Epidemiology of diabetic kidney disease in adult patients with type 1 diabetes in Italy: The AMD-Annals initiative.

BACKGROUND: Patients with type 1 diabetes mellitus are at increased risk of death. This risk appears to be modulated by kidney dysfunction. The aim of this study was to evaluate the prevalence of diabetic kidney disease (DKD), its traits, and clinical correlates in a large sample of patients with type 1 diabetes. METHODS: Clinical data of 20 464 patients with type 1 diabetes were extracted from electronic medical records. Estimated glomerular filtration rate (eGFR) and increased urinary albumin excretion were considered. RESULTS: Mean age of the patients was 46 ± 16 years, 55.0% were males, and duration of diabetes 19 ± 13 years. The frequency of diabetic kidney disease, low eGFR, and albuminuria was 23.5%, 8.1%, and 19.5%, respectively. In the multivariate analysis the presence of diabetic kidney disease was associated with age (odds ratio [OR] = 1.14, 95% confidence interval [CI]: 1.10-1.18), duration of diabetes (OR = 1.05, 95% CI: 1.03-1.07), and worse glycemic control (OR = 1.24, 95% CI: 1.21-1.28, for every 1% glycated hemoglobin increase). Diabetic kidney disease was also independently associated with an atherogenic lipid profile and increased systolic blood pressure. Glucose control, systolic blood pressure, triglycerides, and high density lipoprotein cholesterol were associated with both low eGFR and albuminuria. Male gender, retinopathy and smoke were related to albuminuria, being female was related to low eGFR, while SUA levels were associated with DKD, low eGFR and albuminuria. CONCLUSIONS: In our sample of patients with type 1 diabetes, diabetic kidney disease entails an unsafe cardiovascular risk profile. Hyperglycemia, arterial hypertension, and atherogenic lipid profile affected both low eGFR and albuminuria. Retinopathy and smoking were related only to albuminuria while being female and elevated serum uric acid were associated only with low eGFR.

Variability in HbA1c, blood pressure, lipid parameters and serum uric acid, and risk of development of chronic kidney disease in type 2 diabetes.

AIM: Variability in HbA1c and blood pressure is associated with the risk of diabetic kidney disease (DKD). No evidence exists on the role of variability in lipids or serum uric acid (UA), or the interplay between the variability of different parameters, in renal outcomes. METHODS: Within the AMD Annals database, we identified patients with ≥5 measurements of HbA1c, systolic blood pressure (SBP) and diastolic blood pressure (DBP), total-, high-density lipoprotein (HDL)- and low-density lipoprotein (LDL)-cholesterol, triglycerides, and UA. Patients were followed-up for up to 5 years. The impact of measures of variability on the risk of DKD was investigated by Cox regression analysis and recursive partitioning techniques. RESULTS: Four-thousand, two-hundred and thirty-one patients were evaluated for development of albuminuria, and 7560 for decreased estimated glomerular filtration rate (eGFR; <60 mL/min/1.73 m2 ). A significantly higher risk of developing albuminuria was associated with variability in HbA1c [upper quartile hazard ratio (HR) = 1.3; 95% confidence interval (CI) 1.1-1.6]. Variability in SBP, DBP, HDL-C, LDL-C and UA predicted the decline in eGFR, the association with UA variability being particularly strong (upper quartile HR = 1.8; 95% CI 1.3-2.4). The concomitance of high variability in HbA1c and HDL-C conferred the highest risk of developing albuminuria (HR = 1.47; 95% CI 1.17-1.84), while a high variability in UA (HR = 1.54; 95% CI 1.19-1.99) or DBP (HR = 1.47; 95% CI 1.11-1.94) conferred the highest risk of decline in eGFR. CONCLUSION: The variability of several parameters influences the development of DKD, having a different impact on albuminuria development and on the decline in GFR.

Glucose targets for preventing diabetic kidney disease and its progression.

