2 inhibitors and glucagon‐like peptide‐1 receptor agonists, data are limited on the effects of combination treatment on markers of cardiovascular disease. This study aimed to investigate the effect of empagliflozin, semaglutide, and their combination on vascular function. Materials and Methods: In total, 120 patients with type 2 diabetes were randomized into four groups (n = 30 in each) for 32 weeks: placebo, semaglutide, empagliflozin, and their combination. The study had two co‐primary outcomes: change in arterial stiffness and kidney oxygenation. This paper reports on arterial stiffness assessed as carotid‐femoral pulse wave velocity. Secondary outcomes included 24‐h blood pressure (BP), 24‐h central BP, urinary albumin to creatinine ratio and glycaemic control assessed by both continuous glucose monitoring and glycated haemoglobin. Results: The carotid‐femoral pulse wave velocity did not change significantly in any of the groups compared with placebo. Twenty‐four‐hour systolic BP was reduced by 10 mmHg (95% CI 6–14), p <.001 in the combination group, significantly superior to both placebo and monotherapy (p <.05). Combination treatment increased glycaemic time in range from 72% at baseline to 91% at week 32, p <.001, without increasing time below range. The urinary albumin to creatinine ratio decreased by 36% (95% CI 4–57), p =.03 in the combination group compared with placebo. Conclusions: Empagliflozin, semaglutide, or their combination did not reduce arterial stiffness. Combination treatment showed a substantial and clinically important reduction in 24‐h systolic BP compared with either treatment alone. Combination treatment increased glycaemic time in range without increasing the risk of hypoglycaemia. [ABSTRACT FROM AUTHOR]

It is well known that the multiple factors contributing to the pathogenesis of type 2 diabetes (T2D) confer an increased risk of developing cardiovascular disease (CVD). Although the relationship between hyperglycaemia and increased microvascular risk is well established, the relative contribution of hyperglycaemia to macrovascular events has been strongly debated, particularly owing to the failure of attempts to reduce CVD risk through normalizing glycaemia with traditional therapies in high‐risk populations. The debate has been further fuelled by the relatively recent discovery of the cardioprotective properties of glucagon‐like peptide‐1 receptor agonists and sodium‐glucose cotransporter‐2 inhibitors. Further, as guidelines now recommend individualizing glycaemic targets, highlighting the importance of achieving glycated haemoglobin (HbA1c) goals safely, the previously observed negative influences of intensive therapy on CVD risk might not present if trials were repeated using current‐day treatments and individualized HbA1c goals. Emerging longitudinal data illuminate the overall effect of excess glucose, the impacts of magnitude and duration of hyperglycaemia on disease progression and risk of CVD complications, and the importance of glycaemic control at or early after diagnosis of T2D for prevention of complications. Herein, we review the role of glucose as a modifiable cardiovascular (CV) risk factor, the role of microvascular disease in predicting macrovascular risk, and the deleterious impact of therapeutic inertia on CVD risk. We reconcile new and old data to offer a current perspective, highlighting the importance of effective, early treatment in reducing latent CV risk, and the timely use of appropriate therapy individualized to each patient's needs. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the cardiovascular (CV) efficacy of liraglutide and semaglutide in patients with type 2 diabetes (T2D) and peripheral artery disease (PAD). Materials and Methods: LEADER and SUSTAIN 6 trials investigated subcutaneous liraglutide (≤1.8 mg/day) and semaglutide (0.5 or 1.0 mg/week), respectively, versus placebo in patients with T2D and high CV risk (median follow‐up: 3.8 and 2.1 years, respectively). The primary outcome was a composite of CV death, non‐fatal myocardial infarction or non‐fatal stroke (major adverse CV event [MACE]) according to the presence of PAD at baseline. Results: Overall, 1184/9340 (12.7%) patients in LEADER and 460/3297 (14.0%) in SUSTAIN 6 had PAD at baseline. Patients with PAD were at an ~35% increased risk of MACE versus those without (LEADER: hazard ratio [HR] 1.36, 95% confidence interval [CI] 1.17‐1.58; SUSTAIN 6: HR 1.33, 95% CI 0.94‐1.83). The effects of both therapies on MACE were consistently beneficial in patients with PAD (liraglutide: HR 0.77, 95% CI 0.58‐1.01; semaglutide: 0.61, 0.33‐1.13) and without (liraglutide: HR 0.89, 95% CI 0.79‐1.00; semaglutide: HR 0.77, 95% CI 0.58‐1.01; Pinteraction =.34 for liraglutide and.49 for semaglutide). Absolute risk reductions for MACE were higher in patients with PAD (liraglutide: 4.13%‐point, 95% CI −0.15‐8.42; semaglutide: 4.63%‐point, 95% CI −0.58‐9.84) versus without (liraglutide:1.42%‐point, 95% CI −0.03‐2.87; semaglutide: 1.90%‐point, 95% CI 0.00‐3.80). Conclusion: Both liraglutide and semaglutide reduce MACE with consistent CV efficacy regardless of PAD status. [ABSTRACT FROM AUTHOR]

