Physicians' Academy for Cardiovascular Education

First time randomized trial shows remission of T2DM with dietary and lifestyle intervention

Primary care-led weight management for remission of type 2 diabetes (DiRECT): an open-label, cluster-randomised trial

Literature - Lean MEJ, Leslie WS, Barnes AC et al., - The Lancet, Available online 5 December 2017. https://doi.org/10.1016/S0140-6736(17)33102-1

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Background

Current guidelines for management of type 2 diabetes (T2DM) focus on pharmacological treatment to reduce blood glucose and the associated elevated CV risk. Life expectancy is, however, still markedly reduced in T2DM patients.

The twin cycle hypothesis [1] postulates that T2DM is specifically caused by excess fat accumulation in the liver and pancreas. When the hypothesis was tested by means of inducing negative energy balance with a 600-700 kcal/day diet, liver insulin resistance and fat content normalized within 7 days, with first-phase insulin response and pancreas fat content normalizing over 8 weeks [2]. A subsequent parallel-group study showed that the underlying changes were stable over a 6-month period of isocaloric eating [3].

The current trial tested whether such an intervention is practical in routine primary care, as other studies that have shown weight loss of at least 10-15 kg and normalization of blood glucose in people with short-duration T2Dm, did not show sustained disease remission [4-7].

The Diabetes Remission Clinical Trial (DiRECT) [8] was an open-label, cluster-randomized trial at 49 primary care practices (unit of randomization) in participants diagnosed with T2DM within the previous 6 years, with BMI between 27 and 45 kg/m2. Current insulin use, HbA1c >12%, weight loss of >5 kg within the past 6 months, a recent eGFR <30 mL/min/1.73m2 and severe or unstable HF were among the exclusion criteria. After review of data from the first practices to enter the study, the diagnosis of T2DM were revised to specify that the most recent hbA1c value should be over 6.0%, and if it was <6.5% persons should still be receiving antidiabetic medication.

Participants in the intervention group were asked to follow the Counterweight-Plus weight management program [9] and aim for achieving and maintaining at least 15 kg weight loss. A total diet replacement phase with a low energy formula diet (825-853 kcal/day; 59% carbohydrate, 13% fat, 26% protein, 2% fiber) for 3 months was used, followed by structured food reintroduction of 2-8 weeks (about 50% carbohydrate, 25% total fat, 15% protein) and an ongoing structured program with monthly visits for long-term weight loss maintenance. All oral antidiabetic drugs were discontinued on day 1 of the program, with standard protocols for reintroduction according to national guidelines. Antihypertensive drugs were withdrawn in light of the rapid BP reductions seen upon commencement of a low energy diet. At the start of food reintroduction, physical activity strategies were introduced to help participants in the intervention group to reach and maintain their individual sustainable maximum.

Main results

Conclusion

These results show that T2DM of up to 6 years’ duration can be reversed by weight loss with help of an evidence-based structured weight management program delivered in a community setting, by routine primary care staff. Almost a quarter of participants who followed the intervention achieved at least 15 kg of weight loss at 12 months, and half maintained at least 10 kg reduction. Almost half of patients in the intervention group showed remission of diabetes, and were off antidiabetic medication. Remission was closely related to the degree of weight loss maintained at 12 months. This cohort will be followed up for at least 4 years.

Editorial comment

To date, no findings from large-scale randomized trials were available on the effects of non-pharmacological treatment on remission of T2DM in patients receiving antidiabetic medication. Uusitupa [10] concludes that the obtained results are impressive and provide strong support for the view that T2DM is tightly associated with excessive fat mass in the body. These results, along with some other studies on T2DM prevention and some smaller intervention studies indicated that weight loss should be the primary goal in the treatment of T2DM, since it “results in improved insulin sensitivity in muscles and liver, decreases intra-organ fat content, and it might improve insulin secretion. In the long-term, weight loss might help to preserve β-cell mass. Once of the putative mechanisms could be decreased fat content of the pancreas, but more mechanistic studies are needed.” The role of physical activity and quality of diet, including dietary fibre and fatty acid composition are also important when considering the long-term success of prevention and treatment of T2DM.

The long-term results of the DiRECT study are important, because post-intervention weight regain is common among weight management studies in non-diabetic and diabetic populations. Uusitupa states “In view of the results of the DiRECT trial, a non-pharmacological approach should be revived. In clinical practice, anti- diabetic drugs seldom result in normalisation of glucose metabolism if patients’ lifestyles remain unchanged.”Uusitupa thinks that the time of diabetes diagnosis appears the best time point to start weight reduction and lifestyle changes, because the motivation of a patient is usually high.

References

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Download our slide set about this study Find this article online at The Lancet

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