MANAGING OF TYPE II

DIABETIC PATIENT IN
RAMADAN
DR. MOHAMMAD NASIM
FELLOWSHIP IN ENDOCRINOLOGY,DIABETES AND
METABOLISM,
POSTGRADUATE DIPLOMA IN FAMILY MEDICINE,
SENIOR GP CONSULTANT,
BADRUDDIN MEDICAL GROUP,
JEDDAH,
SAUDI ARABIA

CASE STUDY
A 45-year-old woman with type 2 diabetes arrives for a

follow-up visit . She has been compliant with metformin

1000 mg twice daily. She reports that her home blood
sugar readings have improved slightly but are still high.
She admits to a few dietary indiscretions, such as having
multiple servings of dessert when going out with friends.
For exercise, she has been walking 10 to 15 minutes a
day.

CASE STUDY
She denies polyuria, polydipsia, or blurry vision.
The review of systems is unremarkable.

MEDICAL HISTORY
Her medical history is significant for:
Type 2 diabetes, diagnosed 6 months ago when she
presented with polyuria, blurry vision, and a random
glucose level of 276 mg/dl. Her HbA1c at that time was
9.0%.
She was started on metformin 500 mg twice daily, and
within 3 months her HbA1c dropped to 8.3%. The
metformin was increased to 1000 mg twice daily at that
time. She has not had significant hypoglycemic episodes.

TREATMENT HISTORY
Hypertension, treated with PERINDOPRIL 5mg
daily.
Dyslipidemia, treated with atorvastatin 20 mg
daily.
Esophageal reflux treated with omeprazole 20 mg
daily.

EXAMINATION
Vital signs are :
Blood pressure 122/76 mm Hg, heart rate 82,
respiratory rate 16, temperature 98.0 F,
Height 55, weight 79.0 kg, and BMI 29.0. She
has not gained or lost significant weight since she
started treatment for diabetes.

EXAMINATION
On exam:
The lungs are clear to auscultation, the heart has
a regular rate and rhythm without murmurs, and the
abdomen is non tender.
Peripheral pulses are normal, and there is no lower
extremity edema. The foot exam shows normal
sensation to light touch and no skin or toenail
lesions.

LAB FINDINGS
HbA1c level, determined last week, is 7.8%.
Patients blood glucose log shows morning fasting
glucose ranging from 120 mg/dl to 150 mg/dl, and
postprandial readings at 190 mg/dl to 220 mg/dl.

TA R G E T S O F D I A B E T E S C O N T R O L
The American Diabetes Association (ADA)
recommends :

Target HbA1c of less than 7.0%, fasting glucose less than 130 mg/dl, and
postprandial glucose less than 180 mg/dl for most patients.1

A more ambitious HbA1c target of 6.0% to 6.5% may be appropriate for

patients with a long life expectancy and no cardiovascular disease, provided
that this can be achieved without adverse effects, such as severe
hypoglycemia.
On the other hand, a target HbA1c of 7.5% to 8.0% may be suitable for
patients with significant comorbidities, limited life expectancy, and a history
of severe hypoglycemia. This goal is also reasonable for patients who have not
been able to reach lower HbA1c levels with multiple diabetes medications and
extensive education about diabetes self-management.
Given our patients overall health profile, her target is an HbA1c level of less
than 7.0%, or eventually even 6.0% to 6.5%.

ASSESSMENT
The patients HbA1c has improved since starting metformin,
but is still not at target. Her fasting and postprandial glucose
levels are also too high. The underlying causes for
hyperglycemia in this patient include dietary factors,
inadequate exercise, and obesity. She has no signs or
symptoms of an acute illness that could cause hyperglycemia.
The maximum recommended dose of metformin for adults is
2000 to 2500 mg daily, depending on the formulation. Her
current total daily dose is 2000 mg, and it is unlikely that her
glycemic control will improve significantly just by adding
another 500 mg of metformin.

DISCUSSION
HbA1c is not in the target range on metformin

alone (as in this patient), an additional medication

would be beneficial. Many options are available,
but the ADA recommends choosing one of the
following agents in most cases:

Sulfonylurea
Thiazolidinedione
Glucagon-like peptide (GLP)-1 agonist
Dipeptidyl peptidase (DPP)-4 inhibitor
Insulin

DISCUSSION
A number of issues should be considered when
choosing between these medication classes,
including:
Patient preference for route of administration
and other factors
Efficacy in reducing HbA1c
Potential to cause hypoglycemia
Potential to induce weight gain
Other Side effects

14

FA C T O R S T H AT I N F LU E N C E C H O I C E
O F A N T I H Y P E R G LYC E M I C T H E R A P Y 1
Patient Factors1,2

Patient attitude
Risk associated with adverse events
Disease duration
Life expectancy
Comorbidities
Vascular complications
Resources
Support

1. Inzucchi SE et al. Diabetes Care. 2012;35:13641379.

2. Garber AJ. Endocr Pract. 2013;19:327336.

PATHOPHYSIOLOGY IN
TYPE 2 DM

16

Earlier and Appropriate Intervention May

Improve Patients Chances of Reaching Goal1
Published Conceptual Approach
Diet and
OAD
exercise monotherapy

OAD
OAD
up-titration combination

OAD +
basal insulin

OAD +
multiple daily
insulin
injections

HbA1c,%

10

Mean HbA1c
of patients

9
8
HbA1c goal of 7%

7
6

Duration of Diabetes
Conventional stepwise
treatment approach

Earlier and proactive

intervention approach

OAD=oral antidiabetic agent.

