Trond Jenssen

Effect of valsartan on the incidence of diabetes and cardiovascular events

BACKGROUND It is not known whether drugs that block the renin-angiotensin system reduce the risk of diabetes and cardiovascular events in patients with impaired glucose tolerance. METHODS In this double-blind, randomized clinical trial with a 2-by-2 factorial design, we assigned 9306 patients with impaired glucose tolerance and established cardiovascular disease or cardiovascular risk factors to receive valsartan (up to 160 mg daily) or placebo (and nateglinide or placebo) in addition to lifestyle modification. We then followed the patients for a median of 5.0 years for the development of diabetes (6.5 years for vital status). We studied the effects of valsartan on the occurrence of three coprimary outcomes: the development of diabetes; an extended composite outcome of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, hospitalization for heart failure, arterial revascularization, or hospitalization for unstable angina; and a core composite outcome that excluded unstable angina and revascularization. RESULTS The cumulative incidence of diabetes was 33.1% in the valsartan group, as compared with 36.8% in the placebo group (hazard ratio in the valsartan group, 0.86; 95% confidence interval [CI], 0.80 to 0.92; P<0.001). Valsartan, as compared with placebo, did not significantly reduce the incidence of either the extended cardiovascular outcome (14.5% vs. 14.8%; hazard ratio, 0.96; 95% CI, 0.86 to 1.07; P=0.43) or the core cardiovascular outcome (8.1% vs. 8.1%; hazard ratio, 0.99; 95% CI, 0.86 to 1.14; P=0.85). CONCLUSIONS Among patients with impaired glucose tolerance and cardiovascular disease or risk factors, the use of valsartan for 5 years, along with lifestyle modification, led to a relative reduction of 14% in the incidence of diabetes but did not reduce the rate of cardiovascular events. (ClinicalTrials.gov number, NCT00097786.)

Results of an international, randomized trial comparing glucose metabolism disorders and outcome with cyclosporine versus tacrolimus.

DIRECT (Diabetes Incidence after Renal Transplantation: Neoral C2 Monitoring Versus Tacrolimus) was a 6‐month, open‐label, randomized, multicenter study which used American Diabetes Association/World Health Organization criteria to define glucose abnormalities. De novo renal transplant patients were randomized to cyclosporine microemulsion (CsA‐ME, using C2 monitoring) or tacrolimus, with mycophenolic acid, steroids and basiliximab. The intent‐to‐treat population comprised 682 patients (336 CsA‐ME, 346 tacrolimus): 567 were nondiabetic at baseline. Demographics, diabetes risk factors and steroid doses were similar between treatment groups. The primary safety endpoint, new‐onset diabetes after transplant (NODAT) or impaired fasting glucose (IFG) at 6 months, occurred in 73 CsA‐ME patients (26.0%) and 96 tacrolimus patients (33.6%, p = 0.046). The primary efficacy endpoint, biopsy‐proven acute rejection, graft loss or death at 6 months, occurred in 43 CsA‐ME patients (12.8%) and 34 tacrolimus patients (9.8%, p = 0.211). Mean glomerular filtration rate (Cockcroft–Gault) was 63.6 ± 20.7 mL/min/1.73 m2 in the CsA‐ME cohort and 65.9 ± 23.1 mL/min/1.73 m2 with tacrolimus (p = 0.285); mean serum creatinine was 139 ± 58 and 133 ± 57 μmol/L, respectively (p = 0.005). Blood pressure was similar between treatment groups at month 6, but total cholesterol, LDL‐cholesterol and triglyceride levels were significantly higher with CsA than with tacrolimus (total cholesterol:HDL remained unchanged). The profile and incidence of adverse events were similar between treatments. The incidence of NODAT or IFG at 6 months post‐transplant is significantly lower with CsA‐ME than with tacrolimus without a significant difference in short‐term outcome.

