Vlado Perkovic

Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes

Background Canagliflozin is a sodium–glucose cotransporter 2 inhibitor that reduces glycemia as well as blood pressure, body weight, and albuminuria in people with diabetes. We report the effects of treatment with canagliflozin on cardiovascular, renal, and safety outcomes. Methods The CANVAS Program integrated data from two trials involving a total of 10,142 participants with type 2 diabetes and high cardiovascular risk. Participants in each trial were randomly assigned to receive canagliflozin or placebo and were followed for a mean of 188.2 weeks. The primary outcome was a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. Results The mean age of the participants was 63.3 years, 35.8% were women, the mean duration of diabetes was 13.5 years, and 65.6% had a history of cardiovascular disease. The rate of the primary outcome was lower with canagliflozin than with placebo (occurring in 26.9 vs. 31.5 participants per 1000 patient‐years; hazard ratio, 0.86; 95% confidence interval [CI], 0.75 to 0.97; P<0.001 for noninferiority; P=0.02 for superiority). Although on the basis of the prespecified hypothesis testing sequence the renal outcomes are not viewed as statistically significant, the results showed a possible benefit of canagliflozin with respect to the progression of albuminuria (hazard ratio, 0.73; 95% CI, 0.67 to 0.79) and the composite outcome of a sustained 40% reduction in the estimated glomerular filtration rate, the need for renal‐replacement therapy, or death from renal causes (hazard ratio, 0.60; 95% CI, 0.47 to 0.77). Adverse reactions were consistent with the previously reported risks associated with canagliflozin except for an increased risk of amputation (6.3 vs. 3.4 participants per 1000 patient‐years; hazard ratio, 1.97; 95% CI, 1.41 to 2.75); amputations were primarily at the level of the toe or metatarsal. Conclusions In two trials involving patients with type 2 diabetes and an elevated risk of cardiovascular disease, patients treated with canagliflozin had a lower risk of cardiovascular events than those who received placebo but a greater risk of amputation, primarily at the level of the toe or metatarsal. (Funded by Janssen Research and Development; CANVAS and CANVAS‐R ClinicalTrials.gov numbers, NCT01032629 and NCT01989754, respectively.)

Effects of different regimens to lower blood pressure on major cardiovascular events in older and younger adults: meta-analysis of randomised trials.

Objective To quantify the relative risk reductions achieved with different regimens to lower blood pressure in younger and older adults. Design Meta-analyses and meta-regression analyses used to compare the effects on the primary outcome between two age groups (<65 v ≥65 years). Evidence for an interaction between age and the effects of treatment sought by fitting age as a continuous variable and estimating overall effects across trials. Main outcome measures Primary outcome: total major cardiovascular events. Results 31 trials, with 190 606 participants, were included. The meta-analyses showed no clear difference between age groups in the effects of lowering blood pressure or any difference between the effects of the drug classes on major cardiovascular events (all P≥0.24). Neither was there any significant interaction between age and treatment when age was fitted as a continuous variable (all P>0.09). The meta-regressions also showed no difference in effects between the two age groups for the outcome of major cardiovascular events (<65 v ≥65; P=0.38). Conclusions Reduction of blood pressure produces benefits in younger (<65 years) and older (≥65 years) adults, with no strong evidence that protection against major vascular events afforded by different drug classes varies substantially with age.

Effects of fibrates on cardiovascular outcomes: a systematic review and meta-analysis

BACKGROUND Several clinical trials have reported inconsistent findings for the effect of fibrates on cardiovascular risk. We undertook a systematic review and meta-analysis to investigate the effects of fibrates on major clinical outcomes. METHODS We systematically searched Medline, Embase, and the Cochrane Library for trials published between 1950 and March, 2010. We included prospective randomised controlled trials assessing the effects of fibrates on cardiovascular outcomes compared with placebo. Summary estimates of relative risk (RR) reductions were calculated with a random effects model. Outcomes analysed were major cardiovascular events, coronary events, stroke, heart failure, coronary revascularisation, all-cause mortality, cardiovascular death, non-vascular death, sudden death, new onset albuminuria, and drug-related adverse events. FINDINGS We identified 18 trials providing data for 45 058 participants, including 2870 major cardiovascular events, 4552 coronary events, and 3880 deaths. Fibrate therapy produced a 10% RR reduction (95% CI 0-18) for major cardiovascular events (p=0.048) and a 13% RR reduction (7-19) for coronary events (p<0.0001), but had no benefit on stroke (-3%, -16 to 9; p=0.69). We noted no effect of fibrate therapy on the risk of all-cause mortality (0%, -8 to 7; p=0.92), cardiovascular mortality (3%, -7 to 12; p=0.59), sudden death (11%, -6 to 26; p=0.19), or non-vascular mortality (-10%, -21 to 0.5; p=0.063). Fibrates reduced the risk of albuminuria progression by 14% (2-25; p=0.028). Serious drug-related adverse events were not significantly increased by fibrates (17 413 participants, 225 events; RR 1.21, 0.91-1.61; p=0.19), although increases in serum creatinine concentrations were common (1.99, 1.46-2.70; p<0.0001). INTERPRETATION Fibrates can reduce the risk of major cardiovascular events predominantly by prevention of coronary events, and might have a role in individuals at high risk of cardiovascular events and in those with combined dyslipidaemia. FUNDING National Health and Medical Research Council of Australia.

