Summary Background Laser treatment for diabetic retinopathy is often associated with visual field reduction and other ocular side-effects. Our aim was to assess whether long-term lipid-lowering ...therapy with fenofibrate could reduce the progression of retinopathy and the need for laser treatment in patients with type 2 diabetes mellitus. Methods The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study was a multinational randomised trial of 9795 patients aged 50–75 years with type 2 diabetes mellitus. Eligible patients were randomly assigned to receive fenofibrate 200 mg/day (n=4895) or matching placebo (n=4900). At each clinic visit, information concerning laser treatment for diabetic retinopathy—a prespecified tertiary endpoint of the main study—was gathered. Adjudication by ophthalmologists masked to treatment allocation defined instances of laser treatment for macular oedema, proliferative retinopathy, or other eye conditions. In a substudy of 1012 patients, standardised retinal photography was done and photographs graded with Early Treatment Diabetic Retinopathy Study (ETDRS) criteria to determine the cumulative incidence of diabetic retinopathy and its component lesions. Analyses were by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN64783481. Findings Laser treatment was needed more frequently in participants with poorer glycaemic or blood pressure control than in those with good control of these factors, and in those with a greater burden of clinical microvascular disease, but the need for such treatment was not affected by plasma lipid concentrations. The requirement for first laser treatment for all retinopathy was significantly lower in the fenofibrate group than in the placebo group (164 3·4% patients on fenofibrate vs 238 4·9% on placebo; hazard ratio HR 0·69, 95% CI 0·56–0·84; p=0·0002; absolute risk reduction 1·5% 0·7–2·3). In the ophthalmology substudy, the primary endpoint of 2-step progression of retinopathy grade did not differ significantly between the two groups overall (46 9·6% patients on fenofibrate vs 57 12·3% on placebo; p=0·19) or in the subset of patients without pre-existing retinopathy (43 11·4% vs 43 11·7%; p=0·87). By contrast, in patients with pre-existing retinopathy, significantly fewer patients on fenofibrate had a 2-step progression than did those on placebo (three 3·1% patients vs 14 14·6%; p=0·004). An exploratory composite endpoint of 2-step progression of retinopathy grade, macular oedema, or laser treatments was significantly lower in the fenofibrate group than in the placebo group (HR 0·66, 95% CI 0·47–0·94; p=0·022). Interpretation Treatment with fenofibrate in individuals with type 2 diabetes mellitus reduces the need for laser treatment for diabetic retinopathy, although the mechanism of this effect does not seem to be related to plasma concentrations of lipids.
Atrial fibrillation (AF) is the most common complication after cardiac surgery. We aimed to evaluate, by meta-analysis, all randomized trials testing interventions for preventing AF.
Ninety-four ...trials of prevention of post-operative AF were identified, by standard search methods, and analysed by standard meta-analysis techniques. All five commonly tested interventions, beta-blockers (BBs), sotalol, amiodarone, magnesium, and atrial pacing, were effective in preventing AF. The odds ratio (OR) for the effect of BB on the incidence of AF was 0.36 (95% CI 0.28-0.47, P<0.001), but after trials confounded by post-operative non-study BB withdrawal were excluded was 0.69 (95% CI 0.54-0.87, P=0.002). Sotalol reduced AF, compared with placebo (OR 0.34, 95% CI 0.26-0.45, P<0.001) and compared with conventional BB (OR 0.42, 95% CI 0.26-0.65, P<0.001). Amiodarone reduced AF (OR 0.48, 95% CI 0.40-0.57, P<0.001). Magnesium (Mg) also had an effect (OR 0.57 95% CI 0.42-0.77) but there was significant heterogeneity (P<0.001), partly explained by concomitant BB. The effect of Mg with BB was less (OR 0.83, 95% CI 0.60-1.16). Pacing reduced AF (OR 0.60, 95% CI 0.47-0.77, P<0.001), despite wide variations in techniques. Only amiodarone and pacing significantly reduced length of stay, average -0.60 days (95% CI -0.92 to -0.29) and -1.3 days (95% CI -2.55 to -0.08), respectively. Collectively, all treatments analysed together reduced stroke (OR 0.63, 95% CI 0.41-0.98). Amiodarone was the only intervention that alone significantly reduced stroke rate (OR 0.54, 95% CI 0.30-0.95).
All five interventions reduced the incidence of AF, though the effect of BBs is less than previously thought. The significant reductions in length of stay and stroke in meta-analysis suggest that there are worthwhile benefits from aggressive prevention. Larger studies to confirm these clinical benefits and evaluate their cost-effectiveness would be worthwhile.