Aim: To assess the efficacy and safety of sotagliflozin in patients with type 2 diabetes. Methods: We searched Medline, Embase, the Cochrane Library, and grey literature sources up to August 2021 for randomized controlled trials (RCTs) that compared sotagliflozin with placebo or other antidiabetic agents in patients with type 2 diabetes. Our primary outcome was change in HbA1c from baseline. We additionally assessed three secondary efficacy and 15 safety outcomes. We synthesized data using weighted mean differences (WMDs) and odds ratios (ORs), along with 95% confidence intervals (CIs). Results: We included 11 RCTs comprising 16 411 subjects in the meta‐analysis. Compared with placebo, sotagliflozin reduced HbA1c (WMD −0.42%, 95% CI −0.56 to −0.29), body weight (WMD −1.33 kg, 95% CI −1.57 to −1.09), and systolic blood pressure (WMD −2.44 mmHg, 95% CI −2.81 to −2.07). No difference was evident against other active comparators. Sotagliflozin reduced myocardial infarction (OR 0.72, 95% CI 0.54 to 0.97) and heart failure (OR 0.68, 95% CI 0.58 to 0.79) compared with placebo, and had a neutral effect on all‐cause mortality, cardiovascular mortality, and stroke. Treatment with sotagliflozin was safe regarding the incidence of serious adverse events, hypoglycaemia, and diabetic ketoacidosis. Nevertheless, it was associated with an increased incidence of diarrhoea, genital infections, and volume depletion events. Conclusions: Sotagliflozin reduces blood glucose, body weight, and systolic blood pressure, and demonstrates a beneficial effect on heart failure and myocardial infarction. Its overall safety profile is comparable with other sodium‐glucose co‐transporter‐2 inhibitors. [ABSTRACT FROM AUTHOR]

Aims: For relatively old patients with diabetes, current guidelines recommend adjustment of glycaemic goals based on patients' cognitive function, or coexisting chronic illnesses. However, the evidence which supports the efficacy and safety of intensive glucose lowering in older patients with diabetes is scarce. The objective of the present study was to compare the efficacy and safety of intensive glucose lowering in patients with type 2 diabetes stratified by age (<65 and ≥ 65 years), and examine whether the effects differ according to patients' characteristics in the older patient group. Materials and Methods: The effects of intensive glucose lowering (to a target glycated haemoglobin [HbA1c] concentration of ≤48 mmol/mol [6.5%]) on major clinical outcomes were evaluated by Cox regression models according to subgroups defined by baseline age of <65 or ≥ 65 years in the ADVANCE trial (n = 11 140). Results: Over a median follow‐up of 5 years, intensive glucose lowering significantly decreased the risk of the composite of major macrovascular and microvascular events (hazard ratio 0.90, 95% confidence interval 0.82‐0.98), with no heterogeneity in the effects across age subgroups (p for heterogeneity = 0.44). Relative effects on all‐cause death, cardiovascular death, and components of major vascular events were also similar (P for heterogeneity ≥0.06), except for severe hypoglycaemia, which was of greater risk for patients aged <65 years. Absolute benefits and harms were broadly consistent across subgroups. Among patients aged ≥65 years, randomized treatment effects did not differ significantly across different levels of cognitive function or coexisting chronic illnesses. Conclusions: Our results suggest that an intensive glycaemic control strategy to reduce HbA1c to 48 mmol/mol (6.5%) provided broadly similar benefits and harms and may be recommended for older, as well as younger, patients. [ABSTRACT FROM AUTHOR]

Aim: The effect of the weekly exendin‐based glucagon‐like peptide‐1 receptor agonist efpeglenatide on cardiovascular (CV) outcomes in high‐risk patients with type 2 diabetes (T2DM) with and without chronic kidney disease (CKD) is unknown. Materials and methods: People with T2DM and glycated haemoglobin >7%, ≥18 years old with previous CV disease, or ≥50 years old with CKD [defined as an estimated glomerular filtration rate (eGFR) of 25–59.9 mL/min/1.73 m2], and one or more additional CV risk factors were recruited. Participants were randomized in a 1:1:1 ratio, stratified by current, intended or neither current nor intended use of a sodium‐glucose cotransporter‐2 (SGLT2) inhibitor to receive weekly injections of efpeglenatide (4 mg or 6 mg) or masked placebo. The primary outcome is a major adverse CV event defined as non‐fatal myocardial infarction, non‐fatal stroke or CV death. Secondary outcomes include a composite kidney outcome (new onset macroalbuminuria with an increase from baseline of ≥30%, sustained 40% decrease in eGFR, renal replacement therapy, or sustained eGFR <15 mL/min/1.73 m2). The trial will continue until ≥330 participants have had a major adverse CV event outcome and the sample size was based on accruing enough outcomes to detect non‐inferiority of efpeglenatide versus placebo. Results: Recruitment of 4076 participants (33% women, mean age 64.5 years) occurred between 11 May 2018 and 25 April 2019 at 344 sites in 28 countries. Mean baseline glycated haemoglobin was 8.9% (1.5), 31.6% had an eGFR <60 mL/min/1.73 m2, 89.5% had previous CV disease and 15.0% were on an SGLT2 inhibitor. Conclusions: The results of the AMPLITUDE O trial will inform the use of exendin‐based glucagon‐like peptide‐1 receptor agonist to people with T2DM and high CV risk, with and without CKD, in the presence and absence of an SGLT2 inhibitor. [ABSTRACT FROM AUTHOR]