Albuminuria and Kidney Function Independently Predict Cardiovascular and Renal Outcomes in Diabetes

There are limited data regarding whether albuminuria and reduced estimated GFR (eGFR) are separate and independent risk factors for cardiovascular and renal events among individuals with type 2 diabetes. The Action in Diabetes and Vascular disease: preterAx and diamicroN-MR Controlled Evaluation (ADVANCE) study examined the effects of routine BP lowering on adverse outcomes in type 2 diabetes. We investigated the effects of urinary albumin-to-creatinine ratio (UACR) and eGFR on the risk for cardiovascular and renal events in 10,640 patients with available data. During an average 4.3-yr follow-up, 938 (8.8%) patients experienced a cardiovascular event and 107 (1.0%) experienced a renal event. The multivariable-adjusted hazard ratio for cardiovascular events was 2.48 (95% confidence interval 1.74 to 3.52) for every 10-fold increase in baseline UACR and 2.20 (95% confidence interval 1.09 to 4.43) for every halving of baseline eGFR, after adjustment for regression dilution. There was no evidence of interaction between the effects of higher UACR and lower eGFR. Patients with both UACR >300 mg/g and eGFR <60 ml/min per 1.73 m(2) at baseline had a 3.2-fold higher risk for cardiovascular events and a 22.2-fold higher risk for renal events, compared with patients with neither of these risk factors. In conclusion, high albuminuria and low eGFR are independent risk factors for cardiovascular and renal events among patients with type 2 diabetes.

Effects of statins in patients with chronic kidney disease: meta-analysis and meta-regression of randomised controlled trials

Objective To analyse the benefits and harms of statins in patients with chronic kidney disease (pre-dialysis, dialysis, and transplant populations). Design Meta-analysis. Data sources Cochrane Central Register of Controlled Trials, Medline, Embase, and Renal Health Library (July 2006). Study selection Randomised and quasi-randomised controlled trials of statins compared with placebo or other statins in chronic kidney disease. Data extraction and analysis Two reviewers independently assessed trials for inclusion, extracted data, and assessed trial quality. Differences were resolved by consensus. Treatment effects were summarised as relative risks or weighted mean differences with 95% confidence intervals by using a random effects model. Results Fifty trials (30 144 patients) were included. Compared with placebo, statins significantly reduced total cholesterol (42 studies, 6390 patients; weighted mean difference −42.28 mg/dl (1.10 mmol/l), 95% confidence interval −47.25 to −37.32), low density lipoprotein cholesterol (39 studies, 6216 patients; −43.12 mg/dl (1.12 mmol/l), −47.85 to −38.40), and proteinuria (g/24 hours) (6 trials, 311 patients; −0.73 g/24 hour, −0.95 to −0.52) but did not improve glomerular filtration rate (11 studies, 548 patients; 1.48 ml/min (0.02 ml/s), −2.32 to 5.28). Fatal cardiovascular events (43 studies, 23 266 patients; relative risk 0.81, 0.73 to 0.90) and non-fatal cardiovascular events (8 studies, 22 863 patients; 0.78, 0.73 to 0.84) were reduced with statins, but statins had no significant effect on all cause mortality (44 studies, 23 665 patients; 0.92, 0.82 to 1.03). Meta-regression analysis showed that treatment effects did not vary significantly with stage of chronic kidney disease. The side effect profile of statins was similar to that of placebo. Most of the available studies were small and of suboptimal quality; mortality data were provided by a few large trials only. Conclusion Statins significantly reduce lipid concentrations and cardiovascular end points in patients with chronic kidney disease, irrespective of stage of disease, but no benefit on all cause mortality or the role of statins in primary prevention has been established. Reno-protective effects of statins are uncertain because of relatively sparse data and possible outcomes reporting bias.

Coffee, decaffeinated coffee, and tea consumption in relation to incident type 2 diabetes mellitus: a systematic review with meta-analysis.

