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Proposed paradigm shift in type 2 diabetes treatment to focus on weight loss

In a review article in The Lancet and presented at the European Association for the Study of Diabetes conference, researchers unpack the evidence supporting the primary role of weight loss rather glycaemic control in managing type 2 diabetes.

Obesity is recognised as a disease 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 improve glucose control; loss of 15% or more of body weight can have a disease-modifying effect in people with type 2 diabetes, an outcome unattainable by any other glucose-lowering intervention.

Furthermore, weight loss in this population exerts benefits beyond glycaemic control to improve risk factors for cardiometabolic disease and quality of life.

“It's known that obesity contributes to the progression of diabetes. What’s new is that instead of focusing exclusively on lowering blood sugar, we recommend the primary approach to the treatment of Type 2 diabetes be on the treatment of obesity,” said first author Dr Ildiko Lingvay, professor of Internal Medicine and Population and Data Sciences at UT Southwestern.

The researchers said dropping 15% or more of body weight can have a disease-modifying effect in Type 2 diabetes, an outcome unattainable by any other glucose-lowering intervention. The new focus would require updating current treatment guidelines and providing significant provider education, they note.

The current approach to diabetes treatment relies on clinical studies from the 1980s, which found that lowering blood sugar results in fewer complications. These early results supported treating blood glucose as the key target, said Lingvay.

“But this approach doesn’t address the core problem or offer an opportunity to reverse the disease,” said Lingvay. “We propose a proactive approach. Let's address the cause of the disease: obesity.”

The American Diabetes Association describes Type 2 diabetes as a progressive disease caused by obesity or by abnormalities in metabolism. More than 10% of the US population has been diagnosed with diabetes, and 1.5 million more are diagnosed each year.

Bariatric surgery can be effective for patients with obesity, but not all patients have access to this option. “It’s hard to achieve sustained weight loss. Most lifestyle interventions result in progressive weight loss over six months, followed by a plateau and weight regain over one to three years,” added Lingvay. “New weight loss medications and those in the pipeline will help patients manage their weight over the long term.”

The researchers also stressed the importance of advocating for insurance coverage that supports treatment of obesity and diabetes, and working in public health to increase access to care and reduce disparities.

Study details

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

Prof Ildiko Lingvay, Prof Priya Sumithran, Prof Ricardo V Cohen, Prof Carel W le Roux

Published in The Lancet on 30 September 2021

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.

This advance was driven by studies showing that several glucose-lowering agents, in addition to standard of care, further lower the risk of myocardial infarction, stroke, and cardiovascular death, largely independently of lowering blood glucose concentration.

Yet, even after this landmark evolution, the treatment framework for type 2 diabetes focuse mainly 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. 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.

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. 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 type 2 diabetes, replacing the exclusive focus on glycaemic control that has been long held.

Health economic models that are used to calculate utility gains during health economic assessments or health technology appraisals should be adjusted to allocate values to 10%, 15%, and 20% weight loss as these goals now become more widely accessible for the first time. The broad health benefits in the long term of substantial weight loss should offset the needed upfront investment in effective weight-loss interventions.

Regulators and payers should avoid promoting an arbitrary dichotomy between approval pathways, reimbursement for medications, and care provision for people with obesity and people with type 2 diabetes. These two conditions are intricately related, and it is important to recognise that the upstream intervention of weight loss is the most effective treatment for patients with type 2 diabetes. As such, established and emerging anti-obesity agents have a crucial role in the management of patients with type 2 diabetes, particularly patients with weight-independent benefits on glycaemia. Chronic diseases, likes type 2 diabetes, hypertension, and hyperlipidaemia, are unlikely to be successfully treated with a single medication.

Combinations of agents with complementary mechanisms of action are generally more effective and have fewer dose-limiting adverse effects than do maximum monotherapies. This concept should be applied in obesity management as well and has already been shown with several combination products available and more being developed.

Practice management should refocus to effectively incorporate weight management to treat patients with type 2 diabetes. Since scientific knowledge about obesity and bodyweight regulation is new, having advanced rapidly since the discovery of leptin in 1994, many health-care providers might not be familiar with the science of obesity or even with approaching obesity as a chronic disease. People with type 2 diabetes and obesity are accustomed to the perception that these diseases are self-induced and curable simply by eating less and doing more physical activity.