BACKGROUND: Diabetes is the leading cause of end-stage kidney disease (ESKD) around the world. Blood pressure lowering and glucose control are used to reduce diabetes-associated disability including kidney failure. However there is a lack of an overall evidence summary of the optimal target range for blood glucose control to prevent kidney failure. OBJECTIVES: To evaluate the benefits and harms of intensive (HbA1c < 7% or fasting glucose levels < 120 mg/dL versus standard glycaemic control (HbA1c ≥ 7% or fasting glucose levels ≥ 120 mg/dL for preventing the onset and progression of kidney disease among adults with diabetes. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Specialised Register up to 31 March 2017 through contact with the Information Specialist using search terms relevant to this review. Studies contained in the Specialised Register are identified through search strategies specifically designed for CENTRAL, MEDLINE, and EMBASE; handsearching conference proceedings; and searching the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: Randomised controlled trials evaluating glucose-lowering interventions in which people (aged 14 year or older) with type 1 or 2 diabetes with and without kidney disease were randomly allocated to tight glucose control or less stringent blood glucose targets. DATA COLLECTION AND ANALYSIS: Two authors independently assessed studies for eligibility and risks of bias, extracted data and checked the processes for accuracy. Outcomes were mortality, cardiovascular complications, doubling of serum creatinine (SCr), ESKD and proteinuria. Confidence in the evidence was assessing using GRADE. Summary estimates of effect were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes, and mean difference (MD) and 95% CI for continuous outcomes. MAIN RESULTS: Fourteen studies involving 29,319 people with diabetes were included and 11 studies involving 29,141 people were included in our meta-analyses. Treatment duration was 56.7 months on average (range 6 months to 10 years). Studies included people with a range of kidney function. Incomplete reporting of key methodological details resulted in uncertain risks of bias in many studies. Using GRADE assessment, we had moderate confidence in the effects of glucose lowering strategies on ESKD, all-cause mortality, myocardial infarction, and progressive protein leakage by kidney disease and low or very low confidence in effects of treatment on death related to cardiovascular complications and doubling of serum creatinine (SCr).For the primary outcomes, tight glycaemic control may make little or no difference to doubling of SCr compared with standard control (4 studies, 26,874 participants: RR 0.84, 95% CI 0.64 to 1.11; I2= 73%, low certainty evidence), development of ESKD (4 studies, 23,332 participants: RR 0.62, 95% CI 0.34 to 1.12; I2= 52%; low certainty evidence), all-cause mortality (9 studies, 29,094 participants: RR 0.99, 95% CI 0.86 to 1.13; I2= 50%; moderate certainty evidence), cardiovascular mortality (6 studies, 23,673 participants: RR 1.19, 95% CI 0.73 to 1.92; I2= 85%; low certainty evidence), or sudden death (4 studies, 5913 participants: RR 0.82, 95% CI 0.26 to 2.57; I2= 85%; very low certainty evidence). People who received treatment to achieve tighter glycaemic control probably experienced lower risks of non-fatal myocardial infarction (5 studies, 25,596 participants: RR 0.82, 95% CI 0.67 to 0.99; I2= 46%, moderate certainty evidence), onset of microalbuminuria (4 studies, 19,846 participants: RR 0.82, 95% CI 0.71 to 0.93; I2= 61%, moderate certainty evidence), and progression of microalbuminuria (5 studies, 13,266 participants: RR 0.59, 95% CI 0.38 to 0.93; I2= 75%, moderate certainty evidence). In absolute terms, tight versus standard glucose control treatment in 1,000 adults would lead to between zero and two people avoiding non-fatal myocardial infarction, while seven adults would avoid experiencing new-onset albuminuria and two would avoid worsening albuminuria. AUTHORS' CONCLUSIONS: This review suggests that people who receive intensive glycaemic control for treatment of diabetes had comparable risks of kidney failure, death and major cardiovascular events as people who received less stringent blood glucose control, while experiencing small clinical benefits on the onset and progression of microalbuminuria and myocardial infarction. The adverse effects of glycaemic management are uncertain. Based on absolute treatment effects, the clinical impact of targeting an HbA1c < 7% or blood glucose < 6.6 mmol/L is unclear and the potential harms of this treatment approach are largely unmeasured.

