And Vascular Disease: Preterax And Diamicron Modified Release Controlled Evaluation Research Articles

Lipids and apolipoproteins and the risk of vascular disease and mortality outcomes in women and men with type 2 diabetes in the ADVANCE study.

Whether apolipoproteins (apolipoprotein A1, apolipoprotein B, apolipoprotein B/apolipoprotein A1 [ApoB/ApoA1] ratio) or very-low-density lipoprotein (VLDL) cholesterol are better risk predictors than established lipid risk markers, and whether there are sex differences, is uncertain, both in general populations and in patients with diabetes. The aim of this study was to assess the association between established risk markers, apolipoproteins and the risk of macro- and microvascular disease and death in a large study of women and men with diabetes and to assess the potential sex differences in the associations. Established lipid risk markers were studied in 11 140 individuals with type 2 diabetes from the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified-Release Controlled Evaluation (ADVANCE) trial, and apolipoproteins (A1, B, ApoB/ApoA1 ratio) and VLDL cholesterol from nuclear magnetic resonance (NMR) lipid analyses in biobanked samples from 3586 individuals included in the ADVANCE case-cohort study (ADVANCE CC). Primary outcomes were major macro- and microvascular events and death. Cox proportional hazards models adjusted for confounders were used to quantify the associations (hazard ratio [HR] and 95% confidence intervals [CIs]) between established lipid risk markers and apolipoproteins with study outcomes. To address potential effect modification by sex, we investigated the association between the lipid risk markers and outcomes in subgroup analyses by sex. There was a lower risk of macrovascular complications for high-density lipoprotein (HDL) cholesterol (HR [95%CI] 0.88 [0.82-0.95]), a higher risk for total cholesterol (1.10 [1.04-1.17]), low-density lipoprotein (LDL) cholesterol (1.15 [1.08-1.22]), non-HDL cholesterol (1.13 [1.07-1.20]) and the total cholesterol/HDL ratio (1.20 [1.14-1.27]) but no significant associations with triglycerides from ADVANCE. There was a higher risk of macrovascular complications for the ApoB/ApoA1 ratio (1.13 [1.03-1.24]) from the ADVANCE CC. Only the ApoB/ApoA1 ratio (1.19 [1.06-1.34]), but none of the established lipid risk markers, was associated with a higher risk of microvascular complications. There were no statistically significant sex differences for any of the established lipid risk markers or apolipoproteins with any outcome. Using C-statistics and net reclassification improvement (NRI) did not detect significant improvement in predicting all outcomes by adding lipids or apolipoproteins to the models with confounding factors only. All established lipid risk markers, except triglycerides, were predictors of macrovascular complications, but not microvascular complications, in patients with type 2 diabetes. The ApoB/ApoA1 ratio was associated with major macro- and microvascular complications, but there was no evidence that apolipoproteins are better than established lipid risk markers in predicting cardiovascular complications in patients with type 2 diabetes.

ETHNIC DIFFERENCES IN RISK FACTORS FOR COGNITIVE DECLINE AND DEMENTIA, IN INDIVIDUALS WITH DIABETES: RESULTS FROM THE ADVANCE TRIAL

Objective: Ethnic differences in risk factors for dementia remain underexplored. This project will estimate ethnic differences on the associations between risk factors, and treatment effects, with cognitive decline (CD) and/or dementia, in individuals with type 2 diabetes (T2D). Design and method: This study uses the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial of 11,140 individuals with T2D from 20 countries. Multivariable adjusted multinomial logistic regression models were used to examine the associations between baseline characteristics and odds of subsequent CD/dementia, by Asian and non-Asian ethnicity. Results: There were 4242 (38%) participants of Asian ethnicity. During 5-years (median) follow-up, 1827 participants (40% Asian) had CD/dementia (1718 with CD only (41% Asian); 21 with dementia only (19% Asian); 88 with CD and dementia (32% Asian)), and 929 (30% Asian) died without CD/dementia. Participants of Asian ethnicity had a higher odds of CD/dementia than non-Asians (odds ratio [OR] [95% confidence interval (CI)], 1.25 [1.09, 1.44]). In both Asians and non-Asians, older age, longer diabetes duration was associated with greater odds of CD/dementia; higher years at education completion and taller stature reduced the odds of CD/dementia. Higher baseline cognitive function was associated with a lower odds of CD/dementia in non-Asians 0.93 [0.90, 0.96], but not in Asians 1.01 [0.97, 1.04]. Stroke/transient ischaemic attack, retinal disease, higher body mass index, waist circumference, and current smoker (vs. never), were associated with a higher odds of CD/dementia in non-Asians but not in Asians. Moderate/vigorous physical activity vs none/mild was associated with a higher odds of CD/dementia in Asians 1.26 [1.10, 1.45] but a lower odds in non-Asians 0.81 [0.68, 0.97]. There was no evidence that intensive glucose control (vs. standard control) or blood pressure lowering (vs. placebo) conferred a lower risk of CD/dementia, overall nor by ethnicity. Conclusions: People of Asian ethnicity had a 25% higher risk of CD/dementia than non-Asians in this study. There were some differential effects of risk factors for CD/dementia by ethnicity. More data from Asian populations are required to verify ethnic differences and the mechanisms that underlie these differences.

