DiRECT Data Show 70% Maintenance of Type 2 Remission

Two-year data from DiRECT (n=298) show that 70% of participants who achieved type 2 diabetes remission at one year maintained remission through 24 months, giving an overall 36% rate of remission in the intervention arm (vs. 3% of controls, p<0.001; see publication in The Lancet ). At two years, 11% of the intervention arm achieved ≥15 kg weight loss (p<0.001 vs. 2% of controls). This compares to 46% remission (A1c <6.5% with no diabetes medications) in the intervention arm at one year (vs. 4% in control group), driven by 24% of participants achieving ≥15 kg (~33 lbs) weight loss – the two primary outcomes of the trial. Mean weight loss in the intervention group was 10 kg (~22 lbs) at 12 months and 7.6 kg (~17 lbs) at 24 months, compared to 1 kg (~2.2 lbs) and 2.3 kg (~5.1 lbs) in the control group, respectively. Remission and weight loss, and their maintenance, remain closely linked: At year two, 64% of participants who had lost ≥10 kg were in remission. Those who achieved remission at both time points (n=48) did experience mild weight regain from 12 to 24 months, while those who achieved but then “lost” remission had more serious weight regain (see figure below). From where we stand, it’s hard to over-emphasize the significance of these results: Not only does DiRECT achieve an impressive rate of diabetes remission, but it shows that can be done in the primary care setting through nurses and dieticians with fairly minimal training. We are thrilled to think about this moving to standard of care and all the people that could do so much better with appropriate investment in this intervention.

In the entire population, 24-month remission was linked to greater weight loss from baseline (aOR=1.2 per kg lost) and from 12-24 months (aOR=1.11 per kg lost), and there were slight associations with older age (aOR=1.08 per year) and sex (aOR=0.44 female vs. male). Of particular note, 24-month remission did not vary by baseline BMI or duration of diabetes – the latter is particularly interesting, as data presented by Prof. Roy Taylor at ADA 2018 suggested diabetes duration plays an important role in beta cell recovery and likelihood of remission. However, in one-year data presented by Prof. Mike Lean, older age, lower A1c, and fewer diabetes medications predictedremission, while male gender, shorter diabetes duration, and higher baseline A1c and BMI predicted weight loss ≥15 kg. That said, we’re looking forward to more specific subgroup analyses and anticipate far more insight over the coming year(s). Only 16 of 298 randomized participants withdrew from the intervention during year 2, and 86% of those 298 attended the 24-month review (24 months is the end of the RCT, though we understand that additional follow-up is planned).

  • Secondary outcomes indicate improvements in long-term risk factors, and data suggest a potential impact on CV events and cancer. The DiRECT intervention is associated with a significant, ~4 mmHg reduction in systolic blood pressure (p=0.04 vs. controls), despite lower use of antihypertensives (p=0.006 vs. controls) at 24 months. And despite little impact on cholesterol, the intervention does drive an improvement in triglycerides. Among participants in remission at 24 months, Q-RISK (a measure of 10-year CVD risk) fell from 16.1% to 8.2%, heart age from 70.4 to 60.8 years, and A1c from 7.4% to 5.9%. Unfortunately, the field of weight loss and obesity treatment as a whole still lacks evidence that treating weight – and improving cardiometabolic health through weight loss – translates to an improvement in long term outcomes. On this front, DiRECT is promising: From 12-24 months, the intervention group saw fewer serious adverse events than the control group (p=0.029, NS from 0-12 months and 0-24 months). While this is a small post-hoc analysis, there is a suggestion of a positive impact on both CV events and cancer.
  • These highly-anticipated results follow one-year results from IDF 2017 and the November announcement that NHS would conduct a 5,000-person pilot on diabetes remission informed by the design of DiRECT, to be focused on recently-diagnosed patients. At a high level, we’re impressed by the UK’s clear willingness to invest in both prevention and remission in a huge way – DiRECT (funded by Diabetes UK) cost ~$25,000/person in the intervention arm, though we imagine NHS can likely push this down through scale. The UK seems to have the message about early investment in health and about interventions that are high-investment and high value.
  • While weight regain did occur in DiRECT, presenters emphasized the beneficial impact of “rescue therapy” and that 24-month weight loss was still superior to most lifestyle interventions. Relapse management was used when a participant regained >2 kg or “relapsed” into type 2, and involved some combination of (i) reviewing causes of weight regain, (ii) reviewing behavioral strategies, (iii) brief use of diet replacement/food reintroduction, and (iv) the offer of orlistat (only three participants used this, all in the latter 12 months). While 50% of the intervention group used one or more rescue plans during the trial, this group actually achieved an equivalent rate of remission to the group that didn’t use rescue strategies (despite slightly lower weight loss).
  • Only 40% of intervention participants were taking diabetes medications at 24 months (down from 75% at baseline), compared to 84% of control participants (77% at baseline). That is, ~25% of participants in the intervention arm did not achieve remission but were not taking diabetes meds. To be sure, it’s possible some of these people could have benefitted from taking medications, but this is also an endpoint that’s highly important to patients. If those 25% were managing diabetes successfully, but without quite reaching an A1c <6.5%, we consider that a win. Indeed, on average, the intervention group saw a ~0.55% drop in A1c (6 mmol/mol; p=0.0063 vs. baseline), compared to no change in the control group. We’d like to see further discussion, of course, of medicine designed to reduce cardiovascular and renal complications – we also see this as an investment.

