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Cardiac Autonomic Neuropathy Predicts Cardiovascular Morbidity and Mortality in Type 1 Diabetic Patients With Diabetic Nephropathy Anne Sofie Astrup , MD 1 , Lise Tarnow , DMSC 1 , Peter Rossing , DMSC 1 , Birgitte V. Hansen 1 , Jannik Hilsted , DMSC 2 and Hans-Henrik Parving , DMSC 1 3 1 Steno Diabetes Center, Gentofte, Denmark 2 Rigshospitalet, Copenhagen, Denmark 3 Faculty of Health Science, Aarhus University, Aarhus, Denmark Address correspondence and reprint requests to Anne Sofie Astrup, MD, Steno Diabetes Center, Niels Steensensvej 2, 2820 Gentofte, Denmark. E-mail: ansa{at}steno.dk Abstract OBJECTIVE —Cardiac autonomic neuropathy (CAN) has been associated with a poor prognosis in patients with diabetes. Because CAN is common in patients with diabetic nephropathy, we evaluated the predictive value of CAN in type 1 diabetic patients with and without diabetic nephropathy. RESEARCH DESIGN AND METHODS —In a prospective observational follow-up study, 197 type 1 diabetic patients with diabetic nephropathy and a matched group of 191 patients with long-standing type 1 diabetes and normoalbuminuria were followed for 10.1 years (range 0.0–10.3 years). At baseline, CAN was assessed by heart rate variation (HRV) during deep breathing. HRV was evaluated as a predictor of the primary end point: cardiovascular morbidity and mortality. As secondary end points, all-cause mortality and the influence of HRV on progression of diabetic nephropathy (decline in glomerular filtration rate [GFR]) was evaluated. RESULTS —During the follow-up, 79 patients (40%) with nephropathy reached the combined primary end point vs. 19 patients (10%) with normoalbuminuria (log-rank test, P < 0.0001). The unadjusted hazard ratio (HR) for reaching the primary end point when having an abnormal HRV (≤10 bpm) measured at baseline compared with a normal HRV was 7.7 (range 1.9–31.5; P = 0.004) in patients with nephropathy. Similarly in the normoalbuminuric patients, the unadjusted HR was 4.4 (1.4–13.6; P = 0.009). In patients with nephropathy, abnormal HRV was significantly associated with fatal and nonfatal cardiovascular disease after adjustment for cardiovascular risk factors. The adjusted HR for reaching the primary end point in a patient with nephropathy and an abnormal HRV was 6.4 (1.5–26.3, P = 0.010), as compared with a normal HRV. The unadjusted HR for dying when having an abnormal HRV compared with a normal HRV was 3.3 (95% CI 1.0–10.7; P = 0.043) in patients with diabetic nephropathy. After adjustment for confounding factors, the impact of HRV on all-cause mortality in patients with nephropathy was no longer significant ( P = 0.293). There was no relationship between abnormal HRV and rate of decline in GFR. CONCLUSIONS —HRV is an independent risk factor for cardiovascular morbidity and mortality in type 1 diabetic patients with nephropathy. CAN, cardiac autonomic neuropathy CVD, cardiovascular disease GFR, glomerular filtration rate HRV, heart rate variation Footnotes A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances. A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances. Accepted October 25, 2005. Received July 6, 2005. DIABETES CARE

Cardiovascular autonomic neuropathy (CAN) is associated with increased mortality in diabetes. Since CAN often develops in parallel with diabetic nephropathy as a confounder, we aimed to investigate the isolated impact of CAN on cardiovascular disease in normoalbuminuric patients. Fifty-six normoalbuminuric, type 1 diabetic patients were divided into 26 with (+) and 30 without (-) CAN according to tests of their autonomic nerve function. Coronary artery plaque burden and coronary artery calcium score (CACS) were evaluated using computed tomography. Left ventricular function was evaluated using echocardiography. Blood pressure and electrocardiography were recorded through 24 h to evaluate nocturnal drop in blood pressure (dipping) and pulse pressure. In patients +CAN compared with -CAN, the CACS was higher, and only patients +CAN had a CACS >400. A trend toward a higher prevalence of coronary plaques and flow-limiting stenosis in patients +CAN was nonsignificant. In patients +CAN, left ventricular function was decreased in both diastole and systole, nondipping was more prevalent, and pulse pressure was increased compared with -CAN. In multivariable analysis, CAN was independently associated with increased CACS, subclinical left ventricular dysfunction, and increased pulse pressure. In conclusion, CAN in normoalbuminuric type 1 diabetic patients is associated with distinct signs of subclinical cardiovascular disease.

