Supplementary Online Content

Carter S, Clifton PM, Keogh JB. Effect of intermittent compared with continuous energy
restricted diet on glycemic control in patients with type 2 diabetes: a randomized
noninferiority trial. JAMA Netw Open. 2018;1(3):e180756.
doi:10.1001/jamanetworkopen.2018.0756

eTable 1. Intermittent Energy Restriction Example Meal Plan

eTable 2. Initial Medication Protocol
eTable 3. Medication Changes Using First Protocol
eTable 4. Medication Changes Using Second Protocol
eTable 5. Primary, Secondary, and Exploratory Outcomes From Baseline to 12 Months
for Intermittent vs Continuous Groups, Completers Analysis

This supplementary material has been provided by the authors to give readers additional
information about their work.

© 2018 Carter S et al. JAMA Network Open.

eTable 1. Intermittent Energy Restriction Example Meal Plan
500kcals 600kcals

1 serve of fruit (150g)

Breakfast +
1 tub of diet yoghurt

Small tin of tuna in spring water Add: 1 serve of breads/cereals e.g. ‘thin
Lunch + style’ wrap

1 cup of salad
100g of cooked chicken breast
(1 teaspoon of oil for cooking)
Dinner +
1.5 cups cooked low carbohydrate
vegetables

Note: 2 litres of fluid was recommended. Diet products were allowed e.g. diet jelly.

© 2018 Carter S et al. JAMA Network Open.

eTable 2. Initial Medication Protocol
HbA1c Sulphonylureas Insulin

CER: Reduce by ~10 units/day

Discontinue at IER: Halve insulin dose on intermittent days

<8% baseline for both
groups *If insulin dose before bed was considered to be too high in
preparation for an intermittent diet day, before bed dose was also
decreased.

>8% N/A IER: Reduce by ~10 units on IER days only

Abbreviations: CER, continuous energy restriction; IER, intermittent energy restriction; ~, approximately.

© 2018 Carter S et al. JAMA Network Open.

eTable 3. Medication Changes Using First Protocola
Wt loss Event
Initial Change Events Changes Event Changes
Med. HbA1c Initial after during Final
Grp. Med. Protocol after first (3wks- before (3mth- after
Category (%) Change first first Med.
Dose 2wks 3mths) 3mths 12mths) 3mths
2wks 2wks
CER OHA 6.2 150mg Discont. Yes Yes n/a n/a n/a n/a n/a n/a n/a
Hypers
No OHA on No OHA
IER OHA 6.7 60mg Discont. Yes Yes n/a n/a n/a n/a (non-IER
IER d on IER d
d)
Restarted Discont.
Hypo No OHA
IER OHA 7.3 60mg Discont. Yes No n/a n/a n/a OHA (pt OHA on
(IER d) on IER d
MP) IER d

Added
Hypers back half Hypo Discont.
IER OHA 7.5 120mg Discont. Yes Yes n/a n/a No OHA
(both d) dose (both d) OHA
(60mg)
LONG LONG 22u,
LONG
Insulin 12u, LONG RAPID 11u LONG
25u,
(LONG + RAPID Hypers 16u, (pt MP), 27u,
CER 7.6 RAPID Yes Yes n/a n/a Hypers
RAPID) + 6u, (x3) RAPID 7u LONG 27u, RAPID
12u, OHA
OHA Discont. (pt MP) RAPID 8u 8u
60mg
OHA (pt MP)

15/25u,
Insulin Hypo 20/25u,
CER 8.6 25/45u None Yes Yes 20/30u Hypo Hypo 15/30u 15/30u
(MIX) (x3) 20/20u
(levels inc.)
Insulin
CER 9 88/58u None Yes No n/a n/a W/D
(MIX)
20/15u
(low),
17/10u
Hypo
CER Insulin 9.7 30/22u None Yes Yes 25/17u n/a (low), n/a 20/5u (low) 20/5u
(x1)
20/10u
(levels
inc.)

© 2018 Carter S et al. JAMA Network Open.