Achievement of therapeutic targets in patients with diabetes and chronic kidney disease: insights from the Associazione Medici Diabetologi Annals initiative.

BACKGROUND: Chronic kidney disease (CKD) entails a worse cardiovascular outcome. The aim of our work was to study the relationship between CKD and the achievement of recommended targets for glycated haemoglobin (HbA1c), low-density lipoprotein cholesterol (LDL-c) and blood pressure (BP) in a real-life sample of patients with type 2 diabetes mellitus (T2DM). METHODS: We analysed a sample of 116 777 outpatients from the Network of the Italian Association of Clinical Diabetologists; all patients had T2DM and at least one measurement of HbA1c, LDL-c, BP, serum creatinine and albuminuria in the year 2010. The outcome was the achievement of HbA1c, LDL-c and BP values as recommended by International Guidelines. RESULTS: In the entire sample, the mean value of HbA1c was 7.2 ± 1.2%, of LDL-c was 102 ± 33 mg/dL and of BP was 138/78 ± 19/9 mmHg. CKD and its components were associated with poor glycaemic and BP control, notwithstanding greater use of glucose and BP-lowering drugs, while no association was found with LDL-c values. Factors independently related to unsatisfactory glycaemic control included female gender, body mass index, duration of disease and high albuminuria. Men, older people and those taking statins were more likely to reach LDL-c target levels. Male gender, age and high albuminuria strongly affected the achievement of BP targets. CONCLUSIONS: CKD or its components, mainly high albuminuria, are associated with failure to reach therapeutic targets, especially for HbA1c and BP, despite a greater use of drugs in patients with T2DM.

Management of type 2 diabetes in geriatric patients.

The International Diabetes Federation (IDF) indicates age above 45 years as a major risk factor for diabetes and predicts that the number of persons with the disease, which currently stands at 190 million, will double by the year 2025. Several recent trials suggest that tighter glucose control reduces long-term complications in diabetic patients; however, outcomes of tight blood sugar control in the elderly are not known. Nevertheless, the principles of management of type 2 diabetes in the elderly are not different from those in middle-aged patients. There are several reasons to keep glucose control on target, also in the elderly; nonetheless, it should be considered that the risk of hypoglycemia is more deleterious in the elderly and should be avoided. The old and more recent oral glucose-lowering agents, along with the newer types of insulin, will be discussed in this review.

Overall Quality of Care Predicts the Variability of Key Risk Factors for Complications in Type 2 Diabetes: An Observational, Longitudinal Retrospective Study.

OBJECTIVE: An association between variability in clinical parameters (HbA1c, blood pressure, cholesterol, and uric acid) and risk of complications in type 2 diabetes has been reported. In this analysis, we investigated to what extent such variability is associated with overall quality of care. RESEARCH DESIGN AND METHODS: The quality of care summary score (Q-score) represents a validated, overall quality of care indicator ranging between 0 and 40; the higher the score, the better the quality of care provided by the diabetes center. We identified patients with five or more measurements of clinical parameters after the assessment of the Q-score. Multiple linear regression analyses assessed the role of the Q-score in predicting the variability of the different parameters. RESULTS: Overall, 273,888 patients were analyzed. The variability of all the parameters systematically increased with decreasing Q-score values. At multivariate linear regression analysis, compared with a Q-score >25, a score <15 was associated with a significantly larger variation in HbA1c, blood pressure, uric acid, total cholesterol, and LDL cholesterol and a lower variation in HDL cholesterol. The analysis of standardized ß coefficients show that the Q-score has a larger impact on the variability of HbA1c (0.34; P < 0.0001), systolic blood pressure (0.21; P < 0.0001), total cholesterol (0.21; P < 0.0001), and LDL cholesterol (0.20; P < 0.0001). CONCLUSIONS: The variability of risk factors for diabetic complications is associated with quality of care. Quality of care improvement initiatives should be targeted to increase the achievement of the recommended target while reducing such variability.

On the non-linear association between serum uric acid levels and all-cause mortality rate in patients with type 2 diabetes mellitus.

