ADVANCE ARTICLE: JCEM
THE JOURNAL OF CLINICAL
ENDOCRINOLOGY & METABOLISM
Piloting a Remission Strategy in Type 2 Diabetes: Results of a
Randomized Controlled Trial
Natalia McInnes, Ada Smith, Rose Otto, Jeffrey Vandermey, Zubin Punthakee, Diana
Sherifali, Kumar Balasubramanian, Stephanie Hall, Hertzel C. Gerstein
The Journal of Clinical Endocrinology & Metabolism
Endocrine Society
Submitted: October 05, 2016
Accepted: January 24, 2017
First Online: March 15, 2017
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Diabetes Remission Strategy
Piloting a Remission Strategy in Type 2 Diabetes: Results of a Randomized
Controlled Trial
Department of Medicine, McMaster University, Hamilton, Ontario, Canada
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Population Health Research Institute, Hamilton Health Sciences, Hamilton, Ontario, Canada
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Diabetes Care and Research Program, Hamilton Health Sciences, Hamilton, Ontario, Canada
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School of Nursing, McMaster University, Hamilton, Ontario, Canada
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Received 5 October 2016. Accepted 24 January 2017.
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Context: Medical strategies targeting remission of type 2 diabetes have not been systematically
studied.
Objective: This trial assessed the feasibility, safety and potential to induce remission of a shortterm intensive metabolic strategy.
Design: A randomized, parallel, open-label pilot trial in 83 participants followed for 52 weeks.
Setting: Ambulatory care.
Participants: Patients with type 2 diabetes of up to 3 years in duration.
Interventions: Participants were randomized to: (i) an 8-week intensive metabolic intervention,
(ii) a 16-week intensive metabolic intervention, or (iii) standard diabetes care. During the
intensive intervention period, weight loss and normoglycemia were targeted using lifestyle
approaches and treatment with metformin, acarbose, and insulin glargine. Diabetes drugs were
then discontinued in the intervention groups and participants were followed for hyperglycemic
relapse.
Primary outcome: On-treatment normoglycemia.
Results: At 8 weeks, 50.0% of the 8-week intervention group versus 3.6% of controls achieved
normoglycemia on therapy (RR 14.0, 95% CI 1.97-99.38), and at 16 weeks, these percentages
were 70.4% in the 16-week group and 3.6% in controls (RR 19.7, 2.83-137.13). Twelve weeks
after completion of the intervention, 21.4% of the 8-week group compared to 10.7% of controls
(RR 2.00, 0.55-7.22) and 40.7% of the 16-week group compared to 14.3% of controls (RR 2.85,
1.03-7.87) met HbA1C criteria for complete or partial diabetes remission.
Conclusions: A short course of intensive lifestyle and drug therapy achieves on-treatment
normoglycemia and promotes sustained weight loss. It may also achieve prolonged, drug-free
diabetes remission and strongly supports ongoing studies of novel medical regimens targeting
remission.
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ENDOCRINOLOGY & METABOLISM
Natalia McInnes1,2, Ada Smith1, Rose Otto3, Jeffrey Vandermey3, Zubin Punthakee1,2, Diana
Sherifali3,4, Kumar Balasubramanian2, Stephanie Hall2, Hertzel C. Gerstein1,2
PRECIS: The article summarizes the results of a pilot trial on a novel approach to inducing remission of
type 2 diabetes comprising lifestyle approaches and intensive treatment with insulin and oral drugs.
Introduction
Type 2 diabetes is typically treated using lifestyle approaches and a stepwise addition of oral and
injectable medications. Such regimens lose effectiveness with time due to disease progression
and difficulty adhering to lifestyle changes and multiple drug combinations. For the patient, this
means that a diagnosis of diabetes is the first step on the path of chronic, increasingly complex
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Methods
Study design
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This is a randomized, parallel, open-label pilot trial which was conducted at the Hamilton Health
Sciences in Hamilton, Ontario. The trial was approved by Health Canada and the Hamilton
Integrated Research Ethics Board.
