Review
Combating the dual burden: therapeutic targeting of common pathways in obesity and type 2 diabetes

https://doi.org/10.1016/S2213-8587(14)70004-XGet rights and content

Summary

The increasing prevalence of obesity is contributing substantially to the ongoing epidemic of type 2 diabetes. Abdominal adiposity, a feature of ectopic fat syndrome, is associated with silent inflammation, abnormal hormone secretion, and various metabolic disturbances that contribute to insulin resistance and insulin secretory defects, resulting in type 2 diabetes, and induce a toxic pattern that leads to cardiovascular disease, liver pathologies, and cancer. Despite the importance of weight control strategies in the prevention and management of type 2 diabetes, long-term results from lifestyle or drug interventions are generally disappointing. Furthermore, most of the classic glucose-lowering drugs have a side-effect of weight gain, which renders the management of most overweight or obese people with type 2 diabetes even more challenging. Many anti-obesity pharmacological drugs targeting central control of appetite were withdrawn from the market because of safety concerns. The gastrointestinal lipase inhibitor orlistat was the only anti-obesity drug available until the recent US, but not European, launch of phentermine–controlled-release topiramate and lorcaserin. Improved knowledge about bodyweight regulation opens new prospects for the potential use of peptides derived from the gut or the adipose tissue. Combination therapy will probably be necessary to avoid compensatory mechanisms and potentiate initial weight loss while avoiding weight regain. New glucose-lowering treatments, especially glucagon-like peptide-1 receptor agonists and sodium glucose cotransporter-2 inhibitors, offer advantages over traditional antidiabetic drugs by promoting weight loss while improving glucose control. In this Review, we explore the overlapping pathophysiology and also how various treatments can, alone or in combination, combat the dual burden of obesity and type 2 diabetes.

Introduction

The dramatic rise of the dual epidemics of type 2 diabetes and obesity is associated with increased mortality and morbidity and represents one of the most important public health challenges worldwide.1 Type 2 diabetes is a complex disease in which genetic and epigenetic factors interact with a toxic environment that promotes the development of obesity.2 Environmental risk factors include the consumption of high-calorie and high-fat foods, inadequate physical activity, and recently proposed alternative mechanisms (panel), to create a chronic energy imbalance.3 Abdominal adiposity in particular is associated with a substantially increased risk for type 2 diabetes, and overall 80% of people with type 2 diabetes are overweight or obese. Striking parallel increases in the prevalence of obesity and type 2 diabetes support the importance of body fatness as a contributing factor to the occurrence of diabetes and its complications.4 Furthermore, adipose tissue is an active endocrine and immune organ whose dysfunction (adiposopathy or so-called sick fat) is promoted by excessive caloric balance. Thus, targeting of adiposopathy and not only excess bodyweight should be viewed as a main objective in the management of obese patients with type 2 diabetes.5

Both obesity and type 2 diabetes are associated with many medical complications, especially cardiovascular disease,6 which substantially increase global health-care costs.1 Aggressive treatment, especially prevention of weight gain and ideally facilitation of weight reduction, can minimise and reduce diabetes-associated complications.7 However, weight loss and maintenance are challenging in obese people without diabetes, and even more so in obese people with type 2 diabetes.8

The close link between type 2 diabetes and excess bodyweight emphasises the need to consider the weight effects of different treatment regimens, besides their effects on glucose homoeostasis.9 A shift from a glucocentric to a weight-centric management of type 2 diabetes can be proposed, which emphasises the urgent need for new treatment strategies.10, 11 Some glucose-lowering drugs cause weight loss and some (albeit fewer) anti-obesity drugs improve glucose tolerance; thus, in this Review, we explore the overlapping pathophysiology of obesity and type 2 diabetes and also how the various treatments can, alone or in combination, combat the dual burden of these diseases. We will focus on lifestyle and drug therapy; the notable success of bariatric or metabolic surgery in combating obesity and type 2 diabetes has been covered elsewhere.12

Section snippets

Effect of weight changes on type 2 diabetes

The excess risk for diabetes with even modest weight gain is substantial and absolute weight gain during adulthood is a significant independent risk factor for type 2 diabetes.7 Intentional weight loss is associated with reduced insulin resistance and a subsequent reduction in glucolipotoxicity, which improves overall glucose homoeostasis.4, 13 In both the Finnish and US diabetes prevention programmes, weight loss gradually reduced the risk of type 2 diabetes, and even modest weight loss

