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Type 2 diabetes (T2D) and lower-extremity peripheral artery disease (PAD) are growing global health problems associated with considerable cardiovascular (CV) and limb-related morbidity and mortality, poor quality of life and high healthcare resource use and costs. Diabetes is a well-known risk factor for PAD, and the occurrence of PAD in people with T2D further increases the risk of long-term complications. As the available evidence is primarily focused on the overall PAD population, we undertook a systematic review to describe the burden of comorbid PAD in people with T2D. The MEDLINE, Embase and Cochrane Library databases were searched for studies including people with T2D and comorbid PAD published from 2012 to November 2021, with no restriction on PAD definition, study design or country. Hand searching of conference proceedings, reference lists of included publications and relevant identified reviews and global burden of disease reports complemented the searches. We identified 86 eligible studies, mostly observational and conducted in Asia and Europe, presenting data on the epidemiology (n = 62) and on the clinical (n = 29), humanistic (n = 12) and economic burden (n = 12) of PAD in people with T2D. The most common definition of PAD relied on ankle-brachial index values ≤ 0.9 (alone or with other parameters). Incidence and prevalence varied substantially across studies; nonetheless, four large multinational randomised controlled trials found that 12.5%–22% of people with T2D had comorbid PAD. The presence of PAD in people with T2D was a major cause of lower-limb and CV complications and of all-cause and CV mortality. Overall, PAD was associated with poor quality of life, and with substantial healthcare resource use and costs. To our knowledge, this systematic review provides the most comprehensive overview of the evidence on the burden of PAD in people with T2D to date. In this population, there is an urgent unmet need for disease-modifying agents to improve outcomes. [ABSTRACT FROM AUTHOR]

Aims: To conduct a pooled analysis of Phase 3 trials investigating the efficacy and safety of inclisiran across glycaemic and body mass index (BMI) strata. Materials and Methods: Participants were randomized 1:1 to receive 300 mg inclisiran sodium or placebo twice yearly, after initial and 3‐month doses up to 18 months, with background oral lipid‐lowering therapy. Analyses were stratified by glycaemic status (normoglycaemia, prediabetes, and diabetes) or BMI (<25, ≥25 to <30, ≥30 to <35, and ≥35 kg/m2). Co‐primary endpoints were percentage and time‐adjusted percentage change in low‐density lipoprotein (LDL) cholesterol from baseline. Safety was also assessed. Results: Baseline characteristics were balanced between treatment arms and across strata. Percent LDL cholesterol change (placebo‐corrected) with inclisiran from baseline to Day 510 ranged from −47.6% to −51.9% and from −48.8% to −54.4% across glycaemic/BMI strata, respectively. Similarly, time‐adjusted percentage changes after Day 90 and up to Day 540 ranged from −46.8% to −52.0% and from −48.6% to −53.3% across glycaemic/BMI strata, respectively. Inclisiran led to significant reductions in proprotein convertase subtilisin/kexin type 9 and other atherogenic lipids and lipoproteins versus placebo across the glycaemic/BMI strata. The proportions of individuals achieving LDL cholesterol thresholds of <1.8 mmol/L and <1.4 mmol/L with inclisiran increased with increasing glycaemic and BMI strata. Across the glycaemic/BMI strata, a higher proportion of individuals had mild/moderate treatment‐emergent adverse events (TEAEs) at the injection site with inclisiran (2.8%–7.7%) versus placebo (0.2%–2.1%). Conclusion: Inclisiran provided substantial and sustained LDL cholesterol lowering across glycaemic/BMI strata, with a modest excess of transient mild‐to‐moderate TEAEs at the injection site. [ABSTRACT FROM AUTHOR]

Introduction: The 2021 Canadian Cardiovascular Society (CCS) guidelines recommend intensive low-density lipoprotein cholesterol (LDL-C) reduction for patients with atherosclerotic cardiovascular disease (ASCVD). For patients above LDL-C threshold on maximally tolerated statins, adding ezetimibe and/or a proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i) is recommended. This population-based, real-world study examined cardiovascular (CV) events in patients with ASCVD who are on statins and above current guideline threshold LDL-C levels. Methods: Using administrative health data in Alberta, Canada, we identified patients with myocardial infarction (MI), ischemic stroke (IS), or peripheral artery disease with LDL-C > 1.8 mmol/L on statins between April 1, 2010 and March 31, 2016. Exploratory subgroups included very high-risk patients with ASCVD shown to derive the most benefit from PCSK9i intensification as identified by the CCS guidelines, including those with acute coronary syndrome (ACS) or recent MI. Frequencies and rates of individual and composite CV events (primary outcome: MI, IS, hospitalization for unstable angina, coronary revascularization, cardiovascular death; secondary outcome: MI, IS, CV death) were calculated over follow-up. Results: The study included 32,984 patients with a mean (standard deviation) follow-up of 40.8 (21.0) months. Overall, 17.7% and 15.6% experienced a primary and secondary outcome, respectively, with rates of 5.58 and 4.83 per 100 patient-years, respectively. CV death and MI were the most common events. Subgroups with recurrent MI and comorbid diabetes exhibited higher CV event rates (23.6% and 22.2% had a primary outcome, respectively). Rates of CV events were notably high in patients with ACS or recent MI (49.4% and 54.0% had a primary outcome, respectively). Conclusion: This real-world study confirms that statin-treated high-risk patients with ASCVD and above-threshold LDL-C levels have substantial incidence of recurrent CV events. These findings reinforce the opportunity for lipid-lowering therapy intensification in high-risk patients to levels below guideline-recommended threshold in order to reduce CV risk. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the effect of bempedoic acid on glycaemic and lipid variables in patients with hypercholesterolaemia. Methods: A patient‐level pooled analysis of four phase 3, randomized, double‐blind, placebo‐controlled trials evaluated changes in glycaemia, change from baseline in LDL‐C, and adverse events. Patients (N = 3621) on maximally tolerated statins were randomized 2:1 to oral bempedoic acid 180 mg or placebo once daily for 12 to 52 weeks with the results analysed by baseline glycaemic status (diabetes, prediabetes, or normoglycaemia). Results: The annual rate of new‐onset diabetes for bempedoic acid versus placebo in patients with normoglycaemia at baseline (n = 618) was 0.3% versus 0.8%, and for patients with prediabetes at baseline (n = 1868) it was 4.7% versus 5.9%. In patients with diabetes or prediabetes, bempedoic acid significantly (P <.0001) reduced HbA1c by −0.12% and −0.06%, respectively, and did not worsen fasting glucose versus placebo. Bempedoic acid significantly and consistently lowered LDL‐C levels versus placebo, regardless of baseline glycaemic status (placebo‐corrected difference range, −17.2% to −29.6%; P <.001 for each stratum). The safety of bempedoic acid was comparable with placebo and similar across glycaemic strata. Conclusions: Bempedoic acid significantly lowered LDL‐C across glycaemic strata and did not worsen glycaemic variables or increase the incidence of new‐onset diabetes versus placebo over a median follow‐up of 1 year. [ABSTRACT FROM AUTHOR]

• NIH LDL-C correlated more strongly with ultracentrifugation than Friedewald LDL-C. • NIH LDL-C had higher concordance with ultracentrifugation at LDL-C cut-offs. • The NIH equation produces less non-sensical negative LDL-C values. • NIH equation is more robust to low LDL-C and high TG concentrations. Guideline recommendations for the management of lipids in patients at risk for cardiovascular disease is largely based on low-density lipoprotein cholesterol (LDL-C) concentration. LDL-C is commonly calculated by the Friedewald equation, which has many limitations. The National Institutes of Health (NIH) equation better estimates LDL-C, particularly in patients with hypertriglyceridemia and/or low LDL-C. We validated the NIH LDL-C equation at the first Canadian clinical laboratory to implement this equation. A total of 3161 lipid ultracentrifugation results from a specialized lipid cohort of 2836 patients were included. LDL-C was calculated using the NIH and Friedewald equations and compared to LDL-C measured by ultracentrifugation. We determined the accuracy of these equations at treatment thresholds and developed NIH equation restriction criteria to ensure only accurate results are reported. Ultracentrifugation LDL-C more strongly correlated with NIH-calculated LDL-C (r2 = 0.889) than Friedewald-calculated LDL-C (r2 = 0.807) and resulted in fewer non-sensical negative LDL-C values. The correlation for NIH-calculated LDL-C improved to r2 = 0.975 after applying our restriction criteria. The NIH equation showed equivalent or superior concordance with ultracentrifugation at treatment thresholds. The LDL-C mean absolute difference increased with increasing TG and decreasing LDL-C concentrations, although the NIH equation was more robust under both conditions. We validated the NIH equation against ultracentrifugation in a cohort with a wide lipid concentration range, which supported its superiority over the Friedewald equation. We recommend clinical implementing the NIH equation for all patients except those with type III hyperlipoproteinemia or TG > 9.04 mmol/L, with an LDL-C lower reporting limit of <0.50 mmol/L. [ABSTRACT FROM AUTHOR]