Effect of nateglinide on the incidence of diabetes and cardiovascular events

BACKGROUND The ability of short-acting insulin secretagogues to reduce the risk of diabetes or cardiovascular events in people with impaired glucose tolerance is unknown. METHODS In a double-blind, randomized clinical trial, we assigned 9306 participants with impaired glucose tolerance and either cardiovascular disease or cardiovascular risk factors to receive nateglinide (up to 60 mg three times daily) or placebo, in a 2-by-2 factorial design with valsartan or placebo, in addition to participation in a lifestyle modification program. We followed the participants for a median of 5.0 years for incident diabetes (and a median of 6.5 years for vital status). We evaluated the effect of nateglinide on the occurrence of three coprimary outcomes: the development of diabetes; a core cardiovascular outcome that was a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure; and an extended cardiovascular outcome that was a composite of the individual components of the core composite cardiovascular outcome, hospitalization for unstable angina, or arterial revascularization. RESULTS After adjustment for multiple testing, nateglinide, as compared with placebo, did not significantly reduce the cumulative incidence of diabetes (36% and 34%, respectively; hazard ratio, 1.07; 95% confidence interval [CI], 1.00 to 1.15; P=0.05), the core composite cardiovascular outcome (7.9% and 8.3%, respectively; hazard ratio, 0.94, 95% CI, 0.82 to 1.09; P=0.43), or the extended composite cardiovascular outcome (14.2% and 15.2%, respectively; hazard ratio, 0.93, 95% CI, 0.83 to 1.03; P=0.16). Nateglinide did, however, increase the risk of hypoglycemia. CONCLUSIONS Among persons with impaired glucose tolerance and established cardiovascular disease or cardiovascular risk factors, assignment to nateglinide for 5 years did not reduce the incidence of diabetes or the coprimary composite cardiovascular outcomes. (ClinicalTrials.gov number, NCT00097786.)

Long-term risks for kidney donors

Previous studies have suggested that living kidney donors maintain long-term renal function and experience no increase in cardiovascular or all-cause mortality. However, most analyses have included control groups less healthy than the living donor population and have had relatively short follow-up periods. Here we compared long-term renal function and cardiovascular and all-cause mortality in living kidney donors compared with a control group of individuals who would have been eligible for donation. All-cause mortality, cardiovascular mortality, and end-stage renal disease (ESRD) was identified in 1901 individuals who donated a kidney during 1963 through 2007 with a median follow-up of 15.1 years. A control group of 32,621 potentially eligible kidney donors was selected, with a median follow-up of 24.9 years. Hazard ratio for all-cause death was significantly increased to 1.30 (95% confidence interval 1.11-1.52) for donors compared with controls. There was a significant corresponding increase in cardiovascular death to 1.40 (1.03-1.91), while the risk of ESRD was greatly and significantly increased to 11.38 (4.37-29.6). The overall incidence of ESRD among donors was 302 cases per million and might have been influenced by hereditary factors. Immunological renal disease was the cause of ESRD in the donors. Thus, kidney donors are at increased long-term risk for ESRD, cardiovascular, and all-cause mortality compared with a control group of non-donors who would have been eligible for donation.

Contribution of abnormal muscle and liver glucose metabolism to postprandial hyperglycemia in NIDDM.

To assess the role of muscle and liver in the pathogenesis of postprandial hyperglycemia in non-insulin-dependent diabetes mellitus (NIDDM), we administered an oral glucose load enriched with [14C]glucose to 10 NIDDM subjects and 10 age- and weight-matched nondiabetic volunteers and compared muscle glucose disposal by measuring forearm balance of glucose, lactate, alanine, O2, and CO2 (with forearm calorimetry). In addition, we used the dual-lable isotope method to compare overall rates of glucose appearance (Ra) and disappearance (Rd), suppression of endogenous glucose output, and splanchnic glucose sequestration. During the initial 1-1.5 h after glucose ingestion, plasma glucose increased by approximately 8 mM in NIDDM vs. approximately 3 mM in nondiabetic subjects (P less than 0.01); overall glucose Ra was nearly 11 g greater in NIDDM than nondiabetic subjects (45.1 +/- 2.3 vs. 34.4 +/- 1.5 g, P less than 0.01), but glucose Rd was not significantly different in NIDDM (35.1 +/- 2.4 g) and nondiabetic (33.3 +/- 2.7 g) subjects. The greater overall glucose Ra of NIDDM subjects was due to 6.8 g greater endogenous glucose output (13.7 +/- 1.1 vs. 6.8 +/- 1.0 g, P less than 0.01) and 3.8 g less oral glucose splanchnic sequestration of the oral load (31.4 +/- 1.5 vs. 27.5 +/- 0.9 g, P less than 0.05). Although glucose taken up by muscle was not significantly different in NIDDM and nondiabetic subjects (39.3 +/- 3.5 vs. 41.0 +/- 2.5 g/5 h), a greater amount of the glucose taken up by muscle in NIDDM was released as lactate and alanine (11.7 +/- 1.0 vs. 5.2 +/- 0.3 g in nondiabetic subjects, P less than 0.01), and less was stored (11.7 +/- 1.3 vs. 16.9 +/- 1.5 g, P less than 0.05). We conclude that increased systemic glucose delivery, due primarily to reduced suppression of endogenous hepatic glucose output and, to a lesser extent, reduced splanchnic glucose sequestration, is the predominant factor responsible for postprandial hyperglycemia in NIDDM.