The randomized, double-blind, cardiovascular outcomes trials LEADER (NCT01179048) and SUSTAIN 6 (NCT01720446) showed cardiovascular risk reduction in patients with type 2 diabetes treated with liraglutide and semaglutide, respectively, compared with placebo. This post hoc analysis examined the impact of microvascular disease at baseline on cardiovascular outcomes in these trials, and the efficacy of liraglutide (1.8 mg) and once-weekly semaglutide (0.5-1.0 mg) in patients with and without microvascular disease. In total, 9340 patients from LEADER and 3297 patients from SUSTAIN 6 were included in this analysis; of these, 5761 and 2356 had a history of microvascular disease at baseline and 3835 and 1640 had a history of both microvascular and macrovascular disease, respectively. Patients with microvascular disease were shown to have an increased risk of major adverse cardiovascular events compared with patients without microvascular disease (hazard ratio [95% confidence interval] in LEADER: 1.15 [1.03; 1.29], P = .0136; SUSTAIN 6: 1.56 [1.14; 2.17], P = .0064). Liraglutide and semaglutide consistently reduced cardiovascular risk in patients with and without microvascular disease. [ABSTRACT FROM AUTHOR]

Aims: To examine the manifestation of cardiovascular or renal disease (CVRD) in patients with type 2 diabetes (T2D) initially free from CVRD as well as the mortality risks associated with these diseases. Methods: Patients free from CVRD were identified from healthcare records in England, Germany, Japan, the Netherlands, Norway and Sweden at a fixed date. CVRD manifestation was defined by first diagnosis of cardiorenal disease, or a stroke, myocardial infarction (MI) or peripheral artery disease (PAD) event. The mortality risk associated with single CVRD history of heart failure (HF), chronic kidney disease (CKD), MI, stroke or PAD was compared with that associated with CVRD‐free status. Results: Of 1 177 896 patients with T2D, 772 336 (66%) were CVRD‐free and followed for a mean of 4.5 years. A total of 137 081 patients (18%) developed a first CVRD manifestation, represented by CKD (36%), HF (24%), stroke (16%), MI (14%) and PAD (10%). HF or CKD was associated with increased cardiovascular and all‐cause mortality risk: hazard ratio (HR) 2.02 (95% confidence interval [CI] 1.75–2.33) and HR 2.05 (95% CI 1.82–2.32), respectively. HF and CKD were separately associated with significantly increased mortality risks, and the combination was associated with the highest cardiovascular and all‐cause mortality risk: HRs 3.91 (95% CI 3.02–5.07) and 3.14 (95% CI 2.90–3.40), respectively. Conclusion: In a large multinational study of >750 000 CVRD‐free patients with T2D, HF and CKD were consistently the most frequent first cardiovascular disease manifestations and were also associated with increased mortality risks. These novel findings show these cardiorenal diseases to be important and serious complications requiring improved preventive strategies. [ABSTRACT FROM AUTHOR]

Patients with type 2 diabetes (T2D) are at an increased risk of cardiovascular disease (CVD). Cardiovascular risk in these patients should be considered as a continuum, and comprehensive treatment strategies should aim to target multiple disease risk factors. Large‐scale clinical trials of sodium‐glucose co‐transporter‐2 (SGLT2) inhibitors have shown an impact on cardiovascular outcomes, including heart failure hospitalization and cardiovascular death, which appears to be independent of their glucose‐lowering efficacy. Reductions in major cardiovascular events appear to be greatest in patients with established CVD, particularly those with prior myocardial infarction, but are independent of heart failure or renal risk. Most large‐scale trials of SGLT2 inhibitors predominantly include patients with T2D with pre‐existing CVD and high cardiovascular risk at baseline, limiting their applicability to patients typically observed in clinical practice. Real‐world evidence from observational studies suggests that there might also be beneficial effects of SGLT2 inhibitors on heart failure hospitalization and all‐cause mortality in various cohorts of lower risk patients. The most common adverse events reported in clinical and observational studies are genital infections; however, the overall risk of these events appears to be low and easily managed. Similar safety profiles have been reported for elderly and younger patients. There is still some debate regarding the safety of canagliflozin in patients at high risk of fracture and amputation. Outstanding questions include specific patterns of cardiovascular protection according to baseline risk. [ABSTRACT FROM AUTHOR]

The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) factorial trial was a landmark randomized controlled clinical trial in 11 140 type 2 diabetic patients from 215 centers in 20 countries with a two‐by‐two factorial design. In the blood pressure‐lowering arm, patients were treated using a fixed combination of the ACE‐inhibitor, perindopril, and the thiazide‐like diuretic, indapamide, or placebo, whereas in the glucose‐lowering arm, the intervention compared the sulphonylurea gliclazide plus other glucose‐lowering drugs, targeting a glycated hemoglobin value of 6.5% or less, with standard glucose control. Primary end‐points were major macro‐ and microvascular events in both arms. This review gives an overview of the results of the primary randomized trial, results from observational follow‐up studies, and results of several biomarker studies and discusses the perspectives of these data in the context of recent major outcome trials for current medical treatment. [ABSTRACT FROM AUTHOR]