Cumulative Systolic Blood Pressure Load and Cardiovascular Risk in Patients With Diabetes

BackgroundStandard measures of blood pressure (BP) do not account for both the magnitude and duration of exposure to elevated BP over time. ObjectivesThe purpose of this study was to assess the association between cumulative systolic blood pressure (SBP) load and risk of cardiovascular events in patients with type 2 diabetes. MethodsA post hoc analysis of patients with type 2 diabetes followed by the ADVANCE-ON (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation - Observational Study). Cumulative SBP load was defined as the area under curve for SBP values ≥130 mm Hg divided by the area under curve for all measured SBP values over a 24-month exposure period. HRs for the association between cumulative SBP load with major cardiovascular events and death were estimated using Cox models. ResultsOver a median 7.6 years of follow-up, 1,469 major cardiovascular events, 1,615 deaths, and 660 cardiovascular deaths were observed in 9,338 participants. Each 1-SD increase in cumulative SBP load was associated with a 14% increase in major cardiovascular events (HR: 1.14; 95% CI: 1.09-1.20), 13% increase in all-cause mortality (HR: 1.13; 95% CI: 1.13-1.18), and 21% increase in cardiovascular death (HR: 1.21; 95% CI: 1.13-1.29). For the prediction of cardiovascular events and death, cumulative SBP load outperformed mean SBP, time-below-target SBP, and visit-to-visit SBP variability in terms of Akaike information criterion and net reclassification indexes. ConclusionsCumulative SBP load may provide better prediction of major cardiovascular events compared with traditional BP measures among patients with type 2 diabetes. These findings reinforce the importance of both the magnitude and duration of exposure to elevated SBP in assessing cardiovascular risk. (Action in Diabetes and Vascular Disease Preterax and Diamicron MR Controlled Evaluation Post Trial Observational Study [ADVANCE-ON]; NCT00949286)

Short-Term Changes in Serum Potassium and the Risk of Subsequent Vascular Events and Mortality: Results from a Randomized Controlled Trial of ACE Inhibitors.

Hyperkalemia after starting renin-angiotensin system inhibitors has been shown to be subsequently associated with a higher risk of cardiovascular and kidney outcomes. However, whether to continue or discontinue the drug after hyperkalemia remains unclear. Data came from the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial, which included a run-in period where all participants initiated angiotensin-converting enzyme inhibitor-based therapy (a fixed combination of perindopril and indapamide). The study population was taken as patients with type 2 diabetes with normokalemia (serum potassium of 3.5 to <5.0 mEq/L) at the start of run-in. Potassium was remeasured 3 weeks later when a total of 9694 participants were classified into hyperkalemia (≥5.0 mEq/L), normokalemia, and hypokalemia (<3.5 mEq/L) groups. After run-in, patients were randomized to continuation of the angiotensin-converting enzyme inhibitor-based therapy or placebo; major macrovascular, microvascular, and mortality outcomes were analyzed using Cox regression during the following 4.4 years (median). During active run-in, 556 (6%) participants experienced hyperkalemia. During follow-up, 1505 participants experienced the primary composite outcome of major macrovascular and microvascular events. Randomized treatment of angiotensin-converting enzyme inhibitor-based therapy significantly decreased the risk of the primary outcome (38.1 versus 42.0 per 1000 person-years; hazard ratio, 0.91; 95% confidence interval, 0.83 to 1.00; P=0.04) compared with placebo. The magnitude of effects did not differ across subgroups defined by short-term changes in serum potassium during run-in (P for heterogeneity =0.66). Similar consistent treatment effects were also observed for all-cause death, cardiovascular death, major coronary events, major cerebrovascular events, and new or worsening nephropathy (P for heterogeneity ≥0.27). Continuation of angiotensin-converting enzyme inhibitor-based therapy consistently decreased the subsequent risk of clinical outcomes, including cardiovascular and kidney outcomes and death, regardless of short-term changes in serum potassium. Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE), NCT00145925.