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Participants
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Participants were recruited through the Diabetes Care and Research Program at the Hamilton
Health Sciences. They were included if they were between 30-80 years of age with a BMI ≥23
kg/m2 and type 2 diabetes diagnosed within 3 years prior to enrollment; if they had a HbA1C
≤8.5% (69 mmol/mol) on no oral diabetes drugs or ≤7.5% (58 mmol/mol) on either 1 diabetes
drug or half-maximal doses of 2 drugs at stable doses for at least 8 weeks; had a negative
pregnancy test and an agreement to use a reliable method of birth control (in all females with
childbearing potential); were able to self-monitor capillary blood glucose and willing to selfinject insulin; provided informed consent. Exclusion criteria included: current insulin therapy; a
history of hypoglycemia unawareness, severe hypoglycemia, lactic acidosis or diabetic
ketoacidosis; serum creatinine ≥124 µmol/L; active liver disease, alanine transferase (ALT) ≥2.5
times the upper limit of normal, or excessive alcohol intake; cardiovascular disease, pulmonary
disease with dependence on oxygen, inflammatory bowel disease, colonic ulcers, recent or
significant bowel surgery, predisposition to bowel obstruction, any disease requiring systemic
glucocorticoid treatment, or any major illness with a life expectancy of <3 years; history of any
condition that significantly limited participant’s ability to achieve moderate levels of physical
activity; or a history of hypersensitivity to metformin, acarbose, or insulin glargine. We have
expanded the HbA1C inclusion criterion from 6.5-8.0% (48-64 mmol/mol) on no oral diabetes
drugs to ≤8.5% (69 mmol/mol) on no oral diabetes drugs in February 2012 in order to increase
recruitment. All participants provided written informed consent, and had a baseline
electrocardiogram to screen for any evidence of ischemic heart disease or arrhythmia.
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therapeutic regimens. Recent data suggest that this may not be inevitable and that diabetes may
be partially or even completely reversed, at least in some patients. For example, short-term
intensive insulin therapy(1-12), oral diabetes drugs(9-11), intensive lifestyle therapy(13-15),
low-carbohydrate Mediterranean diet(16) or very-low-calorie diet(17) can reverse diabetes in up
to 40% of patients, and bariatric surgery can induce diabetes remission in up to 95% of
patients(18-23). These data highlight the importance of considering and testing alternative
treatment paradigms for type 2 diabetes that focus on reversing the disease rather than simply
controlling progressive hyperglycemia. They also suggest that achieving normoglycemia on
therapy using one or more approaches may be an important component of any remission
strategy. We therefore conducted a pilot trial to determine whether a short-term intensive
metabolic approach that targeted fasting and postprandial normoglycemia and weight loss using
a combination of pharmacological and lifestyle approaches was feasible and safe, and showed
potential to induce sustained diabetes remission.
Randomization and masking
Eligible participants were randomized 1:1:1 to 3 groups: (i) an 8-week intensive metabolic
intervention followed by cessation of all diabetes drugs; (ii) a 16-week intensive metabolic
intervention followed by cessation of all diabetes drugs; or (iii) standard diabetes therapy using
random permuted blocks of 6 and 9. A randomization schedule was prepared by an independent
statistitian using a computer-generated random number sequence. Allocation was performed
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through a central computerized system to ensure concealment. Due to the nature of the study
interventions, participants and research staff were not blinded to treatment allocation.
Laboratory personnel were blinded to group assignment.
Procedures
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Intervention groups
The two interventions only differed in their duration. They comprised an intensive follow-up
schedule during which lifestyle therapy and treatment with insulin glargine, metformin and
acarbose were reinforced. All other diabetes drugs were discontinued. Participants met with the
research nurse every week for the first 8 weeks, and then every 2 weeks during week 9-16 in the
16-week intervention group. They were also contacted by phone between study visits.
Lifestyle therapy comprised dietary and physical activity intervention. A dietitian estimated
participants’ baseline daily energy requirements using the Mifflin-St. Jeor equation(24) and
activity level, encouraged participants to reduce their daily caloric intake by 500-750 kcal/day by
providing a suggested meal plan, and reinforced caloric reduction during subsequent meetings.