Background: THEMIS (The Effect of Ticagrelor on Health Outcomes in Diabetes Mellitus Patients Intervention Study) (n = 19,220) and its pre-specified THEMIS-PCI (The Effect of Ticagrelor on Health Outcomes in Diabetes Mellitus Patients Intervention Study-Percutaneous Coronary Intervention) (n = 11,154) subanalysis showed, in individuals with type 2 diabetes mellitus (median duration 10.0 years; HbA1c 7.1%) and stable coronary artery disease without prior myocardial infarction (MI) or stroke, that ticagrelor plus aspirin (compared with placebo plus aspirin) produced a favorable net clinical benefit (composite of all-cause mortality, MI, stroke, fatal bleeding, and intracranial bleeding) if the patients had a previous percutaneous coronary intervention.Objectives: In these post hoc analyses, the authors examined whether the primary efficacy outcome (cardiovascular death, MI, stroke: 3-point major adverse cardiovascular events [MACE]), primary safety outcome (Thrombolysis In Myocardial Infarction-defined major bleeding) and net clinical benefit varied with diabetes-related factors.Methods: Outcomes were analyzed across baseline diabetes duration, HbA1c, and antihyperglycemic medications.Results: In THEMIS, the incidence of 3-point MACE increased with diabetes duration (6.7% for ≤5 years, 11.1% for >20 years) and HbA1c (6.4% for ≤6.0%, 11.8% for >10.0%). The relative benefits of ticagrelor plus aspirin on 3-point MACE reduction (hazard ratio [HR]: 0.90; p = 0.04) were generally consistent across subgroups. Major bleeding event rate (overall: 1.6%) did not vary by diabetes duration or HbA1c and was increased similarly by ticagrelor across all subgroups (HR: 2.32; p < 0.001). These findings were mirrored in THEMIS-PCI. The efficacy and safety of ticagrelor plus aspirin did not differ by baseline antihyperglycemic therapy. In THEMIS-PCI, but not THEMIS, ticagrelor generally produced favorable net clinical benefit across diabetes duration, HbA1c, and antihyperglycemic medications.Conclusion: Ticagrelor plus aspirin yielded generally consistent and favorable net clinical benefit across the diabetes-related factors in THEMIS-PCI but not in the overall THEMIS population. [ABSTRACT FROM AUTHOR]

It is unknown if the cardioprotective and renal effects of glucagon‐like peptide‐1 receptor agonists are consistent across blood pressure (BP) categories in patients with type 2 diabetes and at high risk of cardiovascular events. Using data from the LEADER (9340 patients) and SUSTAIN 6 (3297 patients) trials, we evaluated post hoc the cardiorenal effect of liraglutide and semaglutide on major adverse cardiovascular events (MACE) and nephropathy by baseline BP categories using a Cox proportional hazards model (treatment and subgroup as factors; adjusted for cardiorenal risk factors). Data from the two trials were analysed separately. In the LEADER and SUSTAIN 6 trials, the prevalence of stage 1 hypertension was 30% and 31%, respectively, and of stage 2 hypertension 41% and 43%, respectively. There was no statistical heterogeneity across the BP categories for the effects of liraglutide (P =.06 for MACE; P =.14 for nephropathy) or semaglutide (P =.40 for MACE; P =.27 for nephropathy) versus placebo. This implies that liraglutide and semaglutide may be beneficial for patients with type 2 diabetes, irrespective of their baseline BP. [ABSTRACT FROM AUTHOR]

This review addresses the question of the cardiovascular (CV) safety of sulfonylureas (SUs) in patients with type 2 diabetes mellitus (T2DM) when directly tested against comparator agents in CV outcome trials. Presented at a recent symposium entitled "SUs in the treatment of T2DM: a fresh look and new insights" held on Wednesday September 18, 2019 during the 55th Annual Meeting of the European Association for the Study of Diabetes (EASD) in Barcelona Spain, this review discusses the initial evidence that sparked concerns over the CV safety of SUs as well as more recent findings from large studies of SUs (i.e. ADVANCE, TOSCA.IT and CAROLINA trials), highlighting the differences in CV and hypoglycaemia risks among the various SUs. Finally, the impact of glycaemic control on CV outcomes is also discussed, where the data suggest that the recent positive CV outcomes with some antihyperglycaemic agents may have been driven in part by improved glycaemic control. [ABSTRACT FROM AUTHOR]

Objective: Incident type 2 diabetes is common among patients with recent acute coronary syndrome and is associated with an adverse prognosis. Some data suggest that cholesteryl ester transfer protein (CETP) inhibitors reduce incident type 2 diabetes. We compared the effect of treatment with the CETP inhibitor dalcetrapib or placebo on incident diabetes in patients with recent acute coronary syndrome.Research Design and Methods: In the dal-OUTCOMES trial, 15,871 patients were randomly assigned to treatment with dalcetrapib 600 mg daily or placebo, beginning 4-12 weeks after an acute coronary syndrome. Absence of diabetes at baseline was based on medical history, no use of antihyperglycemic medication, and hemoglobin A1c and serum glucose levels below diagnostic thresholds. Among these patients, incident diabetes after randomization was defined by any diabetes-related adverse event, new use of antihyperglycemic medication, hemoglobin A1c ≥6.5%, or a combination of at least two measurements of serum glucose ≥7.0 mmol/L (fasting) or ≥11.1 mmol/L (random).Results: At baseline, 10,645 patients (67% of the trial cohort) did not have diabetes. During a median follow-up of 30 months, incident diabetes was identified in 403 of 5,326 patients (7.6%) assigned to dalcetrapib and in 516 of 5,319 (9.7%) assigned to placebo, corresponding to absolute risk reduction of 2.1%, hazard ratio of 0.77 (95% CI 0.68-0.88; P < 0.001), and a need to treat 40 patients for 3 years to prevent 1 incident case of diabetes. Considering only those with prediabetes at baseline, the number needed to treat for 3 years to prevent 1 incident case of diabetes was 25. Dalcetrapib also decreased the number of patients who progressed from normoglycemia to prediabetes and increased the number who regressed from diabetes to no diabetes.Conclusions: In patients with a recent acute coronary syndrome, incident diabetes is common and is reduced substantially by treatment with dalcetrapib. [ABSTRACT FROM AUTHOR]

Background: Mixed dyslipidemia [elevated non-high-density lipoprotein cholesterol (non-HDL-C) and triglycerides (TGs), and decreased HDL-C] is common in type 2 diabetes mellitus (T2DM) and is associated with increased cardiovascular risk. Non-HDL-C and apolipoprotein B (ApoB) are the preferred therapeutic targets for mixed dyslipidemia. Alirocumab is a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9) that effectively reduces low-density lipoprotein cholesterol (LDL-C), non-HDL-C, ApoB, and lipoprotein(a) (Lp[a]), and is well-tolerated in individuals with T2DM. Methods: The previously reported open-label ODYSSEY DM-DYSLIPIDEMIA trial data demonstrated the effects of alirocumab on individuals with non‐HDL-C ≥ 100 mg/dL and TGs ≥ 150 and < 500 mg/dL receiving stable maximally tolerated statin (n = 413). This post hoc subgroup analysis of the primary trial investigated the effects of alirocumab [75 mg every 2 weeks (Q2W) with possible increase to 150 mg Q2W at Week 12] versus usual care [ezetimibe, fenofibrate, or no additional lipid-lowering therapy (LLT)] on non-HDL-C and other lipids in individuals with T2DM and baseline TGs ≥ 200 mg/dL and HDL-C < 40 mg/dL (men) or < 50 mg/dL (women). Results: Alirocumab significantly reduced non-HDL-C [LS mean difference (standard error (SE)), − 35.0% (3.9)], ApoB [LS mean difference (SE), − 34.7% (3.6)], LDL-C [LS mean difference (SE), − 47.3% (5.2)], LDL particle number [LS mean difference (SE), − 40.8% (4.1)], and Lp(a) [LS mean difference (SE), − 29.9% (5.4)] versus usual care from baseline to Week 24 (all P < 0.0001). Results were similar for alirocumab versus usual care. TG reductions were similar between alirocumab and usual care (no significant difference), but greater with fenofibrate versus alirocumab (P = 0.3371). Overall, alirocumab significantly increased HDL-C versus usual care [LS mean difference (SE), 7.9% (3.6); P < 0.05], although differences with alirocumab versus ezetimibe or fenofibrate were non-significant. Most individuals receiving alirocumab achieved ApoB < 80 mg/dL (67.9%) and non-HDL-C < 100 mg/dL (60.9%). Adverse event frequency was similar between alirocumab (67.2%) and usual care (70.7%). Additionally, no clinically relevant effect of alirocumab on change in glycemic parameters or use of antihyperglycemic agents was observed. Conclusions: Alirocumab is an effective therapeutic option for individuals with T2DM, TGs ≥ 200 mg/dL, and HDL-C < 40 mg/dL (men) or < 50 mg/dL (women). Atherogenic lipid (ApoB and non-HDL) reductions were greater with alirocumab than ezetimibe, fenofibrate, or no LLT. Consistent with previous studies, alirocumab was generally well tolerated. Trial registration Clinicaltrials.gov, NCT02642159. Registered December 24, 2015, https://clinicaltrials.gov/ct2/show/NCT02642159 [ABSTRACT FROM AUTHOR]

