Obesity management as a primary treatment goal for type 2 diabetes: time to reframe the conversation

doi:10.1016/S0140-6736(21)01919-X

The Lancet

Volume 399, Issue 10322, 22–28 January 2022, Pages 394-405

https://doi.org/10.1016/S0140-6736(21)01919-X Get rights and content

Summary

Obesity is now recognised as a disease that is associated with serious morbidity and increased mortality. One of its main metabolic complications is type 2 diabetes, as the two conditions share key pathophysiological mechanisms. Weight loss is known to reverse the underlying metabolic abnormalities of type 2 diabetes and, as such, improve glucose control; loss of 15% or more of bodyweight can have a disease-modifying effect in people with type 2 diabetes, an outcome that is not attainable by any other glucose-lowering intervention. Furthermore, weight loss in this population exerts benefits that extend beyond glycaemic control to improve risk factors for cardiometabolic disease and quality of life. We review the evidence supporting the role of weight loss in the management of type 2 diabetes and propose that many patients with type 2 diabetes would benefit from having a primary weight-centric approach to diabetes treatment. We discuss the logistical challenges to implementing a new weight-centric primary treatment goal in people with type 2 diabetes.

Introduction

Over the past decade, management of patients with type 2 diabetes has undergone a major conceptual change, with treatment objectives shifting to include a cardiocentric goal in the subpopulation with high cardiovascular risk, alongside the singular glucocentric goal that has long been held.¹ This advance was driven by studies showing that several glucose-lowering agents, used in addition to standard of care, further lower the risk of myocardial infarction, stroke, and cardiovascular death,2, 3 largely independently of lowering blood glucose concentration.4, 5 Yet, even after this landmark evolution, the treatment framework for type 2 diabetes is primarily focused on preventing or treating the downstream metabolic consequences, which tend to occur late in the disease course.

A promising opportunity lies in intervening upstream to address the key pathophysiological driver of type 2 diabetes and its associated metabolic complications: obesity (figure 1). Sustained loss of at least 15% bodyweight has a major effect on progression of type 2 diabetes, inducing remission in a large proportion of patients and markedly improving metabolic status in many others.6, 7

Until 2021, the only intervention that could routinely result in maintenance of weight loss of this magnitude was bariatric surgery. However, despite its considerable benefits, a complex surgical procedure is not feasible or scalable as the mainstay for a population-wide intervention. Now, with effective pharmaceuticals to reduce bodyweight in the pipeline, many of which can also directly lower blood glucose concentration, it is time to rethink treatment goals for patients with type 2 diabetes to position obesity management as a principal goal (ie, aiming for substantial weight loss as the primary means to treat patients with type 2 diabetes and reach glycaemic targets). Such a weight-centric intervention would disrupt the underlying pathophysiology of type 2 diabetes, reverse or slow down the disease course, concomitantly benefit other associated cardiovascular risk factors, and prevent microvascular and macrovascular complications of type 2 diabetes in the long term.

Here, we review the clinical evidence supporting weight loss as a fundamental target, propose a novel therapeutic framework, and explore challenges for the widespread implementation of this approach for people with type 2 diabetes.

Section snippets

Type 2 diabetes and obesity are interconnected, heterogeneous diseases

Obesity and type 2 diabetes are heterogeneous conditions. Not all people who are categorised as having obesity (ie, body-mass index ≥30 kg/m²) have excessive adiposity. Moreover, even among people who do have excess adiposity, not all people will have metabolic complications, such as type 2 diabetes.⁸ Conversely, some people with only minimal adiposity develop metabolic complications, prompting the concept that adipose tissue pathology, rather than quantity, might be the primary driver of

Benefits of weight loss across the disease continuum

The disease continuum for type 2 diabetes extends beyond what is captured by glycaemia. The underlying metabolic abnormalities ultimately leading to hyperglycaemia are typically present decades before a diagnosis of type 2 diabetes and are characterised by weight gain, central adiposity, and insulin resistance. The disease progresses to prediabetes, as the β cells’ ability to compensate for the increased demand that is imposed by insulin resistance diminishes, and ultimately to type 2 diabetes.