Aims/hypothesis Fenofibrate caused an acute, sustained plasma creatinine increase in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) and Action to Control Cardiovascular Risk in ...Diabetes (ACCORD) studies. We assessed fenofibrate's renal effects overall and in a FIELD washout sub-study. Methods Type 2 diabetic patients (n = 9,795) aged 50 to 75 years were randomly assigned to fenofibrate (n = 4,895) or placebo (n = 4,900) for 5 years, after 6 weeks fenofibrate run-in. Albuminuria (urinary albumin/creatinine ratio measured at baseline, year 2 and close-out) and estimated GFR, measured four to six monthly according to the Modification of Diet in Renal Disease Study, were pre-specified endpoints. Plasma creatinine was re-measured 8 weeks after treatment cessation at close-out (washout sub-study, n = 661). Analysis was by intention-to-treat. Results During fenofibrate run-in, plasma creatinine increased by 10.0 μmol/l (p < 0.001), but quickly reversed on placebo assignment. It remained higher on fenofibrate than on placebo, but the chronic rise was slower (1.62 vs 1.89 μmol/l annually, p = 0.01), with less estimated GFR loss (1.19 vs 2.03 ml min⁻¹ 1.73 m⁻² annually, p < 0.001). After washout, estimated GFR had fallen less from baseline on fenofibrate (1.9 ml min⁻¹ 1.73 m⁻², p = 0.065) than on placebo (6.9 ml min⁻¹ 1.73 m⁻², p < 0.001), sparing 5.0 ml min⁻¹ 1.73 m⁻² (95% CI 2.3-7.7, p < 0.001). Greater preservation of estimated GFR with fenofibrate was observed with baseline hypertriacylglycerolaemia (n = 169 vs 491 without) alone, or combined with low HDL-cholesterol (n = 140 vs 520 without) and reductions of ≥0.48 mmol/l in triacylglycerol over the active run-in period (pre-randomisation) (n = 356 vs 303 without). Fenofibrate reduced urine albumin concentrations and hence albumin/creatinine ratio by 24% vs 11% (p < 0.001; mean difference 14% 95% CI 9-18; p < 0.001), with 14% less progression and 18% more albuminuria regression (p < 0.001) than in participants on placebo. End-stage renal event frequency was similar (n = 21 vs 26, p = 0.48). Conclusions/interpretation Fenofibrate reduced albuminuria and slowed estimated GFR loss over 5 years, despite initially and reversibly increasing plasma creatinine. Fenofibrate may delay albuminuria and GFR impairment in type 2 diabetes patients. Confirmatory studies are merited. Trial registration ISRCTN64783481 Funding The study was funded by grants from Laboratoires Fournier SA (Dijon, France; now part of Abbott Pharmaceuticals) and the National Health and Medical Research Council, Australia
Lorcaserin, a selective serotonin 2C receptor agonist that modulates appetite, has proven efficacy for weight management in overweight or obese patients. The cardiovascular safety and efficacy of ...lorcaserin are undefined.
We randomly assigned 12,000 overweight or obese patients with atherosclerotic cardiovascular disease or multiple cardiovascular risk factors to receive either lorcaserin (10 mg twice daily) or placebo. The primary safety outcome of major cardiovascular events (a composite of cardiovascular death, myocardial infarction, or stroke) was assessed at an interim analysis to exclude a noninferiority boundary of 1.4. If noninferiority was met, the primary cardiovascular efficacy outcome (a composite of major cardiovascular events, heart failure, hospitalization for unstable angina, or coronary revascularization extended major cardiovascular events) was assessed for superiority at the end of the trial.
At 1 year, weight loss of at least 5% had occurred in 1986 of 5135 patients (38.7%) in the lorcaserin group and in 883 of 5083 (17.4%) in the placebo group (odds ratio, 3.01; 95% confidence interval CI, 2.74 to 3.30; P<0.001). Patients in the lorcaserin group had slightly better values with respect to cardiac risk factors (including blood pressure, heart rate, glycemic control, and lipids) than those in the placebo group. During a median follow-up of 3.3 years, the rate of the primary safety outcome was 2.0% per year in the lorcaserin group and 2.1% per year in the placebo group (hazard ratio, 0.99; 95% CI, 0.85 to 1.14; P<0.001 for noninferiority); the rate of extended major cardiovascular events was 4.1% per year and 4.2% per year, respectively (hazard ratio, 0.97; 95% CI, 0.87 to 1.07; P=0.55). Adverse events of special interest were uncommon, and the rates were generally similar in the two groups, except for a higher number of patients with serious hypoglycemia in the lorcaserin group (13 vs. 4, P=0.04).