A kinesiologist prescribed an individualized moderate-intensity exercise program, encouraged
participants to achieve ≥150 min of moderate intensity physical activity per week by week 16 of
the trial and to maintain it for the duration of the trial, and led weekly small-group gym sessions.
Participants were also provided with a pedometer (Accusplit TM Eagle AE120XLM) and
encouraged to work towards a goal of 10,000 steps per day. The overall lifestyle goal was to
achieve and maintain ≥5% reduction in baseline weight by week 28 of the trial.
Insulin glargine was started at 2-6 units subcutaneously at bedtime and titrated daily in 1 unit
increments by the participant and twice weekly in 2-4 unit increments by the research nurse to
achieve a fasting capillary glucose between 4.0 and 5.3 mmol/L. Metformin-naïve participants
received metformin 500 mg orally once daily for 4 days, 500 mg twice daily for 4 days, then
1,000 mg twice daily. Acarbose was started at 25 mg orally once daily and titrated by 25 mg
every 4 days to a maximum of 50 mg three times daily. In patients already treated with
metformin or acarbose, these agents were titrated to metformin 1,000 mg twice daily and
acarbose 50 mg three times daily or maximal tolerated doses. The overall goal was to finish
medication titration and achieve a fasting capillary glucose 4.0-5.3 mmol/L by week 4 and to
maintain this target for the remaining duration of the intensive metabolic intervention.
After completing the intensive metabolic intervention, participants in both intervention
groups stopped oral diabetes drugs and tapered insulin to zero over a 5-day period. They were
encouraged to continue with lifestyle modifications and regular glucose monitoring (at least three
times per week) during the maintenance phase of the trial. A 75 g oral glucose tolerance test
(OGTT) was done at 12 weeks after randomization in the 8-week intervention group and at 20
and 28 weeks in all groups. An OGTT was done earlier if fasting capillary glucose levels rose
above 7 mmol/L on ≥50% of home glucose readings in the absence of an acute illness.
Hyperglycemia relapse was defined as a fasting plasma glucose ≥6.1 mmol/L or a 2-hour pc
plasma glucose ≥7.8 mmol/L on the OGTT. Participants who met criteria for hyperglycemia
relapse returned to standard glycemic care by their usual diabetes care provider and did not have
further OGTTs.
Control group
Control group participants received standard lifestyle advice and were also provided with a
pedometer as an incentive to be active. They received standard glycemic management by their
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usual diabetes care provider for the duration of the trial. They had a scheduled OGTT at 20 and
28 weeks and were asked to hold diabetes drugs for 48 hours prior to the OGTT.
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Outcomes
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Table 1 summarizes the various definitions of glycemic response used in the study. The primary
outcome was normoglycemia on therapy defined as a mean fasting capillary glucose ≤5.4
mmol/L and a mean 2-hour postprandial glucose ≤6.8 mmol/L calculated from two 7-point
glucose profiles collected during week 8 (8-week group) and week 16 (16-week group) of
therapy. Secondary outcomes included HbA1C, fasting plasma glucose, changes in weight,
BMI, waist circumference, waist/hip ratio from baseline, hypoglycemic episodes, quality of life,
recruitment rate, retention rate, and adherence to therapy. We also evaluated diabetes remission
and regression outcomes based on the results of an OGTT and HbA1C in participants remaining
off glucose-lowering drugs (see Table 1 for definitions). The OGTT-based definition of
complete diabetes remission was included in the study protocol. Other definitions of remission
and regression were added before any statistical analyses were carried out by treatment group.
OGTTs were performed after a minimum of an 8-hour fast. Blood samples for plasma
glucose were collected in a fluoride-containing tube at 0 and 120 minutes after administration of
a 75 g oral glucose load and submitted to the hospital laboratory within 20 minutes of collection.
HbA1C was measured in a clinical laboratory using methods calibrated to the International
Federation of Clinical Chemistry and Laboratory Medicine (IFCC) method.
