Kamel Mohammedi

Cause-specific mortality in diabetes: recent changes in trend mortality

Diabetes is one of the most chronic diseases in Western populations. Mortality rates in diabetic patients are higher than in the general population and their prognosis following any cardiovascular event is generally worse. Type 1 diabetic patients’ acute complications-related mortality decreases with time and the interval free from the diagnosis of diabetes until the development of chronic complications is larger although global mortality is still higher than that of sex- and age-matched healthy individuals. As a consequence of better primary and secondary preventions, recent data in the general population show that there is a trend towards decreased cardiovascular events and increased life expectancy. The same thing applies for type 2 diabetic patients. However, increased survival in the general population associated to epidemic bursts of obesity and sedentarily all over the globe, leads to a higher incidence of type 2 diabetes worldwide. This counteracts the diminution of diabetes-related mortality that would move forward on an ascending slope in the next decades.

Plasma Copeptin and Renal Outcomes in Patients With Type 2 Diabetes and Albuminuria

OBJECTIVE Plasma copeptin, a surrogate for vasopressin, was associated with albuminuria in population-based studies. These associations are consistent with the effect of vasopressin on albuminuria observed in humans and rodents. The objective of this study was to determine whether plasma copeptin is an independent marker of risk of renal events in people with type 2 diabetes and albuminuria. RESEARCH DESIGN AND METHODS We studied 3,101 participants of the DIABHYCAR trial (6-year follow-up) with type 2 diabetes and albuminuria. A renal event was defined as doubling of serum creatinine or development of end-stage renal disease. RESULTS During follow-up, 86 renal events occurred in 76 subjects (2.45%). Incidences by tertiles of baseline plasma copeptin were 1.06% (T1), 1.45% (T2), and 4.84% (T3). They were 2.43% (T1), 5.11% (T2), and 11.81% (T3) for the subset of subjects with macroalbuminuria at baseline (n = 729). Hazard ratio for plasma copeptin tertiles as a risk for renal events was 4.79 (95% CI, 2.48–9.24; P < 0.0001; for T3 vs. T1). In a stepwise regression analysis, urinary albumin excretion and plasma copeptin remained positively associated and HDL cholesterol and estimated glomerular filtration rate were inversely associated with the incidence of renal events. These independent predictors explained ∼18% of the variance of the outcome. The yearly variations of estimated glomerular filtration rate by copeptin tertiles were −1.43 ± 0.51 (T1), −2.29 ± 0.49 (T2), and −3.52 ± 0.44 mL/min/1.73 m2 per year (T3) (P = 0.005) in subjects with macroalbuminuria. CONCLUSIONS Plasma copeptin may help to identify subjects with diabetic chronic kidney disease who are at high risk for renal function decline.

Relationships between common polymorphisms of adenosine triphosphate–binding cassette transporter A1 and high-density lipoprotein cholesterol and coronary heart disease in a population with type 2 diabetes mellitus

Patients with type 2 diabetes mellitus (T2D) have a high coronary risk partly because of low levels of high-density lipoprotein-cholesterol (HDL-C). The adenosine triphosphate-binding cassette transporter A1 (ABCA1) plays a key role in HDL metabolism. We studied the association of common single nucleotide polymorphisms (SNPs) in the ABCA1 gene with HDL-C levels and coronary risk in a cohort of subjects with T2D. We studied 5 SNPs: +69C>T, +378G>C, R219K, I883M, and R1587K. The C allele of +378G>C was significantly associated with lower HDL-C concentrations (P = .04); and the M allele of I883M, with higher HDL-C concentrations (P = .03). No significant association was found between these SNPs and the incidence of new coronary events. Nevertheless, cross-sectional data on entry showed that the frequency of K219 was lower in patients with previous coronary heart disease (angina pectoris and/or myocardial infarction) (odds ratio, OR [95% confidence interval, CI] = 0.80 [0.65-0.98], P = .03, after adjustment for multiple risk factors other than HDL-C). The frequency of K1587 was higher in patients with angina pectoris (OR [95% CI] = 1.27 [1.01-1.58], P = .04, after multiple adjustment). The TT genotype of the C69T SNP was less frequent in subjects with prior myocardial infarction (OR [95% CI] = 0.28 [0.13-0.61], P = .001, after multiple adjustment). These associations persisted after further adjustment for HDL-C levels. In conclusion, common genetic variations of ABCA1 had a moderate influence on HDL-C levels and/or coronary heart disease in patients with T2D. These 2 effects were independent.