BACKGROUND Coffee consumption has been reported to be inversely associated with risk of type 2 diabetes mellitus. Similar associations have also been reported for decaffeinated coffee and tea. We report herein the findings of meta-analyses for the association between coffee, decaffeinated coffee, and tea consumption with risk of diabetes. METHODS Relevant studies were identified through search engines using a combined text word and MeSH (Medical Subject Headings) search strategy. Prospective studies that reported an estimate of the association between coffee, decaffeinated coffee, or tea with incident diabetes between 1966 and July 2009. RESULTS Data from 18 studies with information on 457 922 participants reported on the association between coffee consumption and diabetes. Six (N = 225 516) and 7 studies (N = 286 701) also reported estimates of the association between decaffeinated coffee and tea with diabetes, respectively. We found an inverse log-linear relationship between coffee consumption and subsequent risk of diabetes such that every additional cup of coffee consumed in a day was associated with a 7% reduction in the excess risk of diabetes relative risk, 0.93 [95% confidence interval, 0.91-0.95]) after adjustment for potential confounders. CONCLUSIONS Owing to the presence of small-study bias, our results may represent an overestimate of the true magnitude of the association. Similar significant and inverse associations were observed with decaffeinated coffee and tea and risk of incident diabetes. High intakes of coffee, decaffeinated coffee, and tea are associated with reduced risk of diabetes. The putative protective effects of these beverages warrant further investigation in randomized trials.

Effect of lowering blood pressure on cardiovascular events and mortality in patients on dialysis: a systematic review and meta-analysis of randomised controlled trials

Summary Background Patients undergoing dialysis have a substantially increased risk of cardiovascular mortality and morbidity. Although several trials have shown the cardiovascular benefits of lowering blood pressure in the general population, there is uncertainty about the efficacy and tolerability of reducing blood pressure in patients on dialysis. We did a systematic review and meta-analysis to assess the effect of blood pressure lowering in patients on dialysis. Methods We systematically searched Medline, Embase, and the Cochrane Library database for trials reported between 1950 and November, 2008, without language restriction. We extracted a standardised dataset from randomised controlled trials of blood pressure lowering in patients on dialysis that reported cardiovascular outcomes. Meta-analysis was done with a random effects model. Findings We identified eight relevant trials, which provided data for 1679 patients and 495 cardiovascular events. Weighted mean systolic blood pressure was 4·5 mm Hg lower and diastolic blood pressure 2·3 mm Hg lower in actively treated patients than in controls. Blood pressure lowering treatment was associated with lower risks of cardiovascular events (RR 0·71, 95% CI 0·55–0·92; p=0·009), all-cause mortality (RR 0·80, 0·66–0·96; p=0·014), and cardiovascular mortality (RR 0·71, 0·50–0·99; p=0·044) than control regimens. The effects seem to be consistent across a range of patient groups included in the studies. Interpretation Treatment with agents that lower blood pressure should routinely be considered for individuals undergoing dialysis to reduce the very high cardiovascular morbidity and mortality rate in this population. Funding National Health and Medical Research Council of Australia Program.

Worldwide access to treatment for end-stage kidney disease: a systematic review

BACKGROUND End-stage kidney disease is a leading cause of morbidity and mortality worldwide. Prevalence of the disease and worldwide use of renal replacement therapy (RRT) are expected to rise sharply in the next decade. We aimed to quantify estimates of this burden. METHODS We systematically searched Medline for observational studies and renal registries, and contacted national experts to obtain RRT prevalence data. We used Poisson regression to estimate the prevalence of RRT for countries without reported data. We estimated the gap between needed and actual RRT, and projected needs to 2030. FINDINGS In 2010, 2·618 million people received RRT worldwide. We estimated the number of patients needing RRT to be between 4·902 million (95% CI 4·438-5·431 million) in our conservative model and 9·701 million (8·544-11·021 million) in our high-estimate model, suggesting that at least 2·284 million people might have died prematurely because RRT could not be accessed. We noted the largest treatment gaps in low-income countries, particularly Asia (1·907 million people needing but not receiving RRT; conservative model) and Africa (432,000 people; conservative model). Worldwide use of RRT is projected to more than double to 5·439 million (3·899-7·640 million) people by 2030, with the most growth in Asia (0·968 million to a projected 2·162 million [1·571-3·014 million]). INTERPRETATION The large number of people receiving RRT and the substantial number without access to it show the need to both develop low-cost treatments and implement effective population-based prevention strategies. FUNDING Australian National Health and Medical Research Council.