Statistical analyses
All analyses were performed using the intention-to-treat principle. Participants lost to follow-up
(N=2) were presumed not to have achieved any diabetes remission. A chi-square test (or
Fisher’s exact test) was used to compare dichotomous outcomes and a two-sample t-test (or a
non-parametric equivalent) to compare continuous outcomes. A sample size of 126 participants
was estimated to provide 90% power to show a risk difference of ≥30% for achieving
normoglycemia on therapy in each intervention group versus the control group, assuming this
would be achieved in <5% of the control group. SAS version 9.2 (SAS Institute, Cary, NC) was
used to perform statistical analyses. The trial was registered at ClinicalTrials.gov, identifier
NCT01181674.
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Follow-up
All participants were seen at 8, 16, 20 and 28 weeks after randomization and were contacted by
telephone at least once a month between these visits. After week 28, all study participants
returned to their regular diabetes care provider who continued to manage their diabetes and came
back for one last study visit at 52 weeks after randomization. HbA1C was measured at 8, 20, 28
and 52 weeks. The European Quality of Life 5-dimension (EQ-5D) questionnaire(25-27) was
collected at baseline, 20 and 28 weeks. It is a 2-part instrument which includes a (i) 5-item
descriptive system from which a weighted health utility index score is derived ranging from 0
(death) to 1 (perfect health state) and (ii) a visual analog scale of perceived health status which is
ranked by the participant from 1 (poor) to 100 (perfect) at the time of completion of the
questionnaire.
Results
A total of 132 participants were screened and 83 (mean age 57; 52% females) were randomly
allocated to the 8-week metabolic intervention group (N=28), 16-week metabolic intervention
group (N=27), and control group (N=28) between February 11, 2011 and January 9, 2014.
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Overall, 2 (2.4%) control group participants did not complete the study and had no follow-up
glucose tolerance tests nor HbA1C results available (see Figure 1). At baseline, the mean
(standard deviation, SD) duration of diabetes was 14.6 (10.6) months, HbA1C was 6.6 (0.6)%
[49 (6.6) mmol/mol], BMI was 33.2 (5.8) kg/m2, and 66 (79.5%) participants were taking oral
glucose-lowering drugs. Baseline characteristics of the study participants are summarized in
Table 2, and they were not significantly different when compared between each intervention
group and the control group.
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The mean (SD) fasting and 2-hour capillary glucose levels during week 8 of therapy were 5.3
(0.6) and 6.4 (0.9) mmol/l in the intervention group and 7.3 (1.5) and 8.3 (1.7) mmol/L in the
control group. Normoglycemia on therapy was achieved in 14 (50.0%) of participants in the
intervention group and 1 (3.6%) in the control group (relative risk, RR 14.0, 95% CI 1.97-99.38).
Four weeks after completion of the intervention (Figure 2), 2 (7.1%) participants in both the
intervention and control groups met the OGTT criteria for complete diabetes remission (RR 1.00,
95% CI 0.15-6.61). At this time, 10 (35.7%) participants in the intervention group and 2 (7.1%)
in the control group had either partial or complete diabetes remission (RR 5.00, 95%CI 1.2020.79).
Twelve weeks after completion of the intervention (Figure 2), 2 (7.1%) participants in both
the intervention and control groups met the OGTT criteria for complete remission as well as for
partial or complete remission (RR for both 1.00, 95% CI 0.15-6.61). At this time, the HbA1C
diabetes remission criteria (Figure 3) indicated that 3 (10.7%) intervention versus 1 (3.6%)
control participants maintained complete diabetes remission (RR 3.00, 95% CI 0.33-27.12); 6
(21.4%) versus 3 (10.7%) participants maintained partial or complete remission (RR 2.00,
95%CI 0.55-7.22); and 8 (28.6%) versus 4 (14.3%) participants had either diabetes regression
or remission (RR 2.00, 95% CI 0.68-5.89).
At 52 weeks (44 weeks after completion of the intervention), 4 (14.3%) intervention
participants versus 2 (7.1%) control participants maintained complete diabetes remission (RR
2.00, 95%CI 0.40-10.05); 7 (25.0%) versus 3 (10.7%) maintained either partial or complete
remission (RR 2.33, 95%CI 0.67-8.12); and 8 (28.6%) versus 4 (14.3%) had either diabetes
regression or remission (RR 2.00, 95%CI 0.68-5.89) based on the HbA1C criteria.