Preceding the joint meeting of the 19th annual Diabetic Neuropathy Study Group of the European Association for the Study of Diabetes (NEURODIAB) and the 8th International Symposium on Diabetic Neuropathy in Toronto, Canada, 13-18 October 2009, expert panels were convened to provide updates on classification, definitions, diagnostic criteria, and treatments of diabetic peripheral neuropathies (DPNs), autonomic neuropathy, painful DPNs, and structural alterations in DPNs.

Decreased Myocardial Perfusion Reserve in Diabetic Autonomic Neuropathy Mustafa Taskiran 1 , Thomas Fritz-Hansen 2 , Verner Rasmussen 3 , Henrik B.W. Larsson 3 and Jannik Hilsted 1 1 Department of Endocrinology, H:S Hvidovre University Hospital, Copenhagen, Denmark 2 Department of Magnetic Resonance, H:S Hvidovre University Hospital, Copenhagen, Denmark 3 Department of Cardiology, H:S Hvidovre University Hospital, Copenhagen, Denmark Abstract The pathophysiological mechanisms responsible for increased cardiovascular mortality in diabetic autonomic neuropathy are unknown. To investigate the effect of autonomic neuropathy on myocardial function, we performed dynamic contrast-enhanced magnetic resonance perfusion imaging during baseline conditions and after Dipyridamole-induced vasodilatation in nine type 1 diabetic patients with autonomic neuropathy (AN+), defined by cardiovascular tests, as well as in 10 type 1 diabetic patients without autonomic neuropathy (AN−) and 10 healthy control subjects. Baseline myocardial perfusion index ( K i ) was similar in the three groups (AN+ 88.6 ± 8.7 ml · 100 g −1 · min −1 , AN− 82.6 ± 7.2, control subjects 93.7 ± 9.0) (means ± SE). K i during Dipyridamole vasodilatation was significantly lower in the patients with autonomic neuropathy ( P < 0.001) than in the other groups (AN+ 131.1 ± 13.0 ml · 100 g −1 · min −1 , AN− 177.3 ± 8.6, control subjects 197.2 ± 8.9). Mean blood pressure was unchanged during Dipyridamole infusion in AN− and control subjects, whereas a significant blood pressure decrease was found in AN+ (15.6 ± 2.6 mmHg, P < 0.025). There was a significant correlation between blood pressure response to Dipyridamole and myocardial perfusion reserve index. We conclude that type 1 diabetic patients with autonomic neuropathy have a decreased myocardial perfusion reserve capacity when challenged with a vasodilatator, a finding that may in part be the pathophysiological substrate for the increase in mortality in these patients. The underlying mechanism may be defective myocardial sympathetic vasodilatation, a lack of ability to maintain blood pressure during vasodilatation, or both. Footnotes Address correspondence and reprint requests to J. Hilsted, Department of Endocrinology 541, H:S Hvidovre University Hospital, DK-2650 Hvidovre, Denmark. E-mail: jannik.hilsted{at}hh.hosp.dk . Received for publication 8 February 2002 and accepted in revised form 12 July 2002. H.B.W.L. is currently affiliated with the Magnetic Resonance Center, Medical Section, University Hospital Trondheim, Trondheim, Norway. ECG, electrocardiogram; K i , myocardial perfusion index; LVMI, left ventricular mass index; MIBG, [ 123 I]-metaiodobenzylguanidine; MR, magnetic resonance; MRI, MR imaging; PET, positron emission tomography; ROI, region of interest; SPECT, single-photon emission tomography. DIABETES

