Practice Update: Endocrinology | Volume 1. Number 2. 2016

OBESITY

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EXPERT COMMENTARY Overweight, obesity leads to higher mortality Interview with Prof Jonathan Shaw T his study is the largest meta- analysis studying the effects of BMI on all-cause mortality. study shows that this is only the case when you don’t account for all relevant factors such as smoking and chronic illnesses that contribute to weight loss. their effect is similar in relation to mortality. BMI and mortality risk The Lancet Take-home message

• This meta-analysis of prospective studies was undertaken to assess the association between BMI and mortality risk across four continents. Crude data included over 10 million adults in Europe, North America, Asia, and Australia and New Zealand; however, to reduce confounding factors, the primary analyses included only the 4 million never-smokers without chronic disease who were followed for a minimum of 5 years. Mortality risk increased log-linearly with BMI for BMI >25 kg/m 2 ; the hazard ratio per 5 kg/m 2 higher BMI was 1.29 to 1.39, depending on the continent. • Both overweight and obesity appear to be associated with increased mortality risk across four continents. BACKGROUND Overweight and obesity are increasing worldwide. To help assess their relevance to mortality in different populations we conducted individual- participant data meta-analyses of prospective studies of body-mass index (BMI), limiting confounding and reverse causality by restricting analyses to never- smokers and excluding pre-existing disease and the first 5 years of follow-up. METHODS Of 10,625,411 participants in Asia, Australia and New Zealand, Europe, and North America from 239 prospective studies (median follow-up 13.7 years, IQR 11.4–14.7), 3,951,455 people in 189 studies were never-smokers without chronic diseases at recruitment who survived 5 years, of whom 385 879 died. The primary analyses are of these deaths, and study, age, and sex adjusted hazard ratios (HRs), relative to BMI 22.5–<25.0 kg/m 2 . FINDINGS All-cause mortality was minimal at 20.0–25.0 kg/m 2 (HR 1.00, 95% CI 0.98–1.02 for BMI 20.0–<22.5 kg/m 2 ; 1.00, 0.99–1.01 for BMI 22.5–<25.0 kg/m 2 ), and increased significantly both just below this range (1.13, 1.09–1.17 for BMI 18.5–<20.0 kg/m 2 ; 1.51, 1.43–1.59 for BMI 15.0–<18.5) and throughout the overweight range (1.07, 1.07–1.08 for BMI 25.0–<27.5 kg/m 2 ; 1.20, 1.18–1.22 for BMI 27.5–<30.0 kg/ m 2 ). The HR for obesity grade 1 (BMI 30.0–<35.0 kg/m 2 ) was 1.45, 95% CI 1.41–1.48; the HR for obesity grade 2 (35.0–<40·0 kg/m 2 ) was 1.94, 1.87–2.01; and the HR for obesity grade 3 (40.0–<60.0 kg/m 2 ) was 2.76, 2.60–2.92. For BMI over 25.0 kg/ m 2 , mortality increased approximately log-linearly with BMI; the HR per 5 kg/m 2 units higher BMI was 1.39 (1.34–1.43) in Europe, 1.29 (1.26–1.32) in North America, 1.39 (1.34–1.44) in East Asia, and 1.31 (1.27–1.35) in Australia and New Zealand. This HR per 5 kg/m 2 units higher BMI (for BMI over 25 kg/m 2 ) was greater in younger than older people (1.52, 95% CI 1.47–1.56, for BMI measured at 35–49 years vs 1.21, 1.17–1.25, for BMI measured at 70–89 years; p heterogeneity < 0.0001), greater in men than women (1.51, 1.46–1.56, vs 1.30, 1.26–1.33; p heterogeneity < 0.0001), but similar in studies with self-reported and measured BMI. INTERPRETATION The associations of both overweight and obesity with higher all- cause mortality were broadly consistent in four continents. This finding supports strategies to combat the entire spectrum of excess adiposity in many populations. Body-mass index and all-cause mortality: Individual-participant-data meta- analysis of 239 prospective studies in four continents. Lancet 2016;[EPub ahead of print], The Global BMI Mortality Collaboration. JOURNAL SCAN Relative hypocortisolism is associated with metabolic syndrome in recurrent affective disorders Journal of Affective Disorders Take-home message • This cross-sectional study examined metabolic status in 245 patients with depression or bipolar disorder and 258 controls who participated in a low-dose weight-adjusted dexamethasone-suppression-test (DST). Increased odds ratios for obesity, overweight, large waist, high LDL, low HDL, high LDL/low HDL ratio, high TC/HDL ratio, and meta- bolic syndrome were found in patients with low post-DST cortisol levels compared with patients with normal or high post-DST cortisol levels. • This study demonstrates that cardiovascular risk factors and metabolic disorders are related to hypocortisolism and suggests that long-term stress may be a main contributor. Abstract

Not surprisingly, Australia and New Zealand populations behave similarly to those in Europe and NorthAmerica. It’s the population in East Asia that appears to be slightly different, whereby the prevalence of obesity is lower and the overall effect of obesity on mortality is weaker. However, this analysis is based on cohorts followed during the 1980s, 1990s and early 2000s and with obesity increasing around the world particularly in East Asia, the prevalence of obesity is not as low now as it was then. Overall, this is a good study with large numbers of people that enables a lot of analyses. However, it is still based on a single measurement of BMI at one point in time. The ideal study would track BMI over time in individuals to really be able to identify those who are losing weight due to diagnosed or undiagnosed diseases.