Diet alone

Obesity is usually caused by excess calorie intake in relation to energy expenditure,3 so its treatment should mainly focus on healthy diet and increased physical activity, especially in the presence of type 2 diabetes (figure 2).39 However, implementation and maintenance of the lifestyle changes associated with weight loss can be challenging for many patients.24 Various weight loss strategies with follow-up for at least 6 months have been assessed in people with type 2 diabetes, with varying

Anti-obesity drugs with positive effects on diabetes

Although the obesity epidemic is continually expanding, at very high costs for health-care systems, very few options are available for the pharmacotherapy of obesity because most anti-obesity drugs developed so far have poor efficacy and safety profiles.48 However, several such drugs have shown potential in the prevention and management of type 2 diabetes,49 although the long-term health benefits remain unclear.

Most drugs used as anti-obesity agents have been withdrawn because of safety issues.

Pramlintide

Pramlintide is an analogue of the pancreatic hormone amylin, which is deficient in patients with type 2 diabetes.36 Through mechanisms similar to those of amylin, pramlintide (120–240 μg three times daily) improves overall glycaemic control and reduces bodyweight in patients with type 2 diabetes (figure 3, appendix p 5). In addition to reducing postprandial glucose concentrations, pramlintide treatment is also associated with improvements in markers of oxidative stress and cardiovascular risk.

The future for pharmacology of type 2 diabetes and obesity

Novel pharmacological treatments are under investigation as potential treatments for obesity and type 2 diabetes.48, 50 There are two main avenues of investigation: the first targets the CNS to reduce food intake (with drugs including naltrexone plus bupropion, tesofensine, and zonisamide), but again with the risk of frequent adverse events;95 the second is more innovative and targets complex interrelated hormonal pathways (brain, gut, and adipose tissue) involved in weight regulation and

Conclusions

The management of the obese patient with diabetes remains challenging, but, in any case, weight reduction should be regarded as a key objective. Lifestyle interventions for weight loss are recommended for most patients with type 2 diabetes to improve glycaemic control and reduce associated risk factors for complications. Even modest weight loss can significantly improve glucose homoeostasis and reduce cardiometabolic risk factors, although achievement and especially maintenance of 5–10%

Search strategy and selection criteria

We searched Medline, PubMed, the Cochrane library, and Google Scholar, for mainly original research articles published between January, 1973, and November, 2013, and focused on the dual treatment of obesity and type 2 diabetes. The main search terms used were “obesity”, “type 2 diabetes”, “glucose-lowering”, “antidiabetic”, “anti-obesity”, and “weight loss”. We identified full-text papers without imposing any language restrictions. Reference lists of original studies, narrative reviews, and

References (113)

  • DJ Drucker et al.

    The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes

    Lancet

    (2006)
  • O Ajala et al.

    Systematic review and meta-analysis of different dietary approaches to the management of type 2 diabetes

    Am J Clin Nutr

    (2013)
  • WP James et al.

    Effect of sibutramine on weight maintenance after weight loss: a randomised trial. STORM Study Group. Sibutramine Trial of Obesity Reduction and Maintenance

    Lancet

    (2000)
  • LF Van Gaal et al.

    Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study

    Lancet

    (2005)
  • R Christensen et al.

    Efficacy and safety of the weight-loss drug rimonabant: a meta-analysis of randomised trials

    Lancet

    (2007)
  • EJ Topol et al.

    Rimonabant for prevention of cardiovascular events (CRESCENDO): a randomised, multicentre, placebo-controlled trial

    Lancet

    (2010)
  • KM Gadde et al.

    Effects of low-dose, controlled-release, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults (CONQUER): a randomised, placebo-controlled, phase 3 trial

    Lancet

    (2011)
  • WT Garvey et al.

    Two-year sustained weight loss and metabolic benefits with controlled-release phentermine/topiramate in obese and overweight adults (SEQUEL): a randomized, placebo-controlled, phase 3 extension study

    Am J Clin Nutr

    (2012)
  • JJ Holst et al.

    Is there a place for incretin therapies in obesity and prediabetes?

    Trends Endocrinol Metab

    (2013)
  • A Astrup et al.