Aim: To investigate the associations of blood pressure variability (BPV), expressed as long‐term (visit‐to‐visit) and short‐term (ambulatory blood pressure monitoring [ABPM] and home blood pressure monitoring [HBPM]) and all‐cause mortality, major adverse cardiovascular events (MACEs), extended MACEs, microvascular complications (MiCs) and hypertension‐mediated organ damage (HMOD) in adult patients with type 2 diabetes. Materials and methods: PubMed, Medline, Embase, Cinahl, Web of Science, ClinicalTrials.gov and grey literature databases were searched for studies including patients with type 2 diabetes, at least one variable of BPV (visit‐to‐visit, HBPM, ABPM) and evaluation of the incidence of at least one of the following outcomes: all‐cause mortality, MACEs, extended MACEs and/or MiCs and/or HMOD. The extracted information was analyzed using random effects meta‐analysis and meta‐regression. Results: Data from a total of 377 305 patients were analyzed. Systolic blood pressure (SBP) variability was associated with a significantly increased risk of all‐cause mortality (HR 1.12, 95% CI 1.04–1.21), MACEs (HR 1.01, 95% CI 1.04–1.17), extended MACEs (HR 1.07, 95% CI 1.03–1.11) and MiCs (HR 1. 12, 95% CI 1.01–1.24), while diastolic blood pressure was not. Associations were mainly driven from studies on long‐term SBP variability. Qualitative analysis showed that BPV was associated with the presence of HMOD expressed as carotid intima‐media thickness, pulse wave velocity and left ventricular hypertrophy. Results were independent of mean blood pressure, glycaemic control and serum creatinine levels. Conclusions: Our results suggest that BPV might provide additional information rather than mean blood pressure on the risk of cardiovascular disease in patients with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Aims: Latent autoimmune diabetes in adults (LADA) is diagnosed in up to 12% of adults with clinically diagnosed type 2 diabetes (T2D). LADA tends to have healthier cardiovascular (CV) risk profiles than T2D, but it remains uncertain whether the risk of CV events differs between the two. We examined the risk of CV events in patients enrolled in the United Kingdom Prospective Diabetes Study (UKPDS) according to LADA status. Materials and methods: Diabetes autoantibodies (AAb) were measured in 5062 UKPDS participants. The incidence of major adverse CV events (MACE), defined as CV death, non‐fatal myocardial infarction or non‐fatal stroke, was compared in those with LADA (≥1 AAb test positive) and those without LADA (AAb negative). Results: There were 567 participants (11.2%) with LADA. Compared with participants with T2D, they were younger, with higher mean HbA1c and HDL‐cholesterol values, and with lower body mass index and total cholesterol and systolic blood pressure values (all P < 0.01). After a median (25th, 75th percentile) 17.3 (12.6–20.7) years of follow‐up, MACE occurred in 157 (17.4 per 1000 person‐years) participants with LADA and in 1544 (23.5 per 1000 person‐years) participants with T2D (HR, 0.73; 95% confidence interval [CI], 0.62–0.86; P < 0.001). However, after adjustment for confounders, this difference was no longer significant (HRadj, 0.90; 95% CI, 0.76–1.07; P = 0.22). Conclusions: In adults thought to have newly diagnosed T2D, the long‐term risk of MACE was lower in those with LADA. However, this did not differ after adjustment for traditional CV risk factors, suggesting that measurement of AAb in addition to traditional CV risk factors will not aid in stratification of CV risk in clinically diagnosed T2D. [ABSTRACT FROM AUTHOR]

The prevalence of heart failure (HF) in patients with type 2 diabetes (T2DM) is debatable and no data exist concerning the diagnostic value of mid‐regional pro‐atrial natriuretic peptide (MR‐proANP). We aimed to identify HF prevalence and evaluate the diagnostic value of MR‐proANP in outpatients followed in two specialized diabetes clinics. HF was pre‐defined as HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF). The prevalence of HFrEF and HFpEF was 2.4% and 17.5%, respectively. An MR‐proANP <60 pmol/L ruled out HFrEF in the total population (n = 806) and in patients reporting dyspnea (n = 311) with a sensitivity of 94.7% and 87.5%, a negative predictive value of 99.7% and 99.0%, a specificity of 39.5% and 33.0%, and a positive predictive value of 3.6% and 3.3%, respectively. In a multivariable model including age, sex, T2DM duration, albuminuria, uncontrolled systolic blood pressure, abnormal electrocardiogram and ischaemic heart disease for diagnosis of HF in patients reporting dyspnea, adding MR‐proANP increased the area under the curve from 0.69 to 0.78 (P < 0.001). In conclusion, HFrEF was rare among outpatients with T2DM. MR‐proANP rules out HFrEF and contributes independent information relevant to diagnosis of HF in patients reporting dyspnea. [ABSTRACT FROM AUTHOR]

Aims: Patients with type 2 diabetes have a high risk of cardiovascular disease (CVD). Central obesity has been particularly associated with this risk relationship. We aimed to evaluate waist to height ratio (WHtR) as a predictor of risk in such patients. Methods: WHtR was evaluated as a predictor of the risk of CVD and mortality amongst 11 125 participants with type 2 diabetes in the ADVANCE and ADVANCE‐ON studies, and was compared with body mass index (BMI), waist circumference and waist hip ratio (WHR). Primary outcome was a composite of death from CVD, non‐fatal myocardial infarction or non‐fatal stroke. Secondary outcomes were myocardial infarction, stroke, cardiovascular death and death from any cause. Cox models were used, with bootstrapping to compare associations between anthropometric measures for the primary outcome. Results: Median follow‐up time was 9.0 years. There was a positive association between WHtR and adverse outcomes. The hazard ratio (HR) (confidence interval), per SD higher WHtR, was 1.16 (1.11‐1.22) for the primary endpoint, with no heterogeneity by sex or region, but a stronger effect in individuals aged 66 years or older. The other 3 anthropometric measurements showed similar associations, although there was evidence that WHtR marginally outperformed BMI and WHR. Based on commonly used BMI cut‐points, the equivalent WHtR cut‐points were estimated to be 0.55 and 0.6, with no evidence of a difference across subgroups. Conclusions: In patients with diabetes, WHtR is a useful indicator of future adverse risk, with similar effects in different population subgroups. [ABSTRACT FROM AUTHOR]