2. How to Define Diabetes Remission? Debate Over 6.0% vs. 6.5% Emerges as Professional Societies Aim to Publish Consensus

During a late afternoon session, Prof. Roy Taylor (pro-6.5%) and Dr. Chirag Bakhai (pro-6.0%) debated the merits of these differing definitions of diabetes remission. For context, Diabetes UK, EASD, and ADA are currently working to develop an international consensus on remission of type 2 diabetes, and Diabetes UK recently published an interim position statement on the topic (without naming a definite A1c cutoff). And Prof. Taylor, during his presentation, announced that the Association of British Clinical Diabetologists and the Primary Care Diabetes Society just published their own position statement, stipulating (i) weight loss, (ii) A1c <6.5% or FPG <126 mg/dl, and (iii) attainment of these following cessation of all glucose lowering therapies for the achievement of remission. However, we expect the eventual DUK/EASD/ADA consensus to serve as the most definitive statement in this area; the illustrious working group includes Drs. Will Cefalu, Philip Evans, Roy Taylor, Douglas Twenefour, Francesco Rubino, Philip Schauer, Matthew Riddle, Hertzel Gerstein, Carel le Roux, and Michael Nauck. Of note, the audience was asked to vote on 6.0% vs. 6.5% before and after the debate took place; from start to finish, 6.0% climbed from the minority to the majority, though both votes were on the close side. Find the primary arguments in favor of each below – while we aren’t sure of the “best” answer, we do think this is a highly interesting and increasingly important area of discussion.

  • Prof. Taylor argued in favor of an A1c <6.5% definition with “five good reasons”, stipulating that these must be associated with weight loss, per the statement he co-authored:
    • It is a motivating, achievable, patient-centered definition;
    • normalizing lipid metabolism gives remission of diabetes plus normalization of macrovascular risk;
    • A1c has been shown to remain constant ≥2 years in this range;
    • it’s consistent with the just-released ABCD/PCDS position statement; and
    • DiRECT defined it this way – he implored the audience not to “throw away DiRECT.”

Prof. Taylor also argued strongly in factor of a new term – “post-diabetes” – to describe those in remission: In his assessment, putting type 2 into remission involves a reversal of the pathophysiology underlying diabetes and is actually a lower-risk clinical stage worthy of recognition. He pointed to DiRECT data (those above) suggesting a “clinically significant” reduction in adverse events with remission, and explained that mislabeling remission as prediabetes erroneously implies that adverse consequences are still a present threat.

  • In the counterargument, Dr. Bakhai argued that a cutoff of <6.5% is dangerous for patients and took philosophical issue with the idea that miniscule differences in glycemia could bring a patient in or out of remission. He rephrased the question: Should remission involve a return to normoglycemia, or is it okay to return to “impaired glucose regulation”? Dr. Bakhai noted that ADA’s 2009 statement defined complete remission as <6.0% (vs. “partial remission” at <6.5%) before outlining a potentially problematic scenario: Patients between 6.0% and 6.5% who need to come off diabetes medications to meet the definition of remission – and realize the financial benefits this has in the UK – will feel pressure to do so. In the real, non-DiRECT world, where weight loss and medication use occur simultaneously, this is a problem: It could result in many patients who are doing very well managing their diabetes to creep upward while technically still achieving “remission.” (Or they rebound above 6.5% and have to restart medication.) Dr. Bakhai questioned whether this is really the best outcome for patients and argued that, while microvascular risk is still low at A1c <6.5%, it does exist. Going one step further, he said, some people will get the “cure message,” and people who achieve “cure” and even “remission” will be less likely to come for follow-up – but with a stricter threshold, there would be less worry.

– by Ann Carracher, John Close, and Kelly Close

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