The Impact of Frailty on the Effectiveness and Safety of Intensive Glucose Control and Blood Pressure-Lowering Therapy for People With Type 2 Diabetes: Results From the ADVANCE Trial.

OBJECTIVETo develop a frailty index (FI) and explore the relationship of frailty to subsequent adverse outcomes on the effectiveness and safety of more intensive control of both blood glucose and blood pressure (BP), among participants with type 2 diabetes in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial.RESEARCH DESIGN AND METHODSCox proportional hazard models were used to estimate the effectiveness and safety of intensive glucose control and BP intervention according to frailty (defined as FI >0.21) status. The primary outcomes were macro- and microvascular events. The secondary outcomes were all-cause mortality, cardiovascular mortality, severe hypoglycemia, and discontinuation of BP treatment due to hypotension/dizziness.RESULTSThere were 11,140 participants (mean age, 65.8 years; 42.5% women, 25.7% frail). Frailty was an independent predictor of all primary outcomes and secondary outcomes. The effect of intensive glucose treatment on primary outcomes showed some evidence of attenuation in the frail: hazard ratios for combined major macro- and microvascular events 1.03 (95% CI 0.90–1.19) in the frail versus 0.84 (95% CI 0.74–0.94) in the nonfrail (P = 0.02). A similar trend was observed with BP intervention. Severe hypoglycemia rates (per 1,000 person-years) were higher in the frail: 8.39 (6.15–10.63) vs. 4.80 (3.84–5.76) in nonfrail (P < 0.001). There was no significant difference in discontinuation of BP treatment between frailty groups.CONCLUSIONSIt was possible to retrospectively estimate frailty in a trial population, and this FI identified those at higher risk of poor outcomes. Participants with frailty had some attenuation of benefit from intensive glucose-lowering and BP-lowering treatments.

Sex differences in risk factors for cognitive decline and dementia, including death as a competing risk, in individuals with diabetes: Results from the ADVANCE trial.

To estimate the associations between risk factors and cognitive decline (CD)/dementia, and the sex differences in these risk factors in individuals with type 2 diabetes, while accounting for the competing risk of death. The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial of 11,140 individuals with type 2 diabetes was used to estimate the odds of CD/dementia using multinomial logistic regression. During a median 5-year follow-up, 1827 participants (43.2% women) had CD/dementia (1718 with CD only; 21 with dementia only; 88 with CD and dementia), and 929 (31.0% women) died without CD/dementia. Women had lower odds of CD/dementia than men (odds ratio [OR] [95% confidence interval], 0.88 [0.77, 1.00]); older age, higher total cholesterol, HbA1c, waist circumference, waist-to-height ratio, moderately increased albumin-creatinine ratio, stroke/transient ischaemic attack and retinal disease were each associated with greater odds of CD/dementia; higher years at education completion, baseline cognitive function, taller stature and current alcohol use were inversely associated. Higher waist circumference (women-to-men ratio of ORs [ROR], 1.05 [1.00, 1.10] per 5cm) and presence of anxiety/depression (ROR, 1.28 [1.01, 1.63]) were associated with greater ORs for CD/dementia in women than men. Several risk factors were associated with CD/dementia. Higher waist circumference and mental health symptoms were more strongly associated with CD/dementia in women than men. Further studies should examine the mechanisms that underlie these sex differences.

PLASMA FATTY ACIDS AND THE RISK OF VASCULAR AND MORTALITY OUTCOMES IN INDIVIDUALS WITH TYPE 2 DIABETES: RESULTS FROM THE ADVANCE STUDY