Asymptomatic cytomegalovirus infection is associated with increased risk of new-onset diabetes mellitus and impaired insulin release after renal transplantation

Aims/hypothesisThe human cytomegalovirus (CMV) may increase the risk of diabetes mellitus, but the literature is scarce. The present study was designed to test the hypothesis that asymptomatic CMV infection is associated with increased risk of new-onset diabetes after renal transplantation, and to assess the impact of asymptomatic CMV infection on OGTT-derived estimates of insulin release and insulin action.MethodsA total of 160 consecutive non-diabetic renal transplant recipients on cyclosporine (Sandimmun Neoral)-based immunosuppression were closely monitored for CMV infection during the first 3 months after transplantation. All patients underwent a 75-g OGTT at 10 weeks. Excluded from the analyses were 36 patients with symptomatic CMV infection (disease).ResultsThe incidence of new-onset diabetes was 6% in a control group of recipients without CMV infection (4/63) and 26% in the group with asymptomatic CMV infection (16/61). Asymptomatic CMV infection was associated with a significantly increased risk of new-onset diabetes (adjusted odds ratio: 4.00; 95% CI: 1.19 to 13.43, p=0.025). The group of patients with CMV infection had a significantly lower median insulin release than controls.Conclusions/interpretationOur findings support the hypothesis that asymptomatic CMV infection is associated with increased risk of new-onset post-transplant diabetes mellitus, and suggest that impaired insulin release may involve one pathogenetic mechanism.

Effects of n-3 polyunsaturated fatty acids on glucose homeostasis and blood pressure in essential hypertension : a randomized, controlled trial

