Major Cardiovascular Outcomes Research Articles

<p>Cost–benefit comparison of liraglutide and sitagliptin in the treatment of type 2 diabetes in Thailand</p>

AimLiraglutide, a once-daily subcutaneous glucagon-like peptide-1 (GLP-1) agonist, is approved for treatment of hyperglycemia in patients with type 2 diabetes mellitus (T2DM). For patients with established cardiovascular diseases, liraglutide has also been shown to reduce major cardiovascular events. However, its cost is relatively higher than other oral antidiabetic drugs. This study aims to compare the costs and benefits of liraglutide vs sitagliptin, in treating T2DM in Thailand.MethodsThis study consists of two parts. In part 1, the cost of keeping T2DM under control per patient (HbA1c<7.0% with no reported hypoglycemia and no body weight gain) with liraglutide (1.2 and 1.8 mg daily) was compared with using sitagliptin (100 mg daily). Costs were based on Thai local data. Clinical outcomes were based on head-to-head randomized controlled trials. Part 2 estimated the cost-per-controlled patient, based on major cardiovascular outcomes (cardiovascular death, nonfatal myocardial infarction, non-fatal stroke). Economic benefit was calculated as the reduction in cardiovascular outcomes.ResultsIn Thailand, liraglutide (1.8 mg daily) costs 7.37-times more than sitagliptin 100 mg. The cost per patient achieving a composite clinical endpoint (HbA1c<7.0%, with no weight gain and no hypoglycemic events) in patients with T2DM receiving liraglutide 1.8 mg is 2.80-times higher than patients receiving sitagliptin 100 mg. When cardiovascular benefits (reduced composite endpoint of major cardiovascular events, ie, cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke) were taken into account, it was found that liraglutide had lower cost than sitagliptin, resulting in estimated savings of 20,085 THB (620 USD) per patient per year.ConclusionThe clinical benefits of liraglutide (HbA1c<7.0%, no hypoglycemia, no weight gain, reduced cardiovascular outcomes) partly offset its high price. Therefore, liraglutide should be considered as an appropriate treatment alternative to sitagliptin, particularly for T2DM patients with high cardiovascular risks.

Cardiovascular Effects of Drugs Used to Treat Attention-Deficit/Hyperactivity Disorder Part 2: Impact on Cardiovascular Events and Recommendations for Evaluation and Monitoring.

A variety of psychostimulant and nonpsychostimulant medications have proven to be successful in reducing inattention, impulsivity, and hyperactivity in individuals with attention-deficit/hyperactivity disorder (ADHD). Psychostimulants used to treat ADHD include methylphenidate and related drugs and various amphetamine preparations. Nonpsychostimulant medications used to treat ADHD include atomoxetine and 2 α-2 adrenergic agonists: guanfacine extended-release and clonidine extended-release. The psychostimulants and atomoxetine have been shown, on average, to increase heart rate by 3-10 beats/min, systolic blood pressure by 3-8 mm Hg, and diastolic BP by 2-14 mm Hg. These drugs may also delay ventricular repolarization. The α-2 adrenergic agonists may reduce heart rate and BP. For these reasons, there is concern about the safety of psychostimulant and nonpsychostimulant medications in patients with ADHD. Studies in healthy children adolescents and adults have not consistently shown a disproportionately high risk of major adverse cardiovascular (CV) outcomes, including sudden unexpected death. Those with underlying CV disease have, in general, tolerated these drugs well. Certain high-risk groups have been identified who may benefit from cardiology consultation prior to drug initiation. Several American and Canadian professional societies have published guidelines for CV evaluation, management, and monitoring of patients with ADHD who are candidates for pharmacotherapy.

Elevated serum YKL40 level is a predictor of MACE during the long-term follow up in hypertensive patients

