Piloting a Remission Strategy in Type 2 Diabetes

Abstract and Introduction

Abstract

Objective: This trial assessed the feasibility, safety, and potential to induce remission of a short-term intensive metabolic strategy.

Design: A randomized, parallel, open-label pilot trial with 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: (1) an 8-week intensive metabolic intervention, (2) a 16-week intensive metabolic intervention, or (3) 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 vs 3.6% of controls achieved normoglycemia on therapy [relative risk (RR), 14.0; 95% confidence interval (CI), 1.97 to 99.38), and at 16 weeks, these percentages were 70.4% in the 16-week group and 3.6% in controls (RR, 19.7; 95% CI, 2.83 to 137.13). Twelve weeks after completion of the intervention, 21.4% of the 8-week group compared with 10.7% of controls (RR, 2.00; 95% CI, 0.55 to 7.22) and 40.7% of the 16-week group compared with 14.3% of controls (RR, 2.85; 95% CI, 1.03 to 7.87) met hemoglobin A1C 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.

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 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] a low-carbohydrate Mediterranean diet,^[16] or a 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 whether it showed the potential to induce sustained diabetes remission.

Table 1. Definitions of Glycemic Response to Therapy
Criteria	Glycemic Response	Definition
SMBG criteria	Normoglycemia on therapy	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
OGTT criteria	Complete diabetes remission	A fasting plasma glucose < 6.1 mmol/L and 2-hour plasma glucose < 7.8 mmol/L on an OGTT and no chronic diabetes drugs
	Partial or complete diabetes remission	A fasting plasma glucose < 7.0 mmol/L and 2-hour plasma glucose < 11.1 mmol/L on an OGTT and no chronic diabetes drugs
HbA1C criteria	Complete diabetes remission	HbA1C < 6.0% (42 mmol/mol) and no chronic diabetes drugs
	Partial or complete diabetes remission	HbA1C < 6.5% (48 mmol/mol) and no chronic diabetes drugs
	Diabetes regression or remission	HbA1C < 7.0% (53 mmol/mol) and no chronic diabetes drugs

Table 2. Baseline Characteristics of Study Participants
Characteristic	8-Week Group (N = 28)	16-Week Group (N = 27)	Control Group (N = 28)	Overall (N = 83)
Age, y	55.1 (9.2)	57.9 (10.5)	58.2 (11.1)	57.1 (10.3)
Females, No. (%)	14 (50.0)	15 (55.6)	14 (50.0)	43 (51.8)
European, No. (%)	25 (89.3)	23 (85.2)	25 (89.3)	73 (88.0)
Diabetes duration, mo	12.6 (10.1)	15.3 (10.2)	16.0 (11.4)	14.6 (10.6)
Number of diabetes drugs, No. (%)
None	6 (21.4)	5 (18.5)	6 (21.4)	17 (20.5)
One agent	19 (67.9)	19 (70.4)	20 (71.4)	58 (69.9)
Two agents at half-maximal doses	3 (10.7)	3 (11.1)	2 (7.1)	8 (9.6)
Use of specific diabetes drugs, No. (%)
Biguanide	20 (71.4)	22 (81.5)	21 (75.0)	63 (75.9)
Sulfonylurea	4 (14.3)	2 (7.4)	3 (10.7)	9 (10.8)
DPP4 inhibitor	1 (3.6)	1 (3.7)	0 (0)	2 (2.4)
Daily doses of diabetes drugs, mg
Metformin/metformin ER	1112.5 (489.9)	1284.1 (589.1)	1052.4 (556.9)	1152.4 (548.8)
Gliclazide MR	40 (17.3)	45 (21.2)	30 (NA)	37.5 (13.9)
Sitagliptin	0	50 (NA)	0	50 (NA)
Saxagliptin	5 (NA)	0	0	5 (NA)
Weight, kg	99.5 (23.3)	95.3 (15.2)	89.3 (14.6)	94.7 (18.4)
BMI, kg/m²	34.7 (7.0)	33.3 (5.5)	31.6 (4.4)	33.2 (5.8)
Waist circumference, cm	111.8 (14.6)	110.3 (11.4)	107.0 (10.6)	109.7 (12.4)
Waist-to-hip ratio, cm
Males	1.03 (0.08)	0.99 (0.07)	1.01 (0.06)	1.01 (0.07)
Females	0.93 (0.08)	0.95 (0.08)	0.92 (0.04)	0.94 (0.07)
FPG, mmol/L	6.7 (0.9)	7.0 (1.5)	7.1 (1.4)	6.9 (1.3)
HbA1C
%	6.5 (0.4)	6.6 (0.1)	6.6 (0.6)	6.6 (0.6)
mmol/mol	48 (4.4)	49 (2.9)	49 (6.6)	49 (6.6)
ALT, U/L	29.0 (12.7)	25.3 (12.7)	30.6 (16.9)	28.3 (14.2)