Importance: Additional treatment options are needed for patients who do not achieve sufficient reduction in low-density lipoprotein cholesterol (LDL-C) level with available lipid-lowering therapies.Objective: To assess the efficacy of bempedoic acid vs placebo in patients at high cardiovascular risk receiving maximally tolerated lipid-lowering therapy.Design, Setting, and Participants: Phase 3, randomized, double-blind, placebo-controlled clinical trial conducted at 91 clinical sites in North America and Europe from November 2016 to September 2018, with a final date of follow-up of September 22, 2018. A total of 779 patients with atherosclerotic cardiovascular disease, heterozygous familial hypercholesterolemia, or both met randomization criteria, which included LDL-C level 70 mg/dL (1.8 mmol/L) or greater while receiving maximally tolerated lipid-lowering therapy.Interventions: Patients were randomized 2:1 to treatment with bempedoic acid (180 mg) (n = 522) or placebo (n = 257) once daily for 52 weeks.Main Outcomes and Measures: The primary end point was percent change from baseline in LDL-C level at week 12. Secondary measures included changes in levels of lipids, lipoproteins, and biomarkers.Results: Among 779 randomized patients (mean age, 64.3 years; 283 women [36.3%]), 740 (95.0%) completed the trial. At baseline, mean LDL-C level was 120.4 (SD, 37.9) mg/dL. Bempedoic acid lowered LDL-C levels significantly more than placebo at week 12 (-15.1% vs 2.4%, respectively; difference, -17.4% [95% CI, -21.0% to -13.9%]; P < .001). Significant reductions with bempedoic acid vs placebo were observed at week 12 for non-high-density lipoprotein cholesterol (-10.8% vs 2.3%; difference, -13.0% [95% CI, -16.3% to -9.8%]; P < .001), total cholesterol (-9.9% vs 1.3%; difference, -11.2% [95% CI, -13.6% to -8.8%]; P < .001), apolipoprotein B (-9.3% vs 3.7%; difference, -13.0% [95% CI, -16.1% to -9.9%]; P < .001), and high-sensitivity C-reactive protein (median, -18.7% vs -9.4%; difference, -8.7% [asymptotic confidence limits, -17.2% to -0.4%]; P = .04). Common adverse events included nasopharyngitis (5.2% vs 5.1% with bempedoic acid and placebo, respectively), urinary tract infection (5.0% vs 1.9%), and hyperuricemia (4.2% vs 1.9%).Conclusions and Relevance: Among patients at high risk for cardiovascular disease receiving maximally tolerated statins, the addition of bempedoic acid compared with placebo resulted in a significant lowering of LDL-C level over 12 weeks. Further research is needed to assess the durability and clinical effect as well as long-term safety.Trial Registration: ClinicalTrials.gov Identifier: NCT02991118. [ABSTRACT FROM AUTHOR]

Type 2 diabetes (T2D) is a growing health concern across both developed and developing countries. Cardiovascular disease (CVD) remains the major cause of increased mortality in this patient population. In recent years, effective low density lipoprotein lowering treatments and other risk reduction strategies have substantially reduced the risk of atherosclerotic CVD, yet patients with T2D continue to remain at increased risk for atherosclerotic CVD. Here, we will briefly review various proposed underlying mechanisms for this residual risk with a more in‐depth focus on the potential role of triglyceride‐rich lipoproteins in residual risk and potential avenues to target this pharmacologically. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the efficacy and safety of inclisiran by diabetes status.Research Design and Methods: ORION-1 (ClinicalTrials.gov, NCT02597127) randomized 501 subjects with atherosclerotic cardiovascular disease (ASCVD) or ASCVD risk equivalents and high LDL cholesterol (LDL-C), despite maximally tolerated LDL-C-lowering therapies, to one or two doses of placebo or inclisiran. Levels of lipids and proprotein convertase subtilisin/kexin type 9 (PCSK9) at baseline and day 180 were compared.Results: Inclisiran was associated with marked declines in LDL-C (median -28% to -52%, P < 0.0001 and -28% to -55%, P < 0.005 for all doses in the without- and with-diabetes groups, respectively) and PCSK9. The inclisiran-treated groups also had lower apolipoprotein B, non-HDL cholesterol, and lipoprotein(a) but higher HDL cholesterol. Inclisiran had an adverse profile similar to that of placebo, and adverse events were proportionally balanced in the baseline with- and without-diabetes groups.Conclusions: PCSK9-targeted siRNA-driven strategies may provide a novel therapeutic option for managing dyslipidemia in the presence and absence of diabetes. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Aims To investigate the efficacy and safety of alirocumab in participants with type 2 (T2D) or type 1 diabetes (T1D) treated with insulin who have elevated LDL cholesterol levels despite maximally tolerated statin therapy. Methods Participants at high cardiovascular risk with T2D (n = 441) or T1D (n = 76) and LDL cholesterol levels ≥1.8 mmol/L (≥70 mg/dL) were randomized 2:1 to alirocumab:placebo administered subcutaneously every 2 weeks, for 24 weeks' double-blind treatment. Alirocumab-treated participants received 75 mg every 2 weeks, with blinded dose increase to 150 mg every 2 weeks at week 12 if week 8 LDL cholesterol levels were ≥1.8 mmol/L. Primary endpoints were percentage change in calculated LDL cholesterol from baseline to week 24, and safety assessments. Results Alirocumab reduced LDL cholesterol from baseline to week 24 by a mean ± standard error of 49.0% ± 2.7% and 47.8% ± 6.5% vs placebo (both P < .0001) in participants with T2D and T1D, respectively. Significant reductions were observed in non-HDL cholesterol ( P < .0001), apolipoprotein B ( P < .0001) and lipoprotein (a) ( P ≤ .0039). At week 24, 76.4% and 70.2% of the alirocumab group achieved LDL cholesterol <1.8 mmol/L in the T2D and T1D populations ( P < .0001), respectively. Glycated haemoglobin and fasting plasma glucose levels remained stable for the study duration. Treatment-emergent adverse events were observed in 64.5% of alirocumab- vs 64.1% of placebo-treated individuals (overall population). Conclusions Alirocumab produced significant LDL cholesterol reductions in participants with insulin-treated diabetes regardless of diabetes type, and was generally well tolerated. Concomitant administration of alirocumab and insulin did not raise any safety concerns (NCT02585778). [ABSTRACT FROM AUTHOR]

For patients with type 2 diabetes mellitus, glucagon-like peptide-1 receptor agonists (GLP-1RAs) generally exert robust glucose-lowering effects that are at least as effective as insulin. As monotherapies, changes from baseline in HbA1c with GLP-1RAs ranged from -1.9 to -0.7 % in phase 3 trials. In addition, GLP-1RAs confer a low risk of hypoglycaemia and have a bodyweight advantage (changes from baseline ranging from -4.0 to -0.4 kg). There is also evidence of significant reductions in risk for cardiovascular events with some of these agents, with a number of other trials underway. Gastrointestinal adverse events typically increase with GLP-1RAs, although these are generally mild to moderate in intensity and rarely require treatment discontinuation. The GLP-1RAs that are commercially available or in development vary in structure and pharmacokinetics. These differences affect the frequency of administration and can also affect their relative efficacy and safety. This review summarizes the findings of phase 3 glycaemic control trials of available GLP-1RAs and considers them in the context of the distinct clinical needs of individual patients. [ABSTRACT FROM AUTHOR]