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Glycemic outcomes in the 16-week group
The mean (SD) fasting and 2-hour capillary glucose levels during week 16 of therapy were 4.9
(0.5) and 6.0 (0.7) mmol/l in the intervention group and 6.8 (1.1) and 7.8 (1.9) mmol/L in the
control group. Normoglycemia on therapy was achieved in 19 (70.4%) of participants in the
intervention group and 1 (3.6%) in the control group (RR 19.7, 95% CI 2.83-137.13).
Four weeks after completion of the intervention, 4 (14.8%) participants in the intervention
group and 2 (7.1%) in the control group met the OGTT criteria for complete diabetes remission
(RR 2.07, 95%CI 0.41-10.41; Figure 2). At this time, 12 (44.4%) participants in the intervention
group and 2 (7.1%) in the control group had either partial or complete diabetes remission (RR
6.22, 95%CI 1.53-25.24).
Twelve weeks after completion of the intervention (Figure 2), 2 (7.4%) participants in the
intervention group versus 1 (3.6%) in the control group met the OGTT criteria for complete
remission (RR 2.08, 95%CI 0.20-21.56), and 2 (7.4%) intervention versus 3 (10.7%) control
participants had either partial or complete diabetes remission (RR 0.69, 95%CI 0.13-3.82). At
this time, the HbA1C remission criteria (Figure 3) indicated that 4 (14.8%) intervention versus 2
(7.1%) control participants maintained complete diabetes remission (RR 2.07, 95%CI 0.41-
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Glycemic outcomes in the 8-week group
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10.41); 11 (40.7%) versus 4 (14.3%) participants maintained partial or complete remission (RR
2.85, 95%CI 1.03-7.87); and 13 (48.2%) versus 4 (14.3%) participants had either diabetes
regression or remission (RR 3.37, 95% CI 1.25-9.05).
At 52 weeks (36 weeks after completion of the intervention), 1 (3.7%) intervention
participant versus 2 (7.1%) control participants maintained complete diabetes remission (RR
0.52, 95%CI 0.05-5.39); 6 (22.2%) versus 3 (10.7%) maintained either partial or complete
remission (RR 2.07, 95%CI 0.58-7.47); and 7 (25.9%) versus 4 (14.3%) had either diabetes
regression or remission (RR 1.81, 95%CI 0.60-5.50) based on the HbA1C criteria.
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Figure 4 illustrates the change in weight and waist circumference during the trial. During 28
weeks of follow-up, 10 (35.7%) participants in the 8-week group and 17 (63.0%) in the 16-week
group achieved target ≥5% weight loss from baseline compared to 3 (10.7%) in the control group
(RR 3.33 (1.03-10.84) and 5.88 (1.94-17.8), respectively). The mean (SD) percent weight loss
from baseline peaked at 20 weeks after randomization and was 3.1 (3.4)% in the 8-week group,
5.1 (3.3)% in the 16-week group and 1.4 (2.4)% in controls. The mean (SD) decrease in waist
circumference observed at 20 weeks was 3.2 (2.4) cm in the 8-week group, 4.3 (3.5) cm in the
16-week group and 1.3 (2.3) cm in controls.
During the induction phase of the trial (intensive metabolic intervention period), 21 (38.2%)
participants in the intervention groups required a reduction in dose or temporary withholding of
at least one study medication. Seven (12.7%) participants stopped one study medication
permanently due to side effects (6 participants stopped acarbose and 1 stopped insulin glargine).
The mean (SD) daily insulin glargine doses at the end of the induction phase were 27.5 (16.5)
units in the 8-week group and 21.2 (12.8) units in the 16-week group. The mean daily insulin
doses were 17.2 (14.8) units in participants who achieved remission 12 weeks after stopping
diabetes drugs and 27.8 (14.1) units in those who did not achieve remission.
