Toward The Possibility of Remission
In December 2012, thirteen clinical investigators from the fields of endocrinology, public health, behavioral science, nutrition, and pharmacology published a paper in the Journal of the American Medical Association theorizing that an intensive intervention to accelerate and maintain weight loss could put type 2 diabetes into remission. The authors had been working together since June 2001 as part of a team led by 32 diabetes specialists at 16 U.S. clinical locations on the Action for Health in Diabetes (Look AHEAD) trial.
The remission study, and other Look AHEAD studies to investigate the progression of T2D and its complications, had proceeded under the auspices of the Centers for Disease Control & Prevention (CDC) and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Full remission had been rare, the investigators found, but in their considered judgement partial remission had been achievable and was realistic, and so the idea was well worth further study over a longer term.
The Internet is overrun with claims of miracle diabetes cures. We can see headlines about diets to cure all ills on the cooking magazines next to the tabloids at the checkout line. It’s our job here at SelfRx, or maybe it’s just our go-to default pre-conditioned response to words like “reverse” or “cure” or “remission” appearing in close proximity to “diabetes,” to be skeptical. Two and a half years ago in an article for our sister publication Insulin Nation, I took aim at a politician, and a doctor of unconvincing credentials, who had touted a regimen of cinnamon and chromium picolinate to “reverse” T2D.
Permanent reversal is likely still a long way off. But it’s certainly worthy of serious reporting now for no other reason than that we don’t spend enough time writing about prevention. We know now, from the Look AHEAD trial and three new trials underway that the same measures we ought to take to control the progression of T2D and its complications are those which have resulted, for some people as many a three years after diagnosis, in remission.
It’s been shortsighted of us to assume that people read Type 2 Nation only because they already have T2D, and so we’ve devoted most of our time to what’s new in drug therapy, what’s going on at the Food & Drug Administration, or what’s happening in Congress to help people live with their chronic incurable disease. So, here is a story about a realistic possibility of reversing T2D, or at least treating it with greater success, and possibly lessening the need for anti-diabetes medications.
Think about this: For the very same reasons that motivated CDC and NIDDK to test the hypothesis that:
long term treatment built around (1) getting the body of a pre-diabetic person down to a healthy body mass index through an aggressive dietary intervention, coupled with at least 175 minutes of exercise a week then (2) sticking with a diabetic health promoting diet and with a habit of regular physical activity, could delay or prevent onset of T2D,
our doctors and certified diabetes educators, our loved ones, and for some of us (Dre Johnson included) the Ghost of Christmas Yet to Come, keep on reminding us that:
even if we take our meds, it’s all for naught if we don’t watch what we eat, and keep moving, because without that we’d better be willing and prepared to take on the risk of heart disease, stroke, kidney disease, losing eyesight and feeling in our extremities, and dying before our time.
In the late 1990s CDC and National Institutes of Health (NIH) began convening clinicians and public health experts to brainstorm ways to study the benefits and risks of weight loss through augmented diet and exercise for people with T2D. According to an NIH history of the National Diabetes Prevention Program, the group concluded that “only a randomized clinical trial of intentional weight loss could provide needed guidance on the risks and benefits of weight loss to inform rational clinical and public health policy.” The group recommended evidence-based research carried out at multiple locations that would “focus on obese individuals who already had a comorbid medical illness, both because of the clear public health recommendation of weight loss for such individuals and because of their increased risk of adverse health-related outcomes.” It seemed feasible because there had already been a number of studies that demonstrated measurable diabetic health improvement in people who had lost weight and increased their physical activity over periods of up to three years. Some of the studies were ongoing.
Proposals went out seeking hospitals, universities, and clinics, and diabetic health professionals to serve as investigators for the SHOW (Study Of Outcomes of Weight Loss) program and to organize a central data collection and analysis capability. The study design quickly evolved into the Look AHEAD clinical trial to launch in 2001.This trial would examine the effects of weight loss on non-fatal heart attack and stroke and cardiovascular-related death in overweight or clinically obese individuals with T2D.
At the time it launched, Look AHEAD was the largest clinical trial ever registered with the NIH to examine the long-term effects of diet and lifestyle changes to improve diabetic health. The trial’s primary arm was to assess how cardiovascular health might be protected by adopting and maintaining a clinically supervised low-calorie diet and a regimented exercise routine. Secondarily, the study would measure over eleven years changes in lifespan, health care costs, skeletal and microvascular health, and quality of life.