In a high-risk population of overweight or obese patients, lorcaserin facilitated sustained weight loss without a higher rate of major cardiovascular events than that with placebo. (Funded by Eisai; CAMELLIA-TIMI 61 ClinicalTrials.gov number, NCT02019264 .).
Aims To determine the incidence and predictors of, and effects of fenofibrate on silent myocardial infarction (MI) in a large contemporary cohort of patients with type 2 diabetes in the Fenofibrate ...Intervention and Event Lowering in Diabetes (FIELD) study. Methods and results Routine electrocardiograms taken throughout the study were assessed by Minnesota-code criteria for the presence of new Q-waves without clinical presentation and analysed with blinding to treatment allocation and clinical outcome. Of all MIs, 36.8% were silent. Being male, older age, longer diabetes duration, prior cardiovascular disease (CVD), neuropathy, higher HbA1c, albuminuria, high serum creatinine, and insulin use all significantly predicted risk of clinical or silent MI. Fenofibrate reduced MI (clinical or silent) by 19% hazard ratio (HR) 0.81, 95% confidence interval (CI) 0.69–0.94; P = 0.006, non-fatal clinical MI by 24% (P = 0.01), and silent MI by 16% (P = 0.16). Among those having silent MI, fenofibrate reduced subsequent clinical CVD events by 78% (HR 0.22, 95% CI 0.08–0.65; P = 0.003). Conclusion Silent and clinical MI have similar risk factors and increase the risk of future CVD events. Fenofibrate reduces the risk of a first MI and substantially reduces the risk of further clinical CVD events after silent MI, supporting its use in type 2 diabetes.
Aims/hypothesis
Bilirubin has antioxidant and anti-inflammatory activities. Previous studies demonstrated that higher bilirubin levels were associated with reduced prevalence of peripheral arterial ...disease (PAD). However, the relationship between bilirubin and lower-limb amputation, a consequence of PAD, is currently unknown. We hypothesised that, in patients with type 2 diabetes, bilirubin concentrations may inversely associate with lower-limb amputation.
Methods
The relationship between baseline plasma total bilirubin levels and amputation events was analysed in 9,795 type 2 diabetic patients from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. The analysis plan was pre-specified. Lower-limb amputation was adjudicated blinded to treatment allocation. Relevant clinical and biochemical data were available for analyses. Amputation was a pre-specified tertiary endpoint.
Results
Bilirubin concentrations were significantly inversely associated with lower-limb amputation, with a greater than threefold risk gradient across levels. Individuals with lower bilirubin concentrations had a higher risk for first amputation (HR 1.38 per 5 μmol/l decrease in bilirubin concentration, 95% CI 1.07, 1.79,
p
= 0.013). The same association persisted after adjustment for baseline variables, including age, height, smoking status, γ-glutamyltransferase level, HbA
1c
, trial treatment allocation (placebo vs fenofibrate), as well as previous PAD, non-PAD cardiovascular disease, amputation or diabetic skin ulcer, neuropathy, nephropathy and diabetic retinopathy (HR 1.38 per 5 μmol/l decrease in bilirubin concentration, 95% CI 1.05, 1.81,
p
= 0.019).
Conclusions/interpretation
Our results identify a significant inverse relationship between bilirubin levels and total lower-limb amputation, driven by major amputation. Our data raise the hypothesis that bilirubin may protect against amputation in type 2 diabetes.
Aims/hypothesis The apolipoprotein B (ApoB):apolipoprotein A (ApoA)-I ratio may be a better indicator of cardiovascular disease (CVD) risk in people with type 2 diabetes than traditional lipid risk ...markers (LDL-cholesterol, HDL-cholesterol and triacylglycerol), but whether the ApoB:ApoA-I ratio should be used to indicate lipid-lowering therapy is still debated. Methods The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study randomised 9,795 patients with type 2 diabetes to fenofibrate (200 mg daily) or placebo and followed them up for a median of 5 years. We compared ApoB, ApoA-I, ApoAII and the ApoB:ApoA-I ratio with traditional lipid variables as predictors of CVD risk. We estimated the HR of the effect of 1 SD difference in baseline concentrations of lipids, apolipoproteins and respective ratios on the risk of CVD events and also used receiver operating characteristic curve analysis. Results In the placebo group, the variables best predicting CVD events were non-HDL-cholesterol:HDL-cholesterol, total cholesterol:HDL-cholesterol (HR 1.21, p < 0.001 for both), ApoB:ApoA-I (HR 1.20, p < 0.001), LDL-cholesterol:HDL-cholesterol (HR 1.17, p < 0.001), HDL-cholesterol (HR 0.84, p < 0.001) and ApoA-I (HR 0.85, p < 0.001). In the fenofibrate group, the first four predictors were very similar (but ApoB:ApoA-I was fourth), followed by non-HDL-cholesterol and ApoB. Lipid ratios and ApoB:ApoA-I performed better than any single lipid or apolipoprotein in predicting CVD risk. Conclusions/interpretation In patients with type 2 diabetes in the FIELD study, traditional lipid ratios were as strong as the ApoB:ApoA-I ratio in predicting CVD risk. The data provide little evidence for replacement of traditional lipids and their ratios with measures of ApoB, ApoA-I and their ratio.