Wt loss Event
Initial Change Events Changes Event Changes
Med. HbA1c Initial after during Final
Grp. Med. Protocol after first (3wks- before (3mth- after
Category (%) Change first first Med.
Dose 2wks 3mths) 3mths 12mths) 3mths
2wks 2wks
LONG 15u
LONG
on IER d
20u on
LONG and 20u on LONG
LONG IER d and LONG 30u
Insulin 20u, Hypo non-IER d, 10u on
40u, LONG only on Hypo
IER (LONG + 7.1 RAPID Yes Yes (x2) n/a LONG 10u IER d,
RAPID 30u, non-IER d (both d)
RAPID) 7/7u on (both d) on IER d 20u non-
15/15u RAPID (low)
IER d and 20u IER d
7/7u on
non-IER d
non-IER d
(low)
Hypo
Insulin 40/38u on 20/20u on Hypo 20/10u on
IER 7.3 80/75u Yes No (x3) (IER W/D
(MIX) IER d IER d (IER d) IER d
d)
6/20u
night Hypo
No, > 0/10u on
IER Insulin 8.8 6/41u before Yes (x1) (IER n/a n/a W/D
required IER d
and on d)
IER d
10/30u
10/30u non-IER
10/30u on
non-IER d, d,
IER d and
No, > Hypo 10/10u 10/10u
IER Insulin 8.8 10/50u 25u night Yes n/a n/a n/a n/a
required (IER d) night night
before
before and before
IER d
IER d and IER
d

LONG
Insulin
28/15/28u
IER (LONG + 11.5 None Yes W/D
, RAPID
RAPID)
28/15/28u

a
Recommendations made by the study’s endocrinologist unless otherwise specified. First protocol, eTable 2.
Abbreviations: Grp, group; Med, medication; HbA1c, glycated hemoglobin; Wt, weight; wks, weeks; mths, months; CER, continuous energy restriction; IER, intermittent energy restriction; OHA, oral
hypoglycemic agent (gliclazide unless otherwise stated); Discont, discontinue; hypers, hyperglycemia; hypo, hypoglycemia; low, 72-106mg/dL; inc. increasing; W/D, withdrew; d, day/s; pt, participant; MP,
medical practitioner; Insulin, long-acting insulin (insulin glargine); LONG; long-acting insulin (insulin glargine); MIX, NovaMix; RAPID, NovaRapid; u, units

© 2018 Carter S et al. JAMA Network Open.

eTable 4. Medication Changes Using Second Protocola
Wt loss Event
Initial Change Events Changes Event Changes
Med. HbA1c Initial after during Final
Grp. Med. Protocol after first (3wks- before (3mth- after
Category (%) Change first first Med.
Dose 2wks 3mths) 3mths 12mths) 3mths
2wks 2wks
Discont.
No. At pt
OHA, pt
OHA MP 60mg
CER OHA 6.1 MP Yes n/a n/a n/a n/a n/a n/a
120mg advice, < OHA
decrease
required
to 60mg
OHA
CER OHA 7.4 None Yes Yes n/a n/a n/a n/a W/D
20mg
OHA
CER OHA 7.7 None Yes No n/a n/a n/a n/a W/D
80mg
OHA
CER OHA 8.3 None Yes No n/a n/a n/a n/a n/a n/a n/a
60mg
OHA
CER OHA 8.4 None Yes Yes n/a n/a n/a n/a W/D
60mg

OHA 60mg OHA

CER OHA 9 None Yes Yes n/a n/a n/a W/D
120mg (low)

OHA
CER OHA 10.9 None Yes W/D
80mg
OHA OHA Discont.
IER 6 Yes Yes n/a n/a n/a n/a n/a n/a n/a
(GP) 1mg OHA
Hypers
OHA Discont. (x2)
IER OHA 6.2 Yes Yes n/a n/a n/a n/a n/a n/a
60mg OHA (non-IER
d)
Hypos 30mg OHA
OHA No OHA
IER OHA 7 Yes No n/a n/a (non-IER on non-IER W/D
60mg on IER d
d) d
OHA OHA No OHA Discont.
IER 7 Yes Yes n/a n/a n/a n/a n/a No OHA
(GP) 2mg on IER d OHA (low)

© 2018 Carter S et al. JAMA Network Open.


Wt loss Event
Initial Change Events Changes Event Changes
Med. HbA1c Initial after during Final
Grp. Med. Protocol after first (3wks- before (3mth- after
Category (%) Change first first Med.
Dose 2wks 3mths) 3mths 12mths) 3mths
2wks 2wks
Hypers
OHA No OHA Restart
IER OHA 7.3 Yes No (x2) W/D
60mg on IER d OHA
(both d)
Hypos
(x2)
(non-IER Decrease 60mg
OHA No OHA d) and to 60mg OHA on
IER OHA 7.6 Yes Yes n/a n/a n/a n/a
120mg on IER d Hypers OHA on non-IER
(x5) non-IER d d
(non-IER
d)
OHA No OHA
IER OHA 7.8 Yes No n/a n/a W/D
120mg on IER d
OHA No OHA Hypers Restart OHA
IER OHA 7.9 Yes Yes n/a n/a n/a n/a
120mg on IER d (both d) OHA 120mg
Discont.
OHA No OHA OHA
IER OHA 9.2 Yes Yes n/a n/a n/a n/a n/a No OHA
60mg on IER d completely
(low)
OHA No OHA No OHA
IER OHA 9.5 Yes Yes n/a n/a n/a n/a n/a n/a
60mg on IER d on IER d

LONG LONG
Insulin
36u, 30u, No, < LONG 28u LONG 22u
CER (LONG + 6.2 Yes n/a n/a n/a n/a 22u
RAPID RAPID required (low) (low)
RAPID)
12/12u discont.