Look AHEAD ceased recruiting participants in 2004. Some of the ancillary health outcome studies (described below) have been completed, but the trial is still active and will be until the longer-term overall diabetic health patient follow-up visits are complete. Look AHEAD has been what clinical trial investigators call a “high retention” study. In fact, one of ancillary studies successfully predicted its low incidence of missed visits and drop-outs.
Of the 28,622 patients initially recruited, 7,997 declined to complete the first of two stages of clinical screenings carried out to exclude people who had advanced diabetes-related complications, such as advanced kidney disease or dangerously high blood pressure, or who demonstrated likelihood that they would not remain active in following their treatment protocols and attending scheduled follow-up medical exams.
As the screenings proceeded ahead, the investigators realized that they were assembling a cohort (that eventually became a little over 11,700 after the first round of screenings) that presented opportunities to examine the effect of carefully controlled weight loss on the progression of T2D and its complications and comorbidities. Testing a hypothesis that remission was possible was one such opportunity. In all, there would be more than thirty other ancillary studies, examining a variety of diabetes-related health outcomes. Among them (with first publication dates) were:
- Failure to respond early to lifestyle interventions (April 2014);
- Genetic predisposition to weight gain and loss (August 2015);
- Relationship between variants in the protein-coding GLUL [glutamate-ammonia ligase] gene and all-cause mortality in people with T2D (September 2015);
- Incidence of atrial fibrillation (July 2015);
- Preventing and relieving knee pain (2015);
- Changes in systolic blood pressure (In conjunction with the ACCORD blood pressure trial, February 2015);
- Kidney disease risk and progression (August 2014);
- Bone mineral density loss (July 2014);
- Psychological stress and depression (June 2014);
- Changes in concentration of trans-fatty acids (February 2013);
- Long term effects for severely obese individuals (Preliminary, March 2012, Ongoing); and
- General improvement in cardiovascular fitness (December 2012).
After the second round of screening was complete, the 5,145 candidates remaining were assigned at random into nearly equally divided traditional treatment (DSE) and intensive intervention (ILI) groups. The DSE (diabetes support and education) group served as the control, attending three sessions a year for education and nutritional counseling, continuing their medication protocols, and self-reporting their routine lab results and physician visits.
The ILI (intensive lifestyle intervention) group enrolled in individual and group dietary education and physical training sessions. This group was offered prepared meals, liquid formula diets, and optional weight loss medications to achieve and then maintain over a four year period at least a 7% weight decrease from baseline measured at the beginning of the first year. The most intensive dietary and exercise regimens were applied in the first year and then gradually tapered back in the following years.
The Design of the Look AHEAD Remission Trial and The Ground Rules
The thirteen authors who would eventually report on the remission outcome prefaced their theory with these two qualifications:
First, as “remission” was a term open to ambiguity in the science of diabetes diagnosis, they would rely upon a consensus among clinicians that had been reached in 2009 and endorsed by the American Diabetes Association. Partial remission would be understood as a lowering of glucose to below that for diagnosis of diabetes, even if elevated, in a person not taking antidiabetic medication. Complete remission would be understood as a return to a normal glucose level without continuing any kind of anti-diabetic therapy.
Second, it was likely necessary for there to be at least 20 years of patient follow-up to determine whether a radical change in diet, initiated within two to three years following a diagnosis of T2D, to reduce caloric intake followed by a strict diet to maintain a healthy body mass index, could achieve better and more sustainable diabetic health results than bariatric surgery, continuous antidiabetic medication, or both combined in the long term. Inclusion in the remission subgroup was set at age 55 to 76, and so the odds that anyone in the study population would achieve anything beyond partial remission would be daunting from the outset. Without initiating a successor to the Look AHEAD trial recruiting a younger population, the remission hypothesis could not, the authors acknowledged, be fully tested.
Of course, even with these ground rules in place, there’s still the question of just how long T2D has to have gone away, after diagnosis, before it can be considered in remission. This is partially because T2D is progressive, often diagnosed months or years after tissue begins losing sensitivity to insulin or after pancreatic function begins to erode. For example, Joslin’s current standard, as close to gold-plated as there can be, is this:
Patients diagnosed with type 2 diabetes may discover that if they are overweight at diagnosis and then lose weight and begin regular physical activity, their blood glucose returns to normal. Does this mean diabetes has disappeared? No.The development of type 2 diabetes is a gradual process, too, in which the body becomes unable to produce enough insulin for its needs and/or the body’s cells become resistant to insulin’s effects. Gradually the patient goes from having “impaired glucose tolerance” — a decreased but still adequate ability to convert food into energy — to having “diabetes.”
