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Diabetes Distilled: The time is right to make double-digit weight loss the cornerstone of type 2 diabetes management

Pam Brown
Professor Ildiko Lingvay and colleagues call for “double-digit” weight loss, specifically of 15% or more, to become a central focus and primary treatment goal for the management of type 2 diabetes, alongside and contributing to glycaemic management and cardiovascular and renal risk reduction. Based on three type 2 diabetes phenotypes, they recommend this “weight-centric” approach in those who have significant insulin resistance, a “cardiocentric” approach for those with existing or at high risk of cardiovascular disease, and retaining the older “glucocentric” approach for those with significant beta-cell dysfunction as the key driver, although they perceive overlap in the need for all three approaches. They highlight the significant benefits of weight loss in managing the underlying obesity that is driving the insulin resistance, type 2 diabetes and cardiometabolic complications. By focusing upstream on the underlying obesity rather than waiting for complications to arise and then treating them, there are important benefits in terms of morbidity, mortality, quality of life and costs. They feel the time is right for such a new focus as DiRECT and similar studies, along with recent developments in pharmacotherapy for obesity and type 2 diabetes, mean that it is no longer just bariatric surgery that can achieve this critical double-digit weight loss. However, the authors accept that much change will be needed and barriers will need to be overcome in order to begin moving towards such a focus.

Writing in the Lancet, and speaking at the EASD–Lancet symposium on obesity at the 57th Annual Meeting of the European Association for the Study of Diabetes, Professors Ildiko Lingvay, Priya Sumithran and colleagues have highlighted the need for a new focus, or paradigm shift, in type 2 diabetes management, aiming to help people achieve “double-digit” weight loss, ideally 15% or more, which has been demonstrated to result in remission and long-term improved metabolic benefits, as well as reducing other obesity-related comorbidities.

The authors highlight that until recently it was only bariatric surgery and the intensive DiRECT (Diabetes Remission Clinical Trial) programme that had been able to achieve 15% weight loss and diabetes remission. Remission pilots are now ongoing in England and other countries, and although bariatric surgery has much to offer individuals with obesity and comorbidities, it is recognised that this will never be suitable or upscalable to offer a significant solution to obesity and type 2 diabetes at the population level. Therefore, there is a call for funding and facilitating access to weight loss drugs as an important type 2 diabetes management option, particularly those drugs that have significant effects on both glucose-lowering and weight reduction, such as the GLP-1 receptor agonists liraglutide and semaglutide, the twincretin tirzepatide, long-acting amylin agonists such as the developmental agent cagrilintide (Enebo et al, 2021; Lau et al, 2021), and future drugs targeting GLP-1, GIP and glucagon receptors. However, it is recognised that since obesity and type 2 diabetes are both chronic diseases, management of obesity will also require long-term treatment, whether with lifestyle or drug therapy, rather than just quick fixes.

In support of their new paradigm, the authors divide people with type 2 diabetes into three simplified phenotypes:

  • Adiposity-related diabetes, with insulin resistance as the main pathophysiological driver (approximately 40–70% of people with type 2 diabetes).
  • Diabetes with cardiovascular disease, where atherosclerosis and inflammation are the key drivers (around 20–40% of people).
  • Isolated hyperglycaemia, where beta-cell dysfunction appears to be the key defect (around 10–20% of people).

 

Recommendations for treating these phenotypes (although all three phenotypes will need some overlap in the types of management) are as follows:

  • A “weight-centric” focus for those with adiposity-related diabetes, aiming for the 15% weight loss discussed above.
  • A “cardiocentric” focus for those with atherosclerosis and inflammation, as per current practice and the ADA/EASD (and other) guidelines, using cardiovascular drugs and glucose-lowering agents proven to have cardiovascular as well as weight loss benefits.
  • A “glucocentric” approach for those with beta-cell dysfunction, with a key goal of HbA1c <53 mmol/mol (7.0%).

 

The authors also make recommendations for the most appropriate pharmacotherapy for each group, as shown in Table 1 (adapted from resources and recommendations in the Lancet article).

The paper, authored by physicians from the US, Australia, Brazil and Ireland, writing independently of any organisation, provides a good overview of the current evidence base for achieving weight loss and summarises realistic weight reductions that can be expected with intensive lifestyle interventions, pharmacotherapy and bariatric surgery. The authors also discuss future pharmacotherapies such as semaglutide 2.4 mg weekly; cagrilintide, a weekly subcutaneous amylin analogue; the twincretin (dual GLP-1/GIP receptor agonist) tirzepatide; and other drugs in development targeting gut hormones. Their call to action builds on the work of Roy Taylor, Mike Lean and their teams in the DiRECT study and early data from the ReTUNE study supporting benefits of 10–15% weight loss even in those of normal BMI who have exceeded their “personal fat threshold” and developed type 2 diabetes.

Practical considerations for making weight loss a primary treatment goal in those with type 2 diabetes outlined in the paper include ensuring that glucose-lowering therapies which facilitate weight loss or avoid weight gain are prioritised; updating treatment guidelines to include focus on remission and achieving double-digit weight loss; and licensing changes to avoid different approval pathways for drugs used in type 2 diabetes and obesity, together with significant short- and medium-term investment to fund effective weight loss drugs to attain longer-term patient benefits and cost savings. Alongside these changes, there would be a huge educational and behavioural need to inform and motivate people with type 2 diabetes, and the clinicians who support them, to consider these new choices and to help patients make their own decision whether to pursue double-digit weight loss, remission and new ways to manage their condition. This process of decision-making around pursuing remission is already underway in the UK.

Commenting on the report, Professor Jason Halford, President of the European Association for the Study of Obesity (EASO), based at the University of Leeds, commented: “As the report demonstrates, effective weight management and health promotion strategies through a variety of means are essential in reducing the progression of – and even reversing – both type 2 diabetes and other complications linked with unhealthy excess weight. Appropriate training for obesity management is essential for those working in type 2 diabetes prevention or management.”

This title of the paper encourages us to believe the time is right to “reframe the conversation” and consider double-digit weight loss as a central focus of our type 2 diabetes management, at least for some of the people we support. Many of us have pursued a weight loss focus with our patients, with variable success, for many years and are aware of the barriers and the specialist support that will be needed particularly if drug therapy for obesity is to become more widespread. This paper, and others highlighting where we can make most impact from weight management discussions (Katsoulis et al, 2021), may re-energise our efforts to help more people achieve weight loss and diabetes remission.

Click here to read the article in full.

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