Obesity and diabetes: the final frontier

ABSTRACT

Introduction

Obesity is a key target in the treatment and prevention of diabetes and independently to reduce the burden of cardiovascular disease. We reviewed the options now available and anticipated to deal with obesity.

Areas covered

We considered the epidemiology, genetics, and causation of obesity and the relationship to diabetes, and the dietary, pharmaceutical, and surgical management of the condition. The literature search covered both popular media via Google Search and the academic literature as indexed on PubMed with search terms including obesity, childhood obesity, adipocytes, insulin resistance, mechanisms of satiety, bariatric surgery, GLP-1 receptor agonists, and SGLT2 inhibitors.

Expert opinion

Although bariatric surgery has been the primary approach to treating obese individuals, the emergence of agents impacting the brain satiety centers now promises effective, non-invasive treatment of obesity for individuals with and without diabetes. The GLP-1 receptor agonists have assumed the primary role in treating obesity with significant weight loss. Long-term results with semaglutide and tirzepatide are now approaching the success seen with bariatric surgery. Future agents combining the benefits of satiety control and thermogenesis to dissipate caloric excess are under investigation.

KEYWORDS:

• Obesity
• type 2 diabetes
• prediabetes
• liraglutide
• semaglutide
• tirzapatide

Article highlights

• The majority of patients suffering from type 2 diabetes are overweight or obese

• In addition to promoting the development of diabetes, obesity is associated with hypertension; dyslipidemia; ischemic heart disease; stroke; obstructive sleep apnea; asthma; nonalcoholic steatohepatitis; gastroesophageal reflux disease; degenerative joint disease of the back, hips, knees, and feet; infertility and polycystic ovary syndrome; various malignancies; and depression.

• The primary cause of death in obese patients is cardiovascular disease independently of other risk factors.

• Weight management through lifestyle modification is considered the cornerstone of prevention and management of type 2 diabetes.

• It is estimated that 60–70% of obese adults attempt to lose weight each year, but most patients regain weight lost over the long term.

• The greatest success in achieving weight loss has been through bariatric surgery achieved with a variety of techniques. Mean (SE) reductions in percentage of body weight at 3 years were the greatest after gastric bypass at 25.0% (2.0%), followed by gastric banding 15.0% (2.0%) with lifestyle treatment at 5.7% (2.4%) (P < .01).

• Perioperative mortality in bariatric surgery is low. Complications of surgery including need for repeat surgical interventions involve 20% to 30% of patients.

• Historically, pharmacological therapy of obesity has been less successful than bariatric surgery. Metformin, acarbose, a number of appetite suppressants, and orlistat have had only modest benefit.

• The advent of the SGLT2 inhibitors and the GLP-1 receptor agonists has had a revolutionary impact on the treatment of type 2 diabetes. Both classes have demonstrated major benefit on cardiovascular and renal disease associated with diabetes.

• Several GLP-1 receptor agonists have been used to treat obesity in patients without diabetes. Liraglutide at a dose of 3 mg daily has been an approved agent for the obesity indication for several years. Semaglutide has demonstrated superior weight loss effects in head-to-head studies with liraglutide. Tirzepatide, a combined GLP-1 and GIP agonist, has also had success in recent studies in obese patients.

• Research is ongoing to develop agents with multireceptor activity, targeting not just GLP-1 and GIP receptors, but with possible thermogenic effects to decrease fat mass.

• The degree of weight loss achieved with semaglutide and tirzepatide has approached the levels achieved with bariatric surgery in some studies.

• The SGLT2 inhibitors have achieved modest weight loss but have had major benefit in cardiovascular and renal disease. SGLT2 inhibitors are approved to treat congestive heart failure in patients without diabetes.

• The combination of SGLT2 inhibitors and GLP-1 receptor agonists may herald a new age of control of obesity and the associated health impairments.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The Rose Salter Medical Research Foundation and the Association of Diabetes Investigators.