Objective: This study aimed to quantify the association of essential and other plasma fatty acids biomarkers with macrovascular disease, microvascular disease and death in individuals with type 2 diabetes. Design and method: A case cohort study (N = 3,576), including 654 macrovascular events, 341 microvascular events and 631 deaths during 5 years of median follow-up was undertaken in participants in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) study. The fatty acids measured from baseline plasma samples, by proton nuclear magnetic resonance (NMR) analysis, were omega-3, docosahexaenoic acid (DHA), omega-6, linoleic acid (LA), polyunsaturated (PUFA), monounsaturated (MUFA) and saturated fatty acids (SFA). Hazard ratios (HRs) were modelled per standard deviation higher percentage fatty acid. C-statistics and net reclassification improvement were used to test the added value of fatty acids for risk prediction. Results: After adjustment for traditional cardiovascular risk factors, an inverse association was observed for omega-3 fatty acids and DHA (HR [95%CI]: 0.87 [0.80, 0.95] and 0.88 [0.81, 0.96], respectively per 1SD higher percentage) with the risk of macrovascular events, and for omega-3 fatty acids (HR [95%CI]: 0.91 [0.84, 0.99] per 1SD higher percentage) with death. Such associations were also evident when investigating absolute levels of fatty acids. There were no statistically significant associations between any fatty acids and microvascular disease after adjustment. However, there was limited improvement in predictive ability of models when any fatty acid was added. Conclusions: Plasma omega-3 fatty acids and DHA were found to be inversely associated with macrovascular disease, whilst omega-3 fatty acids was also inversely associated with death. These results provide additional support for regular consumption of food rich in omega-3 fatty acids in type 2 diabetes.

CLINICAL OUTCOMES AND PATIENT CHARACTERISTICS ACCORDING TO THE COMBINATION OF TEN-YEAR RISK OF ATHEROSCLEROTIC CARDIOVASCULAR DISEASE AND SYSTOLIC BLOOD PRESSURE

Abstract Objective: Improving the efficiency of hypertension management has driven treatment indications to be based on cardiovascular disease risk calculations instead of blood pressure or cholesterol management. The aim of this study was to explore the relationship between ten-year risk of atherosclerotic cardiovascular disease (ASCVD) and systolic blood pressure (SBP) in individuals with type 2 diabetes and describe the characteristics of individuals according to their ASCVD risk and SBP cross-classification. The secondary aim was to model the association of ASCVD risk and SBP at study baseline with clinical outcomes (major macrovascular, major microvascular and death). Design and method: This current study used 7,426 individuals from the Action in Diabetes and Vascular Disease: PreterAx and DiamicroN Modified-Release Controlled Evaluation (ADVANCE) randomised clinical trial, that were free from macrovascular disease at baseline. ASCVD risk and SBP were categorised into approximate thirds, reflecting clinically meaningful cut points, defined as intermediate risk: ASCVD &lt; 20 or SBP &lt; 130, high risk: ASCVD 20 -34 or SBP 130–149, and very high risk: ASCVD &gt; = 35 or SBP &gt; = 150. Individuals were cross-classified according to their ASCVD and SBP categories. Characteristics of individuals among the categories were summarised using descriptive statistics. Cox proportional hazards models were fitted to model the association of ASCVD and SBP cross-classification with clinical outcomes. Results: There was a high proportion of women for ASCVD &lt; 20 across the three sequential SBP categories (67.3%, 80.3% and 87.6%). Mean age increased through increasing ASCVD risk categories, in all risk categories the mean age was highest for SBP &lt; 130 and lowest for SBP &gt; = 150. The risk of death increased as ASCVD increased; though there was no significant association of SBP within the ASCVD categories. The risk of major macrovascular events increased sequentially through the combined effect of ASCVD and SBP (see figure). The highest risk of major microvascular events was for SBP &gt; = 150 across all ASCVD categories. Conclusions: The cross-classification of ASCVD and SBP yielded varying associations with death, major macrovascular and major microvascular events, thus indicating that using ASCVD and /or SBP as predictors produces a non-uniform pattern for adverse clinical outcomes.

History of lower-limb complications and risk of cancer death in people with type 2 diabetes

BackgroundIndividuals with diabetes and lower-limb complications are at high risk for cardiovascular and all-cause mortality, but uncertainties remain in terms of cancer-related death in this population. We investigated this relationship in a large cohort of people with type 2 diabetes.MethodsWe used data from the Action in Diabetes and Vascular Disease: PreterAx and DiamicroN Modified-Release Controlled Evaluation (ADVANCE) study. The primary outcome was adjudicated cancer death; secondary outcomes were overall and site-specific incident cancers, determined according to the International Classification of Diseases Code (ICD-10). We compared outcomes in individuals with (versus without) a baseline history of lower-limb complications (peripheral artery disease (PAD) or sensory peripheral neuropathy) using Cox regression models.ResultsAmong 11,140 participants (women 42%, mean age 66 years), lower-limb complications were reported at baseline in 4293 (38%) individuals: 2439 (22%) with PAD and 2973 (27%) with peripheral neuropathy. Cancer death occurred in 316 (2.8%) participants during a median of 5.0 (25th–75th percentile, 4.7–5.1) years of follow-up corresponding to 53,550 person-years and an incidence rate of 5.9 (95% CI 5.3–6.6) per 1000 person-years. The risk of cancer death was higher in individuals with (versus without) lower-limb complication [hazard ratio 1.53 (95% CI, 1.21–1.94), p = 0.0004], PAD [1.32 (1.02–1.70), p = 0.03] or neuropathy (1.41 (1.11–1.79), p = 0.004], adjusting for potential confounders and study allocations. PAD, but not neuropathy, was associated with excess risk of incident cancers.ConclusionsPAD and peripheral neuropathy were independently associated with increased 5-year risk of cancer death in individuals with type 2 diabetes. PAD was also associated with increased risk of incident cancers. Our findings provide new evidence on the non-cardiovascular prognostic burden of lower-limb complications in people with type 2 diabetes.