At 28 weeks or at the time of hyperglycemia relapse if occurred earlier, intervention group
participants returned to their regular diabetes care provider. At 52 weeks after randomization, 8
(28.8%) of participants were on no diabetes drugs, 16 (57.1%) were on 1 agent and 4 (14.3%)
were on 2 agents in the 8-week group; 11 (40.7%) were on no drugs, 14 (51.9%) were on 1 agent
and 2 (7.4%) were on 2 agents in the 16-week group; and 10 (35.7%) were on no drugs, 11
(39.3%) were on 1 agent, 6 (21.4%) were on 2 agents and 1 (3.6%) was on 3 agents in the control
group (see Supplemental Table 1 for details). There were no serious adverse events and no
severe hypoglycemic episodes among study participants. Non-severe symptomatic
hypoglycemic episodes were observed in 9 (32.1%) participants in the 8-week group, 10 (37.0%)
participants in the 16-week group and 1 (3.6%) participant in the control group. Other events
observed during the trial are summarized in the Supplemental Table 2. The EQ-5D health utility
index and visual analogue scale baseline scores and changes in scores from baseline to 20 and 28
weeks were not significantly different when compared between each intervention group and the
control group (see Supplemental Table 3).
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Other Outcomes
Discussion
This randomized controlled pilot trial showed that a short-term, intensive metabolic intervention
targeting fasting and postprandial normoglycemia and weight loss was feasible and safe, and
capable of achieving normoglycemia in more than 50% of patients and inducing ≥5% weight loss
in more than 35% of patients with recently diagnosed type 2 diabetes. The intervention was
implemented by a nurse, dietitian and kinesiologist and included frequent visits, individualized
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Acknowledgments
NM designed the study jointly with HCG and ZP; led study implementation and acquisition of
data; oversaw the analyses and data interpretation; and drafted the original manuscript. AS
implemented the study and acquired data. RO and JV delivered lifestyle intervention. ZP
contributed to study design, DS contributed to study implementation, and SH assisted with data
acquisition and analyses. KB conducted study analyses. HCG conceived study idea; designed
the study together with NM and ZP; contributed to study implementation, analyses and
interpretation of the data; and revised the manuscript. All authors contributed to critical review
and revision of the manuscript.
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dietary, physical activity and drug titration advice, and assistance with setting and attaining
lifestyle goals. The recruitment rate of 2-3 participants per month at one site and no losses to
follow-up in the intervention groups suggest that the intervention was highly accepted. The
finding that up to 41% of the intervention group participants maintained partial or complete
diabetes remission 12 weeks after stopping diabetes drugs challenges the notion that type 2
diabetes is a permanent and progressive disease as previously thought(28-30), and suggests that
it might be possible to achieve diabetes remission by using a combination of lifestyle and
pharmacological approaches. Future trials with at least 1 year of active follow-up off drugs will
be able to provide 1-year remission rates when using the proposed therapeutic approach. The
trial findings also suggest that an 8-week course of intensive metabolic therapy may not be
sufficient for inducing remission, and an induction therapy of a longer duration might be needed.
Previous trials of medical interventions for diabetes have yielded results that are consistent
with the present findings related to the feasibility of achieving remission of type 2 diabetes. One
trial(10) in 382 participants with newly diagnosed type 2 diabetes reported that 45-51% of
patients who achieved tight glycemic goals with short-term intensive insulin therapy and 27% of
those who achieved glycemic goals with oral agents maintained remission after 1 year of followup. Similarly, 20.9% of newly diagnosed patients who achieved tight glycemic goal with shortterm oral drug therapy and 37.9% of those who achieved this glycemic goal with oral drugs plus
insulin maintained good glycemic control without medication for 1 year(11). In another trial in
people with a longer duration of diabetes, intensive lifestyle approaches versus standard diabetes
support and education achieved partial or complete diabetes remission in 11.5% versus 2% of
participants during the first year of follow-up(13).
The strengths of our study include a randomized controlled design with pre-defined
outcomes, intention-to-treat analyses, high adherence, few losses to follow-up, and inclusion of
people with new and established diabetes. Limitations include conducting the study at one site,
the short follow-up period, and the fact that participants returned to usual diabetes care as soon
as they had evidence of abnormal glucose tolerance. Nevertheless, this trial clearly shows that a
multifaceted intensive metabolic strategy that targets normoglycemia and weight loss using
pharmacological and lifestyle approaches may achieve remission, is acceptable to patients, and
may be easily translated into clinical practice. The trial supports further research focused on
identifying the most efficacious combinations of therapies to induce diabetes remission, and
testing whether these approaches can reduce adverse health consequences of type 2 diabetes,
improve quality of life, and reduce the burden of illness associated with type 2 diabetes.
