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Body of Proof

Since 1990, epidemiological trends in comorbid conditions of obesity and type 2 diabetes (T2DM) have shifted geographically, escalating in developing nations to pandemic proportions. The underlying mechanisms causing shared pathophysiology and relative remission patterns are not distinctly understood, however. Different modes of intervention to manage obesity in diabetic patients have been launched in selective populations with considerable success.

Symbiotic Relationship

It is noted that there is a seven-times greater risk of diabetes in obese people compared to those of healthy weight, with a threefold increase in risk for overweight people (1). Although it is known that body fat distribution is an important determinant of increased risk of diabetes, the causation behind this correlation remains uncertain.

It is also unclear why not all people who are obese develop T2DM and why not all people with this condition are obese (1). Being overweight or obese – a body mass index (BMI) of 25kg/m2 or more – is the main modifiable risk factor for T2DM (2). The risk of developing the disease is linked with an increase in body weight during early adulthood (3). In addition, people who have been obese for longer periods of time have been found to be at greater risk of developing T2DM (4).

Though the precise mechanisms and linkage underpinning obesity and T2DM are not clearly understood, theories and observations on obesity-related insulin resistance and progressive-cell dysfunction have been recorded. The difference in glycaemic effects between subcutaneous and visceral fat, and the role of immune cells in adipose tissue, are all ascribed to different influences, depending on the degree of obesity and where in the body the fat accumulates (5).

Some of the molecular mechanisms which supposedly link obesity and T2DM include: heightened production of adipokines/cytokines; implicating tumour necrosis factor-α; resistin; retinol-binding protein 4; and mitochondrial dysfunction evident by decreased mitochondrial mass and function – both of which contribute to insulin resistance (6,7). Genetic or epigenetic factors – like the PDX1 gene – have been shown to influence the predisposal for β-cell decompensation in obese rodents (8).

The trend and epidemiological evolution of obesity in diabetic subjects has not been found uniformly across the globe. People in Asia tend to develop diabetes with a lesser degree of obesity at younger ages, suffer longer with complications and die sooner than people in other regions. Within the continent, a high proportion of body fat and predominance of central obesity are paired with insulin resistance. Asian people have a strong genetic susceptibility to T2DM, characterised by early β-cell failure and prominent central obesity (9). The WHO Asia-Pacific guideline for diagnostic criteria of obesity states that a substantial proportion of Asian people with BMI values lower than 25kg/m2 (currently not classified as overweight) are at high risk of developing T2DM and cardiovascular disease (10).

Management Strategies

It is currently difficult to treat coexistent T2DM and obesity because some antidiabetic agents – including thiazolidinediones, insulin and sulphonylureas – are associated with weight gain. Type 2 diabetics are, therefore, at risk of getting caught up in a vicious circle of increased weight and insulin resistance, requiring further intensification of glycaemic treatment (11). In patients who have already been diagnosed, weight loss may help to slow the natural progression of the disease, and delay the need for the intensification of insulin therapy (12).

The standard strategies for weight management in obese diabetic patients include lifestyle modification, pharmacotherapy and bariatric surgeries. Weight loss with dietary interventions and increased physical activity has been a standard recommendation during diabetes management for many years. Meta-analysis of randomised controlled trials, with a minimum follow-up period of 12 months, demonstrated that lifestyle interventions can result in a modest pooled weight loss of 1.7kg (3.1% of initial body weight) in T2DM adults, with improvements in glycated haemoglobin (HbA1c) of up to 2.6% (13).

The AHEAD trial concluded that intensive lifestyle intervention produced greater reductions in HbA1c, but did not reduce the likelihood of cardiovascular events in overweight or obese adults with T2DM (14). Nonetheless, lifestyle changes alone usually only offer limited long-term glycaemic control, and most patients with T2DM require additional treatment to meet goals in the long-run (15).

Pharmacotherapy

In conjunction with lifestyle modifications, pharmacotherapy should be considered for obese diabetic patients. Orlistat (lipase inhibitor) and liraglutide (GLP-1 receptor agonist) are currently the only drugs to be approved by both the FDA and EMA to treat obesity on a long-term basis. Initiation of treatment with orlistat is generally recommended in patients with a BMI >28kg/m2.

After an initial three-month period, its efficacy should be evaluated and subsequent treatment only continued if satisfactory weight loss is achieved. A reduction of >5% the initial body weight is typically regarded as adequate; however, in the presence of T2DM, less strict goals are accepted (for example >3% weight loss) (16).