A primary goal of the treatment of type 2 mellitus is the prevention of morbidity and mortality associated with cardiovascular disease; however, anti‐hyperglycaemic drugs have the capacity to cause deleterious effects on the circulation, a risk that is not adequately reflected by the endpoints selected for emphasis in large‐scale clinical trials that are designed to evaluate cardiovascular safety. The primary endpoint of the large‐scale studies mandated by regulatory authorities focuses only on 3 to 4 events that depict only a limited view of the circulatory system. One of the most serious adverse effects of many glucose‐lowering drugs is new‐onset or worsening heart failure. Most antidiabetic drugs can aggravate heart failure because they exert anti‐natriuretic actions, and possibly, adverse effects on the myocardium. In addition, certain anti‐hyperglycaemic agents may worsen peripheral vascular disease and trigger cardiac arrhythmias that may lead to sudden death. Initiation of treatment with antidiabetic medications may also cause deterioration of the function of the kidneys, retina and peripheral nerves, which are typically regarded as reflecting microvascular disease. The current confusion about the cardiovascular effects of glucose‐lowering drugs may be exacerbated by conceptual uncertainties about the classification of large and small vessel disease in determining the clinical course of diabetes. Physicians should not be falsely reassured by claims that a new treatment appears to have passed a narrowly defined regulatory test. The management of people with diabetes often carries with it the risk of important cardiovascular consequences, even for drugs that do not overtly increase the risk of myocardial infarction or stroke. [ABSTRACT FROM AUTHOR]

Aims: To determine whether baseline metabolic syndrome (MetS) modifies the effect of intensive blood pressure control on cardiovascular (CV) outcomes, and whether the effects varied by race/ethnicity. Methods: We performed post hoc analyses among non‐Hispanic black, non‐hispanic white and Hispanic participants, with and without MetS, in the Systolic Blood Pressure Intervention Trial (SPRINT), who were randomized to a systolic blood pressure (SBP) target of <120 mm Hg (intensive group, N = 4544) or an SBP target of <140 mm Hg (standard group, N = 4553). The median follow‐up was 3.26 years. The primary outcome was the composite of the first occurrence of myocardial infarction, stroke, heart failure, non‐myocardial infarction acute coronary syndrome or CV death. Results: Overall, 3521/9097 participants (38.7%) met the criteria for MetS at baseline. Baseline characteristics were similar in the two SBP target groups within each MetS subgroup, except body mass index was slightly higher in the standard arm of the MetS subgroup (33.3 ± 5.6 vs 33.0 ± 5.3 kg/m2; P < .01), but were similar across treatment arms in the non‐MetS subgroup. The hazard ratio for the primary outcome was similarly reduced in participants with or without baseline MetS: 0.75 (95% confidence interval [CI] 0.57, 0.96) and 0.71 (95% CI 0.57, 0.87), respectively (adjusted P value for treatment by subgroup interaction = .98). Similarly, there was no evidence of treatment × MetS subgroup interaction for all‐cause mortality (adjusted interaction P value = .98). The findings were also similar across race/ethnic subgroups. Conclusions: In this analysis the CV benefit of intensive SBP control did not differ among participants by baseline MetS status, regardless of race/ethnicity. [ABSTRACT FROM AUTHOR]

Aims To conduct a 10-year, observational follow-up of patients completing PROactive to investigate whether trends of cardiovascular benefit with pioglitazone and imbalances in specific malignancies persisted over time. Methods Macrovascular endpoints and malignancies were compared based on original randomization to pioglitazone or placebo and 'any' versus 'no' pioglitazone use for bladder and prostate cancer. Results Of 4873 patients completing the PROactive trial, 74% entered the follow-up. During follow-up (mean 7.8 years), there were no statistically significant differences in the primary [all-cause mortality, myocardial infarction ( MI), cardiac intervention, stroke, major leg amputation, leg revascularization] or main secondary (death, MI, stroke) endpoints for subjects originally randomized to pioglitazone and placebo, except for leg amputations during follow-up [4.1% pioglitazone, 5.6% placebo; hazard ratio 0.74, 95% confidence interval ( CI) 0.55-0.99; p = 0.046]. During follow-up, the incidence of total malignancies was similar between groups; bladder cancer was reported in 0.8% of patients (n = 14) in the pioglitazone versus 1.2% (n = 21) in the placebo group [relative risk ( RR) 0.65, 95% CI 0.33-1.28], and prostate cancer was reported in 44 men (3.7%) in the pioglitazone versus 29 men (2.5%) in the placebo group ( RR 1.47, 95% CI 0.93-2.34). Conclusions The trends of macrovascular benefits of pioglitazone compared with placebo during PROactive did not persist in the absence of continued pioglitazone during this 10-year follow-up. Trends of decreased bladder cancer and increased prostate cancer were observed in the pioglitazone group during follow-up; however, these imbalances should be interpreted with caution because of the limitations of the observational study design. [ABSTRACT FROM AUTHOR]