Intensive lifestyle interventions for weight loss in people with type 2 diabetes

The value of weight loss in the management of patients with type 2 diabetes has long been known.²² Studies of comprehensive lifestyle interventions have generated impressive data regarding glycaemic control and even remission of type 2 diabetes. The DiRECT randomised controlled trial (RCT) evaluated an intensive dietary intervention in 306 adults with body-mass index of 27–45 kg/m² and type 2 diabetes with a duration less than 6 years.⁷ After 2 years of follow-up, 11% (17 of 149) of people on

Challenges of maintaining weight loss in the long term

The emerging pathophysiology of obesity as a chronic disease with dysregulation of appetite at the level of the brain's subcortical areas helps to explain the counter-regulatory mechanisms that promote weight regain in response to calorie reduction. Weight loss that is induced by dieting causes a multitude of physiological changes that seem to impede the sustained reduction in energy intake that is required for weight loss in the long term.27, 28 The resulting increase in drive to eat and

Bariatric surgery

Bariatric surgery is an established, effective treatment for obesity in people with type 2 diabetes. It decreases blood glucose and allows decreased use of glucose-lowering medications within days of surgery, effectively placing type 2 diabetes into remission in up to 75% of patients in the short term to midterm (ie, up to 5 years)³⁴ and in 37–51% of patients over the long term (ie, up to 20 years).35, 36 Several randomised trials (table 1) comparing bariatric surgery with best medical care

Pharmacotherapy associated with weight loss in type 2 diabetes

Five agents (ie, orlistat, phentermine–topiramate, naltrexone–bupropion, liraglutide 3·0 mg, and semaglutide 2·4 mg) are approved by one or more regulatory authorities worldwide for chronic weight management. Additionally, phentermine is approved for use in the short term (ie, up to 3 months), but its risk–benefit profile for chronic use is not favourable, although as with most anti-obesity medications, some people lose substantial weight.⁵⁷ Phentermine is widely prescribed, mainly in the USA,

Pharmacotherapy pipeline for obesity and potential role in type 2 diabetes

Several agents in development that replicate the action of gut-derived satiety hormones have the potential to change the current landscape, making sustained, substantial weight loss a realistic consideration as a primary goal in treatment for people with type 2 diabetes (appendix p 1). They are particularly appealing in type 2 diabetes because of their additional glucose-lowering effect that is independent of weight.

A novel therapeutic framework: sustained weight loss as a primary treatment goal in type 2 diabetes

With the promise of new options, it is time to consider shifting the treatment focus for patients with type 2 diabetes from the current reactive glucocentric approach to addressing obesity, the core driver of insulin resistance and contributor to β-cell failure.

The evidence that sustained double-digit weight loss can reverse the pathophysiological underpinnings of type 2 diabetes is at a similar level of maturity as was the evidence for prevention of cardiovascular events when the previous

Practical considerations for making sustained weight loss a primary treatment goal

There are important considerations when redefining treatment goals for patients with type 2 diabetes to focus on sustained weight loss. Firstly, the initiative should be driven by updating treatment guidelines to include not only the emerging evidence for remission of type 2 diabetes after double-digit weight loss by lifestyle intervention, pharmacotherapy, and bariatric surgery but also the specific focus on substantial, sustained weight loss as a primary treatment target for patients with

Conclusions

The time is right to consider the addition of substantial (ie, double-digit) weight loss as a principal target for the treatment of many patients with type 2 diabetes. This approach would address the pathophysiology of the disease process for type 2 diabetes; recognise adipose tissue pathology as a key underlying driver of the continuum of obesity, type 2 diabetes, and cardiovascular disease; and reap metabolic benefits far beyond glycaemia. Such a change in treatment goals would recognise

