SECTION III Is Weight Loss Beneficial for Reduction of Morbidity and Mortality? What is the controversy about? PETER M. NILSSON, MD POSSIBLE EXPLANATIONS FOR INCREASED HEALTH RISKS ASSOCIATED WITH The increase of obesity and type 2 diabetes on a global scale has increased the interest in how to WEIGHT LOSS — As weight loss has counteract this epidemic. Improved lifestyle in general is a fundamental approach, but other been associated not only with health ben- remedies such as specific weight reduction or diabetes preventive drugs and surgery have also efits, but also with health hazards (Table been tested. One problem to understand is what really happens after weight loss. Ongoing 1), it is important to find some putative studies will try to address this question, such as the Swedish Obese Subjects (SOS) surgery study, explanations for these paradoxical effects. the Look AHEAD (Action for Health in Diabetes) trial in the U.S. (recruiting obese type 2 diabetic One explanation is simple; the associa- patients), and the Comprehensive Rimonabant Evaluation Study of Cardiovascular End Points tions could be the result of residual con- and Outcomes (CRESCENDO) trial (by use of rimonabant versus placebo). This is very impor- tant, since previously, several observational studies in large population-based cohorts have founding and therefore be spurious and indicated some detrimental effects of weight loss, even after intentional weight loss, with in- classified as artifacts. It is well known that creased morbidity and mortality rates. chronic devastating disease will lead to weight loss in many patients, for example, Diabetes Care 31 (Suppl. 2):S278–S283, 2008 cardiac cachexia or advanced chronic ob- structive pulmonary disease, and thus as- besity is a well-established risk fac- confounding, 2) subclinical disease or de- sociate observational weight loss with tor for many chronic disorders such pression causing both weight loss and in- increased mortality risk. In the studies O as cardiovascular disease (CVD), creased mortality risk, 3) true detrimental from the Nordic countries (7–10), re- type 2 diabetes, and certain cancers, as effects on metabolism by weight loss per searchers have however tried to avoid this well as for increased all-cause mortality se, and 4) weight loss being a marker of fallacy by excluding unhealthy subjects at risk (1–3). It is therefore paradoxical that early general aging (biological involution) baseline for follow-up analyses, as well as weight loss, whether only observational in susceptible individuals, causing pre- excluding the first few years of follow-up or even intentional (in some observational mature morbidity and mortality. It seems regarding mortal events to avoid con- studies) is also associated with an in- that weight loss may well improve medi- founding by subclinical disease. Another explanation is that psychiatric conditions creased mortality risk (4–10). This has cal symptoms, risk factor levels, and qual- such as depression, eventually leading to now been documented from four Nordic ity of life for obese subjects, but the countries (7–10) in recent epidemiologi- suicide, could influence the association paradoxical finding of an increased mor- cal studies based on population-based co- between weight loss due to poor appetite tality risk associated with observational horts followed over time, after an initial in depressed subjects with later mortality assessment of weight loss compared with and even intentional weight loss (10) calls risk. This could well be true for some se- weight stability or weight increase during for more research efforts and a more cau- lect subjects, but cannot be accepted as a the first few years of follow-up. Therefore, tious attitude toward the healthy but more general explanation for larger a clinical controversy exists. obese subject asking for medical advice. groups of people experiencing weight In Malmo¨, Sweden, several studies An alternative approach is to promote loss. A third explanation is based on the have shown the health hazards related to weight stabilization as a goal for the fact that biological involution (e.g., re- obesity (11,12), but also have confirmed healthy but overweight or even mildly duced weight and height) in healthy sub- the association between observational obese individual, because a stable weight jects is part of a normal aging process. weight loss and increased long-term mor- has been associated with less cardiovascu- This is supposed to take a more rapid tality risk in middle-aged men (7). Why is lar risk and less mortality in observational course in subjects showing signs of early there such a paradoxical association? Pos- studies, both in comparison with weight ageing, thereby increasing the risk of ear- sible explanations could include the fol- increase and weight loss (7–10). ly-onset mortality. For CVD, this can be lowing: 1) an artifact due to residual called the early vascular aging syndrome. ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● Finally, it is difficult to rule out the From the Department of Clinical Sciences, University Hospital, Malmo¨, Sweden. possibility that weight loss per se could be Address correspondence and reprint requests to Peter M. Nilsson, Department of Clinical Sciences, hazardous to health, at least in some sus- University Hospital, S-205 02 Malmo¨, Sweden. E-mail: [email protected]. The author of this article has no relevant duality of interest to declare. ceptible individuals. One piece of evi- This article is based on a presentation at the 1st World Congress of Controversies in Diabetes, Obesity and dence supporting this hypothesis is the Hypertension (CODHy). The Congress and the publication of this article were made possible by unrestricted well-known risk of cholelithiasis attacks educational grants from MSD, Roche, sanofi-aventis, Novo Nordisk, Medtronic, LifeScan, World Wide, Eli in obese patients after rapid intentional Lilly, Keryx, Abbott, Novartis, Pfizer, Generx Biotechnology, Schering, and Johnson & Johnson. Abbreviations: CVD, cardiovascular disease; SOS, Swedish Obese Subjects. weight loss (13). If correct, this hypothe- DOI: 10.2337/dc08-s268 sis based on observation could be extrap- © 2008 by the American Diabetes Association. olated to other unwanted health risks and S278 DIABETES CARE, VOLUME 31, SUPPLEMENT 2, FEBRUARY 2008 Nilsson eventually an increased mortality risk in a creased risk of both micro- and macro- LIFESTYLE INTERVENTION subset of people, even after intentional vascular complications (17,20). Similar TO DECREASE RISK OF weight loss. To settle this research di- findings have been noted for the weight DIABETES — In the Finnish Diabetes lemma based on observations, it takes increase, but at the same time, de- Prevention Study, 522 subjects with im- well-designed, randomized, controlled creased risk after smoking cessation or paired glucose tolerance participated intervention studies in large groups of by use of ␤-receptor blocking agents af- (23). The intervention group showed sig- overweight/obese subjects who are losing ter myocardial infarction (secondary nificantly greater improvement in each weight, either after drug treatment or sur- prevention) has been noted. In both intervention goal of weight loss and phys- gery, or a combination of these modes of conditions, the cardiovascular risk is ical exercise. After 1 and 3 years, weight interventions. more or less decreased, forming a para- reductions were 4.5 and 3.5 kg in the in- dox of weight gain–associated clinical tervention group and 1.0 and 0.9 kg in RISK OF CVD AND benefits and risk reduction. the control group, respectively. Measures DIABETES IN RELATION TO of glycemia improved more in the inter- OBESITY — Overweight and obesity vention group. The intensive lifestyle in- are major contributors to both type 2 WEIGHT CONTROL tervention produced long-term beneficial diabetes and CVD. Moreover, individu- ACHIEVEMENT IN TYPE 2 changes in diet, physical activity, and als with type 2 diabetes who also are DIABETES — The common practice clinical and biochemical parameters. It obese are at particularly high risk for to advise diabetes patients to lose weight also substantially reduced the risk of dia- CVD morbidity and mortality, since is based on beliefs of potential benefits betes by 58%, an effect that was at least other risk factors such as hypertension documented in observational studies only partly preserved during long-term post- and dyslipidemia tend to cluster with (21,22). In addition, it may also be diffi- trial follow-up, as recently described (24). obesity (14). Several studies have This is a proof of concept that an effective cult to combine this goal of weight loss shown that obesity gradually increases intervention, including weight loss, could with that of improved glycemic control if the risk of type 2 diabetes, especially if improve glucose metabolism. However, it weight-promoting antidiabetes drugs are located in the abdominal region is difficult to disentangle beneficial effects (15,16). This risk depends on several used (insulin, sulfonylureas, or glita- associated with weight loss from effects pathophysiological mechanisms in- zones). Regretfully enough, we presently caused by other simultaneous interven- cluding decreased insulin sensitivity lack data on clinical end points from ran- tions, especially that of increased physical and secondary impairment of ␤-cell domized intervention trials to really sup- activity. function associated with obesity, the port such common advice to lose weight latter