BACKGROUND AND AIMS: High levels of serum uric acid (SUA) are associated with increased mortality risk in the general population. Contrasting results are available in people with diabetes. The aim of our study was to investigate the association and its functional form between SUA and all cause-mortality in patients with type 2 diabetes mellitus (T2DM). METHODS: We studied three cohorts of patients with T2DM: Gargano Mortality Study, Foggia Mortality Study, Pisa Mortality Study. All-cause mortality rate was the end point of this study. RESULTS: The most reliable relationship between SUA levels and all-cause mortality rate was quadratic, with such model being well approximated by SUA tertiles. Both tertiles 1 and 3 were at higher risk of mortality as compared to tertile 2: Hazard Ratio (HR) [95% Confidence Interval (CI)] = 1.34 (1.07-1.68) and 1.61 (1.29-1.99), respectively. In the pseudo-sample, created from the real pooled sample, the best relationship between SUA and all-cause mortality rate was quadratic. In a tree-based Recursive Partitioning and Regression Tree analysis two subgroups at increased risk of mortality were identified, namely those with SUA levels ≥7.28 mg/dl and with SUA levels <4.16 mg/dl as compared to patients with intermediate SUA levels (i.e. 4.16-7.28), thus providing further evidence on the J-shaped relationship between SUA levels and mortality rate. CONCLUSIONS: SUA was not linearly associated with all-cause mortality rate in patients with T2DM. For clinical and public health purposes such association is J-shaped.

Predictors of chronic kidney disease in type 2 diabetes: A longitudinal study from the AMD Annals initiative.

UNLABELLED: The identification of clinical predictors for the development of chronic kidney disease is a critical issue in the management of patients with type 2 diabetes mellitus.We evaluated 27,029 patients with type 2 diabetes mellitus and estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m and normoalbuminuria from the database of the Italian Association of Clinical Diabetologists network. Primary outcomes were eGFR <60 mL/min/1.73 m and normoalbuminuria; albuminuria and eGFR ≥60 mL/min/1.73 m; and eGFR <60 mL/min/1.73 m and albuminuria. Secondary outcomes were eGFR <60 mL/min/1.73 m and albuminuria. MEASUREMENTS: eGFR from serum creatinine by chronic kidney disease epidemiology collaboration equation (CKD-EPI), urinary albumin excretion, HbA1c, triglycerides, high-density lipoprotein cholesterol (HDL-c) and low-density lipoprotein cholesterol (LDL-c), blood pressure, and body mass index.Over a 4-year period, 33.2% of patients (n = 8973) developed chronic kidney disease, 10.3% (n = 2788) showed a decline in eGFR <60 mL/min/1.73 m, 18.4% (n = 4978) developed albuminuria, and 4.5% (n = 1207) developed both features. Relative risk ratios (RRRs) for age (1.37, P < 0.001 by 5 years), sex (0.77, P < 0.001 for being male), body mass index (1.03, P < 0.001 by 1 kg/m), triglycerides (1.02, P < 0.001 by 10 mg/dL), and LDL-c (0.97, P = 0.004 by 10 mg/dL) were independently related to the onset of eGFR reduction. Age (1.08, P < 0.001 by 5 years), sex (1.36, P < 0.001 for being male), body mass index (1.02, P < 0.001 by 1 kg/m), triglycerides (1.01, P = 0.02 by 10 mg/dL), HDL-c, and LDL-c (0.97, P = 0.008 and 0.99, P = 0.003 by 5 and 10 mg/dL, respectively) were related to the onset of albuminuria. HbA1c and the intensity of antihypertensive treatment showed a weaker association with renal outcome.Reduction in eGFR and albuminuria showed distinct sets of risk factors, suggesting that different mechanisms are involved in the development of these 2 components of diabetic kidney disease.

Plasma Triglycerides and HDL-C Levels Predict the Development of Diabetic Kidney Disease in Subjects With Type 2 Diabetes: The AMD Annals Initiative.

