11th February 2024, A/Prof Chee L Khoo
Significant weight loss of >10% body weight has been associated with remission of type 2 diabetes. It’s not surprising, really, is it? The DiRECT trial which reported in 2018 demonstrated that early in T2D, significant weight loss can lead to remission of T2D (1). Importantly, DiRECT showed that weight loss of >10% can be achieved in primary with minimal support. Perhaps, because the trial was done in UK where getting to see a GP is not always easy and to be part of an organised clinical trial attract a subset of motivated patients who are determined to lose weight. What about real-world patients? These are patients in our practice. Not in a clinical trial setting and may not have the same motivation as patients who volunteered to be in trials. How sustainable is the weight loss anyway?
DiRECT was not the only trial to show that weight loss can lead to T2D remission. It’s not a surprising association. Weight loss reduces insulin resistance. Better diet reduces carbohydrate load. The STAMPEDE trial showed that around one-third of obese people with type 2 diabetes achieved a haemoglobin A1C (HbA1c) level of less than 6% without glucose-lowering drugs (GLDs) 1 year after bariatric surgery [2]. My colleagues at WSU and I published an audit of 34 patients in my solo GP practice in Southwest Sydney who underwent partial meal replacement to lose weight (3). The proportion of participants that met the criteria for diabetes remission was similar at baseline (8.8%) and 12 months (11.8%) but increased to 32.4% at 24 months (P = 0.016).
In primary care, we have patients with T2D at different stages of the disease, have different motivations, have different support networks, have different disease trajectories and have different co-morbidities. The strictly controlled environments and selective participants in clinical trials have inherently limited the generalisability of their findings to broader populations. Evidence from more diverse populations is needed to better understand the feasibility of achieving diabetes remission through weight management in real-world settings to inform clinical practice. More importantly, given the short follow-up time of clinical trials, the long-term incidence, sustainability, and benefits of diabetes remission are largely unknown.
The territory-wide Risk Assessment and Management Programme for Diabetes Mellitus (RAMP-DM) provides regular comprehensive assessments of metabolic control and complication screening for people with diabetes in Hong Kong (4). The Hong Kong HA is a statutory body that governs all public hospitals and the majority of specialist and general outpatient clinics. It provides about 90% of total health services in Hong Kong. In 2000, the HA implemented a territory-wide RAMP-DM in 18 hospital-based diabetes centres to provide regular comprehensive risk assessment and complication screening to people with diabetes referred from outpatient clinics. In 2009, it was expanded to all general outpatient clinics in primary care settings. Approximately 60% of the Hong Kong population with diabetes have been enrolled in this program.
The authors used real-world data to examine the associations between 1-year weight change with conventional management after diabetes diagnosis and the long-term incidence and sustainability of remission of type 2 diabetes and the association between diabetes remission and all-cause and cause-specific mortality. Data from patients between 18-75 years old were included. Patients with extreme BMIs (<15 or >50 kg/m2) and preexisting cardiovascular disease, cancer, or end-stage renal disease were excluded. To avoid inclusion of patients with T1D, patients on insulin therapy at baseline were also excluded. All up, data from 37,326 patients were analysed.
At baseline, the mean age was 56.6 (standard deviation [SD]: 9.9) years, the mean BMI was 26.4 (SD: 4.2) kg/m2, the mean HbA1c was 7.7% (SD: 1.8%), and 65.0% were using glucose lowering drugs. 2.8% of people had a 1-year weight loss of ≥10%, 10.4% had a weight loss of 5% to 9.9%, 40.2% had a weight loss of 0% to 4.9%, and 46.6% had weight gain. People who had a greater 1-year weight loss were more likely to be women, had higher blood pressure and lipid levels, were less likely to be current smokers and alcohol users, and were less likely to use GLDs at baseline. They had higher levels of BMI, waist circumference, and HbA1c at baseline, but lower levels for these measurements 1 year after baseline.
Results
During a median follow-up of 7.9 years, only 6.1% of people achieved diabetes remission. The overall crude incidence rate of diabetes remission was 7.8 (95% CI: 7.5, 8.1) per 1,000 person-years and 88% of the remission events occurred within the first 5 years of the follow-up. Expectedly, the greater the weight loss, the higher the remission rate. 14.4% of people who lost ≥10% of their body weight achieved remission, compared to 9.9% in those with a 5% to 9.9% weight loss, 6.5% in those with a 0% to 4.9% weight loss, and 4.5% in those who experienced weight gain.
Compared to people with weight gain, the adjusted HR for diabetes remission was 3.28 for those with ≥10% weight loss, 2.29 for those with 5% to 9.9% weight loss, and 1.34 for those with 0% to 4.9% weight loss.
