And Vascular Disease: Preterax And Diamicron MR Controlled Evaluation Research Articles

Haptoglobin Phenotype and Intensive Glycemic Control for Coronary Artery Disease Risk Reduction in People With Type 2 Diabetes: The ADVANCE Study.

Intensive glycemic control reduced coronary artery disease (CAD) events among the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study participants with the haptoglobin (Hp)2-2 phenotype but not in participants without the Hp2-2 phenotype. It is unknown whether and how these results translate across different demographic/clinical characteristics and treatment strategies. Haptoglobin phenotype was measured in available samples from the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) biomarker case-cohort study. Weighted multivariable-adjusted Cox regression models were used to evaluate the association between intensive glycemic control (HbA1c target of ≤6.5%) versus standard therapy (based on local guidelines) and major CAD events among participants with (n = 1,327) and without (n = 2,077) the Hp2-2 phenotype separately and within prespecified stratifications by sex, race, previous cardiovascular disease (CVD), diabetes duration, and HDL-cholesterol. While the hazard ratios (HRs) were in the hypothesized differing directions, compared with standard therapy, intensive glycemic control was not significantly associated with risk of CAD events among participants without (1.04, 95% CI 0.82-1.32) or with (0.84, 0.63-1.14, Pinteraction = 0.27) the Hp2-2 phenotype overall. Intensive therapy was associated with lower CAD risk among participants with the Hp2-2 phenotype who had no previous CVD (0.47, 0.29-0.76, Pinteraction = 0.01). Our findings suggest that intensive glycemic control contributes to the prevention of major CAD events among ADVANCE participants with the Hp2-2 phenotype and no previous CVD and are in alignment with our hypothesis that intensive glycemic control may be beneficial in a subset of people with the Hp2-2 phenotype.

Validation and comparison of cardiovascular risk prediction equations in Chinese patients with Type 2 diabetes.

For patients with diabetes, the European guidelines updated the cardiovascular disease (CVD) risk prediction recommendations using diabetes-specific models with age-specific cut-offs, whereas American guidelines still advise models derived from the general population. We aimed to compare the performance of four cardiovascular risk models in diabetes populations. Patients with diabetes from the CHERRY study, an electronic health records-based cohort study in China, were identified. Five-year CVD risk was calculated using original and recalibrated diabetes-specific models [Action in Diabetes and Vascular disease: PreterAx and diamicroN-MR Controlled Evaluation (ADVANCE) and the Hong Kong cardiovascular risk model (HK)] and general population-based models [Pooled Cohort Equations (PCE) and Prediction for Atherosclerotic cardiovascular disease Risk in China (China-PAR)]. During a median 5.8-year follow-up, 46 558 patients had 2605 CVD events. C-statistics were 0.711 [95% confidence interval: 0.693-0.729] for ADVANCE and 0.701 (0.683-0.719) for HK in men, and 0.742 (0.725-0.759) and 0.732 (0.718-0.747) in women. C-statistics were worse in two general population-based models. Recalibrated ADVANCE underestimated risk by 1.2% and 16.8% in men and women, whereas PCE underestimated risk by 41.9% and 24.2% in men and women. With the age-specific cut-offs, the overlap of the high-risk patients selected by every model pair ranged from only 22.6% to 51.2%. When utilizing the fixed cut-off at 5%, the recalibrated ADVANCE selected similar high-risk patients in men (7400) as compared to the age-specific cut-offs (7102), whereas age-specific cut-offs exhibited a reduction in the selection of high-risk patients in women (2646 under age-specific cut-offs vs. 3647 under fixed cut-off). Diabetes-specific CVD risk prediction models showed better discrimination for patients with diabetes. High-risk patients selected by different models varied significantly. Age-specific cut-offs selected fewer patients at high CVD risk especially in women.