Allelic variations in superoxide dismutase-1 (SOD1) gene are associated with increased risk of diabetic nephropathy in type 1 diabetic subjects

BACKGROUND Oxidative stress is involved in the pathophysiology of diabetic nephropathy. The superoxide dismutase (SOD) enzymes play a major role in detoxification of reactive oxygen species and have a protective effect against diabetic nephropathy. We investigated associations of allelic variations in SOD1 gene with nephropathy in patients with type 1 diabetes. METHODS Seven SNPs in SOD1 region were analyzed in 1285 type 1 European Caucasian diabetic patients from the SURGENE prospective study (n=340; ten year follow-up), and the Genesis France-Belgium (n=501) and GENEDIAB (n=444) cross-sectional studies. Cox proportional hazards and logistic regression analyses were used to estimate hazard ratios or odds ratios for incidence and prevalence of diabetic nephropathy. RESULTS In the SURGENE study, the T-allele of rs1041740 was associated with the prevalence of incipient (OR 5.75, 95% CI 1.78-19.39, p=0.004) and established/advanced nephropathy at baseline (OR 8.95, 95% CI 1.51-58.42, p=0.02), and with the incidence of incipient nephropathy during follow-up (HR 1.46, 95% C.I. 1.13-1.90, p=0.004). The variant was also associated with decreased estimated glomerular filtration rate (eGFR) throughout the study. In cross-sectional study of Genesis/GENEDIAB cohorts, the G-allele of rs17880135 was associated with incipient (OR 7.53, 95% CI 2.30-25.45, p=0.001), established (OR 6.04, 95% CI 1.52-23.91, p=0.01) and advanced nephropathy (OR 10.03, 95% CI 2.95-35.44, p=0.0003). CONCLUSIONS SOD1 allelic variations were associated with the prevalence of diabetic nephropathy, with the incidence of microalbuminuria and with decreased eGFR in type 1 diabetic subjects. These results are consistent with an implication of oxidative stress in the pathophysiology of diabetic nephropathy and with the major role for antioxidant enzymes as a mechanism of renal protection.

Plasma Copeptin, AVP Gene Variants, and Incidence of Type 2 Diabetes in a Cohort From the Community

CONTEXT Experimental data support a role for vasopressin in metabolic disorders. OBJECTIVE We investigated associations of plasma copeptin, a surrogate of vasopressin, and of allelic variations in the arginine vasopressin-neurophysin II gene with insulin secretion, insulin sensitivity, and the risk for impaired fasting glucose (IFG) and type 2 diabetes mellitus (T2DM). DESIGN, SETTING, AND PARTICIPANTS We studied 5110 unrelated French men and women from a prospective cohort of the general population (Data from Epidemiological Study on the Insulin Resistance Syndrome cohort, 9-y follow-up). Six single nucleotide polymorphisms were genotyped. MAIN OUTCOME MEASURE Incidence of IFG or T2DM during follow-up. RESULTS The incidence of hyperglycemia (IFG/T2DM) during follow-up by quartiles of baseline plasma copeptin was 11.0% (Q1), 14.5% (Q2), 17.0% (Q3), and 23.5% (Q4), log-rank test P = .003. Participants in the upper quartile of plasma copeptin had significantly lower insulin sensitivity (homeostasis model assessment index) at baseline and during follow-up, as compared with other participants. Cox proportional hazards regression analyses showed significant associations of the CC genotype of rs6084264, the TT genotype of rs2282018, the C-allele of rs2770381, and the CC genotype of rs1410713 with the incidence of hyperglycemia. The genotypes associated with an increased risk of hyperglycemia were also associated with increased plasma copeptin in men but not in women. CONCLUSIONS High plasma copeptin was associated with reduced insulin sensitivity and an increased risk for IFG/T2DM diabetes in this community-based cohort. Moreover, in men, allelic associations support a causal role for vasopressin in these disorders.