ABSTRACTBackground: YKL-40 (human cartilage glycoprotein 39, chitinase-3-like protein 1) is an inflammatory marker secreted mainly by macrophages and has distinctive roles on extracellular matrix remodeling, macrophage maturation, adhesion, and migration. Despite the presence of robust data suggesting the association of YKL-40 with variety of cardiovascular diseases (CV), there is no study up to date evaluating the role of YKL-40 on the long-term prognosis in patients with hypertension (HT).Methods: A single center, prospective, observational cohort study that included 327 consecutive hypertensive patients which were presented to a cardiology outpatient clinic. Patients were followed up for 7.89 ± 0.12 years. Primary outcome of the study was the occurrence of major cardiovascular outcomes (MACE) defined as all-cause mortality, new onset heart failure (HF), and coronary artery disease (CAD) requiring revascularization.Results: A total of 135 patients constituted the final study population [mean age: 52.4 ± 10.2, female: 63 (46%)]. A total of 28 (20.7%) patients had MACE during the follow up. Cox regression analysis revealed that age (HR: 1.046, 1.016–1.093 CI 95%, p = .026), diabetes (HR: 2.278, 1.026–5.057 CI 95%, p = .043), and YKL-40 level (HR: 1.019, 1.013–1.026 CI 95%, p = .005) significantly predicted MACE. We found that sensitivity and specificity of YKL-40 > 93.5 for predicting MACE was 71.4% and 65%, respectively with an area under curve (AUC) 0.723 (0.617–0.828 CI 95%, p < .001)Conclusion: Elevated serum YKL-40 level predicted MACE in hypertensive patients during a long-term follow up.

Prevention of macrovascular complications in patients with type 2 diabetes mellitus: Review of cardiovascular safety and efficacy of newer diabetes medications.

Lack of conclusive beneficial effects of strict glycemic control on macrovascular complications has been very frustrating for clinicians involved in care of patients with diabetes mellitus (DM). Highly publicized controversy surrounding cardiovascular (CV) safety of rosiglitazone resulted in major changes in United States Food and Drug Administration policy in 2008 regarding approval process of new antidiabetic medications, which has resulted in revolutionary data from several large CV outcome trials over the last few years. All drugs in glucagon-like peptide-1 receptor agonist (GLP-1 RA) and sodium-glucose cotransporter-2 (SGLT-2) inhibitor classes have shown to be CV safe with heterogeneous results on CV efficacy. Given twofold higher CV disease mortality in patients with DM than without DM, GLP-1 RAs and SGLT-2-inhibitors are important additions to clinician’s armamentarium and should be second line-therapy particularly in patients with T2DM and established atherosclerotic CV disease or high risks for CV disease. Abundance of data and heterogeneity in CV outcome trials results can make it difficult for clinicians, particularly primary care physicians, to stay updated with all the recent evidence. The scope of this comprehensive review will focus on all major CV outcome studies evaluating CV safety and efficacy of GLP-1 RAs and SGLT-2 inhibitors.

Intensive Glucose Control in Patients with Type 2 Diabetes — 15-Year Follow-up

BackgroundWe previously reported that a median of 5.6 years of intensive as compared with standard glucose lowering in 1791 military veterans with type 2 diabetes resulted in a risk of major cardiovascular events that was significantly lower (by 17%) after a total of 10 years of combined intervention and observational follow-up. We now report the full 15-year follow-up.MethodsWe observationally followed enrolled participants (complete cohort) after the conclusion of the original clinical trial by using central databases to identify cardiovascular events, hospitalizations, and deaths. Participants were asked whether they would be willing to provide additional data by means of surveys and chart reviews (survey cohort). The prespecified primary outcome was a composite of major cardiovascular events, including nonfatal myocardial infarction, nonfatal stroke, new or worsening congestive heart failure, amputation for ischemic gangrene, and death from cardiovascular causes. Death from any cause was a prespecified secondary outcome.ResultsThere were 1655 participants in the complete cohort and 1391 in the survey cohort. During the trial (which originally enrolled 1791 participants), the separation of the glycated hemoglobin curves between the intensive-therapy group (892 participants) and the standard-therapy group (899 participants) averaged 1.5 percentage points, and this difference declined to 0.2 to 0.3 percentage points by 3 years after the trial ended. Over a period of 15 years of follow-up (active treatment plus post-trial observation), the risks of major cardiovascular events or death were not lower in the intensive-therapy group than in the standard-therapy group (hazard ratio for primary outcome, 0.91; 95% confidence interval [CI], 0.78 to 1.06; P=0.23; hazard ratio for death, 1.02; 95% CI, 0.88 to 1.18). The risk of major cardiovascular disease outcomes was reduced, however, during an extended interval of separation of the glycated hemoglobin curves (hazard ratio, 0.83; 95% CI, 0.70 to 0.99), but this benefit did not continue after equalization of the glycated hemoglobin levels (hazard ratio, 1.26; 95% CI, 0.90 to 1.75).ConclusionsParticipants with type 2 diabetes who had been randomly assigned to intensive glucose control for 5.6 years had a lower risk of cardiovascular events than those who received standard therapy only during the prolonged period in which the glycated hemoglobin curves were separated. There was no evidence of a legacy effect or a mortality benefit with intensive glucose control. (Funded by the VA Cooperative Studies Program; VADT ClinicalTrials.gov number, NCT00032487.)