Hypertension is a well-documented risk factor for coronary heart disease, but the widespread use of antihypertensive treatment has not resulted in the expected reduction in coronary heart disease mortality [1]. Persons with hypertension tend to have disturbances in glucose and lipid metabolism [2-4] that may contribute to their excess risk for coronary heart disease. Fish oils rich in polyunsaturated fatty acids of the n-3 family may protect against ischemic cardiovascular disease [5-7]. In hypertensive patients, a modest blood pressure-lowering effect has been shown after fish oil intake in some [8-12] but not all [13-15] studies. Fish oil may favorably affect platelet aggregation [16, 17], hepatic triglyceride and very-low-density lipoprotein (VLDL) cholesterol formation [18-21], and vascular prostaglandin production [9, 16, 22]. It has also been reported to suppress intimal smooth-muscle cell proliferation by inhibiting monocyte and neutrophil chemotaxis [23] and the vascular endothelial production of platelet-derived growth factor-like protein [24]. These antiatherosclerotic effects may be important in preventing the development of coronary heart disease in patients with hypertension [25]. Conflicting results have been published about the effects of fish oil on glucose homeostasis [26-41]. Some [26-31] but not all [32-41] studies have reported that fish oil has detrimental effects on glycemic control in glucose-intolerant persons and in persons with type 2 diabetes. The extent to which the findings from these studies can be generalized is constrained by limitations in study design. Only a few studies [26, 28, 30, 34, 35, 38] have used the classic glucose clamp technique to measure glucose and insulin dynamics, and no studies have examined the effects of fish oil on glucose homeostasis in nondiabetic persons with hypertension. Given the present gaps in the literature, the safety of fish oil supplementation for persons with hypertension has been disputed [42]. We therefore did a randomized, double-blind, placebo-controlled trial in 78 persons with untreated, stable hypertension to study the effects of n-3 polyunsaturated fatty acids on glucose and insulin kinetics, blood pressure, serum lipids, and the incorporation of fatty acid into plasma phospholipids. Methods Participants In 1986-1987, 21 826 persons (81.3% of the population [age range: men, 20 to 61 years; women, 20 to 56 years] living in the municipality of Tromso, Norway, participated in a health survey [43]. On the basis of that survey, 156 hypertensive persons were enrolled in a 10-week trial of dietary supplementation with n-3 polyunsaturated fatty acids [8]. The trial was completed in May 1988. In May 1991 and February 1992, the persons who had participated in the trial were invited to have physical examinations at the Clinical Research Unit of the University Hospital of Tromso as part of recruitment into our study. Of the persons invited, 103 volunteered. Each completed a questionnaire about previous and present illnesses, family history, medication, fish oil intake, physical activity, and smoking and alcohol habits, and each had a laboratory screening that included an oral glucose tolerance test and blood pressure measurements. Fifty-eight participants were receiving no medication and had systolic blood pressure measurements of less than 190 mm Hg and diastolic blood pressure measurements between 90 and 110 mm Hg on three separate occasions. Each had a body mass index of less than 32 kg/m2 body surface area and appeared otherwise healthy. They all participated in the study, as did 26 hypertensive persons recruited from the primary health care services using criteria identical to those described above. Four of these volunteers had been treated with antihypertensive drugs (atenolol, amlodipine, or felodipine); this therapy was discontinued at least 8 weeks before the trial. The 84 participants were encouraged not to change their diets or lifestyles during the study. Those who used cod liver oil supplements were instructed to discontinue this practice 12 months before the study started. The study was approved by the Regional Board of Research Ethics, and each participant gave written informed consent before participation. Study Design The participants were randomly assigned to receive either fish oil or corn oil. A person who was not involved in trial management did the randomization using a Statgraphic random number generator [44]. The list of randomization numbers and the codes were sent to the manufacturer of the fish oil and corn oil capsules (Pronova Biocare, Oslo, Norway). The boxes labeled with the randomization numbers were given to the participants in the sequence at which they met. The researchers doing the experiments were blinded to treatment assignments, and the randomization codes were not broken until all laboratory measurements had been done. The fish oil group received 85% eicosapentaenoic acid (C20:5n3) and docosahexaenoic acid (C22:6n3), 4 g/d, as ethyl esters (Omacor, Pronova Biocare, Oslo, Norway). To compensate for the extra daily energy intake received by those assigned to intervention with polyunsaturated fatty acids, the control group was given corn oil, 4 g/d, containing 56% linoleic acid (C18:2n6) and 26% oleic acid (C18:1n9). The fish and corn oils were given in indistinguishable soft gelatin capsules that each contained 1 g of oil. The intervention period lasted 16 weeks. Compliance was checked by counting leftover capsules and by measuring the concentrations of fatty acids in plasma phospholipids before and after intervention. Glucose tolerance studies were done during the last week before treatment and during the last week of intervention. A weight-maintenance diet was held 3 days before the experiments, and participants were asked to abstain from alcohol during this period. All studies were done at 0800 h after an overnight fast. Side effects, compliance, intercurrent diseases, and blood pressure were assessed by interview and physical examination every fourth week during treatment. Clinical and Laboratory Measurements Three blood pressure measurements were recorded on each of 2 separate days both before and after intervention by the same investigator using the same stethoscope and mercury sphygmomanometer. The mean of these measurements was used in the analysis. Measurements were done after each patient had rested, comfortably seated, for 10 minutes; Korotkoff test phases 1 and 5 were recorded as systolic and diastolic blood pressures, respectively. Mean arterial pressure was calculated as the diastolic pressure plus one third of the pulse pressure. Waist-to-hip ratio was calculated as the body circumference midway between the inferior border of the rib cage and the superior border of the iliac crest, divided by the maximal body circumference at the buttocks [45]. All participants had an oral glucose tolerance test with 1 g of dextrose per kg body weight or a maximum of 75 g of dextrose. The integrated increase of plasma glucose and insulin levels above baseline measurements after an oral glucose tolerance test was calculated as arbitrary incremental area units over the 2-hour sampling time. On a separate day, we used a standard hyperglycemic clamp technique to study both glucose-stimulated insulin secretion and insulin sensitivity [46, 47]. Dextrose was infused into an antecubital vein. We measured the blood sugar level every 5 to 10 minutes to keep it stable at 10 mmol/L for 3 hours by variable infusion rates. Blood was drawn from a cannulated dorsal hand vein without stasis; we arterialized the blood by keeping the hand in a heating device at 65 C [48]. Blood samples for insulin and C-peptide measurements were drawn at 30, 0, 2.5, 5, 7.5, 10, 15, 20, 40, 60, 80, 100, 120, 140, 160, and 180 minutes. First-phase insulin release, which reflects the early insulin peak secreted from the pancreatic -cells in response to glucose stimulation, was calculated as the area under the insulin curve over the initial 10-minute period of the hyperglycemic clamp technique. Second-phase insulin release, which is a measure of -cell function under sustained elevated glucose levels, was calculated as the area under the insulin curve from 120 to 180 minutes of the clamp period. On a third day, we used a euglycemic, hyperinsulinemic clamp technique [46, 47], which is the gold standard for measuring insulin sensitivity. However, this method does not give information about -cell function. In general, insulin is infused at a rate of 40 mU/m2 body surface area per minute for 180 minutes, inducing plasma insulin levels of about 400 pmol/L [46]. At this plasma insulin level, hepatic glucose production is zero. Plasma glucose level was maintained at 5 mmol/L by a variable glucose infusion. The glucose infusion rate therefore equals the uptake rate of glucose in the body. The insulin sensitivity index can be calculated by using both the hyperglycemic and the euglycemic clamp techniques by dividing the mean glucose infusion rate during the last hour of the clamp period (mol/kgmin) by the average plasma insulin level in the same period of time (pmol/L). The insulin sensitivity index measures how efficiently plasma insulin induces glucose uptake in insulin-sensitive tissues, such as fat and muscle. The insulin sensitivity index calculated by using the hyperglycemic clamp technique has been shown to be highly correlated with the insulin sensitivity index calculated by using the classic euglycemic, hyperinsulinemic clamp technique [46, 47]. To compare the insulin sensitivity indexes obtained with the two clamp techniques, we used the euglycemic, hyperinsulinemic clamp technique in 31 randomly selected participants on this third day. Plasma glucose levels were analyzed at the bedside with a Yellow Spring Instruments glucose analyzer (2300 STAT PLUS, Yellow Springs, Ohio). All other blood samples were stored at 70 C until study completion. Plasma in