S-02-4: BLOOD PRESSURE, ANTIHYPERTENSIVES AND DEMENTIA, AN INDIVIDUAL PATIENT DATA META-ANALYSIS

Background: A large number of observational studies show links between hypertension or higher blood pressure (BP) in mid-life and an increased risk of later dementia. In late life, the evidence is more mixed with some studies indicating higher BP is associated with higher dementia risk and some finding U-shaped associations between BP and incident dementia in older age. The clinical trials of antihypertensives to lower BP have shown largely negative results when examining the relationship between antihypertensive use and incident dementia. However, the trials were designed to examine cardiovascular endpoints and several stopped early for cardiovascular benefit thus limiting their statistical power and ability to accrue dementia outcomes. To overcome some of these limitations a pooled individual patient data meta-analysis of five seminal double-blind placebo-controlled randomised trials was undertaken to better define the effects of BP lowering treatment for the prevention of dementia. Methods: The double-blind placebo-controlled randomised antihypertensive trials; Action in Diabetes and Vascular disease: preterAx and diamicroN-MR Controlled Evaluation (ADVANCE), Hypertension in the Very Elderly Trial (HYVET), Perindopril Protection Against Recurrent Stroke Study (PROGRESS), Systolic Hypertension in the Elderly Program (SHEP), and SYSTolic Hypertension in EURope Trial (SYST-EUR) were merged into a single database. Multilevel logistic regression was used to evaluate the treatment effect on incident dementia. Effect modification was assessed for key population characteristics including age, baseline systolic BP, sex, baseline Mini-Mental State Exam (MMSE) score and presence of prior stroke. Results: All trials were balanced across randomised groups. The combined sample was n = 28,008 recruited from 20 countries. Mean baseline age was 69.1 (Standard Deviation 9.3). Median follow-up 4.3 years. Incident dementia occurred in 2.9% and 3.3% of those in active and placebo groups, respectively. Multilevel logistic regression reported an adjusted odds ratio 0.87 (95% confidence interval 0.75, 0.99) in favour of antihypertensive treatment reducing risk of incident dementia with a mean BP lowering of 10/4mmHg. Further multinomial regression taking account of death as a competing risk found similar results. There was no effect modification by age, sex, baseline systolic BP, baseline MMSE or prior stroke. Discussion: This is the first single-stage individual patient data meta-analysis from double-blind placebo-controlled clinical trials. It provides high-quality evidence to support the benefits of antihypertensive treatment in late-mid and later life to lower the risk of dementia. Questions remain as to the potential benefit from antihypertensive treatment commenced earlier in the life-course to reduce the long-term risk of dementia.

Association of visit-to-visit HbA1c variability with cardiovascular diseases in type 2 diabetes within or outside the target range of HbA1c.

Although a growing attention has been recently paid to the role of HbA1c variability in the risk of diabetic complications, the impact of HbA1c variability on cardiovascular diseases (CVD) in type 2 diabetes is still debated. The aim of the study is to investigate the association of HbA1c variability with CVD in individuals within or outside the target range of HbA1c. Using data from Action in Diabetes and Vascular disease: preterAx and diamicroN-MR Controlled Evaluation (ADVANCE), we enrolled 855 patients with type 2 diabetes in China. The primary outcomes included major macrovascular events and major microvascular events. Visit-to-visit HbA1c variability was expressed as the coefficient of variation (CV) of five measurements of HbA1c taken 3-24 months after treatment. Cox proportional hazard models were used to estimate adjusted hazard ratios (aHR). Among 855 patients in the intensive glucose treatment group, 563 and 292 patients were assigned to the group of "within the target range of HbA1c" (WTH) (updated mean HbA1c ≤ 7.0%) and "outside the target range of HbA1c" (OTH) (updated mean HbA1c > 7.0%), respectively. HbA1c variability was positively associated with the risk of major microvascular events in all patients and both the subgroups during a median follow-up period of 4.8 years. Particularly, the risk related to HbA1c variability was higher in patients in WTH group for the new or worsening nephropathy [aHR: 3.35; 95% confidence interval (CI): 1.05-10.74; P = 0.042]. This retrospective cohort study confirmed the positive correlation between HbA1c variability and major microvascular events, especially in subjects in WTH or OTH.