Sibutramine is a tertiary amine that has been shown to induce dose-dependent weight loss and to enhance the effects of a low-calorie diet for up to a year. We did a randomised, double-blind trial to assess the usefulness of sibutramine in maintaining substantial weight loss over 2 years. Eight European centres recruited 605 obese patients (body-mass index 30-45 kg/m 2 ) for a 6-month period of weight loss with sibutramine (10 mg/day) and an individualised 600 kcal/day deficit programme based on measured resting metabolic rates. 467 (77%) patients with more than 5% weight loss were then randomly assigned 10 mg/day sibutramine (n=352) or placebo (n=115) for a further 18 months. Sibutramine was increased up to 20 mg/day if weight regain occurred. The primary outcome measure was the number of patients at year 2 maintaining at least 80% of the weight lost between baseline and month 6. Secondary outcomes included changes in uric acid concentrations and glycaemic and lipid variables. Analysis was by intention to treat. 148 (42%) individuals in the sibutramine group and 58 (50%) in the placebo group dropped out. Of the 204 sibutramine-treated individuals who completed the trial, 89 (43%) maintained 80% or more of their original weight loss, compared with nine (16%) of the 57 individuals in the placebo group (odds ratio 4·64, p<0·001). Patients had substantial decreases over the first 6 months with respect to triglycerides, VLDL cholesterol, insulin, C peptide, and uric acid; these changes were sustained in the sibutramine group but not the placebo group. HDL cholesterol concentrations rose substantially in the second year: overall increases were 20·7% (sibutramine) and 11·7% (placebo, p<0·001). 20 (3%) patients were withdrawn because of increases in blood pressure; in the sibutramine group, systolic blood pressure rose from baseline to 2 years by 0·1 mm Hg (SD 12·9), diastolic blood pressure by 2·3 mm Hg (9·4), and pulse rate by 4·1 beats/min (11·9). This individualised management programme achieved weight loss in 77% of obese patients and sustained weight loss in most patients continuing therapy for 2 years. Changes in concentrations of HDL cholesterol, VLDL cholesterol, and triglyceride, but not LDL cholesterol, exceed those expected either from weight loss alone or when induced by other selective therapies for low concentrations of HDL cholesterol relating to coronary heart disease.

ObjectivesCardiovascular autonomic neuropathy (CAN) and abnormal circadian blood pressure (BP) rhythm are independent cardiovascular risk factors in patients with diabetes and associations between CAN, non-dipping of nocturnal BP and coronary artery disease have been demonstrated. We aimed to test if bedtime dosing (BD) versus morning dosing (MD) of the ACE inhibitor enalapril would affect the 24-hour BP profile in patients with type 1 diabetes (T1D), CAN and non-dipping.SettingSecondary healthcare unit in Copenhagen, Denmark.Participants24 normoalbuminuric patients with T1D with CAN and non-dipping were included, consisting of mixed gender and Caucasian origin. Mean±SD age, glycosylated haemoglobin and diabetes duration were 60±7 years, 7.9±0.7% (62±7 mmol/mol) and 36±11 years.InterventionsIn this randomised, placebo-controlled, double-blind cross-over study, the patients were treated for 12 weeks with either MD (20 mg enalapril in the morning and placebo at bedtime) or BD (placebo in the morning and 20 mg enalapril at bedtime), followed by 12 weeks of switched treatment regimen.Primary and secondary outcome measuresPrimary outcome was altered dipping of nocturnal BP. Secondary outcomes included a measurable effect on other cardiovascular risk factors than BP, including left ventricular function (LVF).ResultsSystolic BP dipping increased 2.4% (0.03–4.9%; p=0.048) with BD compared to MD of enalapril. There was no increase in mean arterial pressure dipping (2.2% (−0.1% to 4.5%; p=0.07)). No difference was found on measures of LVF (p≥0.15). No adverse events were registered during the study.ConclusionsWe demonstrated that patients with T1D with CAN and non-dipping can be treated with an ACE inhibitor at night as BD as opposed to MD increased BP dipping, thereby diminishing the abnormal BP profile. The potentially beneficial effect on long-term cardiovascular risk remains to be determined.Trial registration numberEudraCT2012-002136-90; Post-results.