349-OR: Major Cardiovascular Outcomes among At-Risk High-Deductible Health Plan Members

High-deductible health plan (HDHP) effects on major cardiovascular outcomes are unknown. We studied a 2004-2014 national sample of 63,363 HDHP members aged 40-64 years with diabetes, cardiovascular disease, hypertension, or hyperlipidemia, who were continuously enrolled for 1 year in a low-deductible (≤$500) plan followed by 3 years in a HDHP (≥$1000) after an employer-mandated switch. We matched HDHP members to 539,445 contemporaneous controls who had the same cardiovascular risk factors and whose employers offered only low-deductible plans. Using a controlled interrupted-time-series design, we analyzed cumulative rates of myocardial infarction, stroke, and amputation. We modelled weighted cumulative event rates using aggregate-level segmented regression. HDHP members experienced no detectable absolute change in myocardial infarction (-0.9 events per 10,000 members, 95% confidence interval: -2.7, 0.8) at 3 years of follow-up relative to the end of the baseline year compared to controls. Stroke and amputation declined by 3.4 (-4.0, -2.9) and 6.7 (-9.0, -4.4) events per 10,000 members, respectively, among HDHP members versus controls over the same period. At-risk patients who were switched to HDHPs did not experience increases in major cardiovascular outcomes over 3 follow-up years. Future research should follow patients longer and examine outcomes among low-income populations. Disclosure J. Wharam: None. F. Zhang: None. C. Lu: None. A.F. Hernandez: Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Merck &amp; Co., Inc., Novartis Pharmaceuticals Corporation. Research Support; Self; AstraZeneca, GlaxoSmithKline plc., Merck &amp; Co., Inc., Novartis Pharmaceuticals Corporation. J. Wallace: None. D. Ross-Degnan: None. J.P. Newhouse: Board Member; Self; Aetna Inc. Funding National Institutes of Health

The association of resistance training with mortality: A systematic review and meta-analysis.

The benefits of aerobic exercise are well-studied; there is no consensus on the association between resistance training and major adverse cardiovascular outcomes. This systematic review and meta-analysis aimed to address this issue. We searched for randomized trials and cohort studies that evaluated the association between resistance training and mortality and cardiovascular events. Two investigators screened the identified abstracts and full-texts independently and in duplicate. Cochrane tools were used to assess the risk of bias. We calculated hazard ratios and 95% confidence intervals using random effect models. From the 1430 studies identified, 11 (one randomized trial and 10 cohort studies) met the inclusion criteria, totaling 370,256 participants with mean follow-up of 8.85 years. The meta-analysis showed that, compared with no exercise, resistance training was associated with 21% (hazard ratio (95% confidence interval (CI)), 0.79 (0.69-0.91)) and 40% (hazard ratio (95% CI), 0.60 (0.49-0.72)) lower all-cause mortality alone and when combined with aerobic exercise, respectively. Furthermore, resistance training had a borderline association with lower cardiovascular mortality (hazard ratio (95% CI), 0.83 (0.67-1.03)). In addition, resistance training showed no significant association with cancer mortality. Risk of bias was low to intermediate in the included studies. One cohort study looked at the effect of resistance training on coronary heart disease events in men and found a 23% risk reduction (risk ratio, 0.77, CI: 0.61-0.98). Resistance training is associated with lower mortality and appears to have an additive effect when combined with aerobic exercise. There are insufficient data to determine the potential beneficial effect of resistance training on non-fatal events or the effect of substituting aerobic exercise with resistance training.

Recent evidence for direct oral anticoagulants in chronic kidney disease.

