Ingar Holme

Diabetes Mellitus, Fasting Glucose, and Risk of Cause-Specific Death

BACKGROUND The extent to which diabetes mellitus or hyperglycemia is related to risk of death from cancer or other nonvascular conditions is uncertain. METHODS We calculated hazard ratios for cause-specific death, according to baseline diabetes status or fasting glucose level, from individual-participant data on 123,205 deaths among 820,900 people in 97 prospective studies. RESULTS After adjustment for age, sex, smoking status, and body-mass index, hazard ratios among persons with diabetes as compared with persons without diabetes were as follows: 1.80 (95% confidence interval [CI], 1.71 to 1.90) for death from any cause, 1.25 (95% CI, 1.19 to 1.31) for death from cancer, 2.32 (95% CI, 2.11 to 2.56) for death from vascular causes, and 1.73 (95% CI, 1.62 to 1.85) for death from other causes. Diabetes (vs. no diabetes) was moderately associated with death from cancers of the liver, pancreas, ovary, colorectum, lung, bladder, and breast. Aside from cancer and vascular disease, diabetes (vs. no diabetes) was also associated with death from renal disease, liver disease, pneumonia and other infectious diseases, mental disorders, nonhepatic digestive diseases, external causes, intentional self-harm, nervous-system disorders, and chronic obstructive pulmonary disease. Hazard ratios were appreciably reduced after further adjustment for glycemia measures, but not after adjustment for systolic blood pressure, lipid levels, inflammation or renal markers. Fasting glucose levels exceeding 100 mg per deciliter (5.6 mmol per liter), but not levels of 70 to 100 mg per deciliter (3.9 to 5.6 mmol per liter), were associated with death. A 50-year-old with diabetes died, on average, 6 years earlier than a counterpart without diabetes, with about 40% of the difference in survival attributable to excess nonvascular deaths. CONCLUSIONS In addition to vascular disease, diabetes is associated with substantial premature death from several cancers, infectious diseases, external causes, intentional self-harm, and degenerative disorders, independent of several major risk factors. (Funded by the British Heart Foundation and others.).

Effects of Dalcetrapib in Patients with a Recent Acute Coronary Syndrome

BACKGROUND In observational analyses, higher levels of high-density lipoprotein (HDL) cholesterol have been associated with a lower risk of coronary heart disease events. However, whether raising HDL cholesterol levels therapeutically reduces cardiovascular risk remains uncertain. Inhibition of cholesteryl ester transfer protein (CETP) raises HDL cholesterol levels and might therefore improve cardiovascular outcomes. METHODS We randomly assigned 15,871 patients who had had a recent acute coronary syndrome to receive the CETP inhibitor dalcetrapib, at a dose of 600 mg daily, or placebo, in addition to the best available evidence-based care. The primary efficacy end point was a composite of death from coronary heart disease, nonfatal myocardial infarction, ischemic stroke, unstable angina, or cardiac arrest with resuscitation. RESULTS At the time of randomization, the mean HDL cholesterol level was 42 mg per deciliter (1.1 mmol per liter), and the mean low-density lipoprotein (LDL) cholesterol level was 76 mg per deciliter (2.0 mmol per liter). Over the course of the trial, HDL cholesterol levels increased from baseline by 4 to 11% in the placebo group and by 31 to 40% in the dalcetrapib group. Dalcetrapib had a minimal effect on LDL cholesterol levels. Patients were followed for a median of 31 months. At a prespecified interim analysis that included 1135 primary end-point events (71% of the projected total number), the independent data and safety monitoring board recommended termination of the trial for futility. As compared with placebo, dalcetrapib did not alter the risk of the primary end point (cumulative event rate, 8.0% and 8.3%, respectively; hazard ratio with dalcetrapib, 1.04; 95% confidence interval, 0.93 to 1.16; P=0.52) and did not have a significant effect on any component of the primary end point or total mortality. The median C-reactive protein level was 0.2 mg per liter higher and the mean systolic blood pressure was 0.6 mm Hg higher with dalcetrapib as compared with placebo (P<0.001 for both comparisons). CONCLUSIONS In patients who had had a recent acute coronary syndrome, dalcetrapib increased HDL cholesterol levels but did not reduce the risk of recurrent cardiovascular events. (Funded by F. Hoffmann-La Roche; dal-OUTCOMES ClinicalTrials.gov number, NCT00658515.).

Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis.

