Insight on Treating Diabetes during Ramadan Fasting

Dante Saksono Harbuwono, MD PhD

Division of Metabolism and Endocrinology
Department of Internal Medicine
Faculty of Medicine
University of Indonesia
RAMADAN
PHYSIOLOGY

Changes in Sleeping
Pattern

Changes in Hunger-Satiety

Changes in Cortisol Circadian

Rythm
Diabetes and Ramadan : Practical Guidelines, International Diabetes Federation, in collaboration with the Diabetes and Ramadan (DAR) International Alliance, April 2016
CHANGES IN HUNGER SATIETY
DURING RAMADAN

Diabetes and Ramadan : Practical Guidelines, International Diabetes Federation, in collaboration with the Diabetes and Ramadan (DAR) International Alliance, April 2016
CHANGES IN CORTISOL
CIRCADIAN RYTHM

Changes in cortisol rythm

found on day 7 of Ramadan ,
and this revert to near baseline
as in non-Ramadan condition
by day 21

Diabetes and Ramadan : Practical Guidelines, International Diabetes Federation, in collaboration with the Diabetes and Ramadan (DAR) International Alliance, April 2016
EFFECTS OF FASTING ON GLUCOSE
HOMEOSTASIS IN HEALTHY
INDIVIDUALS

Diabetes and Ramadan : Practical Guidelines, International Diabetes Federation, in collaboration with the Diabetes and Ramadan (DAR) International Alliance, April 2016
EXERCISE TIPS IN RAMADAN
 TYPES OF EXERCISE
Exercise Goals :

Be realistic
NOT the time for focus the progress
NOT the time to be trying new things
Lower intensity, shorter duration
In order to prevent muscle lose and weight

gain
 TYPES OF EXERCISE
How many times per week should I workout?

2-3 times a weekly

the minimum to maintain lean muscle tissue
 TIME
Time recommendation for

exercise is about 1-2 hours

before iftar or 2-3 hours after

iftar

In total 75 minutes is including

warming up and cooling down

14

Vivienna, Nurhayatul, Abdul, Recommendations for optimal competitive exercise performance and effective training induced adaptations when ramadan fasting, June 2015
INTENSITY
Start with low intensity exercise gradually

increased to vigorous

Don’t do high intensity exercise like

sprinting as it can cause joint or muscle

injuries and also lead to complication such

as hypoglycaemia and dizziness

Goals : 60-80% of your maximum heart

rate (MHR). MHR calculation is 220 - age 15

 HYDRATION
• Daily fluid intake up to 2.5 L

• Drink 200ml every 30 minutes of exercise after iftar

• Drink water as much as you can during Iftar and sahur

16

Vivienna, Nurhayatul, Abdul, Recommendations for optimal competitive exercise performance and effective training induced adaptations when ramadan fasting, June 2015
NUTRITION
Sahur : Do not overeat, Focus on taking in foods that are rich in complex carbohydrates (slow digesting) and protein.

Iftar : High carbohydrates with low glycemic index to optimize muscle glycogen storage (Water , Milk , Dates , Fruits)

Avoid salty foods as these will make you thirsty.

Avoid fried and spicy food as they may cause heartburn or indigestion

Vivienna, Nurhayatul, Abdul, Recommendations for optimal competitive exercise performance and effective training induced adaptations when ramadan fasting, June 2015
REST
Take a rest when possible to maintain body fitness

It is advised to take afternoon nap for 30 - 40 minutes

Sleep at least 4 hours at night before sahur

Vivienna, Nurhayatul, Abdul, Recommendations for optimal competitive exercise performance and effective training induced adaptations when ramadan fasting, June 2015
IDEAL TWICE-A-DAY TRAINING SESSIONS MODEL
FOR ATHLETES DURING RAMADAN

19
Key risks associated with fasting for patients with diabetes
Risk Category and religious opinion on fasting
Risk Category and religious opinion on fasting
When to break the Fast?
Medication
 Trial design
LIRA-RAMADAN PHASE IV TRIAL

Key inclusion criteria

• T2DM, HbA1c 7–10%, age ≥18,
BMI ≥20 kg/m2 Metformin + liraglutide 1.8 mg
N=343
• Expressed their intention to fast
(daytime, i.e., between sunrise Metformin + SU
and sunset) during Ramadan Up to 33 weeks
• Stable (≥90 days) metformin
Liraglutide Treatment Ramadan* Post
≥1000 mg/day and SU at
dose maintenance 4 weeks Ramadan
maximum tolerated dose Randomisation (1:1) escalation 6 to 19 weeks 4 weeks FU 1 week
(at least half maximum 3 to 4 weeks
approved dose)