1. Adapted from Del Prato S et al. Int J Clin Pract. 2005;59(11):13451355. Copyright 2005. Adapted with permission of Blackwell Publishing Ltd.

17

As of 2015, an estimated 415 million people have diabetes

worldwide, with type 2 DM making up about 90% of the cases.This
represents 8.3% of the adult population, with equal rates in both
women and men. From 2012 to 2015, diabetes is estimated to have
resulted in 1.5 to 5.0 million deaths each year.Diabetes at least
doubles a person's risk of death. The number of people with
diabetes is expected to rise to 592 million by 2035. The global
economic cost of diabetes in 2014 was estimated to be $612 billion
USD. In the United States, diabetes cost $245 billion in 2012.

18

ADA/EASD Position Statement: Key Points

Glycemic targets and glucose-lowering therapies must be individualized.
Diet, exercise, and education are the foundation of any treatment program.
Metformin is the optimal first-line drug unless there are contraindications.
After metformin, there are limited data to guide therapy. Combination therapy
with an additional 1 to 2 oral or injectable agents is reasonable, aiming to
minimize side effects where possible.
Many patients will eventually require insulin therapy alone or in combination
with other agents to maintain glucose control.
Treatment decisions should be made in conjunction with the patient (when
possible), focusing on patient preferences, needs, and values.
Cardiovascular risk reduction must be a major focus of therapy.

ADA=American Diabetes Association; EASD=European Association for the Study of Diabetes.

1. Inzucchi SE et al. Diabetes Care. 2012;35:13641379.

19

ADA/EASD Advocate a Patient-Centered Approach

to the Management of Hyperglycemia

Approach to management
of hyperglycemia:
Patient attitude and
expected treatment efforts
Risks potentially associated
with hypoglycemia, other
adverse events
Disease duration
Life expectancy
Important comorbidities
Established vascular
complications
Resources, support system

More
stringent
Highly motivated, adherent,
excellent self-care capacities

1. Inzucchi SE et al. Diabetes Care. 2012;35:13641379.

Less motivated, nonadherent,

poor self-care capacities

Low

High

Newly diagnosed

Longstanding

Long

Short

Absent

Few / mild

Severe

Absent

Few / mild

Severe

Readily available

ADA=American Diabetes Association; EASD=European Association for the Study of Diabetes.

Adapted with permission from Inzucchi SE.1

Less
stringent

Limited

20

Potential Advantages of Earlier

Combination Therapy1,2
More rapid achievement of glycemic control
Use of lower doses of individual agents
Opportunity to combine oral antihyperglycemic
agents with complementary modes of action

1. Bailey CJ et al. Int J Clin Pract. 2005;59(11):13091316.

2. Bailey CJ et al. Diab Vasc Dis Res. 2009;6:283287.

21

ADA/EASD Position Statement: General

Recommendations for Antihyperglycemic Therapy
in Patients With Type 2 Diabetes1
In addition to healthy eating, weight control, increased physical activity:

Monotherapy

Metformina

For patients with a baseline A1C 9.0%,

consider combination therapy with 2
agents (noninsulin therapies) or with
insulin itself

Dual Therapy

Metformin
+
SU

Metformin
+
TZD

Not all classes of medications are

reflected here. See Position Statement
for additional information.

If metformin monotherapy does not

achieve individualized A1C target after
about 3 months, add a second agent

Metformin
+
DPP-4i

Metformin Metformin +
+
Insulin
GLP-1-RA (usually basal)

If dual therapy does not achieve the

individualized A1C target after about 3
months, add a third agent in accordance
with labeling recommendations

Unless there are explicit contraindications.

ADA=American Diabetes Association; EASD=European Association for the Study of Diabetes;
DPP-4i=dipeptidyl peptidase 4 inhibitor; GLP-1-RA=glucagon-like peptide-1 receptor agonist; SU=sulfonylurea; TZD=thiazolidinedione.
1. Inzucchi SE et al. Diabetes Care. 2012;35:13641379.
a

22

Sitagliptin and Metformin Target the

Metabolic Defects of Type 2 Diabetes
Sitagliptin improves
markers of beta-cell
function and increases
insulin synthesis and
release.1,2

Sitagliptin reduces
HGO through
suppression of
glucagon from alpha
cells.6
1. Aschner P et al. Diabetes Care. 2006;29:26322637.
2.,Vardarli I et al. Diabetes. 2014;63:663674.
3. Abbasi F et al. Diabetes Care. 1998;21:13011305.
4. Kirpichnikov D et al. Ann Intern Med. 2002;137:2533.
5. Zhou G et al. J Clin Invest. 2001;108:11671174.
6. Solis-Herrera et al. Diabetes Care. 2013;36:27562762.

