Rates and predictors of risk of stroke and its subtypes in diabetes: a prospective observational study

Background 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. Methods 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. Results 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, HbA1c 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. Conclusions 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.FIELD trial sponsored by Laboratoires Fournier SA, Dijon, France (part of Abbott

Effects of fenofibrate on renal function in patients with type 2 diabetes mellitus: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study

Abstract 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 in a FIELD washout sub-study. Methods Type 2 diabetic patients (n=9795) aged 50 to 75 years were randomly assigned to fenofibrate (n=4895) or placebo (n=4900) 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 4 to 6 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 µmol/l 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 during greater reduction over the active run-in period (pre-randomisation) of triacylglycerol (n=186 vs 170) and baseline hypertriacylglycerolaemia (n=89 vs 80) alone, or combined with low HDL-cholesterol (n=71 vs 60). Fenofibrate reduced urine albumin concentrations and hence albumin:creatinine ratio by 24% vs 12% (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, Dijon, France (now part of Solvay and Abbott Pharmaceuticals) and the NHMRC of Australia.Laboratoires Fournier, Dijon, France (now part of Solvay and Abbott Pharmaceuticals

Effects of fenofibrate on renal function in patients with type 2 diabetes mellitus: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study

Abstract 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 in a FIELD washout sub-study. Methods Type 2 diabetic patients (n=9795) aged 50 to 75 years were randomly assigned to fenofibrate (n=4895) or placebo (n=4900) 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 4 to 6 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 µmol/l 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 during greater reduction over the active run-in period (pre-randomisation) of triacylglycerol (n=186 vs 170) and baseline hypertriacylglycerolaemia (n=89 vs 80) alone, or combined with low HDL-cholesterol (n=71 vs 60). Fenofibrate reduced urine albumin concentrations and hence albumin:creatinine ratio by 24% vs 12% (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, Dijon, France (now part of Solvay and Abbott Pharmaceuticals) and the NHMRC of Australia.Laboratoires Fournier, Dijon, France (now part of Solvay and Abbott Pharmaceuticals

The clinical implications of type 2 diabetic renal disease and the use of fenofibrate as a novel therapy

Diabetic renal disease is a serious complication and the FIELD study, a trial of the PPAR agonist fenofibrate in type 2 diabetes, provides an opportunity to address it. We found that eGFR and urinary albumin to creatinine ratio (ACR) are independent predictors of cardiovascular disease. Improvement in eGFR or ACR attenuates cardiovascular risk, reinforcing the importance of risk factor control. Therefore, we identified the predictors of impaired eGFR and elevated ACR. However, novel treatments are still needed. In FIELD, fenofibrate was shown to reduce albuminuria and slow eGFR loss while paradoxically increasing serum creatinine. Although the mechanism is poorly understood, this iatrogenic creatinine rise does not impair true GFR (directly measured by inulin clearance), is fully reversible and does not increase cardiovascular or renal risk. Consequently, fenofibrate’s benefit on eGFR is unmasked only when the artificial reduction in calculated GFR is removed on drug cessation. While the eGFR benefit is associated with baseline dyslipidaemia and the degree of triglyceride reduction, we found no predictors of ACR benefit, implying separate mechanisms. Using murine models of diabetes and PPAR deficiency, we demonstrated a beneficial non-PPAR mediated effect of fenofibrate on albuminuria, laying the foundation for further work in identifying novel therapeutic targets

The clinical implications of type 2 diabetic renal disease and the use of fenofibrate as a novel therapy

Diabetic renal disease is a serious complication and the FIELD study, a trial of the PPAR agonist fenofibrate in type 2 diabetes, provides an opportunity to address it. We found that eGFR and urinary albumin to creatinine ratio (ACR) are independent predictors of cardiovascular disease. Improvement in eGFR or ACR attenuates cardiovascular risk, reinforcing the importance of risk factor control. Therefore, we identified the predictors of impaired eGFR and elevated ACR. However, novel treatments are still needed. In FIELD, fenofibrate was shown to reduce albuminuria and slow eGFR loss while paradoxically increasing serum creatinine. Although the mechanism is poorly understood, this iatrogenic creatinine rise does not impair true GFR (directly measured by inulin clearance), is fully reversible and does not increase cardiovascular or renal risk. Consequently, fenofibrate’s benefit on eGFR is unmasked only when the artificial reduction in calculated GFR is removed on drug cessation. While the eGFR benefit is associated with baseline dyslipidaemia and the degree of triglyceride reduction, we found no predictors of ACR benefit, implying separate mechanisms. Using murine models of diabetes and PPAR deficiency, we demonstrated a beneficial non-PPAR mediated effect of fenofibrate on albuminuria, laying the foundation for further work in identifying novel therapeutic targets