The direct oral anticoagulants (DOACs) have emerged as an effective and safe alternative to vitamin K antagonists (VKAs) for stroke and venous thromboembolism (VTE) prevention. However, patients with chronic kidney disease (CKD) experience an increase in the risk of both thromboembolism and bleeding, and the risk-benefit profile of DOACs, particularly in advanced CKD remains a source of ongoing debate. This review summarizes the recent evidence on the effects of DOACs in CKD across a range of clinical indications including newly emerging indications. Data on early-to-moderate stage CKD derived from pivotal randomized controlled trials in broader atrial fibrillation and VTE populations support the favorable risk-benefit ratio of DOACs compared with VKAs in patients in these groups. However, safety data from observational studies comparing DOACs with VKAs in patients with atrial fibrillation and CKD (moderate to advanced) have been conflicting. Recent trials have evaluated the efficacy of low-dose DOACs on major cardiovascular outcomes, showing promising risk-benefit ratios in high-risk populations with concurrent CKD. Current data on patients with CKD derived from trials in the broader population suggest that DOACs are an effective alternative to VKAs in patients with early-to-moderate stage CKD. However, studies on patients with advanced CKD are lacking. Further randomized controlled trials, particularly those evaluating the risk of any clinically relevant bleeding as part of a more accurate assessment of the risk-benefit profile of DOACs in people with CKD, are needed.

Risk of cardiovascular events in men treated for prostate cancer compared with prostate cancer-free men

BackgroundThe effect of lifestyle, anthropometry and cardiovascular risk factors on cardiovascular disease in men with prostate cancer (PCa) remains unclear.MethodsUsing a population-based cohort of 25,436 Danish, cancer-free men aged 50–64 years, we obtained information on self-reported pre-cancer lifestyle, objectively measured anthropometry and cardiovascular risk factors, and linked them to national health registers for information on major cardiovascular outcomes. We assessed hazard ratios (HRs) of incident acute myocardial infarction (MI), ischaemic stroke (IS) and heart failure (HF) among 1546 men diagnosed with PCa treated with first-line active surveillance, watchful waiting, intended curative or palliative treatment compared with PCa-free men during 18 years of follow-up.ResultsMen who received first-line palliative treatment had higher rates of IS and HF with adjusted HRs of 2.09 (95% CI 1.49–2.93) and 2.05 (95% CI 1.43–2.94), respectively, compared with PCa-free men. The risks were increased from start of treatment. We did not find the same relation for men in any other treatment group. No differences between men treated for PCa and cancer-free controls were observed for MI after adjustment for lifestyle, anthropometry, and cardiovascular risk factors.ConclusionPre-diagnosis lifestyle, anthropometry or cardiovascular risk factors did not explain the risk of IS and HF in PCa patients receiving palliative treatment. The results emphasise the need for balancing disease management and monitoring of cardiovascular health in this patient group.

Triglyceride and Triglyceride/ HDL (High Density Lipoprotein) Ratio Predict Major Adverse Cardiovascular Outcomes in Women With Non-Obstructive CoronaryArtery Disease.

BackgroundWomen with non‐obstructive coronary artery disease have increased cardiovascular morbidity. The role of risk factors in this population has yet to be established. We aimed to study the predictive effect of triglycerides and the triglyceride/high‐density lipoprotein ratio on major adverse cardiovascular events (MACE) in patients with non‐obstructive coronary artery disease, and to explore the role of lipid lowering therapy in modifying this risk.Methods and ResultsThis is a prospective cohort study enrolling patients with anginal symptoms referred to the cardiac catheterization laboratory for suspected ischemia, who were subsequently diagnosed with non‐obstructive coronary artery disease, defined as no stenosis >20% on angiography. All patients had baseline laboratory testing and were followed for 7.8±4.3 years for the development of major adverse cardiovascular events. We performed Cox proportional hazard testing to determine the effect of triglycerides on risk of major adverse cardiovascular events among men and women by baseline statin use. A total of 462 patients were included. Median age was 53 (Q1, Q3: 45, 62) years. In a Cox proportional hazard model stratified by statin use adjusting for confounders, among those not on baseline statins, triglycerides were independently predictive of major adverse cardiovascular events in women (per 50 mg/dL risk ratio: hazard ratio 1.25 [95% CI: 1.06, 1.47]; P=0.01). This was not true among men. The interaction between triglycerides and sex, and triglycerides and statin was statistically significant.ConclusionsTriglyceride levels may play a key role in predicting cardiovascular‐specific risk in women, and statin use may be protective. Further investigation is necessary to better delineate the role of statin use in preventing cardiovascular risk.

Long-term prognostic utility of computed tomography coronary angiography in older populations.