The authors thank the participants for their commitment and participation. The authors also
thank Stephanie Blanchard (data programming, Hamilton Health Sciences), Margaret Kuofie
(data programming, Hamilton Health Sciences), Anka Brozic (lifestyle intervention, Langs
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Community Health Centre), and Dr. Hisham Dokainish (baseline cardiovascular assessments in
some participants, McMaster University) for assistance with project implementation. The study
was funded by the Canadian Diabetes Association (grant #OG-3-11-3447-NY) and the
Population Health Research Institute. D.S. was supported by a Hamilton Health Sciences
Research Early Career Award. N.M. was supported by the McMaster University Department of
Medicine Internal Career Research Award. N.M. dedicates this study to her parents Tatiana and
Nikolai Yakubovich who provided her with invaluable support during her academic journey.
Trial registration: ClinicalTrials.gov, NCT01181674.
Disclosure statement:
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Funding: Canadian Diabetes Association (grant #OG-3-11-3447-NY) and Population Health
Research Institute.
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NM has received grant support from AstraZeneca, Merck and Sanofi outside of the submitted
work. RO has received a honorarium from Abbott Nutrition. ZP has received funding for
speaking, advice and research from Abbott, AstraZeneca, Boehringer Ingelheim, Bristol Myer
Squibb, Eli Lilly, Lexicon, Merck, NovoNordisk and Sanofi. HCG has received grant support
from Sanofi, Lilly, AstraZeneca and Merck, honoraria for speaking from Sanofi, Novo Nordisk,
AstraZeneca and Berlin Chemie, and consulting fees from Sanofi, Lilly, AstraZeneca, Merck,
Novo Nordisk, Abbot, Amgen, Boehringer Ingelheim, and Kaneq Bioscience. AS, JV, DS, KB,
and SH have nothing to disclose.
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Corresponding author and person to whom reprint request should be addressed:
Dr. Natalia McInnes, Department of Medicine, McMaster University, 1280 Main St
West, Hamilton, Ontario, L8S4K1, Canada, Phone: 905-521-2100, Fax: 905-521-4971,
Email: [email protected]
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Figure 1. Consort flow diagram.
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Figure 2. Relative risk of diabetes remission in the intervention groups compared to the control
group based on the OGTT criteria. Complete diabetes remission was defined as a fasting plasma
glucose <6.1 mmol/L and 2-hour plasma glucose <7.8 mmol/L on an oral glucose tolerance test
and no chronic diabetes drugs. Partial or complete diabetes remission was defined as a fasting
plasma glucose <7.0 mmol/L and 2-hour plasma glucose <11.1 mmol/L on an oral glucose
tolerance test and no chronic diabetes drugs.
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Figure 3. Relative risk of diabetes remission and regression in the intervention groups compared
to the control group based on the HbA1C criteria. Complete diabetes remission was defined as
HbA1C<6.0% (42 mmol/mol) and no chronic diabetes drugs. Partial or complete diabetes
remission was defined as HbA1C<6.5% (48 mmol/mol) and no chronic diabetes drugs. Diabetes
regression or remission was defined as HbA1C<7.0% (53 mmol/mol) and no chronic diabetes
drugs.
Figure 4. Anthropometric outcomes. A. Percent weight change from baseline (─■─ 8-week
group; ─▲─ 16-week group; ─○─ control group). Means and standard errors of the means are
shown. 8-week intervention group compared to the control group: p=0.001 at 8 weeks and
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p=0.007 at 16 weeks. 16-week intervention group compared to the control group: p=0.001 at 8
weeks, p=0.0001 at 16 weeks, p<0.0001 at 20 weeks, and p=0.006 at 28 weeks. B. Change in
waist circumference from baseline (─■─ 8-week group; ─▲─ 16-week group; ─○─ control
group). Means and standard errors of the means are shown. 8-week intervention group
compared to the control group: p<0.0001 at 8 weeks, p=0.002 at 16 weeks, and p=0.007 at 20
weeks. 16-week group compared to the control group: p=0.002 at 8 weeks, p=0.002 at 16 weeks,
p=0.001 at 20 weeks, and p=0.01 at 28 weeks.