Cardiovascular Events in People With Type 2 Diabetes: Performance of Framingham, UKPDS, and ADVANCE Risk Equations

The aim of this study was to assess the performance of the Framingham, UK Prospective Diabetes Study (UKPDS), and the Action in Diabetes and Vascular disease: Preterax and Diamicron-MR Controlled Evaluation (ADVANCE) risk equations in the prediction of 4-year cardiovascular disease CVD) in Iranian people with type 2 diabetes. The 4-year risks of CVD were estimated using the three equations in a community of 557 patients with type 2 diabetes and free of CVD at baseline. A trained physician evaluated all of the participants regarding the occurrence of CVD events during follow-up. CVD was defined as major events including fatal/non-fatal myocardial infarction as well as fatal/non-fatal stroke, minor events including treated coronary heart disease (CHD), and established peripheral arterial disease (PAD). During four years of follow-up, 64 CVD events were observed (66% minor CVD events). Despite having a good calibration (estimated to observed ratio ranging from 91.37 to 98.2 percent, Hosmer–Lemeshow χ2 (HLχ2) values <15), both general (Framingham) and diabetes-specific (UKPDS and ADVANCE) equations did not have adequate discriminative ability (Area Under the Curve (AUC) ranging from 0.48 to 0.56). Framingham, UKPDS, and ADVANCE risk equations, regardless of being general or diabetes-specific, could not precisely predict 4-year risk of CVD in Iranian individuals with type 2 diabetes.

Procalcitonin Correlates With Cardiovascular Risk Better Than Highly Sensitive C-Reactive Protein in Patients With Type 2 Diabetes in Sub-Saharan Africa: Results From a Cross-Sectional Study.

ObjectiveInflammatory markers such as C-reactive protein and procalcitonin have been shown to be independent markers of cardiovascular diseases. We aimed to assess the correlation between serum levels of procalcitonin, C-reactive protein and cardiovascular risk in type 2 diabetes.MethodsWe carried out a cross-sectional study at a tertiary level reference hospital in Yaounde, Cameroon. We assessed the cardiovascular risk using the Action in Diabetes and Vascular Disease: Preterax and Diamicron-MR Controlled Evaluation (ADVANCE) cardiovascular risk prediction model in 80 adults with type 2 diabetes. Serum procalcitonin and C-reactive protein were measured in 80 and 76 subjects respectively, using a highly sensitive quantitative enzyme-linked immunosorbent assay (ELISA) method. Correlations were examined using Spearman’s rank correlation test and the correlation coefficients were compared using the Z-test statistic.ResultsFemales represented the majority of the study population (62.5%). The median duration of diabetes was 5 (3-10) years and 62.5% of participants had a high cardiovascular risk score. Median serum procalcitonin levels was significantly higher in females compared to male participants: 2.48 (1.76-3.01 ng/mL) vs 1.42 (0.86-1.87 ng/mL); p<0.001. There was no difference in the serum C-reactive protein levels between females and males: 1.20 (0.33-3.33) mg/L vs 0.85 (0.36-2.77) mg/L; p=0.669. Procalcitonin was moderately correlated with cardiovascular risk (r=0.58, p<0.001). The correlation was slightly higher in females (R=0.56, p<0.001) versus males (R=0.49, p=0.005) although not significantly different (Z-statistic=0.734, p=0.463). Serum C-reactive protein did not show a meaningful correlation with cardiovascular risk (R=0.23, p=0.050). At a threshold of 2 ng/ml, serum procalcitonin identified participants with a high cardiovascular risk score, with a sensitivity and specificity of 64% and 80% respectively.ConclusionCompared to C-reactive protein, procalcitonin may be a better surrogate marker for cardiovascular risk prediction in this population with type 2 diabetes.

Changes in lipidomic profile by anti-retroviral treatment regimen: An ACTG 5257 ancillary study.