The long-term prognostic value of coronary computed tomography angiography (CCTA)-identified coronary artery disease (CAD) has not been evaluated in elderly patients (≥70 years). We compared the ability of coronary CCTA to predict 5-year mortality in older vs. younger populations. From the prospective CONFIRM (COronary CT Angiography EvaluatioN For Clinical Outcomes: An InteRnational Multicenter) registry, we analysed CCTA results according to age <70 years (n = 7198) vs. ≥70 years (n = 1786). The severity of CAD was classified according to: (i) maximal stenosis degree per vessel: none, non-obstructive (1-49%), or obstructive (>50%); (ii) segment involvement score (SIS): number of segments with plaque. Cox-proportional hazard models assessed the relationship between CCTA findings and time to mortality. At a mean 5.6 ± 1.1 year follow-up, CCTA-identified CAD predicted increased mortality compared with patients with a normal CCTA in both <70 years [non-obstructive hazard ratio (HR) confidence interval (CI): 1.70 (1.19-2.41); one-vessel: 1.65 (1.03-2.67); two-vessel: 2.24 (1.21-4.15); three-vessel/left main: 4.12 (2.27-7.46), P < 0.001] and ≥70 years [non-obstructive: 1.84 (1.15-2.95); one-vessel: HR (CI): 2.28 (1.37-3.81); two-vessel: 2.36 (1.33-4.19); three-vessel/left main: 2.41 (1.33-4.36), P = 0.014]. Similarly, SIS was predictive of mortality in both <70 years [SIS 1-3: 1.57 (1.10-2.24); SIS ≥4: 2.42 (1.65-3.57), P < 0.001] and ≥70 years [SIS 1-3: 1.73 (1.07-2.79); SIS ≥4: 2.45 (1.52-3.93), P < 0.001]. CCTA findings similarly predicted long-term major adverse cardiovascular outcomes (MACE) (all-cause mortality, myocardial infarction, and late revascularization) in both groups compared with patients with no CAD. The presence and extent of CAD is a meaningful stratifier of long-term mortality and MACE in patients aged <70 years and ≥70 years old. The presence of obstructive and non-obstructive disease and the burden of atherosclerosis determined by SIS remain important predictors of prognosis in older populations.

Effects of sodium-glucose cotransporter inhibitors on cardiorenal and metabolic systems: Latest perspectives from the outcome trials.

Diabetes mellitus is strongly linked to high risk of cardiovascular and renal disorders. Diabetes management requires coordinated efforts to manage multiple cardiometabolic risk factors. Diabetes mellitus is also associated with poor outcome in patients after cardiovascular events and renal complications. However, whether specific antidiabetic agents are safer and more efficacious than other drugs for preventing and treating these cardiometabolic and renal diseases is debated. To date, results are available from 12 cardiovascular outcome trials focusing mainly on major adverse cardiovascular events and renal outcomes with new antidiabetic agents (4 with dipeptidyl peptidase-4 inhibitors, 3 with sodium-glucose cotransporter-2 (SGLT2) inhibitors, and 5 with glucagon-like peptide-1 analogues). Among them, the studies of SGLT2 inhibitors showed favourable results both for cardiovascular and renal outcomes. It would be crucial to dissect the effects of SGLT2 inhibitors on cardiorenal and metabolic systems, to determine whether it is better to prescribe SGLT2 inhibitors compared with other antidiabetic medications.

Adherence in Hypertension.

The global epidemic of hypertension is largely uncontrolled and hypertension remains the leading cause of noncommunicable disease deaths worldwide. Suboptimal adherence, which includes failure to initiate pharmacotherapy, to take medications as often as prescribed, and to persist on therapy long-term, is a well-recognized factor contributing to the poor control of blood pressure in hypertension. Several categories of factors including demographic, socioeconomic, concomitant medical-behavioral conditions, therapy-related, healthcare team and system-related factors, and patient factors are associated with nonadherence. Understanding the categories of factors contributing to nonadherence is useful in managing nonadherence. In patients at high risk for major adverse cardiovascular outcomes, electronic and biochemical monitoring are useful for detecting nonadherence and for improving adherence. Increasing the availability and affordability of these more precise measures of adherence represent a future opportunity to realize more of the proven benefits of evidence-based medications. In the absence of new antihypertensive drugs, it is important that healthcare providers focus their attention on how to do better with the drugs they have. This is the reason why recent guidelines have emphasize the important need to address drug adherence as a major issue in hypertension management.

Prognostic impact of visit-to-visit glycemic variability on the risks of major adverse cardiovascular outcomes and hypoglycemia in patients with different glycemic control and type 2 diabetes.