Complete diabetes remission
Partial or complete diabetes
remission
HbA1C criteria
Complete diabetes remission
Partial or complete diabetes
remission
Diabetes regression or remission
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OGTT criteria
A mean fasting capillary glucose ≤5.4 mmol/L and a mean 2-hour
postprandial glucose ≤6.8 mmol/L calculated from two 7-point glucose
profiles
A fasting plasma glucose <6.1 mmol/L and 2-hour plasma glucose
<7.8 mmol/L on an oral glucose tolerance test and no chronic diabetes
drugs
A fasting plasma glucose <7.0 mmol/L and 2-hour plasma glucose
<11.1 mmol/L on an oral glucose tolerance test and no chronic
diabetes drugs
HbA1C<6.0% (42 mmol/mol) and no chronic diabetes drugs
HbA1C<6.5% (48 mmol/mol) and no chronic diabetes drugs
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Normoglycemia on therapy
HbA1C<7.0% (53 mmol/mol) and no chronic diabetes drugs
R
SMBG criteria
Control group
N=28
58.2(11.1)
14(50.0)
25(89.3)
16.0(11.4)
Overall
N=83
57.1(10.3)
43(51.8)
73(88.0)
14.6(10.6)
6(21.4)
19(67.9)
3(10.7)
5(18.5)
19(70.4)
3(11.1)
6(21.4)
20(71.4)
2(7.1)
17(20.5)
58(69.9)
8(9.6)
20(71.4)
4(14.3)
1(3.6)
22(81.5)
2(7.4)
1(3.7)
21(75.0)
3(10.7)
0(0)
63(75.9)
9(10.8)
2(2.4)
1112.5(489.9)
40(17.3)
0
5(NA)
99.5(23.3)
34.7(7.0)
111.8(14.6)
1284.1(589.1)
45(21.2)
50(NA)
0
95.3(15.2)
33.3(5.5)
110.3(11.4)
1052.4(556.9)
30(NA)
0
0
89.3(14.6)
31.6( 4.4)
107.0(10.6)
1152.4(548.8)
37.5(13.9)
50(NA)
5(NA)
94.7(18.4)
33.2(5.8)
109.7(12.4)
1.03(0.08)
0.93(0.08)
6.7(0.9)
0.99(0.07)
0.95(0.08)
7.0(1.5)
1.01( 0.06)
0.92( 0.04)
7.1(1.4)
1.01(0.07)
0.94(0.07)
6.9(1.3)
6.5(0.4)
48(4.4)
29.0(12.7)
6.6(0.1)
49(2.9)
25.3(12.7)
6.6(0.6)
49(6.6)
30.6(16.9)
6.6(0.6)
49(6.6)
28.3(14.2)
E
16-week group
N=27
57.9(10.5)
15(55.6)
23(85.2)
15.3(10.2)
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N
Age (years)
Females (%)
European (%)
Diabetes duration (months)
Number of diabetes drugs
None
1 agent
2 agents at ½ maximal doses
Use of specific diabetes drugs
Biguanide (%)
Sulfonylurea (%)
DPP4 inhibitor (%)
Daily doses of diabetes drugs
(mg)
Metformin/metformin ER
Gliclazide MR
Sitagliptin
Saxagliptin
Weight (kg)
BMI (kg/m2)
Waist circumference (cm)
Waist to hip ratio
Males
Females
FPG (mmol/L)
HbA1C
(%)
(mmol/mol)
ALT (U/L)
8-week group
N=28
55.1(9.2)
14(50.0)
25(89.3)
12.6(10.1)
C
Characteristic
A
Table 2. Baseline characteristics of the study participants. Means (standard deviations) or N (%)
are shown.
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Table 1. Definitions of glycemic response to therapy.
ALT – alanine transaminase; BMI – body mass index; DPP4 inhibitor – dipeptidyl peptidase-4 inhibitor; FPG –
fasting plasma glucose; NA – not applicable.
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