OBJECTIVE: Despite the achievement of blood glucose, blood pressure, and LDL cholesterol (LDL-C) targets, the risk for diabetic kidney disease (DKD) remains high among patients with type 2 diabetes. This observational retrospective study investigated whether diabetic dyslipidemia-that is, high triglyceride (TG) and/or low HDL cholesterol (HDL-C) levels-contributes to this high residual risk for DKD. RESEARCH DESIGN AND METHODS: Among a total of 47,177 patients attending Italian diabetes centers, 15,362 patients with a baseline estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2, normoalbuminuria, and LDL-C ≤130 mg/dL completing a 4-year follow-up were analyzed. The primary outcome was the incidence of DKD, defined as either low eGFR (<60 mL/min/1.73 m2) or an eGFR reduction >30% and/or albuminuria. RESULTS: Overall, 12.8% developed low eGFR, 7.6% an eGFR reduction >30%, 23.2% albuminuria, and 4% albuminuria and either eGFR <60 mL/min/1.73 m2 or an eGFR reduction >30%. TG ≥150 mg/dL increased the risk of low eGFR by 26%, of an eGFR reduction >30% by 29%, of albuminuria by 19%, and of developing one abnormality by 35%. HDL-C <40 mg/dL in men and <50 mg/dL in women were associated with a 27% higher risk of low eGFR and a 28% risk of an eGFR reduction >30%, with a 24% higher risk of developing albuminuria and a 44% risk of developing one abnormality. These associations remained significant when TG and HDL-C concentrations were examined as continuous variables and were only attenuated by multivariate adjustment for numerous confounders. CONCLUSIONS: In a large population of outpatients with diabetes, low HDL-C and high TG levels were independent risk factors for the development of DKD over 4 years.

The PPARγ2 P12A polymorphism is not associated with all-cause mortality in patients with type 2 diabetes mellitus.

The high mortality risk of patients with type 2 diabetes mellitus may well be explained by the several comorbidities and/or complications. Also the intrinsic genetic component predisposing to diabetes might have a role in shaping the risk of diabetes-related mortality. Among type 2 diabetes mellitus SNPs, rs1801282 is of particular interest because (i) it is harbored by peroxisome proliferator-activated receptor-γ2 (PPARγ2), which is the target for thiazolidinediones which are used as antidiabetic drugs, decreasing all-cause mortality in type 2 diabetes mellitus, and (ii) it is associated with insulin resistance and related traits, risk factors for overall mortality in type 2 diabetes mellitus. We investigated the role of PPARγ2 P12A, according to a dominant model (PA + AA vs. PP individuals) on incident all-cause mortality in three cohorts of type 2 diabetes mellitus, comprising a total of 1672 patients (462 deaths) and then performed a meta-analysis of ours and all available published data. In the three cohorts pooled and analyzed together, no association between PPARγ2 P12A and all-cause mortality was observed (HR 1.02, 95 % CI 0.79-1.33). Similar results were observed after adjusting for age, sex, smoking habits, and BMI (HR 1.09, 95 % CI 0.83-1.43). In a meta-analysis of ours and all studies previously published (n = 3241 individuals; 666 events), no association was observed between PPARγ2 P12A and all-cause mortality (HR 1.07, 95 % CI 0.85-1.33). Results from our individual samples as well as from our meta-analysis suggest that the PPARγ2 P12A does not significantly affect all-cause mortality in patients with type 2 diabetes mellitus.

Target values of cardiovascular risk factors are not associated with all-cause mortality in patients with type 2 diabetes mellitus.