BACKGROUND Hyperlipidemia has been suggested as a risk factor for stenosis of the aortic valve, but lipid-lowering studies have had conflicting results. METHODS We conducted a randomized, double-blind trial involving 1873 patients with mild-to-moderate, asymptomatic aortic stenosis. The patients received either 40 mg of simvastatin plus 10 mg of ezetimibe or placebo daily. The primary outcome was a composite of major cardiovascular events, including death from cardiovascular causes, aortic-valve replacement, nonfatal myocardial infarction, hospitalization for unstable angina pectoris, heart failure, coronary-artery bypass grafting, percutaneous coronary intervention, and nonhemorrhagic stroke. Secondary outcomes were events related to aortic-valve stenosis and ischemic cardiovascular events. RESULTS During a median follow-up of 52.2 months, the primary outcome occurred in 333 patients (35.3%) in the simvastatin-ezetimibe group and in 355 patients (38.2%) in the placebo group (hazard ratio in the simvastatin-ezetimibe group, 0.96; 95% confidence interval [CI], 0.83 to 1.12; P=0.59). Aortic-valve replacement was performed in 267 patients (28.3%) in the simvastatin-ezetimibe group and in 278 patients (29.9%) in the placebo group (hazard ratio, 1.00; 95% CI, 0.84 to 1.18; P=0.97). Fewer patients had ischemic cardiovascular events in the simvastatin-ezetimibe group (148 patients) than in the placebo group (187 patients) (hazard ratio, 0.78; 95% CI, 0.63 to 0.97; P=0.02), mainly because of the smaller number of patients who underwent coronary-artery bypass grafting. Cancer occurred more frequently in the simvastatin-ezetimibe group (105 vs. 70, P=0.01). CONCLUSIONS Simvastatin and ezetimibe did not reduce the composite outcome of combined aortic-valve events and ischemic events in patients with aortic stenosis. Such therapy reduced the incidence of ischemic cardiovascular events but not events related to aortic-valve stenosis. (ClinicalTrials.gov number, NCT00092677.)

High apolipoprotein B, low apolipoprotein A-I, and improvement in the prediction of fatal myocardial infarction (AMORIS study): a prospective study

BACKGROUND Apolipoprotein B (apoB) and apolipoprotein A-I (apoA-I) are thought to be better predictors of acute myocardial infarction than total cholesterol and LDL-cholesterol. We investigated whether apoB and apoA-I are predictors of risk of fatal myocardial infarction. We also aimed to establish whether apoB and apoA-I add further information about risk of fatal myocardial infarction to that obtained with total cholesterol, triglycerides, and LDL-cholesterol. METHODS We recruited 175553 individuals mainly from screening programmes. We measured concentrations of apoB, apoA-I, total cholesterol, and triglycerides, and calculated apoB/apoA-I ratio and concentrations of LDL-cholesterol and HDL-cholesterol. The relation between death from acute myocardial infarction and initial values for apoB, apoA-I, and the other lipids was examined. FINDINGS Mean follow-up was 66.8 months (SD 41.3) for 98722 men and 64.4 months (41.4) for 76831 women. 864 men and 359 women had fatal myocardial infarction. In univariate analyses adjusted for age and in multivariate analyses adjusted for age, total cholesterol, and triglycerides, the values for apoB and apoB/apoA-I ratio were strongly and positively related to increased risk of fatal myocardial infarction in men and in women. ApoA-I was noted to be protective. In multivariate analysis, apoB was a stronger predictor of risk than LDL-cholesterol in both sexes. INTERPRETATION Although LDL-cholesterol and HDL-cholesterol are known risk factors, we suggest that apoB, apoB/apoA-I, and apoA-I should also be regarded as highly predictive in evaluation of cardiac risk. Although increased throughout the range of values of LDL-cholesterol, apoB and apoA-I might be of greatest value in diagnosis and treatment in men and women who have common lipid abnormalities, but have normal or low concentrations of LDL-cholesterol.