Blood Pressure Lowering in Type 2 Diabetes: A Systematic Review and Meta-analysis

IMPORTANCE Lowering blood pressure (BP) is widely used to reduce vascular risk in individuals with diabetes. OBJECTIVE To determine the associations between BP-lowering treatment and vascular disease in type 2 diabetes. DATA SOURCES AND STUDY SELECTION We searched MEDLINE for large-scale randomized controlled trials of BP-lowering treatment including patients with diabetes, published between January 1966 and October 2014. DATA EXTRACTION AND SYNTHESIS Two reviewers independently extracted study characteristics and vascular outcome data. Estimates were stratified by baseline BP and achieved BP, and pooled using fixed-effects meta-analysis. MAIN OUTCOMES AND MEASURES All-cause mortality, cardiovascular events, coronary heart disease events, stroke, heart failure, retinopathy, new or worsening albuminuria, and renal failure. RESULTS Forty trials judged to be of low risk of bias (100,354 participants) were included. Each 10-mm Hg lower systolic BP was associated with a significantly lower risk of mortality (relative risk [RR], 0.87; 95% CI, 0.78-0.96); absolute risk reduction (ARR) in events per 1000 patient-years (3.16; 95% CI, 0.90-5.22), cardiovascular events (RR, 0.89 [95% CI, 0.83-0.95]; ARR, 3.90 [95% CI, 1.57-6.06]), coronary heart disease (RR, 0.88 [95% CI, 0.80-0.98]; ARR, 1.81 [95% CI, 0.35-3.11]), stroke (RR, 0.73 [95% CI, 0.64-0.83]; ARR, 4.06 [95% CI, 2.53-5.40]), albuminuria (RR, 0.83 [95% CI, 0.79-0.87]; ARR, 9.33 [95% CI, 7.13-11.37]), and retinopathy (RR, 0.87 [95% CI, 0.76-0.99]; ARR, 2.23 [95% CI, 0.15-4.04]). When trials were stratified by mean baseline systolic BP at greater than or less than 140 mm Hg, RRs for outcomes other than stroke, retinopathy, and renal failure were lower in studies with greater baseline systolic BP (P interaction <0.1). The associations between BP-lowering treatments and outcomes were not significantly different, irrespective of drug class, except for stroke and heart failure. Estimates were similar when all trials, regardless of risk of bias, were included. CONCLUSIONS AND RELEVANCE Among patients with type 2 diabetes, BP lowering was associated with improved mortality and other clinical outcomes with lower RRs observed among those with baseline BP of 140 mm Hg and greater. These findings support the use of medications for BP lowering in these patients.

Blood pressure-lowering treatment based on cardiovascular risk: a meta-analysis of individual patient data

BACKGROUND We aimed to investigate whether the benefits of blood pressure-lowering drugs are proportional to baseline cardiovascular risk, to establish whether absolute risk could be used to inform treatment decisions for blood pressure-lowering therapy, as is recommended for lipid-lowering therapy. METHODS This meta-analysis included individual participant data from trials that randomly assigned patients to either blood pressure-lowering drugs or placebo, or to more intensive or less intensive blood pressure-lowering regimens. The primary outcome was total major cardiovascular events, consisting of stroke, heart attack, heart failure, or cardiovascular death. Participants were separated into four categories of baseline 5-year major cardiovascular risk using a risk prediction equation developed from the placebo groups of the included trials (<11%, 11-15%, 15-21%, >21%). FINDINGS 11 trials and 26 randomised groups met the inclusion criteria, and included 67,475 individuals, of whom 51,917 had available data for the calculation of the risk equations. 4167 (8%) had a cardiovascular event during a median of 4·0 years (IQR 3·4-4·4) of follow-up. The mean estimated baseline levels of 5-year cardiovascular risk for each of the four risk groups were 6·0% (SD 2·0), 12·1% (1·5), 17·7% (1·7), and 26·8% (5·4). In each consecutive higher risk group, blood pressure-lowering treatment reduced the risk of cardiovascular events relatively by 18% (95% CI 7-27), 15% (4-25), 13% (2-22), and 15% (5-24), respectively (p=0·30 for trend). However, in absolute terms, treating 1000 patients in each group with blood pressure-lowering treatment for 5 years would prevent 14 (95% CI 8-21), 20 (8-31), 24 (8-40), and 38 (16-61) cardiovascular events, respectively (p=0·04 for trend). INTERPRETATION Lowering blood pressure provides similar relative protection at all levels of baseline cardiovascular risk, but progressively greater absolute risk reductions as baseline risk increases. These results support the use of predicted baseline cardiovascular disease risk equations to inform blood pressure-lowering treatment decisions. FUNDING None.BackgroundWe aimed to investigate whether the benefits of blood pressure-lowering drugs are proportional to baseline cardiovascular risk, to establish whether absolute risk could be used to inform ...