Aims To formulate a combined cardiovascular risk score in diabetes that could be useful both to physicians and healthcare funders. Methods Data were derived from the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation Observational ( ADVANCE-ON) study, a randomized controlled trial (mean duration 5 years) with a post-randomization follow-up (mean 4.9 years), that included 11 140 high-risk patients with diabetes. The outcome analysed was the occurrence of either fatal or non-fatal macrovascular or renal disease. A Cox regression model was used to determine weightings in the risk score. The resultant score was recalibrated to each of three major global regions, as covered by the ADVANCE-ON study. Results Over a median of 9.9 years, 1145 patients experienced at least one component of the combined outcome event. The resultant score, the AD-ON risk score, incorporated 13 demographic or clinical variables. Its discrimination was modest [c-statistic = 0.668 (95% confidence interval 0.651, 0.685)] but its calibration was excellent (predicted and observed risks coincided well, within disparate global regions). In terms of the integrated discrimination improvement index, its performance was marginally superior, over a 10-year risk horizon, to existing risk scores in clinical use, from a restricted version of the same data, for macrovascular and renal disease separately. Conclusions The AD-ON risk score has advantages over the existing vascular risk scores in diabetes that used data from the original ADVANCE trial, which treat macrovascular and renal diseases separately. These advantages include its simplicity of use and global application. [ABSTRACT FROM AUTHOR]

Aims To compare diabetes-associated secondary healthcare utilization in patients with type 2 diabetes ( T2DM) prescribed sulphonylureas ( SUs) versus other oral antihyperglycaemic agents ( OHAs) as an add-on to metformin monotherapy (metformin + SU vs metformin + OHA). Methods This retrospective cohort study used data from the Clinical Practice Research Datalink linked to Hospital Episode Statistics. Adults with T2DM initiated on metformin + SU or metformin + OHA from April 2003 to March 2012 were identified. Patients were matched using propensity scores. Diabetes-associated secondary healthcare visits were counted from >6 months post-initiation of dual therapy until treatment change or end of follow-up. Outcomes were calculated as rate ratios, adjusted for over-dispersion using negative binomial regression and propensity score for covariates. Results After propensity score matching, 1704 patients were included in each cohort. For the primary objective (diabetes-associated inpatient and outpatient visits combined), the metformin + SU cohort had a directionally higher rate of diabetes-associated secondary healthcare utilization than the metformin + OHA cohort [adjusted rate ratio 1.12, 95% confidence interval ( CI) 0.97-1.29]. For the secondary outcomes, the adjusted rate ratio was 1.38 (95% CI 0.95-2.00) for inpatient admissions and 1.10 (95% CI 0.95-1.28) for outpatient visits. Macrovascular complications, accounting for 77.2% of inpatient admissions, occurred at a statistically significantly higher rate in the metformin + SU cohort than in the metformin + OHA cohort (adjusted rate ratio 1.77, 95% CI 1.15-2.71). Conclusions This study found a statistically significant higher rate of inpatient admissions for macrovascular complications and cardiology outpatient visits and, overall, a directionally higher rate of secondary healthcare utilization for patients prescribed metformin + SU than for those prescribed metformin + OHA. This adds to the evidence that long-term and health economic outcomes should be considered in treatment decisions for patients with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Aims To report baseline characteristics and cardiovascular ( CV) risk management by region, age, sex and CV event type for 14 724 participants in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin ( TECOS), a randomized, double-blind, placebo-controlled trial exploring whether sitagliptin added to usual type 2 diabetes ( T2DM) care affects time to first event in the composite endpoint of CV death, non-fatal myocardial infarction ( MI), non-fatal stroke or unstable angina hospitalization. Methods TECOS enrolled patients aged ≥50 years, with T2DM and CV disease from 38 countries in five regions: North America, Eastern Europe, Western Europe, Asia Pacific and Latin America. Participants had a glycated haemoglobin concentration of 6.5-8.0% (48-64 mmol/mol) and were receiving oral and/or insulin-based antihyperglycaemic therapy. Analysis of variance or logistic regression was used to compare regional CV risk factors and treatments, referenced to North America. Results Patients had a mean [1 standard deviation (SD)] age of 66 (8) years, a median (interquartile range) diabetes duration of 9.4 (4.9, 15.3) years, and a mean (SD) body mass index 30.2 (5.7) kg/m2. Compared with North America, blood pressure and lipids were higher in all regions. Statin use was lowest in Latin America (68%) and Eastern Europe (70%) and aspirin use was lower compared with North America in all regions except Asia Pacific. Achievement of treatment targets did not differ by age group or insulin usage, but men and participants with previous MI were more likely than women or those with previous stroke or peripheral arterial disease to reach most treatment goals. Conclusion The CV risk factors of participants in TECOS are reasonably controlled, but differences in CV risk management according to region, sex and history of disease exist. This diversity will enhance the generalizability of the trial results. [ABSTRACT FROM AUTHOR]