Effect of fluvastatin on cardiac outcomes in renal transplant recipients: a multicentre, randomised, placebo-controlled trial

BACKGROUND Renal transplant recipients are at increased risk of premature cardiovascular disease. Although statins reduce cardiovascular risk in the general population, their efficacy and safety in renal transplant recipients have not been established. We investigated the effects of fluvastatin on cardiac and renal endpoints in this population. METHODS We did a multicentre, randomised, double-blind, placebo-controlled trial in 2102 renal transplant recipients with total cholesterol 4.0-9.0 mmol/L. We randomly assigned patients fluvastatin (n=1050) or placebo (n=1052) and follow up was for 5-6 years. The primary endpoint was the occurrence of a major adverse cardiac event, defined as cardiac death, non-fatal myocardial infarction (MI), or coronary intervention procedure. Secondary endpoints were individual cardiac events, combined cardiac death or non-fatal MI, cerebrovascular events, non-cardiovascular death, all-cause mortality, and graft loss or doubling of serum creatinine. Analysis was by intention to treat. FINDINGS After a mean follow-up of 5.1 years, fluvastatin lowered LDL cholesterol concentrations by 32%. Risk reduction with fluvastatin for the primary endpoint (risk ratio 0.83 [95% CI 0.64-1.06], p=0.139) was not significant, although there were fewer cardiac deaths or non-fatal MI (70 vs 104, 0.65 [0.48-0.88] p=0.005) in the fluvastatin group than in the placebo group. Coronary intervention procedures and other secondary endpoints did not differ significantly between groups. INTERPRETATION Although cardiac deaths and non-fatal MI seemed to be reduced, fluvastatin did not generally reduce rates of coronary intervention procedures or mortality. Overall effects of fluvastatin were similar to those of statins in other populations.

The Effect of Warfarin on Mortality and Reinfarction after Myocardial Infarction

BACKGROUND AND METHODS The use of oral anticoagulation in the long-term treatment of survivors of acute myocardial infarction has been highly controversial. We therefore randomly assigned 1214 patients who had recovered from acute myocardial infarction (mean interval from the onset of symptoms to randomization, 27 days) to treatment with warfarin (607 patients) or placebo (607 patients) for an average of 37 months (range, 24 to 63). RESULTS At the end of the treatment period, there had been 123 deaths in the placebo group and 94 in the warfarin group--a reduction in risk of 24 percent (95 percent confidence interval, 4 to 44 percent; P = 0.027). A total of 124 patients in the placebo group had reinfarctions, as compared with 82 in the warfarin group--a reduction of 34 percent (95 percent confidence interval, 19 to 54 percent; P = 0.0007). Furthermore, we observed a reduction of 55 percent (95 percent confidence interval, 30 to 77 percent) in the number of total cerebrovascular accidents in the warfarin group as compared with the placebo group (44 vs. 20; P = 0.0015). Serious bleeding was noted in 0.6 percent of the warfarin-treated patients per year. CONCLUSIONS Long-term therapy with warfarin has an important beneficial effect after myocardial infarction and can be recommended in the treatment of patients who survive the acute phase.

Risk Factors for Injuries in Football

Background The injury risk in football is high, but little is known about causes of injury. Purpose To identify risk factors for football injuries using a multivariate model. Study Design Prospective cohort study. Methods Participants were 306 male football players from the two highest divisions in Iceland. Before the 1999 football season started, the following factors were examined: height, weight, body composition, flexibility, leg extension power, jump height, peak O2 uptake, joint stability, and history of previous injury. Injuries and player exposure were recorded throughout the competitive season. Results Older players were at higher risk of injury in general (odds ratio [OR] = 1.1 per year, P = 0.05). For hamstring strains, the significant risk factors were age (OR = 1.4 [1 year], P < 0.001) and previous hamstring strains (OR = 11.6, P < 0.001). For groin strains, the predictor risk factors were previous groin strains (OR = 7.3, P = 0.001) and decreased range of motion in hip abduction (OR = 0.9 [1°], P = 0.05). Previous injury was also identified as a risk factor for knee (OR = 4.6) and ankle sprains (OR = 5.3). Conclusions Age and previous injury were identified as the main risk factors for injury among elite football players from Iceland.