Table 2. Baseline Characteristics of Study Participants

Characteristic

8-Week Group (N = 28)

16-Week Group (N = 27)

Control Group (N = 28)

Overall (N = 83)

Age, y

55.1 (9.2)

57.9 (10.5)

58.2 (11.1)

57.1 (10.3)

Females, No. (%)

14 (50.0)

15 (55.6)

14 (50.0)

43 (51.8)

European, No. (%)

25 (89.3)

23 (85.2)

25 (89.3)

73 (88.0)

Diabetes duration, mo

12.6 (10.1)

15.3 (10.2)

16.0 (11.4)

14.6 (10.6)

Number of diabetes drugs, No. (%)

None

6 (21.4)

5 (18.5)

6 (21.4)

17 (20.5)

One agent

19 (67.9)

19 (70.4)

20 (71.4)

58 (69.9)

Two agents at half-maximal doses

3 (10.7)

3 (11.1)

2 (7.1)

8 (9.6)

Use of specific diabetes drugs, No. (%)

Biguanide

20 (71.4)

22 (81.5)

21 (75.0)

63 (75.9)

Sulfonylurea

4 (14.3)

2 (7.4)

3 (10.7)

9 (10.8)

DPP4 inhibitor

1 (3.6)

1 (3.7)

0 (0)

2 (2.4)

Daily doses of diabetes drugs, mg

Metformin/metformin ER

1112.5 (489.9)

1284.1 (589.1)

1052.4 (556.9)

1152.4 (548.8)

Gliclazide MR

40 (17.3)

45 (21.2)

30 (NA)

37.5 (13.9)

Sitagliptin

50 (NA)

Saxagliptin

5 (NA)

Weight, kg

99.5 (23.3)

95.3 (15.2)

89.3 (14.6)

94.7 (18.4)

BMI, kg/m²

34.7 (7.0)

33.3 (5.5)

31.6 (4.4)

33.2 (5.8)

Waist circumference, cm

111.8 (14.6)

110.3 (11.4)

107.0 (10.6)

109.7 (12.4)

Waist-to-hip ratio, cm

Males

1.03 (0.08)

0.99 (0.07)

1.01 (0.06)

1.01 (0.07)

Females

0.93 (0.08)

0.95 (0.08)

0.92 (0.04)

0.94 (0.07)

FPG, mmol/L

6.7 (0.9)

7.0 (1.5)

7.1 (1.4)

6.9 (1.3)

HbA1C

6.5 (0.4)

6.6 (0.1)

6.6 (0.6)

mmol/mol

48 (4.4)

49 (2.9)

49 (6.6)

ALT, U/L

29.0 (12.7)

25.3 (12.7)

30.6 (16.9)

28.3 (14.2)

Authors and Disclosures

Natalia McInnes^1,2, Ada Smith¹, Rose Otto³, Jeffrey Vandermey³, Zubin Punthakee^1,2, Diana Sherifali^3,4, Kumar Balasubramanian², Stephanie Hall² and Hertzel C. Gerstein^1,2

¹Department of Medicine, McMaster University, Hamilton, Ontario L8S 4K1, Canada; ²Population Health Research Institute, Hamilton Health Sciences, Hamilton, Ontario L8L 2X2, Canada; ³Diabetes Care and Research Program, Hamilton Health Sciences, Hamilton, Ontario L8N 3Z5, Canada; and ⁴School of Nursing, McMaster University, Hamilton, Ontario L8S 4K1, Canada Context: Medical strategies targeting remission of type 2 diabetes have not been systematically studied.

Address all correspondence and requests for reprints to
Natalia McInnes, MD, Department of Medicine, McMaster University, Room 3V51, 1280 Main Street West, Hamilton, Ontario L8S 4K1, Canada. E-mail: natalia.mcinnes@mcmaster.ca.

Author contributions
N.M. designed the study jointly with H.C.G. and Z.P., led study implementation and acquisition of data, oversaw the analyses and data interpretation, and drafted the original manuscript. A.S. implemented the study and acquired data. R.O. and J.V. delivered lifestyle intervention. Z.P. contributed to study design, D.S. contributed to study implementation, and S.H. assisted with data acquisition and analyses. K.B. conducted study analyses. H.C.G. conceived the study idea, designed the study together with N.M. and Z.P., 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.

Disclosure Summary
N.M. has received grant support from AstraZeneca, Merck, and Sanofi outside of the submitted work. R.O. has received an honorarium from Abbott Nutrition. Z.P. has received funding for speaking, advice, and research from Abbott, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Lexicon, Merck, Novo Nordisk, and Sanofi. H.C.G. 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. The remaining authors have nothing to disclose.

The study was supported by the Canadian Diabetes Association GrantOG-3-11-3447-NY and by 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.

Piloting a Remission Strategy in Type 2 Diabetes

Results of a Randomized Controlled Trial

Abstract and Introduction

Abstract

Introduction

Tables

Tables

References

Authors and Disclosures

Authors and Disclosures

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