Summary Background Whether statin therapy is as effective in women as in men is debated, especially for primary prevention. We undertook a meta-analysis of statin trials in the Cholesterol Treatment ...Trialists' (CTT) Collaboration database to compare the effects of statin therapy between women and men. Methods We performed meta-analyses on data from 22 trials of statin therapy versus control (n=134 537) and five trials of more-intensive versus less-intensive statin therapy (n=39 612). Effects on major vascular events, major coronary events, stroke, coronary revascularisation and mortality were weighted per 1·0 mmol/L reduction in LDL cholesterol and effects in men and women compared with a Cox model that adjusted for non-sex differences. For subgroup analyses, we used 99% CIs to make allowance for the multiplicity of comparisons. Findings 46 675 (27%) of 174 149 randomly assigned participants were women. Allocation to a statin had similar absolute effects on 1 year lipid concentrations in both men and women (LDL cholesterol reduced by about 1·1 mmol/L in statin vs control trials and roughly 0·5 mmol/L for more-intensive vs less-intensive therapy). Women were generally at lower cardiovascular risk than were men in these trials. The proportional reductions per 1·0 mmol/L reduction in LDL cholesterol in major vascular events were similar overall for women (rate ratio RR 0·84, 99% CI 0·78–0·91) and men (RR 0·78, 99% CI 0·75–0·81, adjusted p value for heterogeneity by sex=0·33) and also for those women and men at less than 10% predicted 5 year absolute cardiovascular risk (adjusted heterogeneity p=0·11). Likewise, the proportional reductions in major coronary events, coronary revascularisation, and stroke did not differ significantly by sex. No adverse effect on rates of cancer incidence or non-cardiovascular mortality was noted for either sex. These net benefits translated into all-cause mortality reductions with statin therapy for both women (RR 0·91, 99% CI 0·84–0·99) and men (RR 0·90, 99% CI 0·86–0·95; adjusted heterogeneity p=0·43). Interpretation In men and women at an equivalent risk of cardiovascular disease, statin therapy is of similar effectiveness for the prevention of major vascular events. Funding UK Medical Research Council, British Heart Foundation, Australian National Health and Medical Research Council, European Community Biomed Program.
Small vessel disease is reported to be a more common cause of ischaemic stroke in people with diabetes than in others. However, population based studies have shown no difference between those with ...and those without diabetes in the subtypes of stroke. We determined the rates and predictors of risk of stroke and its subtypes in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial.
9795 patients aged 50-75 years with type 2 diabetes were followed up for a median of 5 years. Annual rates were derived by the Kaplan-Meier method and independent predictors of risk by Cox proportional hazards regression analyses.
The annual rate of stroke was 6.7 per 1000 person years; 82% were ischaemic and caused by small artery disease (36%), large artery disease (17%) and embolism from the heart (13%); 10% were haemorrhagic. Among the strongest baseline predictors of ischaemic or unknown stroke were age (60-65 years, HR 1.98; >65 years, HR 2.35) and a history of stroke or transient ischaemic attack (TIA) (HR 2.06). Other independent baseline predictors were male sex, smoking, history of hypertension, ischaemic heart disease, nephropathy, systolic blood pressure and blood low density lipoprotein (LDL) cholesterol, HbA(1c) and fibrinogen. A history of peripheral vascular disease, low high density lipoprotein, age and history of hypertension were associated with large artery ischaemic stroke. A history of diabetic retinopathy, LDL cholesterol, male sex, systolic blood pressure, smoking, diabetes duration and a history of stroke or TIA were associated with small artery ischaemic stroke.
Older people with a history of stroke were at highest risk of stroke, but the prognosis and prognostic factors of subtypes were heterogeneous. The results will help clinicians quantify the absolute risk of stroke and its subtypes for typical diabetes patients.
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