As designed, Look AHEAD was to continue for thirteen to twenty-one years for participant follow up with intervals and duration based upon the particular outcomes the trial designers hoped to assess. There are participants still checking in for follow up for long-term health assessments begun during Look AHEAD, and some as participants in other diabetes health studies.
In a commentary addressed to physicians published in Medscape on October 19, 2012, University of Southern California Medical School professor Dr. Anne Peters, one of the principal trial investigators, wrote “I can tell you from the outset that we were successful,” even though the primary arm of the trial — reducing incidence of nonfatal heart attacks and strokes, hospitalization for angina, and death — didn’t show that the ILI group fared materially better than the DSE group.
Dr. Peters is a diabetes clinician of international stature. Her success argument, based on the patients she had followed, is this:
Overall, her patients achieved an 8.6% weight reduction in year one. The four year goal was 7%.
Even the patients in the control (DSE) group shed weight, relatively modestly compared to the ILI group patients, but also overall, very few DSE patients gained weight.
There were anecdotal reports of improvement among all participants of relief from urinary incontinence and less dependence on medication to control glucose, and for patients in the ILI group relief from sleep apnea.
The results reinforced that T2D is better controlled among people who pursue healthy lifestyle choices, and that it’s preventable.
For the remission arm of the Look AHEAD trial, the results at four years can be summed up this way:
In the cases of more than 4,500 overweight adults with type 2 diabetes, a confirmationthat complete remission associated with an intensive lifestyle intervention — defined by glucose normalization without need for anti-diabetic medication — was rare.
However, partial remission — defined as a transition to prediabetic or normal glucose levels without drug treatment for a specific period — was an obtainable goal.
The numbers: Of the ILI group 11.5% achieved a partial or complete remission within the first year of intervention, and 7% were in partial or complete remission after 4 years.
Since Look AHEAD
Even though the trial hasn’t yet yielded breakthrough results and may not by the January 2021 endpoint, it has without doubt reinforced the value of continuous exercise and conscientiously managed caloric intake. And there remains a cohort of several thousand people who have T2D who had the benefit of a carefully planned program of healthy eating and regular exercise, and who can be expected to remain available for retrospective study of their experiences maintaining renal and cardiovascular health, mobility, vision, and quality of life.
As Dr. Peters wrote in her commentary “we got our patients to lose weight, increase their physical activity, and do it over a long period of time — for up to 11 years.”
The legacy of the Look AHEAD remission study has carried on and will continue:
In 2015, four researchers at Joslin Clinic conducted a review of records of 120 of the clinic’s T2D patients treated with intensive medication therapy, structured diets, individualized exercise programs, group diabetes education, and individual behavioral counseling between September 2005 and June 2008. After one year in the clinic’s WAIT (Weight Achievement and Intensive Treatment) Program, almost 22% attained (by the Joslin standard) major improvement in glycemic control, and 4.6% reached some degree of remission, with 2.3% at partial remission and 2.3% considered at full remission.
In 2016, eight clinicians associated with McMaster University in Hamilton, Ontario and the University of British Columbia conducted a one-year trial for 83 T2D patients randomized to participate in eight week or 16-week intensive metabolic treatment consisting of personalized exercise plans and 500-700 calorie per day diets. Forty per cent of participants met the
A1c criteria for complete or partial remission three months after discontinuation of their oral or injectable medications without any serious adverse events or hyperglycemic episodes.
In 2017, two researchers at the University of Glasgow and Newcastle University in the U.K. who had recruited 306 T2D patients being treated by general practitioners with oral and injectable medications reported initial success in the DiRECT (Diabetes Remission Clinical Trials), a successor to two smaller scale trials funded by Diabetes UK. DiRECT participants following an eight week 800 calorie per day diet of vitamin fortified soups and shakes have undergone MRI liver and pancreas scans that have shown remarkable loss of liver fat and fat surrounding the pancreas. Nine in ten have experienced improvement in pancreatic function, but the researchers consider the results preliminary. They are seeking additional funding to expand participation and pinpoint the connection between eliminating liver and pancreas fat and restoration of insulin production.
When the politician mentioned at the top of the story finally came clean on Face the Nation in May 2015, he got rather testy. He backpedaled the cinnamon and chromium picolinate Diabetes Solution Kit cure furiously enough to tip a stationary bike backward and he told Bob Schieffer that he’d stopped making infomercials since he’d become a presidential candidate.
But eight years earlier, he’d told Men’s Health that a hospital-prescribed diet and exercising with a trainer helped him to lose 100 pounds and “reverse” his Type 2 diabetes.
Here’s to your health in 2018.
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