Search strategy and selection criteria

References for this Review were identified by searching MEDLINE, PubMed, and the ClinicalTrials.gov registration site using the search terms: “overweight”, “obesity”, “weight gain”, “weight loss”, “weight management”, “body weight”, “morbid obesity”, “obesity pharmacotherapy”, “adiposity”, and “bariatric surgery” in combination with the term “type 2 diabetes”. We included references from relevant articles that were identified during the search. Articles published in English between Jan 1, 1990,

Declaration of interests

IL received research grants (paid to the institution) from Novo Nordisk, Sanofi, Boehringer Ingelheim, Merck, Pfizer, Mylan, and the National Institutes of Health; participated in scientific advisory roles or engaged in consulting for Novo Nordisk, Eli Lilly, Sanofi, AstraZeneca, Boehringer Ingelheim, Janssen, Intercept, Intarcia, TARGETPharma, Mannkind, Valeritas, Merck, Bayer, and Zealand Pharma; received non-financial support from Novo Nordisk, Eli Lilly, Sanofi, AstraZeneca, Boehringer

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Options for the treatment of type 2 diabetes mellitus (T2DM) and obesity have recently been expanded by the results of several large clinical trials with incretin-based peptide therapies. Most of these studies have been conducted with the glucagon-like peptide-1 (GLP-1) receptor agonist semaglutide, which is available as a once weekly subcutaneous injection and once daily tablet, and the once weekly injected dual agonist tirzepatide, which interacts with receptors for GLP-1 and glucose-dependent insulinotropic polypeptide (GIP). In individuals with T2DM these therapies have achieved reductions of glycated haemoglobin (HbA1c) by > 2% and lowered body weight by > 10%. In some studies, these agents tested in non-diabetic, obese individuals at much higher doses have lowered body weight by > 15%. Emerging evidence suggests these agents can also offer cardio-protective and potentially reno-protective effects. Other incretin-based peptide therapies in early clinical development, notably a triple GLP-1/GIP/glucagon receptor agonist (retatrutide) and a combination of semaglutide with the amylin analogue cagrilintide (CagriSema), have shown strong efficacy. Although incretin therapies can incur adverse gastrointestinal effects these are for most patients mild-to-moderate and transient but result in cessation of treatment in some cases. Thus, the efficacy of new incretin-based peptide therapies is enhancing the opportunity to control body weight and blood glucose and improve the treatment of T2DM and obesity.
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Traditional approaches to prevention of the complications of type 2 diabetes (T2D) and obesity have focused on reduction of blood glucose and body weight. The development of new classes of medications, together with evidence from dietary weight loss and bariatric surgery trials, provides new options for prevention of heart failure, chronic kidney disease, myocardial infarction, stroke, metabolic liver disease, cancer, T2D, and neurodegenerative disorders. Here I review evidence for use of lifestyle modification, SGLT-2 inhibitors, GLP-1 receptor agonists, selective mineralocorticoid receptor antagonists, and bariatric surgery, for prevention of cardiorenal and metabolic complications in people with T2D or obesity, highlighting the contributions of weight loss, as well as weight loss-independent mechanisms of action. Collectively, the evidence supports a tailored approach to selection of therapeutic interventions for T2D and obesity based on the likelihood of developing specific complications, rather than a stepwise approach focused exclusively on glycemic or weight control.
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Over the past decade, the treatment approach for type 2 diabetes mellitus has shifted from being “glucocentric” to preventative and “weight-centric” in combating the diabesity health burden. This is based on observations that sustained weight loss of greater than 15% has a disease-modifying effect. In this chapter, we review nonpharmacological, pharmacological, and surgical treatment options for weight reduction and the resultant effects on obesity-related cardiometabolic disorders. Firstly, we focus on the results of clinical studies in lifestyle interventions for weight loss in the prevention and remission of type 2 diabetes mellitus. We additionally discuss the wider impact of accompanying changes in anthropometric, glycaemic, blood pressure, and lipid parameters on cardiovascular risk as well as comorbid metabolic status. Secondly, we review the pharmacological approach for weight loss, including the evidence-base of landmark trials behind the use of GLP-1 analogues in type 2 diabetes mellitus, and other emerging therapies. Finally, we discuss the clinical impact of weight reduction, and the mechanisms underlying improved glucose control, following obesity surgery.
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ReviewObesity management as a primary treatment goal for type 2 diabetes: time to reframe the conversation