It has been reported that orlistat treatment over the period of a year reduces weight by 3.9-6.2kg, compared to 1.3-4.3kg with a placebo, and leads to significant improvements in HbA1c (0.28–1.1%) (17). Meanwhile, liraglutide was approved recently for chronic weight management in individuals with a BMI of 30kg/m2 or greater (obesity), or 27kg/m2 and greater (overweight), in the presence of at least one weight-related comorbidity such as hypertension, diabetes or dyslipidemia (18).

Bariatric Surgery


Since diabetes remission was observed to be an additional outcome following treatment of morbid obesity, there has been a rise in the number of surgeries to treat obese diabetics. Certain types of bariatric surgeries can be restrictive, malabsorptive, or a combination of both.

The most commonly used procedures include vertical banded gastroplasty, laparoscopic adjustable gastric banding (LAGB), Roux-en-Y gastric bypass partitioned, biliopancreatic diversion with duodenal switch, and sleeve gastrectomy.

A recent systematic review found that bariatric surgery leads to greater weight loss and higher remission rates of T2DM, plus greater reductions in use of antidiabetic, antihypertensive and lipid lowering drugs, when compared with non-surgical treatment for obesity (19). However, results were limited to two years of follow-up and based on a small number of studies and individuals.

Meta-analysis on 621 studies undertaken between 1990 to 2006 showed that 78.1% of diabetic patients had complete resolution after bariatric surgery, and diabetes was improved or resolved in 86.6% of patients (20). The responses were more pronounced in procedures associated with greater percentage of body weight loss, maintained for two years or more. Dixon et al reported a randomised controlled trial comparing LAGB to conventional T2DM management in subjects with BMI 30-40kg/m2 who had early (<2 years duration) and relatively mild diabetes (21). LAGB saw significantly larger reductions in fasting blood sugar, HbA1c and diabetes medication usage.

Global Treatment Practices

The International Diabetes Federation (IDF), American Diabetes Association and Canadian Diabetes Association now recommend bariatric surgery in their treatment guidelines for obese patients with T2DM (22-24). Citing the remission rates in diabetic patients following bariatric surgeries, the UK’s National Institute for Health and Care Excellence (NICE) issued improved guidance in November 2014 to include the surgery as part of a treatment pathway, whereby the need to undergo these surgeries should increase so that the spending amount on diabetes could be reduced (25). In the UK, BMI of >35kg/m2 is the prevailing cut-off point for considering bariatric surgeries in type 2 diabetic patients. NICE has also recommended assessment for bariatric surgery in people of Asian origin, whose newly-diagnosed T2DM is at a lower BMI than other populations.

In Asia, the burden of T2DM is rapidly increasing. It is predicted that China, India, Pakistan, Indonesia and Bangladesh are among the top 10 countries expected to have the highest number of diabetes mellitus citizens by 2030 (26). In Africa, 76% of deaths due to diabetes are in people under the age of 60. People in Asia develop diabetes at a lower degree of obesity, at a younger age, suffer longer with chronic diabetic complications, and die sooner than those in Western countries (9). The prevalence of comorbid conditions like hypertension and cardiovascular complications are also increasing disproportionately in developing countries.

Currently, there is no sufficient epidemiological data to estimate the economic implications of obesity prevention and control in diabetic patients in developing countries – and this is a genuine area of concern. This difference in predisposition and disease pattern warrants tailored treatment pathways with comprehensive and integrated public health programmes to manage obese diabetics.

Targeted Intervention

In 2014, the IDF estimated that 387 million people suffer from diabetes; by 2035, this will rise to 592 million. Some 77% of people with diabetes live in low and middle income countries. For a complete understanding of the role of obesity in diabetes prognosis, and to establish a therapeutic advantage by tailoring individualised intervention, more research into its heterogeneity and pathophysiology is required. But, with the current level of evidence we have at our disposal, it can be safely asserted that controlled management of obesity will augment well with long-term diabetes prognosis. Further epidemiologic studies in emerging countries is highly recommended to understand the disease and economic burden, and to plan timely intervention strategies.