Primary objective: to compare the effect of liraglutide vs. SU on change in glycaemic control during
Ramadan in patients with T2DM
Secondary objectives: to compare the effect of liraglutide vs. SU on glycaemic control, body weight,
safety and tolerability

*Ramadan period lasts between 29–30 days

BMI, body mass index; HbA1c, glycosylated haemoglobin; FU, follow up; Met, metformin; SU, sulphonylurea; T2DM, type 2 diabetes mellitus
Azar et al. Diabetologia 2016 Submitted
Change in fructosamine
320

Change in fructosamine (μmol/L)

316 0
312 -5
Fructosamine (μmol/L)

308
-10
304
300 -15
296 -20
292 -25
288
-30
284 Lira 1.8 mg; n=151
280 SU; n=165 -35
276 -40
272 -45
268
Baseline to end of Ramadan During Ramadan -50
264
260
2 3 4 5 6 7 8 9 10 11 12 13 14
Visit
• Randomisation Liraglutide dose escalation
Reduction in fructosamine from baselineTreatment
to end of Ramadan Post-Ramadan
: -39.6 μmol/L liraglutide
Ramadan versus -
• Reduction in fructosamine during Ramadan:
3–4 weeks -12.8
maintenance 6– μmol/L liraglutide versus -16.4 μmol/L SU
4 weeks
29.3 μmol/L SU 19 weeks
4 weeks
• ETD during Ramadan: 3.51; 95% CI [-5.26; 12.28]; p=0.4311
• ETD from baseline to end of Ramadan: -10.3 μmol/L; 95% CI [-18.7; -1.89]; p=0.0165

Estimated means +/- standard error

The responses are analysed using a mixed model for repeated measurement with visit, treatment, country,
stratification groups as fixed factors and baseline as a covariate, all nested within visit.
CI, confidence interval; ETD, estimated treatment difference; Lira, liraglutide; SU, sulphonylurea
Azar et al. Diabetologia 2016 Submitted
Change in HbA1c Mean change from
baseline to Visit 12
ETD: -0.59
95% CI
8.50 [-0.79; -0.38] 0.25
p<0.0001
8.25 0.00

Change in HbA1c (%)

8.00 -0.25
7.75 -0.50
HbA1c (%)

7.50 -0.75
7.25 -1.00
7.00 -1.25
Lira 1.8 mg; n=151
6.75 SU; n=165 -1.50
6.50 -1.75
6.25 -2.00
6.00
2 3 4 5 6 7 8 9 10 11 12 13 14
Visit
Randomisation Liraglutide dose escalation Treatment Ramadan Post-Ramadan
3–4 weeks maintenance 6– 4 weeks 4 weeks
19 weeks

Estimated means +/- standard error from mixed model for repeated measurements
HbA1c, glycosylated haemoglobin; Lira, liraglutide; SU, sulphonylurea
Azar et al. Diabetologia 2016 Submitted
Change in FPG
170
0

Change in FPG (mg/dL)

165
-5
160
-10
FPG (mg/dL)

155
-15
150
-20
145
Lira 1.8 mg; n=147 -25
140 SU; n=164
-30
135
Baseline to end to
Baseline of end
Ramadan During Ramadan
of treatment
130
2 3 4 5 6 7 8 9 10 11 12 13 14
Visit
• Change in FPG baseline to end of Ramadan:
Treatment: -29.3
-30.9with
withliraglutide
liraglutideversus
versus-10.4
-19.2mg/dL
mg/dL
• Change in FPG during Ramadan: -3.32 with liraglutide versus 2.98 mg/dL with SU
with SU
• ETD during Ramadan: -6.3; 95% CI: [-18.6; 6.0]; p=0.3142
• ETD baseline to end of Ramadan:
Treatment:-18.9;
-11.7;95%
95%CICI[-28.5;
[-20.8;-9.3];
-2.7];p=0.0001
p=0.0115

Estimated means +/- standard error from mixed model for repeated measurements
CI, confidence interval; FPG, fasting plasma glucose; Lira, liraglutide; SU, sulphonylurea
Azar et al. Diabetologia 2016 Submitted
Body weight (kg) during Ramadan
85
2

Change in body weight (kg)

84
1
83
Body weight (kg)