Estimated glomerular filtration rate and albuminuria are independent predictors of cardiovascular events and death in type 2 diabetes mellitus: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study

Background We investigated effects of renal function and albuminuria on cardiovascular outcomes in 9795 low-risk patients with diabetes in the Fenofibrate Intervention and Event Lowering in Diabetes study. Methods Baseline and year 2 renal status were examined in relation to clinical and biochemical characteristics. Outcomes included total cardiovascular (CVD), cardiac and non-cardiac mortality over 5-years. Results Lower eGFR versus eGFR ≥ 90 ml min–11.73m–2 was a risk factor for total CVD events: [HR (95% CI): 1.14 (1.01–1.29) for eGFR 60–89 ml min–11.73m–2; 1.59 (1.28–1.98) for eGFR 30–59 ml min–11.73m–2; p<0.001], adjusted for other characteristics. Albuminuria increased CVD risk: microalbuminuria and macroalbuminuria increased total CVD [HR 1.25 (1.01–1.54) and 1.19 (0.76–1.85), respectively (trend p=0.001)] when eGFR ≥ 90 ml min–11.73m–2. CVD risk was further modified by renal status changes over the first 2 years. In multivariable analysis, 77% of eGFR and 81% of ACR’s effects were accounted for by other variables, principally low HDL-cholesterol and elevated blood pressure. Conclusions Reduced eGFR and albuminuria are independent risk factors for cardiovascular events and mortality in a low-risk population of mainly European ancestry. While their independent contributions to CVD risk appear small when other risk factors are considered, because they capture risk related to a number of other characteristics, they remain excellent surrogate markers in clinical practice. Therefore, both should be considered when assessing prognosis and treatment strategies in patients with diabetes, and should be included in risk models. This study was prospectively registered (ISRCTN 64783481)Laboratoires Fournie

Estimated glomerular filtration rate and albuminuria are independent predictors of cardiovascular events and death in type 2 diabetes mellitus: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study

Background We investigated effects of renal function and albuminuria on cardiovascular outcomes in 9795 low-risk patients with diabetes in the Fenofibrate Intervention and Event Lowering in Diabetes study. Methods Baseline and year 2 renal status were examined in relation to clinical and biochemical characteristics. Outcomes included total cardiovascular (CVD), cardiac and non-cardiac mortality over 5-years. Results Lower eGFR versus eGFR ≥ 90 ml min–11.73m–2 was a risk factor for total CVD events: [HR (95% CI): 1.14 (1.01–1.29) for eGFR 60–89 ml min–11.73m–2; 1.59 (1.28–1.98) for eGFR 30–59 ml min–11.73m–2; p<0.001], adjusted for other characteristics. Albuminuria increased CVD risk: microalbuminuria and macroalbuminuria increased total CVD [HR 1.25 (1.01–1.54) and 1.19 (0.76–1.85), respectively (trend p=0.001)] when eGFR ≥ 90 ml min–11.73m–2. CVD risk was further modified by renal status changes over the first 2 years. In multivariable analysis, 77% of eGFR and 81% of ACR’s effects were accounted for by other variables, principally low HDL-cholesterol and elevated blood pressure. Conclusions Reduced eGFR and albuminuria are independent risk factors for cardiovascular events and mortality in a low-risk population of mainly European ancestry. While their independent contributions to CVD risk appear small when other risk factors are considered, because they capture risk related to a number of other characteristics, they remain excellent surrogate markers in clinical practice. Therefore, both should be considered when assessing prognosis and treatment strategies in patients with diabetes, and should be included in risk models. This study was prospectively registered (ISRCTN 64783481)Laboratoires Fournie