Obesity-related cardiovascular risk factors after weight loss: a clinical trial comparing gastric bypass surgery and intensive lifestyle intervention

Objective Weight reduction improves several obesity-related health conditions. We aimed to compare the effect of bariatric surgery and comprehensive lifestyle intervention on type 2 diabetes and obesity-related cardiovascular risk factors. Design One-year controlled clinical trial (ClinicalTrials.gov identifier NCT00273104). Methods Morbidly obese subjects (19–66 years, mean (s.d.) body mass index 45.1 kg/m2 (5.6), 103 women) were treated with either Roux-en-Y gastric bypass surgery (n=80) or intensive lifestyle intervention at a rehabilitation centre (n=66). The dropout rate within both groups was 5%. Results Among the 76 completers in the surgery group and the 63 completers in the lifestyle group, mean (s.d.) 1-year weight loss was 30% (8) and 8% (9) respectively. Beneficial effects on glucose metabolism, blood pressure, lipids and low-grade inflammation were observed in both groups. Remission rates of type 2 diabetes and hypertension were significantly higher in the surgery group than the lifestyle intervention group; 70 vs 33%, P=0.027, and 49 vs 23%, P=0.016. The improvements in glycaemic control and blood pressure were mediated by weight reduction. The surgery group experienced a significantly greater reduction in the prevalence of metabolic syndrome, albuminuria and electrocardiographic left ventricular hypertrophy than the lifestyle group. Gastrointestinal symptoms and symptomatic postprandial hypoglycaemia developed more frequently after gastric bypass surgery than after lifestyle intervention. There were no deaths. Conclusions Type 2 diabetes and obesity-related cardiovascular risk factors were improved after both treatment strategies. However, the improvements were greatest in those patients treated with gastric bypass surgery.