The prognostic impact of visit-to-visit glycemic variability on clinical outcomes in patients with different glycemic control and type 2 diabetes remains obscure. We investigated glucose variability and clinical outcomes for patients in the groups of Good glycemic control (GC), Insufficient glycemic control (IC), and Poor glycemic control (PC) in a prospective cohort study. By using data from Action in Diabetes and Vascular disease: preterAx and diamicroN-MR Controlled Evaluation (ADVANCE), 930 patients were enrolled from 61 centers in China and grouped into GC, IC, and PC according to their glycated hemoglobin A1c (HbA1c) and fasting plasma glucose (FPG). Visit-to-visit glycemic variability was defined using the coefficient of variation (CV) of five measurements of HbA1c and FPG taken 3-24 months after treatment. Multivariable Cox proportional hazards models were employed to estimate adjusted hazard ratio (aHR). Among 930 patients in the intensive glucose control, 82, 538, and 310 patients were assigned to GC, IC, and PC, respectively. During the median of 4.8 years of follow-up, 322 patients were observed hypoglycemia and 244 patients experienced major adverse cardiovascular events (MACE). The CV of HbA1c and FPG was significantly lower for GC (6.0 ± 3.8, 11.2 ± 6.2) than IC (8.3 ± 5.6, 17.9 ± 10.6) and PC (9.5 ± 6.3, 19.3 ± 10.8). High glycemic variability was associated with a greater risk of MACE (aHR: 2.21; 95% confidence interval (CI): 1.61-3.03; p < 0.001) and hypoglycemia (aHR: 1.36; 95% CI: 1.04-1.79; p = 0.025) than low glycemic variability in total patients. The consistent trend was also found in subgroups of GC, IC, and PC. This prospective cohort study showed that glycemic variability was significantly lower for GC than IC and PC. Furthermore, glycemic variability was associated with the risk of MACE and hypoglycemia in total patients and subgroups of different glycemic control.

Dipeptidyl peptidase-4 inhibitor compared with sulfonylurea in combination with metformin: cardiovascular and renal outcomes in a propensity-matched cohort study

BackgroundTo determine the impact of dipeptidyl peptidase-4 inhibitor (DPP4i) on the risk of major cardiocerebrovascular and renal outcomes compared with sulfonylurea (SU) combined with metformin in patients with type 2 diabetes from a population-based cohort.MethodsFrom a nationwide cohort in Korea (2008–2013), 23,674 patients with type 2 diabetes treated with DPP4i plus metformin or SU plus metformin were selected and matched by propensity score. Composite cardiocerebrovascular events including incident ischemic heart disease (IHD), ischemic stroke (IS), hospitalization for heart failure (HHF), and cardiocerebrovascular death, as well as renal events including incident end-stage renal disease or initiation of renal-replacement therapy were assessed by Cox proportional-hazards models.ResultsDuring a median follow-up of 19.6 months (interquartile range 7.2–36.4), 762 composite cardiocerebrovascular events and 17 end-stage renal events occurred. There was no significant difference in the risk of IHD (hazard ratio [HR], 1.00; 95% CI 0.81–1.23), IS (HR, 0.95; 95% CI 0.74–1.23), or cardiocerebrovascular death (HR, 0.74; 95% CI 0.46–1.18) in the DPP4i group compared to that in the SU group. Likewise, DPP4i therapy was not associated with the risk of end-stage renal outcomes (HR, 1.23; 95% CI 0.41–3.62). However, the risk of HHF was significantly higher in the DPP4i group than in the SU group (HR, 1.47; 95% CI 1.07–2.04).ConclusionsThis real-world database analysis showed that DPP4i therapy did not increase the overall risk of major cardiovascular and renal outcomes compared to SU therapy. However, the DPP4i-associated risk of HHF remained significant.

Baseline fasting plasma insulin levels predict risk for major adverse cardiovascular events among patients with diabetes and high-risk vascular disease: Insights from the ACCELERATE trial.