A novel drug response score more accurately predicts renoprotective drug effects than existing renal risk scores.

Background:Risk factor-based equations are used to predict risk of kidney disease progression in patients with type 2 diabetes order to guide treatment decisions. It is, however, unknown whether these models can also be used to predict the effects of drugs on clinical outcomes.Methods:The previously developed Parameter Response Efficacy (PRE) score, which integrates multiple short-term drug effects, was first compared with the existing risk scores, Kidney Failure Risk Equation (KFRE) and The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) renal risk score, in its performance to predict end-stage renal disease (ESRD; KFRE) and doubling of serum creatinine or ESRD (ADVANCE). Second, changes in the risk scores were compared after 6 months’ treatment to predict the long-term effects of losartan on these renal outcomes in patients with type 2 diabetes and chronic kidney disease.Results:The KFRE, ADVANCE and PRE scores showed similarly good performance in predicting renal risk. However, for prediction of the effect of losartan, the KFRE risk score predicted a relative risk change in the occurrence of ESRD of 3.1% [95% confidence interval (CI) −5 to 12], whereas the observed risk change was −28.8% (95% CI −42.0 to −11.5). For the composite endpoint of doubling of serum creatinine or ESRD, the ADVANCE score predicted a risk change of −12.4% (95% CI −17 to −7), which underestimated the observed risk change −21.8% (95% CI −34 to −6). The PRE score predicted renal risk changes that were close to the observed risk changes with losartan treatment [−24.0% (95% CI −30 to −17) and −22.6% (95% CI −23 to −16) for ESRD and the composite renal outcome, respectively].Conclusion:A drug response score such as the PRE score may assist in improving clinical decision making and implement precision medicine strategies.

Excellent Outcome of Protocol-Based Treatment of Motivated Type 2 Diabetes Mellitus (T2DM) Patients: A Real World Follow-Up for 11 Years

Introduction and aimTo evaluate the real-world clinical outcome of guideline-based treatment among adherent and committed type 2 diabetes mellitus (T2DM) patients.MethodsThe study reports the outcomes of an 11-year clinic-based standard care regime, based on the American Diabetes Association (ADA) guidelines and implemented in the authors’ practices. Records of 145 T2DM patients, who were regularly followed up, were reviewed. Descriptive and inferential statistical analysis was carried out with the Statistical Analysis System (SAS) (SAS Institute Inc., Cary, NC, USA) and with Statistical Package for Social Sciences (SPSS) (IBM Corp., Armonk, NY, USA), with Microsoft Word and Excel to generate graphs and tables.ResultsApart from a significant increase of body weight (but not of body mass index, BMI) and a significant decrease of diastolic blood pressure (DBP), there were insignificant changes in all major biochemical parameters, fasting plasma glucose (FPG), postprandial plasma glucose (PPG), glycated hemoglobin (HbA1c), low-density lipoprotein cholesterol (LDL-C), creatinine, estimated glomerular filtration rate (eGFR) and urine albumin creatinine ratio (ACR), over the 11 years of follow-up.ConclusionADA guideline-based management effectively maintained treatment goals among treatment adherent and committed T2DM patients over 11 years. Glycemic parameters (FPG, PPG, and HbA1c) and renal parameters (serum creatinine, eGFR, and ACR levels) remained stable. Our outcomes data were better than those recorded in the landmark United Kingdom Prospective Diabetes Study (UKPDS) and Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE).

Is it time to ban sulfonylureas?

Is it time to ban sulfonylureas?

Alternative kidney filtration markers and the risk of major macrovascular and microvascular events, and all-cause mortality in individuals with type 2 diabetes in the ADVANCE trial.