Diabetes is associated with the development of premature atherosclerotic disease, including coronary heart disease and acute coronary syndromes. A late consequence of this process is the development of chronic heart failure, which contributes to the increased cardiovascular ( CV) morbidity and mortality associated with diabetes. Reduction of cholesterol with statins and intensive blood pressure control significantly reduce vascular events in people with diabetes. Intensive treatment of glycaemia reduces microvascular complications, especially retinopathy and nephropathy, but has only a modest effect in reducing macrovascular complications. Attention has therefore focused on individual antidiabetic drugs or drug classes to determine if these have effects in reducing CV events beyond the reduction of blood glucose. Glucagon-like peptide 1 ( GLP-1) receptor agonists are a class of injected therapies that enhance the incretin effect, increasing insulin release from the pancreas and reducing glucagon production. They also have a central effect, increasing satiety, and in routine clinical use are associated with reductions in body weight. Another possibly beneficial effect of these drugs is a slight but significant reduction in systolic blood pressure. Data from cohort studies have indicated no increase in CV events with GLP-1 receptor agonists, and perhaps some reductions in CV events. The safety and possible CV benefit of these drugs is now being tested in large, multicentre, randomized, placebo-controlled trials. [ABSTRACT FROM AUTHOR]

Aims Several studies have investigated the effects of metformin treatment in patients with type 1 diabetes mellitus ( T1DM). No study has hitherto examined its effects on endothelial function in these patients. In this study we sought to evaluate the effect of metformin on endothelial function in type 1 diabetic patients. Methods Forty-two uncomplicated T1DM patients were randomized in a placebo-controlled, double-blind, 6-month trial to treatment with either metformin or placebo. Glycometabolic and clinical parameters as well as flow-mediated dilation ( FMD) and nitrate-mediated dilation ( NMD) of the right brachial artery were measured at baseline and at the end of the study. Glycaemic variability ( GV, calculated from continuous glucose monitoring data) and a biomarker of oxidative stress [urinary 8-iso-prostaglandin F2 α ( PGF2 α)] were also assessed. Results Baseline data were similar in the two groups. Compared with placebo, metformin significantly reduced body weight [−2.27 kg (95% confidence interval: −3.99; −0.54); p = 0.012] whilst improved FMD [1.32% (0.30; 2.43); p = 0.013] and increased PGF2 α [149 pg/mg creatinine (50; 248); p = 0.004]. Notably, the improvement of FMD did not correlate with the decrease of body weight (r2 < 1%). NMD, haemoglobin A1c, GV, daily insulin dose and other parameters did not significantly change after the treatment comparing the two groups. Conclusions Our pilot trial showed that, in uncomplicated type 1 diabetic subjects, metformin improved FMD and increased PGF2 α, a marker of oxidative stress, irrespective of its effects on glycaemic control and body weight. Randomized, blinded clinical trials are needed to evaluate the benefits and risks of metformin added to insulin in type 1 diabetes. [ABSTRACT FROM AUTHOR]

Aims Preliminary data from randomized trials with metabolic outcomes have shown that treatment with dipeptidyl peptidase-4 inhibitors ( DPP4i) could be associated with a reduced incidence of major cardiovascular events ( MACE). The present meta-analysis is aimed at verifying this protective effect, collecting all available data from randomized trials. Methods A comprehensive search for published and unpublished trials with a duration ≥24 weeks comparing DPP4i with placebo or other drugs was performed, retrieving all MACE reported as serious adverse events together with death from any cause. Mantel-Haenzel odds ratio ( MH-OR) was calculated with random effect models for MACE, myocardial infarction, stroke and mortality. When available, effects on glycated haemoglobin, lipid profile and blood pressure were also assessed and used for the estimation of the modification of risk for myocardial infarction using the UKPDS risk engine. Results A total of 70 trials, enrolling 41 959 patients with a mean follow-up of 44.1 weeks, was collected and included in the analysis. The MH-OR (95% Confidence Interval) was 0.71[0.59;0.86], 0.64[0.44;0.94], 0.77[0.48;1.24] and 0.60[0.41;0.88] for MACE, myocardial infarction, stroke and mortality, respectively. Conclusions Treatment with DPP4i reduces the risk of cardiovascular events (particularly myocardial infarction) and all-cause mortality in patients with type 2 diabetes. The reduction in the incidence of myocardial infarction is greater than what predicted on the basis of conventional risk factors, suggesting a role for other mechanisms. [ABSTRACT FROM AUTHOR]

Aim: The effect of glucose-lowering agents on diabetes-related complications including cardiovascular (CV) events is of major importance. In the absence of a long-term study, we simulated such a trial using a mathematical model where subjects were given exenatide once-weekly (EQW), which has been shown to improve glycaemic control and reduce weight, systolic blood pressure (SBP) and lipids in patients with type 2 diabetes mellitus (T2DM). Methods: Using the Archimedes Model, we followed a simulated population derived from individuals with T2DM in NHANES who were drug-naïve or on oral agents only. We modelled the effects of four treatment strategies including standard care (SC, maintaining levels of control seen in NHANES), intensive glycaemic control (IGC, target HbA1c < 7% with conventional antidiabetic agents) and two versions of EQW added to SC: one with glycaemic and weight reduction only (EQW-1) and one with additional improvements in SBP and lipids (EQW-2). EQW strategies were derived from 52-week clinical trial data. Endpoints included macrovascular and microvascular outcomes. Results: Simulated EQW treatment resulted in earlier benefit and 2-3 times greater relative reductions in major adverse CV events than IGC when compared to SC (6% relative reduction by year 20 for IGC vs. 12 and 17% for the EQW strategies). For microvascular complications, EQW showed comparable benefit to IGC for neuropathy but significantly greater impact on renal complications. Conclusions: This analysis shows that the novel drug EQW has the potential to greatly reduce CV events through its combined effects on glycaemia, weight and other CV risk factors. [ABSTRACT FROM AUTHOR]