High cardiovascular disease risk in people living with HIV is partly attributed to antiretroviral therapy (ART). Lipid response to ART has been extensively studied, yet, little is known how small molecule lipids respond to Integrase inhibitor-based (INSTI-based) compared to Protease inhibitor-based (PI-based) ART regimens.Ancillary study to a phase 3, randomized, open-label trial [AIDS Clinical Trial Group A5257 Study] in treatment-naive HIV-infected patients randomized in a 1:1:1 ratio to receive ritonavir-boosted atazanavir (ATV/r), ritonavir-boosted darunavir (DRV/r) (both PI-based), or raltegravir with Tenofovir Disoproxil Fumarate-TDF plus emtricitabine (RAL, INSTI-based).We examined small molecule lipid response in a subcohort of 75 participants. Lipidomic assays of plasma samples collected pre- and post-ART treatment (48 weeks) were conducted using ultra-performance liquid chromatography coupled to time-of-flight mass spectrometry. The effect of ART regimens was regressed on lipid species response adjusting for the baseline covariates (lipids, age, sex, race, CD4 level, BMI, and smoking). Results were validated in the Centers for AIDS Research Network of Integrated Clinical Systems study (N = 16).Out of 417 annotated lipids, glycerophospholipids (P = .007) and sphingolipids (P = .028) had a higher response to ATV/r and DRV/r compared to RAL. The lysophosphatidylcholine (LPCs(16:1),(17:1),(20:3)) and phosphophatidylcholine species (PCs(40:7),(38:4)) had an opposite response to RAL versus ATV/r in the discovery and validation cohort. The INSTI-based regimen had an opposite response of ceramide species ((d38:1), (d42:2)), PCs((35:2), (38:4)), phosphatidylethanolamines (PEs(38:4), (38:6)), and sphingomyelin(SMd38:1) species compared with the PI-based regimens. There were no differences observed between 2 PI-based regimens.We observed differences in response of small molecule lipid species by ART regimens in treatment-naive people living with HIV.

The effect of age on blood pressure response by 4-week treatment perindopril: A pooled sex-specific analysis of the EUROPA, PROGRESS, and ADVANCE trials.

Previous studies showed that postmenopausal women are more likely to have poorly controlled hypertension than men of the same age. Whether this is caused by inadequate treatment or poor response to antihypertensive agents remains unknown. The aim of this study is to analyze treatment response to the most potent renin angiotensin aldosterone system (RAAS) inhibitor perindopril in different age categories in women and men. Individual patient data were used from the combined European Trial on Reduction of Cardiac Events With Perindopril (EUROPA), Perindopril Protection Against Recurrent Stroke Study (PROGRESS), and Action in Diabetes and Vascular disease: Preterax and Diamicron‐MR Controlled Evaluation (ADVANCE) trials, which include patients with vascular disease (n = 29,463). We studied the relative and absolute changes in systolic blood pressure (SBP) and diastolic blood pressure (DBP) during a 4‐week run‐in phase in which all patients were treated with the perindopril‐based treatment in different age categories. In total, 8366 women and 21,097 men were included in the analysis. Women greater than 65 years of age showed a significantly smaller blood pressure reduction after perindopril treatment (2.8 mmHg [95% confidence interval {CI} = 0.1–5.5] less reduction compared to women ≤45 years, p = 0.039). In men, the SBP reduction after perindopril in patients greater than 55–65 and greater than 65 years was lower compared to the age category less than or equal to 45 years (adjusted mean difference >55–65: 2.8 mmHg [95% CI = 1.8–3.7], p < 0.001, >65: 3.7 mmHg [95% CI = 2.7–4.7], p < 0.001). A trend of less blood pressure reduction was seen with ageing in both men and women (p < 0.001). To conclude, we observed that in both women and men the perindopril leads to less SBP reduction with increasing age, whereas the DBP reduction increases with age. More research is needed to determine whether it would be beneficial to use age‐adjusted perindopril dosages.

How Significant Is Severe Hypoglycemia in Older Adults With Diabetes?

Severe hypoglycemia is a devastating event in the lives of people with diabetes treated with insulin and/or insulin secretogogues. Severe hypoglycemia is defined as an episode in which the person with diabetes requires the assistance of another to increase blood glucose, usually by administration of glucagon or contacting a medical professional. These occurrences are not rare. More than 10% of adult patients in the T1D Exchange registry reported at least one episode of severe hypoglycemia over the past 12 months (1). These events elicit profound fear in patients with diabetes. By depriving the brain of glucose, severe hypoglycemia acutely alters brain function, resulting in neuroglycopenic symptoms, seizures, or even death. The impact extends beyond the acute event. The Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial reported that patients with type 2 diabetes who experience severe hypoglycemia were at higher risk for a major macrovascular event or death over the subsequent 12 months (2). As the population ages, there remains a critical need to understand the significance and impact of severe hypoglycemia in older patients with diabetes. In this issue of Diabetes Care , complementary articles provide new insights into the consequences of severe hypoglycemia in older adults. Lacy et al. (3) report that severe hypoglycemia is associated with reduced cognitive function in older adults with type 1 diabetes, and Standl et al. (4) confirm the bidirectional nature of the association between severe hypoglycemia and cardiovascular (CV) events in adults with type 2 diabetes. Both investigations …