No, <
CER Insulin 6.9 20u None Yes n/a n/a n/a n/a n/a n/a n/a
required
No, all pt
would
CER Insulin 7.1 12u 10u agree No n/a n/a n/a 9u (low) n/a 8u (low)
too, <
required

© 2018 Carter S et al. JAMA Network Open.


Wt loss Event
Initial Change Events Changes Event Changes
Med. HbA1c Initial after during Final
Grp. Med. Protocol after first (3wks- before (3mth- after
Category (%) Change first first Med.
Dose 2wks 3mths) 3mths 12mths) 3mths
2wks 2wks
Insulin 22/30u, 15/20u,
No, >
CER (MIX) + 7.5 OHA Discont. Yes n/a n/a Hyper 15/25u Hypers 17/27u 17/27u
required
OHA 120mg OHA

Insulin + 26u,
No, < 20u, 18u, 14u, 12u,
CER OHA 7.8 OHA None Yes n/a n/a Hypo n/a 10u
required 16u 10u (low)
(GP) 4mg
CER Insulin 8.3 36u None Yes W/D
n/a (pt n/a (pt
Hypers n/a (pt MP n/a (pt MP
CER Insulin 8.5 80/34u None Yes Yes MP Hypers Hypers MP
(x5) advice) advice)
advice) advice)
Hypers 35u, 38u,
CER Insulin 8.8 30u None Yes No n/a n/a n/a Hypers 40u
(x4) 40u
70/70u
CER Insulin 9.3 75/75u None Yes Yes n/a n/a n/a n/a n/a 70/70u
(low)
Insulin + 25u,
CER OHA 10 OHA None Yes Yes n/a n/a Low 20u W/D
(GP) 4mg
10/10u,
10/15u
no OHA 10/15u on
Insulin 45/45u, on IER d,
on IER d, No, < 25/30 non- IER d,
IER (MIX) + 5.7 OHA Yes n/a n/a Hyper Hypers 15/30u
25/25u required IER d 15/30u on
OHA 60mg non-IER
on non- non-IER d
d
IER d
No
insulin
Hypers
16u, the night
Insulin + (x4) 18u non- 16u non- 16u non-
IER 7.5 OHA before or Yes Yes n/a n/a n/a
OHA (non-IER IER d IER d (low) IER d
60mg on IER d,
d)
no OHA
on IER d

© 2018 Carter S et al. JAMA Network Open.

 Wt loss Event
Initial Change Events Changes Event Changes
Med. HbA1c Initial after during Final
Grp. Med. Protocol after first (3wks- before (3mth- after
Category (%) Change first first Med.
Dose 2wks 3mths) 3mths 12mths) 3mths
2wks 2wks
40/40u 30/30u on
10/10u, Hypos
non-IER d non-IER d
no OHA No, all pt (x6)
and no and no
70/70u, on IER d would (both d), Hypos 20/20u
Insulin + 50/50u Hypos insulin insulin
IER 7.6 OHA and 10u agree Yes Hypers (non-IER non-IER
OHA non-IER d (both d) night night
60mg the night too, < (x2) d) d
before IER before IER
before on required (non-IER
d or on IER d or on IER
IER d d)
d d, 20/20u
No. Pts
30u on
IER Insulin 7.7 40u MP, < Yes n/a n/a n/a n/a n/a n/a 30u
IER d
required
65/65u on
No Hypers non-IER d,
Insulin
IER 7.8 40/40u insulin on Yes No n/a n/a n/a n/a (non-IER 30/30u on 30/30u
(MIX)
IER d d) non-IER d
(low)
44/24u No MIX 10u of
Insulin Hypers
MIX, 6u night RAPID on
IER (MIX + 7.9 Yes No (x14) n/a n/a n/a n/a n/a
RAPID before or IER d as
RAPID) (both d)
as req. on IER d req.
No
Hypo
insulin Hypo
(x1) 25u on 20u on
IER Insulin 8.7 32u night Yes Yes (non-IER W/D
(non-IER non-IER d non-IER d
before or d)
d)
on IER d
20u non-
5u night 10u night
Decrease IER d,
Insulin + 26u, before Hypers 10u night before IER
No, < Hypo to 5u night Hypers 10u night
IER OHA 9 OHA IER d Yes (x12) before d, 20u on
required (IER d) before IER (both d) before
(GP) 4mg and none (both d) IER d non-IER d
d and none
on IER d (low)
on IER d