Exercises to prevent lower limb injuries in youth sports: cluster randomised controlled trial

Abstract Objective To investigate the effect of a structured warm-up programme designed to reduce the incidence of knee and ankle injuries in young people participating in sports. Design Cluster randomised controlled trial with clubs as the unit of randomisation. Setting 120 team handball clubs from central and eastern Norway (61 clubs in the intervention group, 59 in the control group) followed for one league season (eight months). Participants 1837 players aged 15-17 years; 958 players (808 female and 150 male) in the intervention group; 879 players (778 female and 101 male) in the control group. Intervention A structured warm-up programme to improve running, cutting, and landing technique as well as neuromuscular control, balance, and strength. Main outcome measure The rate of acute injuries to the knee or ankle. Results During the season, 129 acute knee or ankle injuries occurred, 81 injuries in the control group (0.9 (SE 0.09) injuries per 1000 player hours; 0.3 (SE 0.17) in training v 5.3 (SE 0.06) during matches) and 48 injuries in the intervention group (0.5 (SE 0.11) injuries per 1000 player hours; 0.2 (SE 0.18) in training v 2.5 (SE 0.06) during matches). Fewer injured players were in the intervention group than in the control group (46 (4.8%) v (76 (8.6%); relative risk intervention group v control group 0.53, 95% confidence interval 0.35 to 0.81). Conclusion A structured programme of warm-up exercises can prevent knee and ankle injuries in young people playing sports. Preventive training should therefore be introduced as an integral part of youth sports programmes.

Single blind, randomised controlled trial of pelvic floor exercises, electrical stimulation, vaginal cones, and no treatment in management of genuine stress incontinence in women

Abstract Objective:To compare the effect of pelvic floor exercises, electrical stimulation,vaginal cones, and no treatment for genuine stress incontinence. Design:Stratified, single blind, randomised controlled trial. Setting:Multicentre. Participants: 107 women with clinically and urodynamically proved genuine stress incontinence. Mean (range) age was 49.5 (24-70) years, and mean (range) duration of symptoms 10.8 (1-45) years. Interventions: Pelvic floor exercise (n=25) comprised 8-12 contractions 3 times a day and exercise in groups with skilled physical therapists once a week. The electrical stimulation group (n=25) used vaginal intermittent stimulation with the MS 106 Twin at 50 Hz 30 minutes a day. The vaginal cones group (n=27) used cones for 20 minutes a day. The untreated control group (n=30) was offered the use of a continence guard. Muscle strength was measured by vaginal squeeze pressure once a month. Main outcome measures: Pad test with standardised bladder volume, and self report of severity. Results:Improvement in muscle strength was significantly greater (P=0.03) after pelvic floor exercises (11.0 cm H2O (95% confidence interval 7.7 to 14.3) before v 19.2 cm H2O (15.3 to 23.1) after) than either electrical stimulation (14.8 cm H2O (10.9 to 18.7) v 18.6 cm H2O (13.3 to 23.9)) or vaginal cones (11.8 cm H2O (8.5 to 15.1) v 15.4 cm H2O (11.1 to 19.7)). Reduction in leakage on pad test was greater in the exercise group (−30.2 g; −43.3 to 16.9) than in the electrical stimulation group (−7.4 g; −20.9 to 6.1) and the vaginal cones group (−14.7 g; −27.6 to −1.8). On completion of the trial one participant in the control group, 14 in the pelvic floor exercise group, three in the electrical stimulation group, and two in the vaginal cones group no longer considered themselves as having a problem. Conclusion: Training of the pelvic floor muscles is superior to electrical stimulation and vaginal cones in the treatment of genuine stress incontinence.

Comprehensive warm-up programme to prevent injuries in young female footballers: cluster randomised controlled trial

Objective To examine the effect of a comprehensive warm-up programme designed to reduce the risk of injuries in female youth football. Design Cluster randomised controlled trial with clubs as the unit of randomisation. Setting 125 football clubs from the south, east, and middle of Norway (65 clusters in the intervention group; 60 in the control group) followed for one league season (eight months). Participants 1892 female players aged 13-17 (1055 players in the intervention group; 837 players in the control group). Intervention A comprehensive warm-up programme to improve strength, awareness, and neuromuscular control during static and dynamic movements. Main outcome measure Injuries to the lower extremity (foot, ankle, lower leg, knee, thigh, groin, and hip). Results During one season, 264 players had relevant injuries: 121 players in the intervention group and 143 in the control group (rate ratio 0.71, 95% confidence interval 0.49 to 1.03). In the intervention group there was a significantly lower risk of injuries overall (0.68, 0.48 to 0.98), overuse injuries (0.47, 0.26 to 0.85), and severe injuries (0.55, 0.36 to 0.83). Conclusion Though the primary outcome of reduction in lower extremity injury did not reach significance, the risk of severe injuries, overuse injuries, and injuries overall was reduced. This indicates that a structured warm-up programme can prevent injuries in young female football players. Trial registration ISRCTN10306290.