Despite optimal treatment, type II diabetes mellitus remains associated with an increased risk for future cardiovascular events. We sought to determine the association between baseline fasting plasma insulin levels and major adverse cardiovascular outcomes in patients with type II diabetes mellitus and high-risk vascular disease enrolled in the ACCELERATE (Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition with Evacetrapib in Patients at a High Risk for Vascular Outcomes) trial. We included all patients with type II diabetes mellitus who had a central laboratory measured fasting plasma insulin level drawn at baseline as part of the study protocol. Hazard ratios were generated for the risk of major adverse cardiovascular outcomes (composite of cardiovascular death, non-fatal myocardial infarction, stroke, hospitalization for unstable angina and coronary revascularization) with increasing quartile of baseline fasting plasma insulin level. We then performed a multivariable regression adjusting for significant baseline characteristics. Among 12,092 patients in ACCELERATE, 2042 patients with type II diabetes mellitus had a baseline fasting plasma insulin level drawn. Median follow-up was 28 months. The study population had a mean age of 66.6 years, 79.2% male and 96.2% had established coronary artery disease. During follow-up, major adverse cardiovascular outcomes occurred in 238 patients (11.6%); of these events, 177 were coronary revascularization (8.7%). We observed a statistically significant relationship between rates of revascularization and rising quartile of baseline fasting plasma insulin level which was not noted for the other individual components of major adverse cardiovascular outcomes. Patients with type II diabetes mellitus who underwent revascularization were noted to have significantly higher baseline fasting plasma insulin levels (27.7 vs 21.4 mU/L, p-value = 0.009) although baseline haemoglobin A1c (6.63% vs 6.55%), body mass index (31.5 vs 31.1 kg/m2) and medical therapy were otherwise similar to the group not undergoing revascularization. Following multivariable regression adjusting for significant characteristics including exposure to evacetrapib, the log of baseline fasting plasma insulin level was found to be an independent predictor for major adverse cardiovascular outcomes (hazard ratio = 1.36, 95% confidence interval = 1.09-1.69, p-value = 0.007); this was driven by need for future revascularization (hazard ratio = 1.56, 95% confidence interval = 1.21-2.00, p-value = 0.001). In a contemporary population of patients with type II diabetes mellitus and high-risk vascular disease on optimum medical therapy, baseline hyperinsulinaemia was an independent predictor for major adverse cardiovascular outcomes and need of future coronary revascularization. These results suggest a pathophysiological link between hyperinsulinaemia and progression of atherosclerotic vascular disease among diabetics.

Blood Pressure Lowering and Sodium-Glucose Co-transporter 2 Inhibitors (SGLT2is): More Than Osmotic Diuresis.

This is an update of data regarding changes in blood pressure using sodium-glucose co-transporter 2 inhibitors (SGLT2i) for the treatment of diabetes. The mechanism of blood pressure lowering by SGLT2i was thought to be due to their osmotic diuretic effects. New data, however, has emerged from meta-analyses and studies of people with impaired kidney function demonstrating similar or greater magnitudes of blood pressure reduction in the absence of significant glycosuria. Potential additional mechanisms are proposed and reviewed. Two separate meta-analyses in over 10,000 participants combined demonstrate an average of 4/2 mmHg reduction in blood pressure by SGLT2i. This includes consistency between measurements of in-office and ambulatory blood pressure monitoring. This reduction extends to decreases in nocturnal blood pressure of 2.6 mmHg systolic pressure. These reductions in blood pressure by SGLT2i are also present when added to ongoing treatment with ACE inhibitors or ARBs. In one study, dapagliflozin, when added to a regimen of a renin-angiotensin-aldosterone system (RAAS) antagonist and a diuretic, further lowered in-office systolic pressure by 2.4 mmHg. In contrast, when prescribed to those on a RAAS antagonist plus a calcium channel blocker or RAAS antagonist plus a beta blocker, systolic pressure decreased 5.4 mmHg. Lastly, post hoc analyses of major cardiovascular outcome trials across the spectrum of estimated glomerular filtration rates from 30 to 80 ml/min/1.73 m2 demonstrated similar magnitudes of BP reduction in spite of far less reduction in glucosuria among those with advanced kidney disease. Moreover, recent data implicate the potential for increased ketones associated with SGLT2i contributing to blood pressure lowering in advanced-stage kidney disease. SGLT2i are well established to lower blood pressure. Their mechanism appears to be multifactorial and has a hemodynamic as well as metabolic component contributing to this reduction.

Prognostic value of left atrial function by cardiovascular magnetic resonance feature tracking in hypertrophic cardiomyopathy.