Insulin + 34u, 17u on

22u on No, < 15u on IER 12u on IER
IER OHA 9.8 OHA Yes n/a IER d n/a n/a 12u
IER d required d (low) d (low)
(GP) 4mg (low)

a
Recommendations made by the study’s endocrinologist unless otherwise specified. Second protocol detailed in manuscript.

© 2018 Carter S et al. JAMA Network Open.

Abbreviations: Grp, group; Med, medication; HbA1c, glycated hemoglobin; Wt, weight; wks, weeks; mths, months; CER, continuous energy restriction; IER, intermittent energy restriction; OHA, oral
hypoglycemic agent (gliclazide unless otherwise stated); GP, glimepiride; Discont, discontinue; hypers, hyperglycemia; hypo, hypoglycemia; low, 72-106mg/dL; d, day/s; W/D, withdrew; pt, participant; MP,
medical practitioner; Insulin, long-acting insulin (insulin glargine); LONG; long-acting insulin (insulin glargine); MIX, NovaMix; RAPID, NovaRapid; u, units

© 2018 Carter S et al. JAMA Network Open.

eTable 5. Primary, Secondary and Exploratory Outcomes From Baseline to 12 Months for
Intermittent vs Continuous Groups (Completers Analysis)a
Mean (SEM) [95% CI]

All
P Value for P Value for
Participants Continuous Intermittent
Variable Time Diet by Time
(n = 97)

Primary Outcome

-0.4 (0.09) -0.4 (0.2) -0.3 (0.1)

HbA1c, % <.001 .62
[-0.6 to -0.1] [-0.8 to -0.05] [-0.6 to -0.01]

Secondary Outcomes

-6.1 (0.7) -5.0 (0.8) -7.1 (1.1)

Weight, kgb <.001 .15
[-7.8 to -4.3] [-7.0 to -3.0] [-9.9 to -4.4]
-2.1 (0.2) -1.8 (0.3) -2.5 (0.4)
BMI, kg/m2 <.001 .19
[-2.7 to -1.5] [-2.5 to -1.1] [-3.4 to -1.6]
-2.2 (0.4) -1.7 (0.4) -2.8 (0.8)
Total Body Fat, %c <.001 .21
[-3.3 to -1.1] [-2.7 to -0.6] [-4.7 to -0.9]
-4.4 (0.6) -3.7 (0.7) -5.2 (0.9)
Total Fat Mass, kgc <.001 .22
[-5.9 to -3.0] [-5.4 to -1.9] [-7.5 to -2.9]
-1.8 (0.2) -1.3 (0.3) -2.2 (0.3)
Total FF Mass, kgc <.001 .02
[-2.3 to -1.3] [-2.1 to -0.5] [-2.9 to -1.5]
-3.3 (0.7) -2.1 (0.5) -4.5 (1.2)
Android Fat, %c <.001 .07
[-5.0 to -1.6] [-3.4 to -0.8] [-7.6 to -1.4]
-0.7 (0.1) -0.6 (0.1) -0.9 (0.1)
Android Fat Mass, kgc <.001 .14
[-0.9 to -0.5] [-0.9 to -0.3] [-1.2 to -0.5]
-0.2 (0.04) -0.3 (0.05) -0.2 (0.06)
Android FF Mass, kgc <.001 .80
[-0.3 to -0.1] [-0.2 to 0.1] [-0.2 to 0.1]
-0.2 (0.07) -0.2 (0.09) -0.3 (0.1)
VAT, kgc <.001 .38
[-0.4 to -0.1] [-0.4 to -0.05] [-0.5 to -0.05]

Abbreviations: HbA1c, glycated hemoglobin; BMI, body mass index; FF, fat free; VAT, visceral adipose tissue.
a
Data were included for 97 participants (CER group: n=46; IER group: n=51) unless otherwise stated: mean (SEM) and [95% CI] were estimated with
repeated-measures ANOVA.
b
Total analysed: n=94 (CER group: n=44; IER group: n=50) 3 participants did not attend final appointment, GP sent HbA1c results.
c
Total analysed: n=81 (CER group: n=39; IER group: n=42) weight >130kg or declined DEXA scan.

© 2018 Carter S et al. JAMA Network Open.