Creatinine-based estimated glomerular filtration rate (eGFR) is biased in the setting of obesity and other conditions. Alternative kidney filtration markers may be useful in adults with diabetes, but few studies examined the associations with risk of clinical outcomes. In the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial, we evaluated whether baseline levels and change in eGFR based on creatinine (Cr), cystatin c (Cys), β2 -microglobulin (B2M), eGFRCr-Cys , and the average of three estimates (eGFRCr-Cys-B2M ) assessed in 7217 participants at baseline and a random sample of 640 participants at the 1-year visit are associated with clinical outcomes. We examined associations with major macrovascular and microvascular events together and separately and all-cause mortality using Cox regression models, adjusting for established risk factors. Over a median follow-up of 5 years, 1313 major macrovascular (n = 748) and microvascular events (n = 637), and 743 deaths occurred. Lower levels of eGFR based on all filtration markers individually and combined were associated with 1.4 to 3.0 times higher risk of major macrovascular and microvascular events (combined and separately) and all-cause mortality. Per 30% decline in eGFRCys , eGFR Cr-Cys , and eGFRCr-Cys-B2M were associated with a >2-fold higher risk of all clinical outcomes. In adults with type 2 diabetes, baseline levels of eGFR based on alternative filtration markers and per 30% decline in eGFRCys , eGFR Cr-Cys , and eGFRCr-Cys-B2M were associated with clinical outcomes. Measurement of alternative filtration markers, particularly B2M in adults with type 2 diabetes may be warranted.

Plasma fatty acids and the risk of vascular disease and mortality outcomes in individuals with type 2 diabetes: results from the ADVANCE study

Aims/hypothesisThis biomarker study aimed to quantify the association of essential and other plasma fatty acid biomarkers with macrovascular disease, microvascular disease and death in individuals with type 2 diabetes.MethodsA case-cohort study (N = 3576), including 654 macrovascular events, 341 microvascular events and 631 deaths during 5 years of (median) follow-up, was undertaken as a secondary analysis of the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified-Release Controlled Evaluation (ADVANCE) study (full details of the study design and primary endpoints of the ADVANCE trial and its case-cohort have been published previously). This current study considers new data: fatty acids measured from baseline plasma samples by proton NMR analysis. The fatty acids measured were n-3, docosahexaenoic acid (DHA), n-6, linoleic acid, and polyunsaturated, monounsaturated and saturated fatty acids. HRs were modelled per SD higher (percentage) fatty acid. C statistics and continuous net reclassification improvement were used to test the added value of fatty acids compared with traditional cardiovascular risk factors.ResultsAfter adjustment for traditional cardiovascular risk factors, an inverse association was observed for n-3 fatty acids and DHA with the risk of macrovascular events (HR [95% CI]: 0.87 [0.80, 0.95] and 0.88 [0.81, 0.96], respectively, per 1 SD higher percentage), and for n-3 fatty acids with the risk of death (HR 0.91 [95% CI 0.84, 0.99] per 1 SD higher percentage). Such associations were also evident when investigating absolute levels of fatty acids. There were no statistically significant associations between any fatty acids and microvascular disease after adjustment. However, there was limited improvement in the predictive ability of models when any fatty acid was added.Conclusions/interpretationPlasma n-3 fatty acids and DHA were found to be inversely associated with macrovascular disease, while n-3 fatty acids were also inversely associated with death. These results support the cardioprotective effects of n-3 fatty acids and DHA and further merit testing the role of high-dose supplementation with n-3 fatty acids in individuals with type 2 diabetes.Trial registrationClinicalTrials.gov NCT00145925.Graphical abstract

Observational analyses from ADVANCE and ADVANCE-ON.

To explain, and document, the epidemiological work associated with the action in diabetes and vascular disease: preterax and diamicron-modified release controlled evaluation (ADVANCE) clinical trial. ADVANCE was designed as a randomized controlled multicentre factorial trial in high-risk patients with diabetes. The two interventions were blood pressure lowering medications versus placebo, and intensive glucose control versus standard glucose control. Following termination of the trial, an observational study of surviving participants, able to join, was mounted: the ADVANCE - observational study (ADVANCE-ON). Other epidemiological analyses that were undertaken treated the trial as a cohort study, including using biomarkers from the blood samples taken from ADVANCE subjects as risk exposures. More than 50 publications have reported epidemiological results from ADVANCE. The main results from ADVANCE-ON suggested attenuated benefits of ADVANCE's blood pressure lowering treatment on all-cause and cardiovascular death, but no such long-term benefits for intensive glucose control, although this did give persistent benefit for end-stage renal disease. The other epidemiological studies found, amongst other things, strong effects of NT-terminal pro-B-type natriuretic peptide and high-sensitivity cardiac troponin T on macrovascular events, microvascular events and all-cause death. Embedding post-randomization and epidemiological analyses into clinical trials is worthwhile and can be highly productive in advancing scientific knowledge.