ALLELIC VARIATIONS IN SUPEROXIDE DISMUTASE-1 (SOD1) GENE AND RENAL AND CARDIOVASCULAR MORBIDITY AND MORTALITY IN TYPE 2 DIABETIC SUBJECTS

BACKGROUND Oxidative stress is involved in the pathophysiology of renal and cardiovascular complications of diabetes. Superoxide dismutase (SOD) enzymes play a major role in detoxification of reactive oxygen species and protection against oxidative stress. Associations of SOD1 gene variants with diabetic nephropathy were reported in patients with type 1 diabetes. We investigated associations of allelic variations in SOD1 gene with nephropathy and cardiovascular complications in patients with type 2 diabetes. METHODS Seven SNPs in SOD1 region were analyzed in 3744 type 2 European Caucasian diabetic patients from the DIABHYCAR (a 6-year prospective study) and DIABHYCAR_GENE cohorts. Odds ratios or hazard ratios for prevalence and incidence of diabetic nephropathy and cardiovascular events were estimated. RESULTS We observed an association of rs1041740 with the prevalence of microalbuminuria at baseline (OR 1.51, 95% CI 1.10-2.10, p=0.01). No association with the incidence of renal events (doubling of the serum creatinine levels or the requirement of hemodialysis or renal transplantation) or cardiovascular events (myocardial infarction or stroke) was observed during follow-up. However, three variants were associated with increased risk of death from cardiovascular causes (sudden death, fatal myocardial infarction or stroke) during the follow-up: rs9974610 (HR 0.64, 95% CI 0.46-0.88, p=0.005), rs10432782 (HR 1.71, 95% CI 1.16-2.48, p=0.007) and rs1041740 (HR 1.78, 95% CI 1.10-2.78, p=0.02). CONCLUSIONS Our results are consistent with a major role for SOD1 in the mechanisms of cardiovascular protection against oxidative stress in type 2 diabetic subjects.

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

OBJECTIVE 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. RESEARCH DESIGN AND METHODS 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. RESULTS 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). CONCLUSIONS Microvascular disease, particularly macroalbuminuria and retinal photocoagulation therapy, strongly predicts major PAD in patients with type 2 diabetes, but macrovascular disease does not.

Associations of the −344 T>C and the 3097 G>A Polymorphisms of CYP11B2 Gene With Hypertension, Type 2 Diabetes, and Metabolic Syndrome in a French Population