PDB43 COST COMPARISON OF GLICAZIDE MODIFIED-RELEASE AND GENERIC GLICLAZIDE IN PREVENTING END STAGE RENAL DISEASE IN TYPE 2 DIABETES MELLITUS IN THE PUBLIC SECTOR OF MALAYSIA

Among the long-term complications arising from poor control of type 2 diabetes mellitus (T2DM), renal failure is the most expensive due to the enormous resources required for management. Evidence has shown that intensive glucose-lowering regimens may offer better protection against the development of end stage renal disease (ESRD). Gliclazide has been available as a once-daily modified release formulation (Diamicron MR) for enhancing patient’s compliance leading to better control. However, generic glicazide immediate release (IR) remains the first line therapy for new T2DM patients in Malaysia. This study compares the economic impact of Diamicron MR and generic glicazide IR in preventing diabetic ESRD in Malaysia. The model originally developed for Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial was used to compare the cost and cost-effectiveness of Diamicron MR and generic gliclazide IR in preventing ESRD. Efficacy, prevalence and adverse effect data were from published overseas literature. Cost data was obtained from local literature and government website. All cost data was adjusted to 2018 using the Purchasing Power Parity (PPP) index. The study was performed from the Malaysia government’s perspective. Based on the ADVANCE model, the cost of prevention per episode of ESRD is substantially reduced by 61.8% for Diamicron MR as compared to generic gliclazide IR (USD150.8 vs 57.6). Deterministic sensitivity analysis was also in support of this finding. ICER for each ESRD avoided for Diamicron MR was found to be USD6,780. We bench-marked our results to the willingness-to-pay for Malaysia which is USD6,835 from an earlier study. Based on projection using the ADVANCE model, the cost of prevention per episode of ESRD appears to be less for Diamicron MR compared to generic gliclazide IR and Diamicron MR appears to be cost-effective from the Malaysia government’s perspective.

The relationship between eGFR slope and subsequent risk of vascular outcomes and all-cause mortality in type 2 diabetes: the ADVANCE-ON study

Aims/hypothesisSome studies have reported that annual change in eGFR (eGFR slope) is associated with the future risk of end-stage kidney disease, cardiovascular disease and death in general or chronic kidney disease cohorts. However, the benefits of using eGFR slopes for prediction of major clinical outcomes in diabetes are unclear.MethodsWe used data from the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial and the ADVANCE Post-Trial Observational Study (ADVANCE-ON). After excluding the first 4 months during which an acute fall in eGFR was induced by the initiation of an ACE inhibitor and diuretic combination agent, eGFR slopes were estimated by linear mixed models, using three measurements of eGFR at 4, 12 and 24 months after randomisation over 20 months, and categorised according to quartiles. Cox regression models were used to evaluate adjusted HRs for the study’s primary outcome, a composite of major renal events, major macrovascular events and all-cause mortality during the subsequent follow-up from 24 months after randomisation.ResultsA total of 8,879 participants (80%) were included in this cohort. The mean age was 65.6 years (SD 6.3), the mean eGFR was 75 ml min−1 (1.73 m)−2 (SD 17) and the median urinary albumin/creatinine ratio was 14 μg/mg (interquartile range 7–38). The mean eGFR slope was −0.63 ml min−1 (1.73 m)−2 year−1 (SD 1.75). Over a median follow-up of 7.6 years following the 20-month eGFR slope ascertainment period, 2,221 participants (25%) met the primary outcome. An annual substantial decrease in eGFR (lowest 25%, <−1.63 ml min−1 [1.73 m]−2 year−1) was significantly associated with the subsequent risk of the primary outcome (HR 1.30 [95% CI 1.17, 1.43]) compared with a stable change in eGFR (middle 50%, −1.63 to 0.33). An annual substantial increase in eGFR (highest 25%, >0.33) had no significant association with the risk of the primary outcome (HR 0.96 [95% CI 0.86, 1.07]).Conclusions/interpretationOur study supports the utility of eGFR slope in type 2 diabetes as a surrogate endpoint for renal outcomes, as well as a prognostic factor for identifying individuals at high risk of cardiovascular disease and all-cause mortality.Trial registry numberClinicalTrials.gov registration no. NCT00145925 and no. NCT00949286