Type 1 diabetes is associated with increased cardiovascular (CV) morbidity and mortality, and cardiovascular autonomic neuropathy (CAN) is an important CV risk factor. The study aimed to explore associations between CAN and altered cardiac chamber sizes in persons with type 1 diabetes. This was a cross-sectional study of 71 asymptomatic, normoalbuminuric participants with long-term type 1 diabetes (39 with CAN, determined by >1 abnormal autonomic function test) examined with cardiac multi detector computed tomography scans, which allowed measurements of left ventricular mass and all four cardiac chamber volumes. Cardiac chambers were indexed according to body surface area (ml/m2 or g/m2). Persons with and without CAN had mean ± SD age of 57 ± 7 and 50 ± 8 years (p < 0.001) and diabetes duration of 36 ± 11 and 32 ± 9 years (p < 0.05), respectively. Increasing autonomic dysfunction, evaluated by decrease in heart rate variability during deep breathing (in beats per minute), was associated with larger right (−0.5, 95% CI −1.0 to −0.0, p < 0.05) and trend towards larger left (−0.4, 95% CI −0.8–0.0, p < 0.1) ventricular volumes in multivariable linear regression. Our results suggest that impaired autonomic function may be associated with modest enlargement of ventricular volumes; this might be an early sign of progression towards heart failure.

Introduction Cardiac autonomic neuropathy (CAN) and elevated nocturnal blood pressure are independent risk factors for cardiovascular disease in patients with diabetes. Previously, associations between CAN, non-dipping of nocturnal blood pressure and coronary artery calcification have been demonstrated. The present protocol describes a trial to test the efficacy of bedtime dosing of the ACE inhibitor enalapril on night time blood pressure and left ventricular mass in patients with type 1 diabetes. Materials and methods In a randomised, double-blind, two-way cross-over study, 24 normoalbuminuric patients with type 1 diabetes with CAN will be treated for 12 weeks with either morning or bedtime dosing of 20 mg enalapril, followed by 12 weeks of switched treatment regimen. During each treatment period, two 24 h ambulatory blood pressure measurements will be performed and after each treatment period left ventricular mass will be determined by multisliced CT. Primary end points will be reduction in blood pressure and reduction in left ventricular mass. Ethics and dissemination The study has been approved by the Danish Medicines Agency, the Scientific-Ethical Committee of the Capital Region of Denmark and the Danish Data Protection Agency. An external monitoring committee (the Good Clinical Practice Unit at Copenhagen University Hospital) will oversee the study. The results of the study will be presented at national and international scientific meetings and publications will be submitted to peer-reviewed journals. Trial registration number EudraCT (2012- 002136-90).

BACKGROUND:: In this report we assess pre-treatment determinants of weight loss and maintenance outcome in The Sibutramine Trial of Obesity Reduction and Maintenance (STORM), a 2 y randomized, double-blind, placebo-controlled, European multicenter study examining the effect of sibutramine (Sib) on inducing and maintaining weight loss in obese subjects. MATERIAL:: A total of 605 obese patients (BMI: 30-45 kg/m2 ) of both gender were included from eight European centers and treated for 24 months. The patients were treated for the initial 6 months by Sib (10 mg/day) and a low-fat low-energy, individualized diet (600 kcal/day deficit). The 467 patients who achieved >5% weight loss after 6 months were randomized 3:1 to Sib (10 mg/day) (Sib/Sib) and placebo (Sib/Pla) for weight maintenance over a further 18 months. MAIN OUTCOME AND ANALYSES:: Pre-treatment individual characteristics were assessed as predictors of 6 months weight loss (kg) and 24 months weight maintenance using simple and multivariate correlation and regression analyses. RESULTS:: In univariate analyses, the 6 month weight loss (n=505) was positively associated with pre-treatment body weight (r=0.27), height (r=0.18), fat-free mass (r=0.21) (all P<0.001), fat mass (r=0.13, P<0.03), and resting metabolic rate (r=0.13, P<0.003). However, no relation was found with age, gender, smoking status, age at onset of obesity, or number of previous slimming attempts. The same predictors were found for weight change to endpoint in the Sib/Sib group (n=350), while no predictors were identified in the Sib/Pla (n=114). In the multivariate regression analysis only pre-treatment body weight predicted weight loss at 6 months (P<0.001). Weight change (kg) to 24 month was predicted by: 4.34+0.07*body weight (kg)-4*treatment (Sib=1, Pla=0)-0.06*age (y), (r2 =8%, P<0.001). CONCLUSION:: Only pre-treatment body weight seems to be an important independent predictor of 6 months weight loss and 24 month weight maintenance in this study on diet and Sib. As only 8% of the variation in 24 months weight change could be explained by the predictors, the clinical value of this information is limited. INTERNATIONAL JOURNAL OF OBESITY: (2001) 25, 496-501