Insulin Resistance after Renal Transplantation: The Effect of Steroid Dose Reduction and Withdrawal

Cardiovascular disease is a prevalent and serious complication after solid organ transplantation. Treatment with glucocorticoids is associated with increased risk for diabetes mellitus, insulin resistance, weight gain, hypercholesterolemia, and hypertension, all shown to be independent risk factors for cardiovascular disease. We sought to test the hypothesis that tapering of prednisolone (TAP) the first year after renal transplantation improves insulin sensitivity (IS), and to assess the effect of complete steroid withdrawal (SW) on IS in patients on a cyclosporine-based immunosuppressive regimen. All patients (n = 57) completed two consecutive hyperinsulinemic euglycemic glucose clamp procedures, a TAP group (n = 34) and a control group (n = 12) at 3 and 12 mo after transplantation, and a SW group (n = 11) before and 5 mo after SW. The IS index (ISI) was calculated as the glucose disposal rate divided by mean serum insulin the last 60 min of the clamp. In the TAP group, the mean (range) daily prednisolone was reduced from 16 (10 to 30) to 9 (5 to 12.5) mg accompanied by an average increased ISI of 24% (P = 0.008). In contrast, no significant change in ISI was observed in the control group (0%, P = 0.988). In the SW group, withdrawal of 5 mg prednisolone did not influence mean ISI significantly (-8%, P = 0.206). Lowering daily prednisolone toward 5 mg/d has beneficial effects on insulin action after renal transplantation, but withdrawal of 5 mg prednisolone may not influence IS significantly.

Parathyroid hormone, but not vitamin D, is associated with the metabolic syndrome in morbidly obese women and men: A cross-sectional study

BackgroundThe prevalence of vitamin D insufficiency and secondary hyperparathyroidism is high among morbidly obese subjects. Further, low serum levels of 25-hydroxyvitamin D (25 [OH]D) and magnesium have been associated with increased risk of the metabolic syndrome (MS), and recently, a possible link between PTH and MS has been reported. Although it is well known that the synthesis and secretion of PTH is regulated by serum levels of calcium, phosphate, magnesium and 25(OH)D, less is known about the possible clustered affiliation of these parameters with MS. We aimed to explore whether MS is associated with abnormal serum levels of PTH, 25(OH)D and magnesium in a population of morbidly obese patients.MethodsFasting serum levels of 25(OH)D, PTH and magnesium were assessed in a cross-sectional cohort study of 1,017 consecutive morbidly obese patients (68% women). Multiple logistic regression analyses were used to assess the independent effect of PTH, 25(OH)D and magnesium on the odds for MS (National Cholesterol Education Program [NCEP]) after adjustment for confounding factors.ResultsSixty-eight percent of the patients had MS. Patients with MS had lower mean serum magnesium (P < 0.001) and higher mean PTH (P = 0.067) than patients without MS, whereas mean 25(OH)D did not differ significantly. Patients with PTH levels in the second to fourth quartiles had higher odds of prevalent MS (odds ratio 1.47 [95% CI 0.92–2.35], 2.33 [95% CI 1.40–3.87] and 2.09 [95% CI 1.23–3.56], respectively), after adjustment for 25(OH)D, magnesium, calcium, phosphate, creatinine, age, gender, season of serum sampling, BMI, current smoking, albuminuria, CRP, insulin resistance and type 2 diabetes. Further, PTH was significantly correlated with systolic and diastolic pressure (both P < 0.001), but not with the other components of MS. The levels of 25(OH)D and magnesium were not associated with MS in the multivariate model.ConclusionThe PTH level, but not the vitamin D level, is an independent predictor of MS in treatment seeking morbidly obese Caucasian women and men. Randomized controlled clinical trials, including different therapeutic strategies to lower PTH, e.g. calcium/vitamin D supplementation and weight reduction, are necessary to explore any cause-and-effect relationship.