SAT-287 eGFR SLOPE AND THE SUBSEQUENT RISK OF CLINICAL OUTCOMES IN TYPE 2 DIABETES

Diabetic kidney disease (DKD) develops in approximately 40% of patients with diabetes and can lead to poor prognosis. Evaluating DKD progression is critical for identifying patients at high risk of clinical outcomes for both clinical and research purposes. Recent studies have suggested that an annual change in eGFR, defined as an eGFR slope, is associated with the subsequent risk of end-stage kidney disease (ESKD), cardiovascular disease (CVD) and mortality. However, the benefits of using eGFR slopes in diabetes are unclear. The aim of the study was to determine whether eGFR slopes are useful to predict the risk of clinical outcomes in type 2 diabetes. We used data from the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) and ADVANCE Post-Trial Observational Study (ADVANCE-ON). Excluding the first 4 months in which an acute fall in eGFR was induced by the initiation of a renin-angiotensin-aldosterone-system blocker, eGFR slopes were estimated by linear mixed models, using 3 measurements of eGFR at 4th, 12th, and 24th month after randomisation over the 20-month baseline period and categorised according to quartiles. The risk factors associated with eGFR slopes were assessed in multivariable analyses using linear mixed models. Cox proportional hazards models were used to evaluate adjusted hazard ratios (HRs) of the study’s primary outcome, a composite of major renal events, major macrovascular events, and all-cause mortality. Secondary outcomes included the individual components of the primary outcome. A total of 8879 participants (80%) were included. The mean eGFR slope was -0.63 mL/min/1.73 m2/year (SD 1.75). Overall, 127 (1%), 298 (3%), 695 (8%), 1595 (18%), and 3408 (38%) participants had experienced an annual change in eGFR of -5, -4, -3, -2, and -1 mL/min/1.73 m2/year, respectively. In the multivariable analyses, the mean eGFR slope was steeper in participants with older age, higher albuminuria and HbA1c, and lower HDL cholesterol, while the mean eGFR slope was flatter in patients with lower eGFR. Over a median follow-up of 7.6 years, 2221 participants (25%) developed 1395 major macrovascular events (16%), 117 major renal events (1%), and 1450 deaths (16%). An annual decrease in eGFR (1st quarter, <-1.63 mL/min/1.73 m2/year) was significantly associated with the subsequent risk of primary outcome (HR 1.25; 95%CI 1.13–1.38) compared with a stable change in eGFR (2nd and 3rd quarters, -1.63 to 0.33 mL/min/1.73 m2/year) and showed 301%, 22%, and 32% higher risk of major renal events, major macrovascular events, and all-cause mortality, respectively. An annual increase in eGFR (4th quarter, >0.33 mL/min/1.73 m2/year) had no significant association with the risk of primary outcome. The greater annual declines in eGFR were associated with higher risk of study outcomes compared with no change in eGFR. An annual decrease in eGFR over the 20-month baseline period was strongly associated with future risk of clinical events and death in type 2 diabetes, supporting the potential of using eGFR slopes as a surrogate endpoint for predicting adverse kidney outcomes. The present analysis suggests that monitoring eGFR over time is beneficial to identify diabetic patients at high risk of ESKD, CVD and death.

Predicting, preventing, and managing cardiovascular and chronic kidney disease progression in people with type 2 diabetes: How to improve on traditional strategies.

Predicting, preventing, and managing cardiovascular and chronic kidney disease progression in people with type 2 diabetes: How to improve on traditional strategies.

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

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

Cause-specific risk of major adverse cardiovascular outcomes and hypoglycemic in patients with type 2 diabetes: a multicenter prospective cohort study.