A return to T2D
We all know how hard it is to keep the weight loss, don’t we? During a median follow-up of 3.1 years from the date of diabetes remission, 67.2% of people who had achieved diabetes remission returned to hyperglycaemia. Around 39% of people retuned to hyperglycaemia within 3 years and 58% within 5 years after achieving remission. During the follow-up, mean body weight increased by 0.82% (SD: 5.8%) compared to the weight measured at 1 year after diabetes diagnosis in people who returned to hyperglycaemia, whereas it decreased by 0.88% (SD: 7.7%) in those who maintained remission. The median time to return to hyperglycaemia was 3.6 years.
Greater 1-year weight loss after diabetes diagnosis was associated with a decreased risk of returning to hyperglycaemia. The more weight you lose at the 1-year mark, the less likely you return to hyperglycaemia. Compared to people with weight gain, the adjusted HR for returning to hyperglycaemia was 0.52 (95% CI: 0.41, 0.65; p < 0.001) for those with ≥10% weight loss, 0.78 (95% CI: 0.68, 0.92; p = 0.002) for those with 5% to 9.9% weight loss, and 0.90 (95% CI: 0.80, 1.01; p = 0.073) for those with 0% to 4.9% weight loss. Similarly, the HR for returning to hyperglycaemia decreased with larger reduction in waist circumference.
The benefits of diabetes remission?
People who experienced diabetes remission had a significant 31% decreased risk of all-cause mortality compared to those not achieving diabetes remission. There was a trend towards lower mortality in those who achieved remission but later returned to hyperglycaemia. Of note, the longer duration the remission was, the lower the all-cause mortality was (although this effect was not statistically significant).
Thus, remission had benefits even if it was temporary.
Lessons learnt?
In the DiRECT trial, 24% of the participants achieved weight loss of >15kg and overall, 46% of the participants achieved diabetes remission. As expected, the more weight you lose, the higher the remission rate is. In fact, 73% of participants who lost 10 kg or more body weight achieved diabetes remission.
In the DIADEM-I randomised controlled trial, intensive lifestyle intervention amongst primary and community patients with T2D, 21% achieved >15kg weight loss. 61% achieved diabetes remission (5). Once again, like the DiRECT trial, this is in a clinical trial setting.
In this RAMP-DM study, participants were not in a clinical trial setting. The overall incidence of diabetes remission was pretty low with only 6% patients achieving remission over a median follow up of 8 years. It was comparable to similar epidemiological studies, though. A cohort study of 122,781 US adults with type 2 diabetes, reported a diabetes remission incidence of 2.8 per 1,000 person-years in the overall study population and 8.8 per 1,000 person-years among those with new-onset diabetes (19). study of 2 million people with type 2 diabetes in primary care settings in England, using the same remission definition as our study, reported an incidence of 9.7 per 1,000 person-years in the overall population and 44.9 per 1,000 person-years among people with newly diagnosed diabetes [14].
The RAMP-DM study also tell us that even if remission is lost in subsequent years, there are still mortality benefits. And the longer we can keep them in remission, the greater those benefits are.
In summary, diabetes remission is possible with significant weight loss but achieving significant weight loss is not easy in primary care settings. These patients need our support to keep them motivated to achieve weight loss and keep the loss off. Most importantly, even if they regain hyperglycaemia and lose their remission, the mortality benefits is still there.
References:
- Lean ME, Leslie WS, Barnes AC, Brosnahan N, et al. Primary care-led weight management for remission of type 2 diabetes (DiRECT): an open-label, cluster-randomised trial. Lancet. 2018 Feb 10;391(10120):541-551. doi: 10.1016/S0140-6736(17)33102-1. Epub 2017 Dec 5. PMID: 29221645.
- Mingrone G, Panunzi S, De Gaetano A, Guidone C, Iaconelli A, Leccesi L, et al. Bariatric surgery versus conventional medical therapy for type 2 diabetes. N Engl J Med. 2012; 366(17):1577–1585. https://doi.org/10.1056/NEJMoa1200111
- Khoo CL, Chimoriya R, Simmons D, Piya MK. Partial meal replacement for people with type 2 diabetes: 2-year outcomes from an Australian general practice. Aust J Prim Health. 2023 Feb;29(1):74-80. doi: 10.1071/PY22180. PMID: 36318919.
- Wu H, Yang A, Lau ESH, Zhang X, Fan B, Ma RCW, et al. (2024) 1-year weight change after diabetes diagnosis and long-term incidence and sustainability of remission of type 2 diabetes in real-world settings in Hong Kong: An observational cohort study. PLoS Med 21(1): e1004327. https://doi.org/10.1371/journal.pmed.1004327
- Taheri S, Zaghloul H, Chagoury O, Elhadad S, et al. Effect of intensive lifestyle intervention on bodyweight and glycaemia in early type 2 diabetes (DIADEM-I): an open-label, parallel-group, randomised controlled trial. Lancet Diabetes Endocrinol. 2020 Jun;8(6):477-489. doi: 10.1016/S2213-8587(20)30117-0. PMID: 32445735.