Aim: To examine and to quantify the impact of concurrent macrovascular co-morbidities (MVC) on healthcare resource utilization among patients with type 2 diabetes mellitus (T2DM) in Europe. Methods: This is a matched cohort study based on the Real-Life Effectiveness and Care Patterns of Diabetes Management study, a multicentre, observational study with retrospective medical chart reviews of T2DM patients in Spain, France, UK, Norway, Finland, Germany and Poland. Included patients were aged ≥30 years at time of diagnosis of T2DM who added a sulfonylurea or a PPAR γ agonist to failing metformin monotherapy (index date) and had concurrent MVC (cases). A control cohort with T2DM but without concurrent MVC was identified using 1:1 propensity score matching. Logit models were used to identify the relationship between concurrent MVC and the likelihood of emergency room admission, receiving medical/surgical procedures, and hospitalization during the study period after controlling for baseline demographics, clinical information and baseline treatment. Negative binomial models were used to predict the number of office visits and length of hospital stay per year attributable to the concurrent MVC. Results: Relative to controls, patients with MVC were significantly more likely to have emergency department admissions [odds ratio (OR) 2.69; 95% CI: 1.56–4.65], receiving medical/surgical procedures (OR 2.57; 95% CI: 1.56–4.21) and hospitalizations (OR 2.58; 95% CI: 1.64–4.07) after controlling for other predictors. Similarly, MVC were associated with 1.49 additional office visits per year (p = 0.036) and 0.32 days of hospital stay per year (p = 0.023). Conclusions: Within a seven-country European sample, this study showed that T2DM patients with MVC were more likely to use healthcare resources compared with T2DM patients without MVC. [ABSTRACT FROM AUTHOR]

Aims: Young adults with type 2 diabetes (T2Dm) present the clinician with the problem of when to start therapies for the primary prevention of vascular disease and how to identify those at most vascular risk. We examine whether the metabolic syndrome (MetS) can be a useful clinical tool to stratify vascular risk in this context. Methods: Data were collected from 5928 subjects with T2Dm, and subjects were categorized as having MetS by World Health Organization criteria (body mass index criteria modified for Asians using >23 kg/m2). The prevalence of macrovascular disease was examined by MetS status and age. Results: The overall MetS prevalence was 72.3%. MetS was associated with an increased prevalence of ischaemic heart disease (IHD) (17.2% MetS vs. 11.6% no MetS, p < 0.0001), coronary artery bypass graft (7.6 vs. 4.7%, p < 0.0003), peripheral vascular disease (PVD) (4.7 vs. 3.7%, p = 0.08) and stroke (6 vs. 3.9%, p = 0.002) across all age groups. MetS subjects had an IHD prevalence equivalent to that seen in subjects who were one decade older without MetS. The most significant impact of MetS was for the age group of 40–49 years with much lesser impact seen with progressively increasing age [odds ratio (OR) = 2.1 for IHD in MetS compared with no MetS at age 40–50 years, p < 0.05; falling progressively to OR = 1.5 at age >70 years, p > 0.05]. Similar trends were seen for coronary artery by-pass graft (CABG) and PVD. There was a strong relationship between the number of MetS risk factors and IHD prevalence (r = 0.99, p = 0.0001). Conclusions: These data suggest that MetS is particularly useful in stratifying vascular risk in younger T2Dm patients and in those with a high number of MetS components. For patients with MetS, especially those with a full house of MetS risk factors, commencing risk-lowering interventions 10 years earlier than their MetS-free counterparts could be considered. [ABSTRACT FROM AUTHOR]

Aims To use the Archimedes model to estimate the consequences of delays in oral antidiabetic drug ( OAD) treatment intensification on glycaemic control and long-term outcomes at 5 and 20 years. Materials and methods Using real-world data, we modelled a cohort of hypothetical patients with glycated haemoglobin ( HbA1c) ≥8%, on metformin, with no history of insulin use. The cohort included 3 strata based on the number of OADs taken at baseline. The first add-on in the intensification sequence was a sulphonylurea, next was a dipeptidyl peptidase-4 inhibitor, and last, a thiazolidinedione. The scenarios included either no delay or delay, based on observed and extrapolated times to intensification. Results At 1 year, HbA1c was 6.8% for patients intensifying without delay, and 8.2% for those delaying intensification. For no delay vs delay, risks of major adverse cardiac events, myocardial infarction, heart failure and amputations were reduced by 18.0%, 25.0%, 13.7%, and 20.4%, respectively, at 5 years; severe hypoglycaemia risk, however, increased to 19% for the no delay scenario vs 12.5% for delay. At 20 years, the results showed similar trends to those at 5 years. Conclusions Timing of intensification of OAD therapy according to guideline recommendations led to greater reductions in HbA1c and lower risks of complications, but higher risks of hypoglycaemia than delaying intensification. These results highlight the potential impact of timely treatment intensification on long-term outcomes. [ABSTRACT FROM AUTHOR]