Background: Type 2 diabetes mellitus (T2DM) is often associated with mixed dyslipidaemia, where non-highdensity lipoprotein cholesterol (non-HDL-C) levels may more closely align with cardiovascular risk than low-density lipoprotein cholesterol (LDL-C). We describe the design and rationale of the ODYSSEY DM-DYSLIPIDEMIA study that assesses the efficacy and safety of alirocumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, versus lipid-lowering usual care in individuals with T2DM and mixed dyslipidaemia at high cardiovascular risk with non- HDL-C inadequately controlled despite maximally tolerated statin therapy. For the first time, atherogenic cholesterollowering with a PCSK9 inhibitor will be assessed with non-HDL-C as the primary endpoint with usual care as the comparator. Methods: DM-DYSLIPIDEMIA is a Phase 3b/4, randomised, open-label, parallel group, multinational study that planned to enrol 420 individuals. Main inclusion criteria were T2DM and mixed dyslipidaemia (non-HDL-C ≥100 mg/dl [≥2.59 mmol/l], and triglycerides ≥150 and <500 mg/dl [≥1.70 and <5.65 mmol/l]) with documented atherosclerotic cardiovascular disease or ≥1 additional cardiovascular risk factor. Participants were randomised (2:1) to alirocumab 75 mg every 2 weeks (Q2W) or lipid-lowering usual care on top of maximally tolerated statin (or no statin if intolerant). If randomised to usual care, investigators were able to add their pre-specified choice of one of the following to the patient's current statin regimen: ezetimibe, fenofibrate, omega-3 fatty acids or nicotinic acid, in accordance with local standard-of-care. Alirocumab-treated individuals with non-HDL-C ≥100 mg/dl at week 8 will undergo a blinded dose increase to 150 mg Q2W at week 12. The primary efficacy endpoint is non-HDL-C change from baseline to week 24 with alirocumab versus usual care; other lipid levels (including LDL-C), glycaemia-related measures, safety and tolerability will also be assessed. Alirocumab will be compared to fenofibrate in a secondary analysis. Results: Recruitment completed with 413 individuals randomised in 14 countries worldwide. Results of this trial are expected in the second quarter of 2017. Conclusions: ODYSSEY DM-DYSLIPIDEMIA will provide information on the efficacy and safety of alirocumab versus lipid-lowering usual care in individuals with T2DM and mixed dyslipidaemia at high cardiovascular risk using non-HDLC as the primary efficacy endpoint. [ABSTRACT FROM AUTHOR]

The article presents a clinical trial conducted to examine the efficacy of liraglutide on cardiovascular outcomes and mortality in 9340 patients with type 2 diabetes mellitus. It states that with an additional 10% having statin added during the course of the study, 72% of patents were on a statin at baseline. It found that MACEs across the 3 LDL-C groups was consistently reduced using Liraglutide.

Aims To examine the safety and efficacy of linagliptin in patients with type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD) using pooled data from the global clinical trials program. Methods Patient-level data were pooled from randomized, placebo-controlled clinical trials of linagliptin (5 mg, monotherapy or combination therapy). Safety/efficacy analyses were conducted for patients with CAD and ≥ 12 and ≥ 24 weeks of treatment, respectively. Results The safety analysis included 19 trials (linagliptin, n = 451; placebo, n = 272) and the efficacy analysis, 12 trials (linagliptin, n = 328; placebo, n = 198); mean (± standard deviation) exposure to study treatment was 212 (144) days linagliptin and 245 (171) days placebo. Occurrence of cardiac adverse events (AEs) was similar for linagliptin- and placebo-treated patients (9.1% and 9.2%, respectively); exposure-adjusted incidence rates (per 100 patient-years) were 16.6 and 14.0, respectively. Overall incidence of AEs was numerically lower with linagliptin than placebo. After 24 weeks, mean adjusted change (standard error) from baseline glycosylated hemoglobin was − 0.64% (0.04) with linagliptin vs. –0.08% (0.05) with placebo ( P < .001). Conclusions This comprehensive pooled analysis showed that addition of linagliptin to treatment regimens of patients with T2DM and CAD was not associated with an increased incidence of cardiac AEs, was well tolerated, and was effective. [ABSTRACT FROM AUTHOR]

Introduction: Canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, has demonstrated sustained improvements in glycemic control and body weight reductions with treatment for up to 104 weeks in a broad range of patients with type 2 diabetes mellitus (T2DM). Methods: This was a post hoc analysis of individual patient data ( N = 1450) from a randomized, double-blind, placebo-controlled, Phase 3 study comparing canagliflozin with glimepiride as add-on to metformin in patients with T2DM during a 52-week core period followed by a 52-week extension period. The number of patients who achieved a reduction from baseline in both HbA1c and body weight with canagliflozin 100 and 300 mg and glimepiride was assessed at Weeks 52 and 104. Safety was recorded as adverse events (AEs) during the study. Results: Canagliflozin 100 and 300 mg provided durable glycemic improvements and body weight reductions compared with glimepiride over 104 weeks. At Week 52, the proportion of patients who achieved reductions in both HbA1c and body weight was 72.4% with canagliflozin 100 mg, 78.5% with canagliflozin 300 mg, and 26.8% with glimepiride; similar results were observed at Week 104 (65.5%, 71.1%, and 26.8% with canagliflozin 100 and 300 mg and glimepiride, respectively). The AE profile of canagliflozin was comparable to that observed in previous studies, with increased incidence of AEs related to the mechanism of SGLT2 inhibition (e.g., genital mycotic infections, urinary tract infections, and osmotic diuresis-related AEs) and a low risk of hypoglycemia. Conclusion: More patients treated with canagliflozin experienced reductions in both HbA1c and body weight compared with glimepiride for up to 104 weeks. Canagliflozin was generally well tolerated in patients with T2DM when used in combination with metformin. Clinical Trial Registration: ClinicalTrials.gov identifier, NCT00968812. Funding: Janssen Research & Development, LLC. [ABSTRACT FROM AUTHOR]

Aim: The 6-months titration profile of a new scored gliclazide modified release (MR) formulation (MR 60 mg) was explored in individuals with type 2 diabetes.Methods: This international study enrolled 7170 individuals, age ≥ 35 years with HbA1c ≥ 7.5% (59 mmol/mol) and not on insulin. Participants were started on 30-120 mg gliclazide MR 60 mg once daily as a first line (FIRST), add-on (ADD) or switch from a previous oral antihyperglycemic treatment strategy (SWITCH). Uptitration was capped at 120 mg.Results: Women comprised 58.5% of the cohort. Mean baseline age was 58.9 years, body mass index 30.1 kg/m(2) and diabetes duration 5.1 years. Mean baseline HbA1c for the FIRST (n=2023), ADD (n=3136) and SWITCH (n=1834) groups was 8.9% (74 mmol/mol), 8.8% (73 mmol/mol) and 8.8% (73 mmol/mol), respectively. Probability of reaching optimal dose at months 1, 2, 3 and 6 was 15%, 39%, 59% and 92%, respectively. Mean HbA1c changes from baseline to month 6 were FIRST: -1.98%, ADD: -1.74% and SWITCH: -1.61% (all p<0.01). Overall, 65.3% achieved HbA1c ≤ 7.0% (53 mmol/mol); average duration for achieving glucose control was 80.1 days. Mean weight loss ranged from -1.45 to -1.27 kg. Severe hypoglycemia was experienced by 0.06% of participants. Most (95.5%) indicated a greater likelihood of adherence with the gliclazide MR 60 mg regime relative to their previous therapy.Conclusions: In this large, real world study, progressive uptitration with gliclazide MR 60 mg once daily appears to be efficacious and safe in individuals with suboptimal glycemic control at various stages of the diabetes continuum. [ABSTRACT FROM AUTHOR]

Cardiovascular safety of oral semaglutide in patients with type 2 diabetes: rationale, design and patient baseline characteristics for the PIONEER 6 trial. Keywords: antidiabetic drug; cardiovascular disease; semaglutide; type 2 diabetes EN antidiabetic drug cardiovascular disease semaglutide type 2 diabetes 2388 2392 5 07/04/23 20230801 NES 230801 BACKGROUND Epidemiological studies have shown that elevated triglycerides (TGs) is associated with higher cardiovascular (CV) risk[[1]] and may help to identify patients at persistent risk of CV events despite treatment with statins and other evidence-based therapies.[[3]] Evidence suggests that some, but not all, pharmacological treatments that appear to reduce TGs might also reduce the occurrence of fatal or non-fatal CV events in individuals at high risk. [Extracted from the article]

The article provides facts and tips to help in the appropriate prescription of liraglutide, the first glucagon-like protein-1 receptor agonist (GLP-1 RA) with a cardiovascular indication. Topics discussed include background on cardiovascular outcomes studies evaluating GLP-1, way liraglutide lowers glucose, and most common side effects associated with liraglutide. Practical considerations on treatment with liraglutide are also mentioned.