Renal protection: What have we learnt from ADVANCE about kidney disease in type 2 diabetes?

The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) factorial trial was a landmark randomized controlled clinical trial in 11 140 type 2 diabetic patients from 215 centers in 20 countries with a two-by-two factorial design. In the blood pressure-lowering arm, patients were treated using a fixed combination of the ACE-inhibitor, perindopril, and the thiazide-like diuretic, indapamide, or placebo, whereas in the glucose-lowering arm, the intervention compared the sulphonylurea gliclazide plus other glucose-lowering drugs, targeting a glycated hemoglobin value of 6.5% or less, with standard glucose control. Primary end-points were major macro- and microvascular events in both arms. This review gives an overview of the results of the primary randomized trial, results from observational follow-up studies, and results of several biomarker studies and discusses the perspectives of these data in the context of recent major outcome trials for current medical treatment.

Effects of Intensive Glycemic Control on Clinical Outcomes Among Patients With Type 2 Diabetes With Different Levels of Cardiovascular Risk and Hemoglobin A1c in the ADVANCE Trial

To study whether the effects of intensive glycemic control on major vascular outcomes (a composite of major macrovascular and major microvascular events), all-cause mortality, and severe hypoglycemia events differ among participants with different levels of 10-year risk of atherosclerotic cardiovascular disease (ASCVD) and hemoglobin A1c (HbA1c) at baseline. We studied the effects of more intensive glycemic control in 11,071 patients with type 2 diabetes (T2D), without missing values, in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial, using Cox models. During 5 years' follow-up, intensive glycemic control reduced major vascular events (hazard ratio [HR] 0.90 [95% CI 0.83-0.98]), with the major driver being a reduction in the development of macroalbuminuria. There was no evidence of differences in the effect, regardless of baseline ASCVD risk or HbA1c level (P for interaction = 0.29 and 0.94, respectively). Similarly, the beneficial effects of intensive glycemic control on all-cause mortality were not significantly different across baseline ASCVD risk (P = 0.15) or HbA1c levels (P = 0.87). The risks of severe hypoglycemic events were higher in the intensive glycemic control group compared with the standard glycemic control group (HR 1.85 [1.41-2.42]), with no significant heterogeneity across subgroups defined by ASCVD risk or HbA1c at baseline (P = 0.09 and 0.18, respectively). The major benefits for patients with T2D in ADVANCE did not substantially differ across levels of baseline ASCVD risk and HbA1c.

Abstract P274: Kidney Filtration Markers and the Risk of Clinical Outcomes in Individuals With Type 2 Diabetes in the Advance Trial

Introduction: Creatinine-based estimated glomerular filtration rate (eGFR) is biased in the setting of obesity and other conditions. Alternative kidney filtration markers may be particularly useful in adults with diabetes, but few studies examined the risk of clinical outcomes associated with filtration markers in adults with type 2 diabetes. Objective: We evaluated whether baseline levels and change in eGFR based on creatinine (Cr), cystatin C (Cys), and B 2 -microglobulin (B2M) were associated with the risk of clinical outcomes among individuals with type 2 diabetes. Methods: In the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial, Cr, Cys, and B2M were measured in 7,217 participants at baseline and a random sample of 640 participants at the 1 year visit. We categorized baseline eGFR Cr , eGFR Cys , eGFR B2M , and the average across the 3 eGFR estimates (eGFR avg ) into quarters, and examined associations with major macrovascular and microvascular events together, and separately, and all-cause mortality using Cox regression models, adjusting for established risk factors. We also examined associations with continuous eGFR decline and increase (per 30%). Results: Over a median follow-up of 5 years, 1,313 combined major macrovascular (n=748) and microvascular events (n=637), and 743 deaths occurred. Lower levels of eGFR based on all three filtration markers individually and combined were associated with 1.5 to 2.2 times higher risk of combined major macrovascular and microvascular events, with similar patterns for other outcomes ( Table ). Per 30% decline in eGFR Cys and eGFR avg were associated with a &gt;2-fold higher risk of all clinical outcomes, after additional adjustment of baseline eGFR. Conclusions: In adults with type 2 diabetes, baseline levels of eGFR based on alternative filtration markers and per 30% decline in eGFR Cys and eGFR avg were consistently associated with all clinical outcomes.