BACKGROUND: To investigate prospectively the relationship between target values of glycated hemoglobin, blood pressure and LDL-cholesterol, as considered in a combined fashion, and all-cause mortality in patients with type 2 diabetes mellitus. METHODS: Two cohorts of patients with type 2 diabetes mellitus, the Gargano Mortality Study (n=810) and the Foggia Mortality Study (n=929), were investigated. A weighted target risk score was built as a weight linear combination of the recommended targets reached by each patient. RESULTS: In the Gargano Mortality Study and in the Foggia Mortality Study (mean follow up=7.4 and 5.5 years, respectively), 161 (19.9%) and 220 (23.7%) patients died, with an age and sex adjusted annual incidence rate of 2.1 and 2.8 per 100 person-years, respectively. In both study samples the weighted target risk score tended to be linearly associated with all-cause mortality (HR for one point increment=1.30, 95% CI: 1.11-1.53, p=0.001, and HR=1.08, 95% CI: 0.95-1.24, p=0.243, respectively). When the two cohorts were pooled and analyzed together, a clear association between weighted target risk score and all-cause mortality was observed (HR for one point increment=1.17, 95% CI:1.05-1.30, p=0.004). This counterintuitive association was no longer observable in a model including age, sex, body mass index, smoking habit, estimated glomerular filtration rate, albuminuria and anti-diabetic, anti-hypertensive and anti-dyslipidemic treatment as covariates (HR for one point increment=0.99, 95% CI: 0.87-1.12, p=0.852). CONCLUSIONS: In a real life clinical set of patients with type 2 diabetes mellitus, the combination of recommended target values of established cardiovascular risk factors is not associated with all-cause mortality.

Serum Uric Acid and Risk of CKD in Type 2 Diabetes.

BACKGROUND AND OBJECTIVE: Serum uric acid may predict the onset and progression of kidney disease, but it is unclear whether uric acid is an independent risk factor for diabetic nephropathy. Our aim was to study the relationship between uric acid levels and the development of CKD components in patients with type 2 diabetes. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Longitudinal study of a cohort of patients with type 2 diabetes from the database of the Italian Association of Clinical Diabetologists network. From a total of 62,830 patients attending the diabetes centers between January 1, 2004, and June 30, 2008, we considered those with baseline eGFR values ≥60 ml/min per 1.73 m2 and normal albumin excretion (n=20,142). Urinary albumin excretion, GFR, and serum uric acid were available in 13,964 patients. We assessed the association of serum uric acid quintiles with onset of CKD components by multinomial logistic regression model adjusting for potential confounders. We calculated the relative risk ratios (RRRs) for eGFR <60 ml/min per 1.73 m2, albuminuria, and their combination at 4 years. RESULTS: At 4-year follow-up, 1109 (7.9%) patients developed GFR <60 ml/min per 1.73 m2 with normoalbuminuria, 1968 (14.1%) had albuminuria with eGFR ≥60 ml/min per 1.73 m2, and 286 (2.0%) had albuminuria with eGFR <60 ml/min per 1.73 m2. The incidence of eGFR <60 ml/min per 1.73 m2 increased in parallel with uric acid quintiles: Compared with the lowest quintile, RRRs were 1.46 (95% confidence interval [CI], 1.14 to 1.88; P=0.003), 1.44 (95% CI, 1.11 to 1.87; P=0.006), 1.95 (95% CI, 1.48 to 2.58; P<0.001), and 2.61 (95% CI, 1.98 to 3.42; P<0.001) for second, third, fourth, and fifth quintiles, respectively. Serum uric acid was significantly associated with albuminuria only in presence of eGFR <60 ml/min per 1.73 m2. CONCLUSIONS: Mild hyperuricemia is strongly associated with the risk of CKD in patients with type 2 diabetes.

Role of relationship between HbA1c, fibrinogen and HDL-cholesterol on cardiovascular disease in patients with type 2 diabetes mellitus.

OBJECTIVE: To assess the impact of relationship between glycated hemoglobin (HbA(1c)), fibrinogen and HDL-cholesterol (HDL-c) on cardiovascular disease in type 2 diabetes. METHODS: We investigated i) the relationship of HbA1c, fibrinogen and HDL-c in 375 coronary artery disease (CAD)-negative and 320 CAD-positive diabetic patients and ii) the association between clustering of these three factors and incident major cardiovascular events in 317/320 CAD-positive patients. RESULTS: i) The relationships between HbA1c and both fibrinogen and HDL-c and between HDL-c and fibrinogen were significant only in CAD-positive patients (ß = 10.655, p = 0.002; ß = -1.056, p = 0.013; ß = -1.751, p = 0.000008, respectively); ii) patients with worse-than-median levels of the three factors showed higher risk for major cardiovascular events than others (HR: 2.22, 95%CI = 1.23-4.02, p = 0.008). Both findings were independent of LDL-c, blood pressure or ongoing therapies. CONCLUSION: Our findings suggest interwoven actions of poor glycemic control, low grade inflammation and low HDL-c on atherosclerotic processes in type 2 diabetes.