OBJECTIVE To assess the efficacy and safety of dapagliflozin, a selective sodium-glucose cotransporter 2 inhibitor, compared with placebo in patients with type 2 diabetes (T2D), documented pre-existing cardiovascular disease (CVD), and a history of hypertension. RESEARCH DESIGN AND METHODS Patients (N = 922) were randomized to receive 10 mg dapagliflozin or placebo in a double-blind trial for 24 weeks, followed by a 28-week extension period. In patients receiving insulin, the insulin dose was reduced by 25% at randomization. Patients were stratified by age, insulin use, and time from the most recent qualifying cardiovascular (CV) event. Co-primary end points were a change from baseline in hemoglobin A1c (HbA1c) and the proportion of patients achieving a combined reduction in HbA1c of ≥0.5% (5.5 mmol/mol), body weight (BW) of ≥3%, and systolic blood pressure (SBP) of ≥3 mmHg. RESULTS At 24 weeks, dapagliflozin significantly reduced HbA1c (20.38% [24.2 mmol/mol]) from baseline (8.18%) compared with a slight increase with placebo from baseline (8.08%) (0.08% [0.9 mmol/mol]). Significantly more patients met the three-item end point with treatment with dapagliflozin than with placebo (11.7% vs. 0.9%, respectively). Changes were maintained over 52 weeks. Although ~42% of patients were ≥65 years old, similar results were observed in both age-stratified groups. Serious adverse events, hypoglycemia, urinary tract infections, and cardiac disorders were similar between groups. Adverse events of hypotension, dehydration, hypovolemia, genital infection, and renal failure or impairment occurred more often with dapagliflozin treatment. CONCLUSIONS In this study that evaluated T2D patients who were at high risk for future CVD events, dapagliflozin administration had significantly greater effects in reducing HbA1c, BW, and SBP, without adversely impacting CV safety when compared with placebo treatment. [ABSTRACT FROM AUTHOR]

OBJECTIVE To examine the safety and cardiovascular (CV) effects of saxagliptin in the predefined elderly (≥65 years) and very elderly (≥75 years) subpopulations of the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) trial. RESEARCH DESIGN AND METHODS Individuals ≥40 years (n = 16,492; elderly, n = 8,561; very elderly, n = 2,330) with HbA1c ≥6.5% (47.5 mmol/mol) and ≤12.0% (107.7 mmol/mol) were randomized (11) to saxagliptin (5 or 2.5 mg daily) or placebo in a double-blind trial for a median follow-up of 2.1 years. RESULTS The hazard ratio (HR) for the comparison of saxagliptin versus placebo for the primary end point (composite of CV mortality, myocardial infarction, or ischemic stroke) was 0.92 for elderly patients vs. 1.15 for patients <65 years (P = 0.06) and 0.95 for very elderly patients. The HR for the secondary composite end points in the entire cohort, elderly cohort, and very elderly cohort were similar. Although saxagliptin increased the risk of hospitalization for heart failure in the overall saxagliptin population, there was no age-based treatment interaction (P = 0.76 for elderly patients vs. those <65 years; P = 0.34 for very elderly patients vs. those <75 years). Among saxagliptin-treated individuals with baseline HbA1c ≥7.6% (59.6 mmol/mol), the mean change from baseline HbA1c at 2 years was -0.69%, -0.64%, -0.66%, and -0.66% for those ≥65, <65, ≥75, and <75 years, respectively. The incidence of overall adverse events (AEs) and serious AEs was similar between saxagliptin and placebo in all cohorts; however, hypoglycemic events were higher for saxagliptin versus placebo regardless of age. CONCLUSIONS The SAVOR-TIMI 53 trial supports the overall CV safety of saxagliptin in a robust number of elderly and very elderly participants, although the risk of heart failure hospitalization was increased irrespective of age category. AEs and serious AEs as well as glycemic efficacy of saxagliptin in elderly patients are similar to those found in younger patients. [ABSTRACT FROM AUTHOR]

OBJECTIVE To assess the efficacy/safety of canagliflozin, a sodium--glucose cotransporter 2 inhibitor, compared with glimepiride over 104 weeks in patients with type 2 diabetes inadequately controlled with metformin. RESEARCH DESIGN AND METHODS In this randomized, double-blind study, patients (N = 1,450) received canagliflozin 100 or 300 mg or glimepiride (titrated up to 6 or 8 mg/day) during a 52-week core period followed by a 52-week extension. RESULTS At week 104, reductions from baseline in A1C were -0.65%, -0.74%, and -0.55% (-7.1, -8.1, and -6.0 mmol/mol) with canagliflozin 100 and 300 mg and glimepiride, respectively. Durability analyses showed sustained A1C lowering with both canagliflozin doses versus glimepiride. Reductions in bodyweight (-4.1%, -4.2%, and 0.9%, respectively) and systolic blood pressure (-2.0, -3.1, and 1.7 mmHg, respectively) were seen with canagliflozin 100 and 300 mg compared with glimepiride at week 104. The overall adverse event (AE) incidence was 73.3%, 77.9%, and 78.4% with canagliflozin 100 and 300 mg and glimepiride; the incidence of AE-related discontinuations was low across groups (6.2%, 9.5%, and 7.3%, respectively). Incidences of genital mycotic infections, urinary tract infections, and osmotic diuresis--related AEs were higher with canagliflozin than glimepiride; these were generally mild to moderate in intensity and led to few discontinuations. Fewer patients had hypoglycemia episodes with canagliflozin 100 and 300 mg than glimepiride (6.8%, 8.2%, and 40.9%). Mild decreases in estimated glomerular filtration rate occurred initially with canagliflozin; these attenuated over 104 weeks. CONCLUSIONS Canagliflozin provided durable glycemic improvements compared with glimepiride and was generally well tolerated in patients with type 2 diabetes receiving background treatment with metformin over 104 weeks. [ABSTRACT FROM AUTHOR]

OBJECTIVE To evaluate weekly subcutaneous albiglutide versus daily sitagliptin in renally impaired patients with type 2 diabetes and inadequately controlled glycemia on a regimen of diet and exercise and/or oral antihyperglycemic medications. RESEARCH DESIGN AND METHODS In this phase III, randomized, double-blind, multicenter, 52-week study, the primary study end point was HbA1c change from baseline at week 26 in patients with renal impairment, as assessed with estimated glomerular filtration rate and categorized as mild, moderate, or severe (≥60 to ≤89, ≥30 to ≤59, and ≥15 to ≤29 mL/min/1.73 m², respectively). Secondary end points included fasting plasma glucose (FPG), weight, achievement of treatment targets, hyperglycemic rescue, and safety. RESULTS Baseline demographics were similar across treatment and renal impairment groups with overall mean age of 63.3 years, BMI of 30.4 kg/m², HbA1c of 8.2% (66 mmol/mol), and diabetes disease duration of 11.2 years. HbA1c change from baseline at week 26 was significantly greater for albiglutide than sitagliptin (-0.83% vs. -0.52%, P = 0.0003). Decreases in HbA1c, FPG, and weight were seen through week 52. Time to hyperglycemic rescue through week 52 was significantly longer for albiglutide than sitagliptin (P = 0.0017). Results of safety assessments were similar between groups, and most adverse events (AEs) were mild or moderate. The incidences of gastrointestinal AEs for albiglutide and sitagliptin were as follows: overall, 31.7%, 25.2%; diarrhea, 10.0%, 6.5%; nausea, 4.8%, 3.3%; and vomiting, 1.6%, 1.2%, respectively. CONCLUSIONS Once-weekly albiglutide therapy in renally impaired patients with type 2 diabetes provided statistically superior glycemic improvement with almost similar tolerability compared with daily sitagliptin therapy. [ABSTRACT FROM AUTHOR]

We have previously reported that once-weekly albiglutide was noninferior to thrice-daily lispro for glycemic lowering, with decreased weight and risk of hypoglycemia, in patients inadequately controlled on basal insulin over 26 weeks. Findings after 52 weeks reveal similar responses to albiglutide as an add-on to insulin glargine. [ABSTRACT FROM AUTHOR]