Acute Increase in Creatinine after Starting ACE Inhibitor and Vascular Events and Premature Death in Patients with Type 2 Diabetes—The ADVANCE Trial

Background: An acute increase in serum creatinine (AICr) after starting ACE inhibitor is frequently observed, and consideration of discontinuation has been recommended if creatinine values increased 30% or more. However, the long term effect of continuation or discontinuation of that therapy is unclear. Objective: To examine the association of AICr after starting a fixed combination of perindopril-indapamide and its continuation or discontinuation, with clinical outcomes using data from the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial. Research Design and Methods: A total of 11,140 diabetes patients were randomly assigned to a fixed combination of perindopril-indapamide or placebo after a 6-week active run-in period. These analyses included 11,066 patients with 2 measurements of serum creatinine, before and during the active run-in period (3 weeks apart). AICr was determined using these 2 measurements, classified into 4 groups: &amp;lt;10%, 10-19%, 20-29%, and ≥30%. Results: AICr after starting perindopril-indapamide in the run-in period was subsequently associated with an increased risk of a composite of major macrovascular events, new or worsening nephropathy, all-cause mortality, in both randomized groups (P for trend &amp;lt;0.for each). However, a consistent benefit of randomized treatment for the outcome was observed across subgroups defined by AICr, with no heterogeneity in the magnitude of the effects (P for heterogeneity = 0.94). Similar results were observed for major macrovascular events alone, new or worsening nephropathy alone, and all-cause mortality alone. Conclusions: AICr after starting ACE inhibitor was associated with an increased risk of clinical outcomes, irrespective of continuation or discontinuation of the therapy. However, randomized treatment effects are consistent and beneficial across subgroups defined by AICr. Disclosure T. Ohkuma: None. M. Jun: None. M. Woodward: None. J. Chalmers: Research Support; Self; Servier. Other Relationship; Self; Servier. V. Perkovic: Speaker's Bureau; Self; Mitsubishi Tanabe Pharma Corporation. Advisory Panel; Self; Merck Sharp &amp; Dohme Corp.. Consultant; Self; AbbVie Inc.. Advisory Panel; Self; Janssen Global Services, LLC.. Speaker's Bureau; Self; Novo Nordisk Inc.. Advisory Panel; Self; Novartis Pharmaceuticals Corporation, AstraZeneca, Gilead Sciences, Inc.. Consultant; Self; Servier. Speaker's Bureau; Self; Boehringer Ingelheim GmbH. Advisory Panel; Self; Eli Lilly and Company. A. Rodgers: Other Relationship; Self; George Health Enterprises.

Circulating amino acids and the risk of macrovascular, microvascular and mortality outcomes in individuals with type 2 diabetes: results from the ADVANCE trial

Aims/hypothesesWe aimed to quantify the association of individual circulating amino acids with macrovascular disease, microvascular disease and all-cause mortality in individuals with type 2 diabetes.MethodsWe performed a case-cohort study (N = 3587), including 655 macrovascular events, 342 microvascular events (new or worsening nephropathy or retinopathy) and 632 all-cause mortality events during follow-up, in a secondary analysis of the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) study. For this study, phenylalanine, isoleucine, glutamine, leucine, alanine, tyrosine, histidine and valine were measured in stored plasma samples by proton NMR metabolomics. Hazard ratios were modelled per SD increase in each amino acid.ResultsIn models investigating associations and potential mechanisms, after adjusting for age, sex and randomised treatment, phenylalanine was positively, and histidine inversely, associated with macrovascular disease risk. These associations were attenuated to the null on further adjustment for extended classical risk factors (including eGFR and urinary albumin/creatinine ratio). After adjustment for extended classical risk factors, higher tyrosine and alanine levels were associated with decreased risk of microvascular disease (HR 0.78; 95% CI 0.67, 0.91 and HR 0.86; 95% CI 0.76, 0.98, respectively). Higher leucine (HR 0.79; 95% CI 0.69, 0.90), histidine (HR 0.89; 95% CI 0.81, 0.99) and valine (HR 0.79; 95% CI 0.70, 0.88) levels were associated with lower risk of mortality. Investigating the predictive ability of amino acids, addition of all amino acids to a risk score modestly improved classification of participants for macrovascular (continuous net reclassification index [NRI] +35.5%, p < 0.001) and microvascular events (continuous NRI +14.4%, p = 0.012).Conclusions/interpretationWe report distinct associations between circulating amino acids and risk of different major complications of diabetes. Low tyrosine appears to be a marker of microvascular risk in individuals with type 2 diabetes independently of fundamental markers of kidney function.