Development and validation of a predicting model of all-cause mortality in patients with type 2 diabetes.

OBJECTIVE: To develop and validate a parsimonious model for predicting short-term all-cause mortality in patients with type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS: Two cohorts of patients with T2DM were investigated. The Gargano Mortality Study (GMS, n = 679 patients) was the training set and the Foggia Mortality Study (FMS, n = 936 patients) represented the validation sample. GMS and FMS cohorts were prospectively followed up for 7.40 ± 2.15 and 4.51 ± 1.69 years, respectively, and all-cause mortality was registered. A new forward variable selection within a multivariate Cox regression was implemented. Starting from the empty model, each step selected the predictor that, once included into the multivariate Cox model, yielded the maximum continuous net reclassification improvement (cNRI). The selection procedure stopped when no further statistically significant cNRI increase was detected. RESULTS: Nine variables (age, BMI, diastolic blood pressure, LDL cholesterol, triglycerides, HDL cholesterol, urine albumin-to-creatinine ratio, and antihypertensive and insulin therapy) were included in the final predictive model with a C statistic of 0.88 (95% CI 0.82-0.94) in the GMS and 0.82 (0.76-0.87) in the FMS. Finally, we used a recursive partition and amalgamation algorithm to identify patients at intermediate and high mortality risk (hazard ratio 7.0 and 24.4, respectively, as compared with those at low risk). A web-based risk calculator was also developed. CONCLUSIONS: We developed and validated a parsimonious all-cause mortality equation in T2DM, providing also a user-friendly web-based risk calculator. Our model may help prioritize the use of available resources for targeting aggressive preventive and treatment strategies in a subset of very high-risk individuals.

The ENPP1 Q121 variant predicts major cardiovascular events in high-risk individuals: evidence for interaction with obesity in diabetic patients.

OBJECTIVE: Insulin resistance (IR) and cardiovascular disease may share a common genetic background. We investigated the role of IR-associated ENPP1 K121Q polymorphism (rs1044498) on cardiovascular disease in high-risk individuals. RESEARCH DESIGN AND METHODS: A prospective study (average follow-up, 37 months) was conducted for major cardiovascular events (myocardial infarction [MI], stroke, cardiovascular death) from the Gargano Heart Study (GHS; n = 330 with type 2 diabetes and coronary artery disease), the Tor Vergata Atherosclerosis Study (TVAS; n = 141 who had MI), and the Cardiovascular Risk Extended Evaluation in Dialysis (CREED) database (n = 266 with end-stage renal disease). Age at MI was investigated in cross-sectional studies of 339 type 2 diabetic patients (n = 169 from Italy, n = 170 from the U.S.). RESULTS: Incidence of cardiovascular events per 100 person--years was 4.2 in GHS, 10.8 in TVAS, and 11.7 in CREED. Hazard ratios (HRs) for KQ+QQ versus individuals carrying the K121/K121 genotype (KK) individuals were 1.47 (95% CI 0.80-2.70) in GHS, 2.31 (95% CI 1.22-4.34) in TVAS, and 1.36 (95% CI 0.88-2.10) in CREED, and 1.56 (95% CI 1.15-2.12) in the three cohorts combined. In the 395 diabetic patients, the Q121 variant predicted cardiovascular events among obese but not among nonobese individuals (HR 5.94 vs. 0.62, P = 0.003 for interaction). A similar synergism was observed in cross-sectional studies, with age at MI being 3 years younger in Q121 carriers than in KK homozygotes among obese but not among nonobese patients (P = 0.035 for interaction). CONCLUSIONS: The ENPP1 K121Q polymorphism is an independent predictor of major cardiovascular events in high-risk individuals. In type 2 diabetes, this effect is exacerbated by obesity. Future larger studies are needed to confirm our finding.