Objectives To assess the efficacy of dapagliflozin, a sodium-glucose cotransporter 2 inhibitor, for the treatment of individuals with type 2 diabetes mellitus (T2 DM) and preexisting cardiovascular disease ( CVD). Design Randomized, double-blind, age-stratified (<65 and ≥65), 24-week clinical trial with a 28-week extension. Setting One hundred seventy-three centers in 10 countries. Participants Individuals (N = 964) with T2 DM, glycosylated hemoglobin (HbA1c) of 7.0% to 10.0%, and documented CVD. Intervention Dapagliflozin 10 mg/d or placebo was added to usual care. Participants receiving insulin had their total daily insulin dose reduced by 25% at randomization. Measurements Two equal primary end points: change from baseline in HbA1c and proportion of participants achieving a three-item end point (reduction of ≥0.5% in HbA1c, ≥3% in body weight, and ≥3 mmHg in systolic blood pressure) at 24 weeks. Results Forty-seven percent were aged 65 and older, 7.7% were aged 75 and older, mean duration of T2 DM was 13 years, mean baseline HbA1c was 8.1%, and approximately 60% were taking insulin. The placebo-corrected change in HbA1c with dapagliflozin was −0.4% at 24 weeks. Significantly more participants achieved the three-item end point with dapagliflozin (10.0%) than with placebo (1.9%). The placebo-corrected percentage change in body weight for dapagliflozin was −1.9% (−1.8 kg). Similar results were observed in both age strata, and changes were maintained over 52 weeks. More than one-quarter (28.2%) of participants receiving dapagliflozin and 25.3% of those receiving placebo experienced hypoglycemia. More participants receiving dapagliflozin had vulvovaginitis, balanitis, or urinary tract infection. Conclusion When added to a usual background regimen in an older population with advanced T2 DM and preexisting comorbid CVD, dapagliflozin improved glycemic control without an increase in hypoglycemic risk, promoted weight loss, and was well tolerated. [ABSTRACT FROM AUTHOR]

Background Sodium-glucose cotransporter 2 (SGLT2) inhibitors improve glycaemia in patients with type 2 diabetes by enhancing urinary glucose excretion. We compared the efficacy and safety of canagliflozin, an SGLT2 inhibitor with glimepiride in patients with type 2 diabetes inadequately controlled with metformin. Methods We undertook this 52 week, randomised, double-blind, active-controlled, phase 3 non-inferiority trial at 157 centres in 19 countries between Aug 28, 2009, and Dec 21, 2011. Patients aged 18-80 years with type 2 diabetes and glycated haemoglobin A1c (HbA1c) of 7.0-9.5% on stable metformin were randomly assigned (1:1:1) by computer generated random sequence via an interactive voice or web response system to receive canagliflozin 100 mg or 300 mg, or glimepiride (up-titrated to 6 mg or 8 mg per day) orally once daily. Patients, study investigators, and local sponsor personnel were masked to treatment. The primary endpoint was change in HbA1c from baseline to week 52, with a non-inferiority margin of 0.3% for the comparison of each canagliflozin dose with glimepiride. If non-inferiority was shown, we assessed superiority on the basis of an upper bound of the 95% CI for the difference of each canagliflozin dose versus glimepiride of less than 0.0%. Analysis was done in a modified intention-to-treat population, including all randomised patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00968812. Findings 1450 of 1452 randomised patients received at least one dose of glimepiride (n=482), canagliflozin 100 mg (n=483), or canagliflozin 300 mg (n=485). For lowering of HbA1c at 52 weeks, canagliflozin 100 mg was non-inferior to glimepiride (least-squares mean difference -0.01% [95% C1-0.11 to 0.09]), and canagliflozin 300 mg was superior to glimepiride (-0.12% [-0.22 to -0- 02]). 39 (8%) patients had serious adverse events in the glimepiride group versus 24 (5%) in the canagliflozin 100 mg group and 26 (5%) in the 300 mg group. In the canagliflozin 100 mg and 300 m groups versus the glimepiride group, we recorded a greater number of genital mycotic infections (women: 26 [11%] and 34 [14%] vs five [2%]; men: 17 [7%] and 20 [8%] vs three [1%]), urinary tract infections (31 [6%] for both canagliflozin doses vs 22 [5%]), and osmotic diuresis-related events (pollakiuria: 12 [3%] for both doses vs one [<1%]; polyuria: four [<1%] for both doses vs two [<1%]). Interpretation Canagliflozin provides greater HbA1c reduction than does glimepiride, and is well tolerated in patients with type 2 diabetes receiving mefformin. These findings support the use of canagliflozin as a viable treatment option for patients who do not achieve sufficient glycaemic control with mefformin therapy. [ABSTRACT FROM AUTHOR]

Objective: Insulin degludec/insulin aspart (IDegAsp) is a soluble co-formulation of insulin degludec (70%) and insulin aspart (IAsp: 30%). Here, we compare the efficacy and safety of IDegAsp, an alternative IDegAsp formulation (AF: containing 45% IAsp), and biphasic IAsp 30 (BIAsp 30). Design: Sixteen-week, open-label, randomised, treat-to-target trial. Methods: Insulin-naive subjects with type 2 diabetes (18-75 years) and a HbA1c of 7-11% were randomised to twice-daily IDegAsp (n=61), AF (n=59) or BIAsp 30 (n=62), all in combination with metformin. Insulin was administered pre-breakfast and dinner (main evening meal) and titrated to pre-breakfast and pre-dinner plasma glucose (PG) targets of 4.0-6.0 mmol/l. Results: Mean HbA1c after 16 weeks was comparable for IDegAsp, AF and BIAsp 30 (6.7, 6.6 and 6.7% respectively). With IDegAsp, 67% of subjects achieved HbA1c <7.0% without confirmed hypoglycaemia in the last 4 weeks of treatment compared with 53% (AF) and 40% (BIAsp 30). Mean fasting PG was significantly lower for IDegAsp vs BIAsp 30 (treatment difference (TD): K0.99 mmol/l (95% confidence interval:-1.68; 0.29)) and AF vs BIAsp 30 (TD: K0.88 mmol/l (K1.58; K0.18)). A significant, 58% lower rate of confirmed hypoglycaemia was found for IDegAsp vs BIAsp 30 (rate ratio (RR): 0.42 (0.23; 0.75)); rates were similar for AF vs BIAsp 30 (RR: 0.92 (0.54; 1.57)). IDegAsp and AF had numerically lower rates of nocturnal confirmed hypoglycaemia vs BIAsp 30 (RR: 0.33 (0.09; 1.14) and 0.66 (0.22; 1.93) respectively). Conclusions: IDegAsp provided comparable overall glycaemic control to BIAsp 30 with a significantly lower rate of hypoglycaemia. [ABSTRACT FROM AUTHOR]

The investigators review the evidence of the potential role of renin-angiotensin system (RAS) blockers in delaying or preventing the onset and progression of diabetes mellitus (DM) and cardiovascular disease and the suggested mechanisms by which these agents exert their favorable metabolic and cardiovascular effects. Data from clinical trials suggest that RAS blockade not only reduces cardiovascular risk in patients with DM but also may prevent or delay DM onset in at-risk subjects. These observations set the stage for further studies evaluating the risk for developing DM as a primary end point: the Diabetes Reduction Approaches With Ramipril And Rosiglitazone Medications (DREAM) trial, in which ramipril significantly increased regression to normoglycemia (although it did not reduce the primary end point of new-onset DM or death), and the ongoing Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial, the only DM prevention trial also powered to evaluate whether a reduced risk for DM is associated with a reduction in cardiovascular disease events. In conclusion, overwhelming evidence suggests that the RAS plays an important role in the pathogenesis of DM and its associated cardiovascular risks. [Copyright &y& Elsevier]

The percentage of change from baseline in low-density lipoprotein (LDL) cholesterol after the addition of ezetimibe 10 mg to atorvastatin 40 mg was compared with uptitration to atorvastatin 80 mg. In this multicenter, double-blind, parallel-group study, adult hypercholesterolemic patients using atorvastatin 40 mg/day were randomly assigned to atorvastatin 40 mg plus ezetimibe 10 mg or uptitration to atorvastatin 80 mg. After 6 weeks of treatment, compared with atorvastatin 80 mg, atorvastatin 40 mg plus ezetimibe significantly reduced the primary end point of LDL cholesterol by −27% versus atorvastatin 80 mg by −11% (p <0.001), as well as significantly reduced non–high-density lipoprotein cholesterol, apolipoprotein B, total cholesterol, and triglycerides significantly more than atorvastatin 80 mg (all p <0.001). Percentages of change in high-sensitivity C-reactive protein, high-density lipoprotein cholesterol, and apolipoprotein A-I were similar between groups. Significantly more patients treated with atorvastatin 40 mg plus ezetimibe reached LDL cholesterol <70 mg/dl versus patients treated with atorvastatin 80 mg (74% vs 32%; p <0.001). Safety and tolerability profiles and incidence of liver and muscle adverse experiences were generally similar between groups. In conclusion, these results showed that adding ezetimibe to atorvastatin 40 mg was significantly more effective than uptitrating to atorvastatin 80 mg at lowering LDL cholesterol and other lipid parameters. Both treatments were generally well tolerated (clinical trial no. NCT00276484). [Copyright &y& Elsevier]