Left atrium (LA) size has an important role in determining prognosis and risk stratification in hypertrophic cardiomyopathy (HCM). Cardiovascular magnetic resonance myocardial feature tracking (CMR-FT) is a novel technique for the quantification of LA function. Our aim was first to evaluate LA function by CMR-FT and volumetric analysis in patients with HCM; and secondly we sought to determine the association of LA-longitudinal strain (LA-LS) with major cardiovascular outcomes, particularly all cause mortality and heart failure. 75 patients with HCM and 75 control subjects underwent a conventional CMR study including assessment of LA function by CMR-FT (LA-LS) and volumetric analysis. A primary endpoint of all-cause mortality and secondary combined endpoint of hospital admission related to heart failure, lethal ventricular arrhythmias or cardiovascular death were defined. Compared to controls, LA-LS and all volumetric indices of LA function were significantly impaired in HCM even in patients with normal LA volume and normal LV filling pressures. LA-LS showed moderate-high correlation with LA-emptying fraction (total, active and passive LA-EF, r = 0.68, r = 0.67, r = 0.31, p < 0.001 for all) and with parameters of diastolic function (E/é, r = 0.4, p < 0.001). The age, minimum LA volume and % of LGE were independent predictors of LA-LS (p < 0.01 for all). During a mean follow-up of 3.3 ± 1.2years LA-LS was associated with the primary (HR: 0.85 (0.73-0.98), p = 0.02) and the secondary end-point (HR: 0.88 (0.82-0.96), p = 0.003). LA-LS by CMR-FT provides accurate measurements of LA function in HCM patients. LA-LS may become a novel potential predictor of poor cardiac outcomes, particularly cardiovascular mortality and HF.

The role of aliskiren in the management of hypertension and major cardiovascular outcomes: a systematic review and meta-analysis.

The role of the direct renin inhibitor aliskiren in hypertension is not fully established and use of aliskiren in diabetic patients is especially controversial. A systematic review investigating both short-term diastolic and systolic blood pressure (DBP and SBP) reduction and long-term cardiovascular outcomes has not been conducted. Therefore, we aimed to fill this gap by investigating BP reduction, major cardiovascular outcomes, and mortality of aliskiren compared to other antihypertensive therapy. We searched PubMed and Embase databases for relevant randomized controlled trials (RCTs). Using a random-effects model, weighted mean difference (WMD) and relative risk (WRR) with 95% confidence interval (CI) were used to measure the effect of aliskiren therapy in the management of hypertension and major cardiovascular outcomes. Thirty seven RCTs with a total of 35,916 patients were included. Aliskiren induced slightly greater DBP and SBP reductions than other antihypertensive agents (WMD -0.77 mmHg, 95% CI [-2.01;0.46 mmHg] and WMD -1.14 mmHg, 95% CI [-2.78;0.50 mmHg], respectively). Aliskiren did not reduce total mortality or cardiovascular death. In patients with diabetes, aliskiren add-on therapy may have the potential to increase total mortality and cardiovascular death (WRR 1.06, 95% CI [0.88;1.28] and WRR 1.09, 95% CI [0.94;1.24], respectively). Despite superior BP-reducing effect, aliskiren is not recommended as first-line treatment in hypertensive patients as it does not reduce mortality and major cardiovascular outcomes. Dual renin-angiotensin-aldosterone system inhibition with aliskiren should be avoided in diabetic patients, while the use of aliskiren monotherapy remains to be investigated.

Impact of eplerenone on major cardiovascular outcomes in patients with systolic heart failure according to baseline heart rate.

Increased resting heart rate is a risk factor for cardiovascular mortality and morbidity. Mineralocorticoid receptor antagonists (MRAs) have been shown to improve cardiac sympathetic nerve activity, reduce heart rate and attenuate left ventricular remodelling. Whether or not the beneficial effects of MRA are affected by heart rate in heart failure patients with reduced ejection fraction (HFREF) is unclear. We undertook a secondary analysis of data from the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure study to assess if clinical outcomes, as well as the efficacy of eplerenone, varied according to heart rate at baseline. High resting heart rate of 80bpm and above predisposed patients to greater risk of all outcomes in the trial, regardless of treatment allocation. The beneficial effects of eplerenone were observed across all categories of heart rate. Eplerenone reduced the risk of primary endpoint, the composite of cardiovascular death and hospitalisation for heart failure, by 30% (aHR 0.70; 95% CI 0.54-0.91) in subjects with heart rate ≥ 80bpm, and by 48% (aHR 0.52; 95% CI 0.33-0.81) in subjects with heart rate ≤ 60bpm. Eplerenone also reduced the risks of hospitalisation for heart failure, cardiovascular deaths and all-cause deaths independently of baseline heart rate. Baseline heart rate appears to be an important predictor of major clinical outcome events in patients with HFREF, as has been previously reported. The benefits of eplerenone were preserved across all categories of baseline heart rate, without observed heterogeneity in the responses.