Furthermore, until 2021, losing and maintaining the loss of 15% or more bodyweight was not considered realistic without bariatric surgery; therefore, many health-care providers and patients might still regard obesity treatment from a viewpoint of therapeutic nihilism, which will need to be updated as treatment options evolve to make substantial weight loss an attainable goal.

Many people with type 2 diabetes might not want to use dietary interventions, medications, or surgery for obesity treatment, and even if these interventions were highly sought after, some, like surgery or even life-long injectable medications, would be difficult to scale to reach everyone who could potentially benefit. One of the major contributions of bariatric surgery is showing that strategies that result in substantial and durable weight loss can disrupt the disease course of type 2 diabetes, adding to the drive to develop more effective non-invasive interventions.

These alternatives will be presented to people only if the clinical community embraces the evidence-based idea of substantial weight loss as an effective treatment for patients with type 2 diabetes.

Conclusions
The time is right to consider the addition of substantial (ie, double-digit) weight loss as a principal target for the treatment of patients with type 2 diabetes. This approach would address the pathophysiology of the disease process; 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. This change in treatment goals would recognise obesity as a disease with reversible complications and require a shift in clinical care.

Study presented at 57th EASD (European Association for the Study of Diabetes) (27 September-1 October)

Effect of semaglutide 2.4 mg on glucose metabolism and body weight in adults with overweight or obesity and type 2 diabetes in the STEP 2 trial

S.D. Pedersen1, M. Davies, L. Færch, O.K. Jeppesen, A. Pakseresht, L. Perreault, J. Rosenstock, I. Shimomura, A. Viljoen, T. Wadden, I. Lingvay

Background and aims: The STEP 2 trial showed mean weight loss of 9.6% with semaglutide 2.4 mg vs 7.0% with semaglutide 1.0 mg and 3.4% with placebo (both p<0.0001). We present detailed glucose metabolism outcomes.

Materials and methods: Adults with BMI ≥27 kg/m2, type 2 diabetes and HbA1c 7-10% (53-86 mmol/mol) were randomised to 68 weeks’ once-weekly s.c. semaglutide 2.4 mg (N=404), 1.0 mg (N=403) or placebo (N=403). Glucose metabolism outcomes were secondary or exploratory endpoints. Treatment comparisons were done using an ANCOVA model with treatment and stratification factors as fixed effects and baseline endpoint values as covariate (all patients in the full analysis set).

Results: At baseline, patients had a mean age of 55 years, body weight 99.8 kg, HbA1c 8.1% (65.3 mmol/mol) and diabetes duration 8.0 years; 88% were on 1-2 oral antihyperglycaemic drugs. From weeks 0 to 68, semaglutide 2.4 mg and 1.0 mg reduced HbA1c to a greater extent vs placebo (estimated treatment difference -1.2% [-13.5 mmol/mol] and -1.1% [-11.8 mmol/mol]; both p<0.0001) and improved fasting plasma glucose, HOMA-IR and -β, and reduced oral antihyperglycaemic drug use (Table). With semaglutide 2.4 mg, more patients achieved HbA1c <7.0% and ≤6.5%, and composite endpoints of HbA1c <7.0% with weight loss ≥10% or ≥15% vs semaglutide 1.0 mg or placebo (Table). Exploratory analyses showed that a greater proportion of patients receiving semaglutide at either dose decreased their oral antihyperglycaemic medication intensity vs placebo by week 68.

Conclusion: Weight loss with semaglutide 2.4 mg was accomplished with improvements in insulin resistance and β-cell function, two key mechanistic drivers and pathophysiologic abnormalities that cause type 2 diabetes and fuel diabetes progression. With semaglutide 2.4 mg, more patients achieved HbA1c <7.0% and weight loss ≥10% (composite endpoint) vs placebo or semaglutide 1.0 mg, and reduced oral antihyperglycaemic drug use vs placebo.

 

The Lancet article – Obesity management as a primary treatment goal for type 2 diabetes: time to reframe the conversation (Open access)

 

EASD conference abstract – Effect of semaglutide 2.4 mg on glucose metabolism and body weight in adults with overweight or obesity and type 2 diabetes in the STEP 2 trial (Open access)

 

See more from MedicalBrief archives:

 

Type 2 diabetes study shows 'obesity paradox'

 

Fruit but not fruit juice to lower type 2 diabetes risk — AusDiab study

 

Over 4.5m people now living with diabetes in SA, as numbers continue to rise

 

Fat mass index, not BMI, associated with CVD events in people with diabetes

 

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