Aims: Our objective was to examine risk factor modification targets and treatment in relation to duration of diabetes.Methods: The Diabetes Mellitus Status in Canada (DM-SCAN) study collected data on 5109 patients with type 2 diabetes mellitus (T2DM) in 2012 in primary care. We compared the prevalence of vascular complications, treatment targets, and interventions between patients with diagnosed diabetes duration ≤10 and > 10 years.Results: Physicians more frequently assigned HbA1c (glycated hemoglobin) targets of 7.1-8.5% (54-69 mmol/mol) to patients with longer duration of diabetes (n = 1647) (19.8% vs 9.5%, p < 0.001). Patients with longer duration of diabetes were less likely to achieve HbA1c targets of ≤7.0% (53 mmol/mol) (39% vs. 55%, p < 0.001), had similar likelihood of achieving blood pressure targets of ≤130/80 mmHg (38% vs. 36%, p = 0.26) and were more likely to achieve LDL-C targets of ≤2.0 mmol/L (≤77.3 mg/dL) (63% vs. 53%, p < 0.001) compared to patients with shorter duration of diabetes (n = 3462). Achievement of all three targets between both groups were similar (13% vs. 13%, p = 0.82). Overall, patients with longer duration of diabetes were more likely to be prescribed anti-hyperglycemic, anti-hypertensive, lipid-lowering medications and referred for diabetes education.Conclusions: Only 13% of patients achieved glycemic, blood pressure, and LDL-C targets irrespective of duration of diabetes. Despite being managed with more medications, patients with longer duration of diabetes were less likely to achieve glycemic targets. More focus is needed on developing methods to bridge best care and real-world practice. [ABSTRACT FROM AUTHOR]

The article presents a study on reaching low density lipoprotein (LDL) targets in patients with diabetes or metabolic syndrome in the U.S. The study investigates whether using an algorithm to select the starting dose of a statin would facilitate achieving lipid targets in patients with diabetes or metabolic syndrome. The result reveals that a targeted starting dose of atorvastatin allows most patients with type 2 diabetes or the metabolic syndrome in achieving their LDL-C target safely, the strategic therapy may help overcome the treatment gap until observed in the treatment of lipids in diabetes.

Among individuals with diabetes mellitus, cardiovascular disease remains the leading cause of death, despite the many treatment modalities that have been developed over time. The PPAR family, including PPAR-alpha, play important roles in glucose and lipid metabolism and atherosclerosis and thus are potential therapeutic targets. Fibrates act upon PPAR-alpha and appear to target the typical dyslipidaemia of diabetes. Several large prospective clinical trials have shown both primary prevention and secondary prevention benefit with fibrates, although they only had small subgroups of patients with diabetes. The first large outcome study to exclusively study those with diabetes was the FIELD study, which showed no reduction in the primary cardiovascular end-point and only some benefit in the secondary end-point. There are many potential explanations for these results; however, it would appear that at present, there is no role for fibrates as monotherapy for the reduction of cardiovascular risk among those with diabetes. However, their potential role in combination with statin therapy remains to be further elucidated with ongoing studies. [ABSTRACT FROM AUTHOR]

Abstract: Despite the widespread dissemination of clinical practice guidelines on the prevention and treatment of cardiovascular disease (CVD), CVD causes one third of deaths worldwide and almost half of all deaths in the developed world. It is therefore likely that, although some aspects of CVD management have improved, there is still a significant shortfall between what is known about CVD prevention and what is put into action. Twenty-one experts in the field of CVD from around the world attended a focus panel meeting in Marlow-on-Thames, UK (see acknowledgements for a list of meeting participants). These experts were invited to discuss practical strategies and tactics for overcoming barriers to the implementation of guidelines on CVD prevention, and lipid management in particular. This article reviews and updates the key topics presented during the course of the meeting, captures the essence of the group discussions, and summarizes the meeting outcomes. The participants concluded that initial efforts to implement CVD prevention guidelines more effectively are best directed at high-risk patients who have already been identified. Once current patients achieve their targets, more attention can be paid to finding untreated patients at risk. Recommendations from the expert panel included: [•] Harmonize guidelines; focus on common areas of consensus rather than state-of-the-art science [•] Remove the boundary between primary and secondary prevention and focus on level of overall risk [•] Help policy makers understand the different components of CVD [•] Include professional societies from different specialties in guideline development and implementation, to increase ownership and decrease fragmentation of guideline committees. [Copyright &y& Elsevier]

The article discusses the effect of statin therapy on diabetic patients especially those with increase low density lipoprotein (LDL) cholesterol levels. The cardiovascular risk of diabetic patients are minimized through administration of aggressive statin therapy irrespective of their baseline LDL. Statins are the ideal therapy of choice for the decrease in LDL cholesterol levels including small and dense LDL. It is involved in the reduction of triglycerides and High Density Lipoprotein (HDL). The cardiovascular morbidity and mortality of patients with congenital heart disease are decreased after an aggressive treatment with statins.

Abstract: Type 2 diabetes and cardiovascular disease are inextricably linked. Patients with type 2 diabetes are at increased risk of cardiovascular events and mortality. However, controlling blood glucose, which until recently had often been the focus of the diabetologist, is only one component of optimal cardiovascular risk reduction. Vascular protection of the patient with diabetes also includes management of hypertension and dyslipidaemia and lifestyle changes such as smoking cessation. Now both cardiologists and diabetologists need to optimise all components of vascular protection, including glycaemic control, in patients with diabetes. An elevated blood glucose is predictive of poor outcomes in patients with acute coronary syndromes, even if frank diabetes is not present. Early control of hyperglycaemia should be achieved: a strategy that results in improved outcomes. More than two-thirds of patients with coronary artery disease (CAD) have abnormal glucose regulation, which is a predictor of poor outcome. Therefore, the presence of diabetes (and/or glucose intolerance) should be routinely screened for in cardiac patients on admission to hospital. Early identification and treatment of CAD in patients with diabetes is important for optimal prevention of cardiovascular events. However, screening all diabetes patients for CAD is not feasible, and selection of patients for non-invasive cardiac testing remains a challenge for both the diabetologist and cardiologist. Optimal care of diabetic and cardiac patients requires a multidisciplinary team approach, with key roles for the cardiologist and diabetologist. [Copyright &y& Elsevier]

Abstract: Patients with diabetes are at significantly increased risk for coronary heart disease (CHD); even those patients without a history of a previous myocardial infarction (MI) have as high a risk of a fatal or nonfatal MI as nondiabetic patients with a history of previous MI. As a result it is now generally recommended that cardiovascular risk factors be treated as aggressively in patients with diabetes as in nondiabetic patients with a history of CHD. Results from the recently published Collaborative Atorvastatin Diabetes Study (CARDS) and meta-analysis of primary and secondary interventions trials confirm that there is a uniform relative risk reduction across a wide range of high-risk patients including diabetes patients without established CHD. A highly significant 22–24% reduction in risk of future vascular events is evident when patients with diabetes are treated with statins in trials. Current guidelines, including the recently updated National Cholesterol Education Program (NCEP) guidelines, endorse aggressive, early intervention in very-high-risk patients, such as those with diabetes plus cardiovascular disease (CVD), regardless of baseline low-density lipoprotein cholesterol (LDL-C) level in order to achieve an LDL-C goal of 70mg/dL (1.8mmol/L). However, despite increasing evidence and knowledge of the value of lipid lowering, a recent survey of diabetes specialists indicates that many patients with diabetes remain untreated or undertreated. The availability of more effective statins should help to close this ‘action gap’, in concert with other measures such as initiatives to improve patient compliance. [Copyright &y& Elsevier]

Introduction: Formal didactic continuing medical education (CME) is relatively ineffective for changing physician behaviur. Diabetes mellitus is an increasingly prevalent disease, and interventions to improve adherence to clinical practice guidelines (CPGs) are needed. Methods: A stratified, cluster-randomized, controlled trial design was used to evaluate the effects of a teleconferenced educational detailing (TED) CME on glycemic control (hemoglobin [Hb] A1c) and family physician adherence to national diabetes guidelines. TED employed sequential, small-group, case-based education using CPGs delivered by a diabetes specialist. Medical record audit data from baseline through the end of a 12-month postintervention period were compared for the control and intervention groups. Satisfaction with the intervention was evaluated. Results: Sixty-one physicians provided 660 medical records. The intervention did not affect mean Hb A1c levels but did significantly (p = .04) alter the distribution of patients by category of glycemic control, with fewer in the intervention group in inadequate control (15.8% versus 23.9%). More patients took insulin (alone or with oral agents) in the intervention group (21.2% versus 12.0%, p = .03), and more took oral agents only in the control group (89.0% versus 82.9%, p = .005). More patients in the intervention group had documentation of body mass index (7.8% versus 1.9%, p < .02), eye exam (12.1% versus 5.1%, p = .02), and treatment plan (43.5% versus 23.6%, p = .01) and used a flow sheet (14.6% versus 7.7%, p < .03). Although there was general satisfaction with the teleconferencing format, specialist educators found the format more challenging than the family physicians. Discussion: CME delivered by teleconference was feasible, well attended, well received by participants, and improved some key diabetes management practices and outcomes. [ABSTRACT FROM AUTHOR]

Focuses on Rosuvastatin, a synthetic single enantiomer formulated and administered as a calcium salt for the treatment of dyslipidemia. Chemistry; Pharmacodynamics; Pharmacokinetics; Efficacy; Tolerability; Clinical use; Safety profile.