It supports the idea that individuals who are overweight and at all levels of obesity are at higher risk of death. In fact, the BMI–mortality link has been a point of debate over the last few years. There have been studies reporting that overweight and lower levels of obesity are associated with reduced levels of mortality. This

This analysis also shows that the association between overweight and obesity and mortality applies across major racial and ethnic groups. So despite the different manifestations and prevalence of overweight and obesity in different ethnic groups

Prof Jonathan Shaw is Head of Clinical Diabetes and

Domain Head of Population Health at Baker IDI Heart and Diabetes

Institute in Melbourne, and chief investigator of the AusDiab Study.

JOURNAL SCAN Addition of gastric bypass to medical management for uncontrolled diabetes and obesity Diabetes Care Take-home message • The authors of this randomised trial evaluated the effectiveness of lifestyle-medical management plus Roux-en-Y gastric bypass (24 months of medical management followed by gastric bypass) compared with lifestyle-medical management alone in 120 patients with obesity and poorly controlled diabetes. At 36 months, they found that the primary endpoint (HbA 1c <7%, LDL <100 mg/dL, and SBP <130 mmHg) was achieved in 9% of the medical management group and 28% of the gastric bypass group (P = 0.01); patients in the gastric bypass group lost more weight, used fewer medications, and were more likely to have diabetes remission. Significant adverse events were more common in the gastric bypass groups compared with the medical management group (51 vs 24, respectively). • Lifestyle-medical management followed by gastric bypass appears to be more effective than lifestyle– medical management alone for improving glycaemic control, weight loss, and meeting other diabetes goals, but gastric bypass also appears to be associated with more adverse events, and the positive effects appear to decrease over time. Abstract

ratios (OR) for obesity (OR=4.0), overweight (OR=4.0), large waist (OR=2.7), high LDL (OR=4.2), low HDL (OR=2.4), high LDL/HDL ratio (OR=3.3), high TC/HDL ratio (OR=3.4) and metabolic syndrome (OR=2.0). A similar pattern but less pronounced was also found in the control sample. LIMITATIONS The cross sectional study design and absence of analyses addressing lifestyle factors. CONCLUSIONS Our findings suggest that a substantial portion of the metabolic disor- ders and cardiovascular risk factors seen in recurrent affective disorders are found among individuals exhibiting hypocortisolism. This might indicate that long-term stress is a central contributor to metabolic abnormali- ties and CVD mortality in recurrent affective disorders. Relative hypocortisolism is associated with obesity and the metabolic syndrome in recurrent affective disorder. J Affect Disord 2016;204:187–196, Maripuu M, Wikgren M, Karling P, et al.

BACKGROUND Cardiovascular disease (CVD) is one of the main causes of excess deaths in affective disorders. Affective disorders are as- sociated with increased frequencies of CVD risk-factors such as obesity, dyslipidaemia, and metabolic syndrome. Stress-induced chronic cortisol excess has been suggested to promote obesity and metabolic syndrome. Chronic stress with frequent or persisting hypothalamic- pituitary-adrenal-axis (HPA-axis) hyperactivity may, over time, lead to a state of low HPA- axis activity, also denoted hypocortisolism. A low-dose weight-adjusted dexamethasone- suppression-test (DST) is considered to be a sensitive measure of hypocortisolism. METHODS 245 patients with recurrent depres- sion or bipolar disorder and 258 controls participated in a low-dose DST and were also examined with regard to metabolic status. RESULTS Patients with hypocortisolism (low post-DST cortisol) compared with patients without hypocortisolism (normal or high post-DST cortisol) exhibited increased odds

diabetes at 36 months, whereas 17% of gastric bypass patients had full remission and 19% had partial remis- sion. Lifestyle-medical management patients used more medications than gastric bypass patients: mean (SD) 3.8 (3.3) vs 1.8 (2.4). Percent weight loss was mean (SD) 6.3% (16.1) in lifestyle-medical management vs 21.0% (14.5) in gastric bypass; P < 0.001. Over 3 years, 24 serious or clinically significant adverse events were observed in lifestyle-medical management vs 51 with gastric bypass. CONCLUSIONS Gastric bypass is more effective than life- style – medical management intervention in achieving diabetes treatment goals, mainly by improved glycae- mic control. However, the effect of surgery diminishes with time and is associated with more adverse events. Durability of addition of Roux-en-Y gastric bypass to lifestyle intervention and medical management in achieving primary treatment goals for uncon- trolled type 2 diabetes in mild-to-moderate obesity: A randomised control trial. Diabetes Care 2016 Jun 16;[Epub ahead of print], Ikramuddin S, Korner J, Lee WJ, et al.

OBJECTIVE We compared 3-year achievement of an American Diabetes Association composite treatment goal (HbA 1c <7.0%, LDL cholesterol <100 mg/dL, and systolic blood pressure <130 mmHg) after 2 years of intensive lifestyle-medical management intervention, with and without Roux-en-Y gastric bypass, with one additional year of usual care. RESEARCH DESIGN AND METHODS A total of 120 adult participants, with BMI 30.0–39.9 kg/m 2 and HbA 1c ≥8.0%, were randomised 1:1 to two treatment arms at three clinical sites in the US and one in Taiwan. All patients received the lifestyle–medical management intervention for 24 months; half were randomised to also receive gastric bypass. RESULTS At 36 months, the triple end point goal was met in 9% of lifestyle-medical management patients and 28% of gastric bypass patients (P = 0.01): 10% and 19% lower than at 12 months. Mean (SD) HbA 1c values at 3 years were 8.6% (3.5) and 6.7% (2.0) (P < 0.001). No lifestyle-medical management patient had remission of

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