0
82
-1
81
-2
80
-3
79
Lira 1.8 mg; n=165 -4
78
SU; n=168
-5
77
-6
76 Baseline to end to
Baseline of end
Ramadan During Ramadan
of treatment
75
2 3 4 5 6 7 8 9 10 11 12 13 14
Visit

•• Significantly
Significantly greater
greater reduction
reduction in
in body
body weight
weight for
for liraglutide
liraglutide versus
versus SU
SU from baseline
during Ramadanto end of
Ramadan,
treatment,estimated
estimateddifference
differencein
inmean
meanchange
changein inbody
bodyweight
weight-3.94;
-3.95;
• Estimated
95% difference in mean change in body weight -0.54; 95% CI [-0.94; -0.14]; p=0.0091
CI [-4.54;
[-4.57; -3.33]; p<0.0001

Estimated means +/- standard error from mixed model for repeated measurements
CI, confidence interval; Lira, liraglutide; SU, sulphonylurea
Azar et al. Diabetologia 2016 Submitted
Confirmed hypoglycaemia during Ramadan
(fasting)
Liraglutide 1.8 mg SU

N (%) E R N (%) E R

All 3 (2.0) 3 246 7 (4.3) 8 623

Nocturnal 0 (0.0) 0 0 2 (1.2) 2 156

• In the SU treatment group, 3 subjects on glimepiride, 2 subjects on

gliclazide and 2 subjects on glibenclamide/glyburide experienced an
episode of confirmed hypoglycaemia during Ramadan

Confirmed: blood glucose value <2.8 mmol/L (50 mg/dL) or plasma glucose value <3.1 mmol/L
(56 mg/dL) or an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions.
N, number of subjects with at least one event; %, percentage of subjects; E, number of events; R, rate of events per 1000 subject years of exposure. SU, sulphonylurea
Difference between treatment groups not tested
Azar et al. Diabetologia 2016 Submitted
Confirmed hypoglycaemia: Overall study period

Liraglutide 1.8 mg SU

N (%) E R N (%) E R

All 5 (2.9) 6 88 16 (9.4) 28 393

Nocturnal 0 (0.0) 0 0 3 (1.8) 3 42

• Estimated rate ratio (all confirmed; liraglutide/SU): 0.2; 95% CI

[0.1; 0.5]; p=0.0027

Confirmed: blood glucose value <2.8 mmol/L (50 mg/dL) or plasma glucose value <3.1 mmol/L
(56 mg/dL) or an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions.
N, number of subjects with at least one event; %, percentage of subjects; E, number of events;
R, rate of events per 1000 subject years of exposure. SU, sulphonylurea
Azar et al. Diabetologia 2016 Submitted
 Confirmed nocturnal hypoglycaemia
From baseline to
During Ramadan end of treatment
300 300

Episodes per 1000 PYE

Episodes per 1000 PYE

225 225

150 150
156

75 75

0 0 42
0 0

Lira 1.8 mg (N=151) SU (N=165)

Lira, liraglutide; PYE, participant years of exposure; SU, sulphonylurea

Nocturnal hypoglycaemia is defined as hypoglycaemia with time of onset between 00:01 and 05:59, both inclusive
Azar et al. Diabetologia 2016 Submitted
ADA documented symptomatic hypoglycaemia during
Ramadan by SU

16. 14.8

12.
% of subjects

9.8

8.

4.
2.0

0.
Documented symptomatic hypoglycaemia
Liraglutide Glimepiride/gliclazide/ Glybenclamide/
glipizide glyburide

Novo Nordisk data on file: NN2211-3987.

 ADA-classified documented symptomatic
hypoglycaemic episodes
The liraglutide group had less documented symptomatic hypoglycaemic episodes than the SU group:

From baseline to
During Ramadan
1.0 1.0 end of treatment

Number of episodes
Number of episodes

ERR (liraglutide/SU): ERR (liraglutide/SU):

0.8 0.8

per participant
per participant

0.1 [0.0, 0.4]95%CI, p=0.0009 0.2 [0.1, 0.4]95%CI, p<0.0001

0.6 0.6

0.4 0.4

0.2 0.2

0.0 0.0
0 1 2 3 4 0 7 14 21 28
Weeks since start of Ramadan Treatment week
Liraglutide 1.8 mg; N=152 SU; N=163 Liraglutide 1.8 mg; N=171 SU; N=170

CI, confidence interval; EOT, end of treatment; ERR, estimated rate ratio; SU, sulphonylurea
Azar et al. Diabetologia 2016 Submitted