Glycated hemoglobin A1c (HbA1c) and fasting plasma glucose (FPG) was identified to account for the risk of cardiovascular diseases in type 2 diabetic patients, but no study evaluated the risk based on both HbA1c and FPG levels. We described the risk of major adverse cardiovascular events (MACE) and hypoglycemic in type 2 diabetic patients according to both HbA1c and FPG levels. With the usage of databases of Action in Diabetes and Vascular disease: preterAx and diamicroN-MR Controlled Evaluation (ADVANCE), 1815 patients from 61 centers in China was identified and grouped according to the criterion value of HbA1c and FPG: Good glycemic control (HbA1c < 6.5%, FPG < 6.1 mmol/L); Insufficient glycemic control (HbA1c < 6.5%, FPG ≥ 6.1 mmol/L or HbA1c ≥ 6.5%, FPG < 6.1 mmol/L); Poor glycemic control (HbA1c ≥ 6.5%, FPG ≥ 6.1 mmol/L). Time-varying multivariable Cox proportional hazards models were employed. Average age was 64.8 ± 5.8 years, with a median of 4.8 years of follow-up. Overall, the incidence rates of MACE were 20.6 per 1000-person-years in Good glycemic control compared with 45.9 per 1000-person-years in Insufficient glycemic control (adjusted hazard ratio (aHR): 1.99; 95% CI 1.11-3.56; p = 0.02) and 54.7 per 1000-person-years in Poor glycemic control (aHR: 2.46; 95% CI 1.38-4.40; p = 0.002), respectively. The risk of hypoglycemic was highest in Insufficient glycemic control; 67.3 per 1000-person-years compared with 46.3 per 1000-person-years in Good glycemic control (aHR: 1.62; 95% CI 1.03-2.56; p = 0.04). Apart from this, we also observed that both MACE (aHR:1.41; 95% CI 1.13-1.77; p = 0.003) and hypoglycemic episodes (aHR: 1.82; 95% CI 1.48-2.24; p < 0.001) were sufficiently more frequent in the insulin-exposed group than the non-exposed group. In a post-hoc analysis, the risk of MACE (aHR:1.43; 95% CI 1.09-1.86; p = 0.01) and hypoglycemic (aHR: 1.99; 95% CI 1.46-2.69; p < 0.001) were more pronounced in Insufficient glycemic control with insulin exposure. We observed a significant association of cause-specific risk of MACE and hypoglycemic with Insufficient glycemic control, particularly with insulin exposure.

Performance of Cardiovascular Disease Risk Scores in People Diagnosed With Type 2 Diabetes: External Validation Using Data From the National Scottish Diabetes Register.

To evaluate the performance of five cardiovascular disease (CVD) risk scores developed in diabetes populations and compare their performance to QRISK2. A cohort of people diagnosed with type 2 diabetes between 2004 and 2016 was identified from the Scottish national diabetes register. CVD events were identified using linked hospital and death records. Five-year risk of CVD was estimated using each of QRISK2, ADVANCE (Action in Diabetes and Vascular disease: preterAx and diamicroN-MR Controlled Evaluation), Cardiovascular Health Study (CHS), New Zealand Diabetes Cohort Study (NZ DCS), Fremantle Diabetes Study, and Swedish National Diabetes Register (NDR) risk scores. Discrimination and calibration were assessed using the Harrell C statistic and calibration plots, respectively. The external validation cohort consisted of 181,399 people with type 2 diabetes and no history of CVD. There were 14,081 incident CVD events within 5 years of follow-up. The 5-year observed risk of CVD was 9.7% (95% CI 9.6, 9.9). C statistics varied between 0.66 and 0.67 for all risk scores. QRISK2 overestimated risk, classifying 87% to be at high risk for developing CVD within 5 years; ADVANCE underestimated risk, and the Swedish NDR risk score calibrated well to observed risk. None of the risk scores performed well among people with newly diagnosed type 2 diabetes. Using these risk scores to predict 5-year CVD risk in this population may not be appropriate.

Cardiovascular Protection in People With Diabetes.

Cardiovascular Protection in People With Diabetes.

Estimation of individual beneficial and adverse effects of intensive glucose control for patients with type 2 diabetes.