    Effects of liraglutide in the treatment of obesity: a randomised, double-blind, placebo-controlled study

    Lancet

    (2009)
  • T Billyard et al.

    Potential therapies based on antidiabetic peptides

    Best Pract Res Clin Endocrinol Metab

    (2007)
  • FL Greenway et al.

    Effect of naltrexone plus bupropion on weight loss in overweight and obese adults (COR-I): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial

    Lancet

    (2010)
  • L Chen et al.

    The worldwide epidemiology of type 2 diabetes mellitus—present and future perspectives

    Nat Rev Endocrinol

    (2012)
  • SE Kahn et al.

    Mechanisms linking obesity to insulin resistance and type 2 diabetes

    Nature

    (2006)
  • LF Van Gaal et al.

    Mechanisms linking obesity with cardiovascular disease

    Nature

    (2006)
  • S Schwartz et al.

    Weight reduction in diabetes

    Adv Exp Med Biol

    (2012)
  • AA Mavian et al.

    Managing type 2 diabetes: balancing HbA1c and body weight

    Postgrad Med

    (2010)
  • LF Meneghini et al.

    Weight beneficial treatments for type 2 diabetes

    J Clin Endocrinol Metab

    (2011)
  • K Niswender

    Diabetes and obesity: therapeutic targeting and risk reduction—a complex interplay

    Diabetes Obes Metab

    (2010)
  • RA DeFronzo

    Banting lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus

    Diabetes

    (2009)
  • WC Knowler et al.

    10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study

    Lancet

    (2009)
  • RR Wing et al.

    Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes

    N Engl J Med

    (2013)
  • RR Wing et al.

    Type II diabetic subjects lose less weight than their overweight nondiabetic spouses

    Diabetes Care

    (1987)
  • AJ Scheen

    Current management strategies for coexisting diabetes mellitus and obesity

    Drugs

    (2003)
  • K Hermansen et al.

    Bodyweight changes associated with antihyperglycaemic agents in type 2 diabetes mellitus

    Drug Saf

    (2007)
  • SE Inzucchi et al.

    Management of hyperglycaemia in type 2 diabetes: a patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD)

    Diabetologia

    (2012)
  • A Barnett et al.

    A review of the effects of antihyperglycaemic agents on body weight: the potential of incretin targeted therapies

    Curr Med Res Opin

    (2007)
  • AH Barnett

    Impact of sodium glucose cotransporter 2 inhibitors on weight in patients with type 2 diabetes mellitus

    Postgrad Med

    (2013)
  • BW Smith et al.

    Nonalcoholic fatty liver disease and diabetes mellitus: pathogenesis and treatment

    Nat Rev Endocrinol

    (2011)
  • SK Garg et al.

    Diabetes and cancer: two diseases with obesity as a common risk factor

    Diabetes Obes Metab

    (2013)
  • MR Bonsignore et al.

    Sleep apnoea and metabolic dysfunction

    Eur Respir Rev

    (2013)
  • M Dirani et al.

    Are obesity and anthropometry risk factors for diabetic retinopathy? The diabetes management project

    Invest Ophthalmol Vis Sci

    (2011)
  • T Laitinen et al.

    Cardiovascular autonomic dysfunction is associated with central obesity in persons with impaired glucose tolerance

    Diabet Med

    (2011)
  • AW Drong et al.

    The genetic and epigenetic basis of type 2 diabetes and obesity

    Clin Pharmacol Ther

    (2012)
  • AJ Garber

    Obesity and type 2 diabetes: which patients are at risk?

    Diabetes Obes Metab

    (2012)
  • TL Hectors et al.

    Environmental pollutants and type 2 diabetes: a review of mechanisms that can disrupt beta cell function

    Diabetologia

    (2011)
  • G Musso et al.

    Interactions between gut microbiota and host metabolism predisposing to obesity and diabetes

    Annu Rev Med

    (2011)
  • TA Lutz

    Effects of amylin on eating and adiposity

    Handb Exp Pharmacol

    (2012)
  • M Amitani et al.

    The role of leptin in the control of insulin–glucose axis

    Front Neurosci

    (2013)
  • S Klein et al.

    Weight management through lifestyle modification for the prevention and management of type 2 diabetes: rationale and strategies: a statement of the American Diabetes Association, the North American Association for the Study of Obesity, and the American Society for Clinical Nutrition

    Diabetes Care

    (2004)
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