References

1. Abdullah A, Peeters A, de Courten M et al, The magnitude of association between overweight and obesity and the risk of diabetes: A meta-analysis of prospective cohort studies, Diabetes Research & Clinical Practice 89(3): pp309-319, 2010
2. National Institute for Health and Care Excellence, PH35, Preventing type 2 diabetes: Population and community-level interventions, 2011. Visit: http://publications.nice.org.uk/ preventing-type-2-diabetes-population-and-community-level -interventions-ph35
3. Kodama S, Horikawa C, Fujihara K et al, Quantitative relationship between body weight gain in adulthood and incident type 2 diabetes: A meta-analysis, Obes Rev 15(3): pp202-214, 2014
4. Abdullah A, Stoelwinder J, Shortreed S et al, The duration of obesity and the risk of type 2 diabetes, Public Health Nutr 14(1): pp119-126, 2011
5. Eckel RH, Kahn SE, Ferrannini E et al, Obesity and type 2 diabetes: What can be unified and what needs to be individualized? Diabetes Care 34(6): pp1,424-1,430, 2011
6. Deng Y and Scherer PE, Adipokines as novel biomarkers and regulators of the metabolic syndrome, Annals N Y Acad Sci 1(50): p1,212, 2010
7. Bournat JC, Brown CW, Mitochondrial dysfunction in obesity, Curr Opin Endocrinol Diabetes Obes 17: pp446-452, 2010
8. Leibowitz G, Ferber S, Apelqvist A et al, IPF1/PDX1 deficiency and b-cell dysfunction in Psammomys obesus, an animal with type 2, Diabetes 50: pp1,799-1,806, 2001
9. Yoon KH, Lee JH et al, Epidemic obesity and type 2 diabetes in Asia, The Lancet 368: pp1,681-1,688, 2006
10. World Health Organization, International Obesity Task Force, The Asian-Pacific perspective: Redefining obesity and its treatment, 2000
11. Julia Kenkrae et al, Treating the obese diabetic, Expert Rev Clin Pharmacol 6(2): pp171-183, 2013
12. Knowler WC, Fowler SE, Hamman RF et al, Diabetes Prevention Program Research Group, 10-year follow-up of diabetes incidence and weight loss, Diabetes Prevention Program Outcomes Study 374: pp1,677- 1,686, 2009
13. Norris SL, Zhang X, Avenell A et al, Long-term nonpharmacologic weight loss interventions for adults with type 2 diabetes, Cochrane Database Syst Rev 2: CD004095, 2005
14. Rena R et al, Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes, N Engl J Med 369: pp145-154, 2013
15. Nathan DM, Buse JB, Davidson MB et al, Medical management of hyperglycaemia in type 2 diabetes mellitus: A consensus algorithm for the initiation and adjustment of therapy, Diabetologia 52: pp17-30, 2009
16. NICE Guidelines, Obesity: The prevention, identification, assessment and management of overweight and obesity in adults and children (CG43), Visit: www.nice.org.uk/nicemedia/ pdf/cg43niceguideline.pdf
17. Lloret-Linares C, Greenfield JR and Czernichow S, Effect of weight-reducing agents on glycaemic parameters and progression to type 2 diabetes: A review, Diabet Med 25: pp1,142-1,150, 2008
18. US Department of Health and Human Services, FDA approves weight-management drug Saxenda. Visit: www.fda.gov/ newsevents/newsroom/pressannouncements/ucm427913.htm
19. Gloy VL, Briel M, Bhatt DL et al, Bariatric surgery versus non-surgical treatment for obesity: A systematic review and meta-analysis of randomised controlled trials, BMJ 347, 2013
20. Buchwald H and Estok R, Weight and type 2 diabetes after bariatric surgery: Systematic review and meta-analysis, The American Journal of Medicine 122(3): pp248-256, 2009
21. Dixon JB, O’Brien PE, Playfair J et al, Laparoscopic adjustable gastric banding in severely obese adolescents: A randomized trial, JAMA 299: pp316-323, 2008
22. American Diabetes Association, Standards of medical care in diabetes, Diabetes Care 36(1): S11-S66, 2013
23. Dixon JB, Zimmet P, Alberti KG et al, Bariatric Surgery: An IDF statement for obese type 2 diabetes, Diabet Med 28(6): pp628-642, 2011
24. Weight Management in Diabetes, Canadian Journal of Diabetes 37(1): S82, April 2013
25. NICE Guidelines, Obesity: Identification, assessment and management of overweight and obesity in children, young people and adults, CG189, 2014
26. Shaw JE, Sicree RA and Zimmet PZ, Global estimates of the prevalence of diabetes for 2010 and 2030, Diabetes Res Clin Pract 87(1): pp4-14, 2010


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Dr Mohamed El Malt is a Chief Medical Consultant at Europital. He is an oncology surgeon and expert scientific researcher with more than 31 years of experience as a medical doctor. Mohamed’s expertise includes 16 years of clinical research and drug development in academic medical centres, pharma companies and CROs, as an investigator, project leader and medical director.

Dr Vijayanand Rajendran is a Clinical Research Physician at Europital. He is a qualified physician with over eight years of clinical and research experience spanning safety monitoring in Phase 1-4 trials and a variety of therapeutic areas, including oncology, haematology, gastroenterology and the musculoskeletal system.
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Vijayanand Rajendran
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