Aims/hypothesisIntensive glucose control reduces the risk of vascular complications while increasing the risk of severe hypoglycaemia at a group level. We sought to estimate individual beneficial and adverse effects of intensive glucose control in patients with type 2 diabetes.MethodsWe performed a post hoc analysis of the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial, a randomised controlled trial evaluating standard vs intensive glucose control (HbA1c target ≤6.5% [48 mmol/mol]). In 11,140 participants, we estimated the individual 5 year absolute risk reduction (ARR) for the composite outcome of major micro- and macrovascular events and absolute risk increase (ARI) for severe hypoglycaemia for intensive vs standard glucose control. Predictions were based on competing risks models including clinical characteristics and randomised treatment.ResultsBased on these models, 76% of patients had a substantial estimated 5 year ARR for major vascular events (>1%, 5 year number-needed-to-benefit [NNTB5] <100) and 1% had a small ARR (<0.5%, NNTB5 >200). Similarly, 36% of patients had a substantial estimated ARI for severe hypoglycaemia (5 year number-needed-to-harm [NNTH5] <100) and 29% had a small ARI (NNTH5 >200). When assigning similar or half the weight to severe hypoglycaemia compared with a major vascular event, net benefit was positive in 85% or 99% of patients, respectively. Limiting intensive treatment to the 85% patient subgroup had no significant effect on the overall incidence of major vascular events and severe hypoglycaemia compared with treating all patients.Conclusions/interpretationTaking account of the effects of intensive glucose control on major micro- and macrovascular events and severe hypoglycaemia for individual patients, the estimated net benefit was positive in the majority of the participants in the ADVANCE trial. The estimated individual effects can inform treatment decisions once individual weights assigned to positive and adverse effects have been specified.Trial registration:ClinicalTrials.gov NCT00145925Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-016-4082-5) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Microvascular and Macrovascular Disease and Risk for Major Peripheral Arterial Disease in Patients With Type 2 Diabetes.

Peripheral arterial disease (PAD) is a common manifestation of atherosclerosis in type 2 diabetes, but the relationship between other vascular diseases and PAD has been poorly investigated. We examined the impact of previous microvascular and macrovascular disease on the risk of major PAD in patients with type 2 diabetes. We analyzed 10,624 patients with type 2 diabetes free from baseline major PAD in the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) clinical trial. The primary composite outcome was major PAD defined as PAD-induced death, peripheral revascularization, lower-limb amputation, or chronic ulceration. The secondary end points were the PAD components considered separately. Major PAD occurred in 620 (5.8%) participants during 5 years of follow-up. Baseline microvascular and macrovascular disease were both associated with subsequent risk of major PAD after adjustment for age, sex, region of origin, and randomized treatments. However, only microvascular disease remained significantly associated with PAD after further adjustment for established risk factors. The highest risk was observed in participants with a history of macroalbuminuria (hazard ratio 1.91 [95% CI 1.38-2.64], P < 0.0001) and retinal photocoagulation therapy (1.60 [1.11-2.32], P = 0.01). Baseline microvascular disease was also associated with a higher risk of chronic lower-limb ulceration (2.07 [1.56-2.75], P < 0.0001) and amputation (1.59 [1.15-2.22], P = 0.006), whereas baseline macrovascular disease was associated with a higher rate of angioplasty procedures (1.75 [1.13-2.73], P = 0.01). Microvascular disease, particularly macroalbuminuria and retinal photocoagulation therapy, strongly predicts major PAD in patients with type 2 diabetes, but macrovascular disease does not.

Prediction of excessive weight gain in insulin treated patients with type 2 diabetes.

Weight gain is an ongoing challenge when initiating insulin therapy in patients with type 2 diabetes mellitus (T2DM). However, if prediction of insulin-associated weight gain was possible on an individual level, targeted initiatives could be implemented to reduce weight gain. The aim of the present study was to identify predictors of weight gain in insulin-treated patients with T2DM. In all, 412 individuals with T2DM were, in addition to metformin or placebo, randomized into 18-month treatment groups with three different insulin analog treatment regimens (biphasic, aspart, detemir). Participants with excessive weight gain were defined as the group with weight gain in the 4th quartile (>6.2 kg).We developed a pattern classification method to predict individuals prone to excessive weight gain. Over the 18-month treatment period, median weight gain among all 412 patients was 2.4 kg (95% prediction interval [PI] -5.6, 12.4 kg), whereas median weight gain for those in the upper 4th quartile (n = 103) was 8.9 kg (95% PI 6.3, 15.2 kg). No clinical baseline data were strong predictors of excessive weight gain. However, the weight gain during the first 3 months of the trial and the subsequent dose of insulin yielded a useful predictor for weight gain at the 18-month follow-up. Combining these two predictors into a prediction model with other clinical available information produced a receiver operating characteristic area under the curve of 0.80. We have developed a prediction model that could help identify a substantial proportion of individuals with T2DM prone to large weight gain during insulin therapy.