Summary

Introduction

Section snippets

Type 2 diabetes and obesity are interconnected, heterogeneous diseases

Benefits of weight loss across the disease continuum

Intensive lifestyle interventions for weight loss in people with type 2 diabetes

Challenges of maintaining weight loss in the long term

Bariatric surgery

Pharmacotherapy associated with weight loss in type 2 diabetes

Pharmacotherapy pipeline for obesity and potential role in type 2 diabetes

A novel therapeutic framework: sustained weight loss as a primary treatment goal in type 2 diabetes

Practical considerations for making sustained weight loss a primary treatment goal

Conclusions

Search strategy and selection criteria

Declaration of interests

Lancet Diabetes Endocrinol

Lancet

Lancet

Lancet Diabetes Endocrinol

J Am Coll Cardiol

Lancet

Lancet

Endocr Pract

Cell Metab

Lancet Diabetes Endocrinol

J Am Diet Assoc

Lancet

Am J Cardiol

Lancet

Lancet

Diabetes Metab

Lancet

Lancet

Lancet

Lancet

9. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes-2021

Diabetes Care

Association of SGLT2 inhibitors with cardiovascular and kidney outcomes in patients with type 2 diabetes: a meta-analysis

JAMA Cardiol

How does empagliflozin reduce cardiovascular mortality? Insights from a mediation analysis of the EMPA-REG OUTCOME Trial

Diabetes Care

Weight change-adjusted effects of gastric bypass surgery on glucose metabolism: 2- and 10-year results from the Swedish Obese Subjects (SOS) Study

Diabetes Care

Mechanisms linking obesity to insulin resistance and type 2 diabetes

Nature

Heterogeneity in the relationship between ethnicity, BMI, and fasting insulin

Diabetes Care

Obesity

How do we define cure of diabetes?

Diabetes Care

Consensus report: definition and interpretation of remission in type 2 diabetes

Diabet Med

Advances in the science, treatment, and prevention of the disease of obesity: reflections from a Diabetes Care Editors' Expert Forum

Diabetes Care

Weight loss interventions in chronic kidney disease: a systematic review and meta-analysis

Clin J Am Soc Nephrol

Effect of gastric bypass vs best medical treatment on early-stage chronic kidney disease in patients with type 2 diabetes and obesity: a randomized clinical trial

JAMA Surg

Effect of carbohydrate restriction in obese diabetics: relationship of control to weight loss

BMJ

Association of an intensive lifestyle intervention with remission of type 2 diabetes

JAMA

Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes

N Engl J Med

Association of the magnitude of weight loss and changes in physical fitness with long-term cardiovascular disease outcomes in overweight or obese people with type 2 diabetes: a post-hoc analysis of the Look AHEAD randomised clinical trial

Lancet Diabetes Endocrinol

The defence of body weight: a physiological basis for weight regain after weight loss

Clin Sci (Lond)

Describing the weight-reduced state: physiology, behavior, and interventions

Obesity (Silver Spring)

Weight maintenance and additional weight loss with liraglutide after low-calorie-diet-induced weight loss: the SCALE Maintenance randomized study

Int J Obes

Effect of subcutaneous semaglutide vs placebo as an adjunct to intensive behavioral therapy on body weight in adults with overweight or obesity: the STEP 3 randomized clinical trial

JAMA

Multicenter, placebo-controlled trial of lorcaserin for weight management

N Engl J Med

Medication use for the treatment of diabetes in obese individuals

Diabetologia

Review
Obesity management as a primary treatment goal for type 2 diabetes: time to reframe the conversation