BACKGROUND Aldosterone can affect both blood pressure (BP) and glucose metabolism. We assessed the association of two polymorphisms -344 T>C and the 3097 G>A in the aldosterone synthase gene (CYP11B2) with prevalent and incident hypertension (HT), type 2 diabetes (T2D), and the metabolic syndrome (MetS). METHODS We studied the 5,212 participants to D.E.S.I.R. (Data from Epidemiologic Study on the Insulin Resistance syndrome), a cohort from French general population. Genotyping was done by a TaqMan assay. Analysis of covariance, multivariate logistic regression (adjusted for age, MetS components) and haplotype analysis were performed. RESULTS The prevalences and 9-year incidences were 16.7 and 36.1% for HT, 2.6 and 6.2% for T2D, and 19.3 and 25.1% for the MetS. Risk for incident HT was reduced with the AA genotype of 3097 G>A, adjusted odds ratios (OR): 0.67; p = 0.04. The prevalence of HT was lower in women carrying the C allele of -344 T>C, OR 0.75; p = 0.03 for the TC genotype and 0.69; p = 0.03 for the CC genotype. In men, incident T2D was associated with both polymorphisms, adjusted OR for -344 T>C: 1.63; p = 0.04 for TC genotype and 2.12; p = 0.008 for CC genotype; for the 3097 G>A: the AA genotype was associated with a lower risk, OR 0.23; p = 0.02. In men, incident MetS was associated with 3097 G>A, OR: 0.57; p = 0.02 for AA genotype. Significant associations between haplotype combinations and the prevalence or incidence of the three diseases were also found. CONCLUSION The -344 T>C and 3097 G>A polymorphisms in the CYP11B2 are associated with T2D, hypertension and the MetS in European subjects with gender variations.

A novel device for measuring arterial stiffness using finger-toe pulse wave velocity: Validation study of the pOpmètre®

BACKGROUND The finger-toe pathway could be a good alternative for assessing arterial stiffness conveniently. AIM To evaluate the accuracy of the pOpmètre®--a new device that measures finger-toe pulse wave velocity (ft-PWV). METHODS The pOpmètre has two photodiode sensors, positioned on the finger and the toe. Pulse waves are recorded continuously for 20 seconds, and the difference in pulse wave transit time between toe and finger (ft-TT) is calculated. The travelled distance is estimated using subject height. Study 1 compared ft-PWV with carotid-femoral PWV (cf-PWV) obtained by the reference method (SphygmoCor®) in 86 subjects (mean age 53±20 years), including 69 patients with various pathologies and 17 healthy normotensives. Study 2 compared changes in ft-PWV and cf-PWV during a cold pressor test in 10 healthy subjects. Study 3 assessed repeatability in 45 patients. RESULTS ft-PWV correlated significantly with cf-PWV (R2=0.43; P<0.0001). A better correlation was found in terms of transit time (R2=0.61; P<0.0001). The discrepancy between transit times was related to age. The cold pressor test induced parallel changes in cf-PWV and ft-PWV, with increased aortic stiffness that was reversible during recovery. Intra-session repeatability was very good, with a coefficient of variation of 4.52%. CONCLUSION The pOpmètre® allows measurement of arterial stiffness in routine clinical practice. The greatest advantages of ft-PWV are simplicity, rapidity, feasibility, acceptability by patients and correct agreement with the reference technique. Further studies are needed to adjust for bias and to validate the pOpmètre in larger populations.

Prevention of cardiovascular disease through reduction of glycaemic exposure in type 2 diabetes: A perspective on glucose-lowering interventions

Type 2 diabetes is a leading cause of cardiovascular disease (CVD). Observational studies have consistently shown an association between glycaemic level and risk of major adverse cardiovascular events (MACE); however, intervention studies have provided limited evidence supporting a reduction in the cardiovascular burden of diabetes through intensive glucose control. In the present review, we aimed to examine the concept of cumulative glycaemic exposure with regard to protection against CVD in diabetes. We address how we can move from a binary approach in trials, to a more quantitative approach based on differences in cumulative glycaemic exposure. We plotted the association between differing glycaemic exposures between study arms and the hazard ratio for MACE in randomized controls trials comparing intensive with conventional glycaemic control in type 2 diabetes. We found a strikingly strong correlation between differential exposure and cardiovascular risk reduction. Similar results were obtained for trials comparing antidiabetes drugs with placebo. The results suggest that a minimum study duration and a minimum gain in glycated haemoglobin (HbA1c) reduction are necessary to drive a relevant risk reduction in CVD risk, and we provide a quantitative perspective in that respect. The present analysis underlines that the duration of the intensification of glycemic control, and the amplitude of the resulting reduction in HbA1c, are important notions for clinical decision‐making.