Objective: The purpose of this study was to assess the effect of orlistat, a gastrointestinal lipase inhibitor, on body weight, glycemic control, and cardiovascular risk factors in metformin-treated type 2 diabetic patients.Research Design and Methods: A 1-year multicenter, randomized, double-blind, placebo-controlled trial of 120 mg orlistat t.i.d. (n = 249) or placebo (n = 254) combined with a reduced-calorie diet was conducted in overweight and obese patients with suboptimal control of type 2 diabetes.Results: After 1 year of treatment, mean (+/-SE) weight loss was greater in the orlistat than in the placebo group (-4.6 +/- 0.3% vs. -1.7 +/- 0.3% of baseline wt, P < 0.001). Orlistat treatment caused a greater improvement in glycemic control than placebo, as evidenced by a greater reduction in serum HbA(1c), adjusted for changes in metformin and sulfonylurea therapy (-0.90 +/- 0.08 vs. -0.61 +/- 0.08, P = 0.014); a greater proportion of patients achieving decreases in HbA(1c) of > or = 0.5 and > or = 1.0% (both P < 0.01); and a greater reduction in fasting serum glucose (-2.0 +/- 0.2 vs. -0.7 +/- 0.2 mmol/l, P = 0.001). Compared with the placebo group, patients treated with orlistat also had greater decreases in total cholesterol, LDL cholesterol, and systolic blood pressure (all P < 0.05). Although more subjects treated with orlistat experienced gastrointestinal side effects than placebo (83 vs. 62%, P < 0.05), more subjects in the placebo group withdrew prematurely from the study than in the orlistat group (44 vs. 35%, P < 0.05).Conclusions: Orlistat is a useful adjunctive treatment for producing weight loss and improving glycemic control, serum lipid levels, and blood pressure in obese patients with type 2 diabetes who are being treated with metformin. [ABSTRACT FROM AUTHOR]

Presents information on a study which examined the prevalence of undiagnosed diabetes and glucose intolerance among middle-aged individuals who contacted their family physicians for routine care. Ratio of family physicians and the urban/rural population in Canada; Use of blood glucose tests on subjects; Provision of primary care to patients with diabetes; Methodology; Results and discussion.

Aim: To compare the efficacy and safety of a simple daily titration algorithm compared with a weekly dose adjustment of iGlarLixi in people with type 2 diabetes. Materials and Methods: LixiLan ONE CAN (NCT03767543), a randomized, 26‐week, open‐label, multicentre phase 3 trial conducted in Canada, involved 265 people with type 2 diabetes and an HbA1c of ≥7.5% to ≤ 10.5% or less (≥58 to ≤91 mmol/mol) on basal insulin for 6 months or longer. Participants were randomized 1:1 with instructions to self‐titrate iGlarLixi daily (1 unit/day) or once weekly (2 or 4 units/week) to a common target fasting plasma glucose of 4.4 to 5.6 mmol/L (79 to 101 mg/dl). The primary objective was to show non‐inferiority of the daily versus weekly titration algorithm. Results: At 26 weeks, daily titration of iGlarLixi was not inferior to a weekly titration for both the prespecified primary endpoint of change in HbA1c from baseline (least square [LS] mean change: −1.24% vs. −0.92%, respectively; LS mean difference: 0.32%; 95% CI [0.07, 0.57]; P <.0001) and for the secondary endpoint of change in weight from baseline (LS mean change: −0.22 vs. +0.81 kg, respectively; LS mean difference: 1.03 kg; 95% CI [0.01, 2.06]; P <.0001). Indeed, for both the primary and secondary outcome, the daily titration of iGlarLixi was superior. There were no statistically significant differences in hypoglycaemia incidence between the two titration strategies during the 26‐week study. Conclusion: A daily titration algorithm for switching basal insulin to iGlarLixi was shown to be non‐inferior and superior for glycaemic control and weight compared with weekly titration. [ABSTRACT FROM AUTHOR]

Sodium-glucose cotransporter 2 (SGLT2) inhibitors improve health status in heart failure (HF) across the left ejection fraction ejection spectrum. However, the effects of SGLT1 and SGLT2 inhibition on health status are unknown. These prespecified analyses of the SOLOIST-WHF (Effect of Sotagliflozin on Cardiovascular Events in Patients with Type 2 Diabetes Post Worsening Heart Failure) trial examined the effects of sotagliflozin vs placebo on HF-related health status. SOLOIST-WHF randomized patients hospitalized or recently discharged after a worsening HF episode to receive sotagliflozin or placebo. The primary endpoint was total number of HF hospitalizations, urgent HF visits, and cardiovascular death. Kansas City Cardiomyopathy Questionnaire-12 (KCCQ-12) score was a prespecified secondary endpoint. This analysis evaluated change in the KCCQ-12 score from baseline to month 4. Of 1,222 patients randomized, 1,113 (91%) had complete KCCQ-12 data at baseline and 4 months. The baseline KCCQ-12 score was low overall (median: 41.7; Q1-Q3: 27.1-58.3) and improved by 4 months in both groups. Sotagliflozin vs placebo reduced the risk of the primary endpoint consistently across KCCQ-12 tertiles (P trend = 0.54). Sotagliflozin-treated patients vs those receiving placebo experienced modest improvement in KCCQ-12 at 4 months (adjusted mean change: 4.1 points; 95% CI: 1.3-7.0 points; P = 0.005). KCCQ-12 improvements were consistent across prespecified subgroups, including left ventricular ejection fraction <50% or ≥50%. More patients receiving sotagliflozin vs those receiving placebo had at least small (≥5 points) improvements in KCCQ-12 at 4 months (OR: 1.38; 95% CI: 1.06-1.80; P = 0.017). Sotagliflozin improved symptoms, physical limitations, and quality of life within 4 months after worsening HF, with consistent benefits across baseline demographic and clinical characteristics. (Effect of Sotagliflozin on Cardiovascular Events in Participants With Type 2 Diabetes Post Worsening Heart Failure [SOLOIST-WHF]; NCT03521934) [ABSTRACT FROM AUTHOR]

Aims Materials and Methods Results Conclusions To develop a clinical risk model to identify individuals at higher risk of developing new‐onset diabetes and who might benefit more from weight loss pharmacotherapy.A total of 21 143 patients without type 2 diabetes at baseline from two TIMI clinical trials of stable cardiovascular patients were divided into a derivation (~2/3) and validation (~1/3) cohort. The primary outcome was new‐onset diabetes. Twenty‐seven candidate risk variables were considered, and variable selection was performed using multivariable Cox regression. The final model was evaluated for discrimination and calibration, and for its ability to identify patients who experienced a larger benefit from the weight loss medication lorcaserin in terms of risk of new‐onset diabetes.During a median (interquartile range) follow‐up of 2.3 (1.8–2.7) years, new‐onset diabetes occurred in 1013 patients (7.7%). The final model included five independent predictors (glycated haemoglobin, fasting glucose, age, body mass index, and triglycerides/high‐density lipoprotein). The clinical risk model showed good discrimination (Harrell's C‐indices 0.802, 95% confidence interval [CI] 0.788–0.817 and 0.807, 95% CI 0.788–0.826) in the derivation and validation cohorts. The calibration plot demonstrated adequate calibration (2.5‐year area under the curve was 81.2 [79.1–83.5]). While hazard ratios for new‐onset diabetes with a weight‐loss therapy were comparable across risk groups (annual risks of <1%, 1%–5%, and >5%), there was a sixfold gradient in absolute risk reduction from lowest to highest risk group (p = 0.027).The developed clinical risk model effectively predicts new‐onset diabetes, with potential implications for personalized patient care and therapeutic decision making. [ABSTRACT FROM AUTHOR]