Beta-Cell
Dysfunction

Insulin Resistance

Metformin has insulinsensitizing properties.3

5

(Liver > Muscle)

Hepatic Glucose
Overproduction (HGO)

Metformin decreases
HGO by targeting the
liver to decrease
gluconeogenesis and
glycogenolysis.4

23

Initial Therapy With Sitagliptin/Metformin FDC vs

Metformin Monotherapy: Study Design1

Sitagliptin/metformin FDC 50/1,000 mg bida (n=625)

T2DM, aged
1878 yrs, OHA
naive, HbA1c
7.5%

R
Metformin 1,000 mg bidb (n=621)

Screening
period

Phase A

Phase B

1 week

18 weeks

26 weeks

Screening

Day 1
Randomization

Glycemic rescue criteria

FPG criteria
to week 18

Week 18
>16.7 mmol/l Day 1 to
Week 6

Week 44
>14.4 mmol/l Week 6
to Week 12

bid=twice daily; FDC=fixed-dose combination; OHA=oral antihyperglycemic agent; R=randomization; T2DM=type 2 diabetes mellitus.
a
Sitagliptin/metformin FDC was initiated at 50/500 mg bid and uptitrated to the full dose over 4 weeks.
b
Metformin was initiated at 500 mg bid and titrated up to 1,000 mg bid over 4 weeks.
1. Adapted with permission from Reasner C et al. Diabetes Obes Metab. 2011;13:644-652.

>12.8 mmol/l Week 12

to Week 18

24

Initial Therapy With Sitagliptin/Metformin FDC vs

Metformin Monotherapy: Change in HbA1c at 18 Weeks1
FAS Populationa
Mean baseline HbA1c , %

9.9

9.8

LS Mean (95% CI) HbA1c

Change From Baseline, %

1.8
2.4

0.6 (0.8, 0.4)b; P<0.001

bid=twice a day; CI=confidence interval; FAS=full analysis set; FDC=fixed-dose combination; LS=least-squares.
a
Excludes data obtained after initiation of additional antihyperglycemic agents.
b
Between-groups difference.
1. Reasner C et al. Diabetes Obes Metab. 2011;13:644-652.

Sitagliptin/metformin FDC 50/1,000 mg bid

(n=559)
Metformin 1,000 mg bid (n=564)

25

Initial Therapy With Sitagliptin/Metformin FDC vs

Metformin Monotherapy: Change in HbA1c at 18 Weeks1
FAS Populationa

LS Mean (SE) Change in

HbA1C From Baseline, %

LS means difference
0.6; P<0.001

3
0

12

18

Week
Sitagliptin/metformin FDC 50/1,000 mg bid (n=559)
Mean baseline HbA1c =9.9%

Metformin 1,000 mg bid (n=564)

Mean baseline HbA1c =9.8%

bid=twice a day; FAS=full analysis set; FDC=fixed-dose combination; LS=least-squares; SE=standard error.
a
Excludes data obtained after initiation of additional antihyperglycemic agents.
1. Used with permission from Blackwell Publishing Ltd. Reasner C et al. Diabetes Obes Metab. 2011;13:644-652. Copyright 2011 Blackwell Publishing Ltd.

Initial Therapy With Sitagliptin/Metformin FDC vs

Metformin Monotherapy: Change in HbA1c at 18 Weeks by
Median Baseline HbA1C Subgroups1
26

FAS Populationa

LS Mean ( SE) HbA1c Change

From Baseline, %

Baseline
HbA1c median (9.7%)
n=288

n=291

Baseline
HbA1c > median (9.7%)
n=271

n=273

1.1
2

1.5
P<0.001

2.4

3.3
4

P<0.001

bid=twice a day; CI=confidence interval; FAS=full analysis set; FDC=fixed-dose combination; LS=least-squares; SE=standard error.
a
Excludes data obtained after initiation of additional antihyperglycemic agents.
1. Adapted with permission from Reasner C et al. Diabetes Obes Metab. 2011;13:644-652.

Sitagliptin/metformin FDC 50/1,000 mg

bid (n=559)
Metformin 1,000 mg bid (n=564)

27

Initial Therapy With Sitagliptin/Metformin FDC vs

Metformin Monotherapy: Proportion of Patients at HbA1c
Goal of <7% at 18 Weeks1
FAS Populationa
P<0.001

Patients at Goal, %

60
50

49

40

34

30
20
10
0
Mean Baseline HbA1c : 9.89.9%

bid=twice a day; FAS=full analysis set; FDC=fixed-dose combination.

a
Excludes data obtained after initiation of additional antihyperglycemic agents.
1. Adapted with permission from Reasner C et al. Diabetes Obes Metab. 2011;13:644-652.

Sitagliptin/metformin
50/1,000 mg FDC bid (n=559)
Metformin 1,000 mg bid (n=564)

28

Initial Therapy With Sitagliptin/Metformin FDC vs

Metformin Monotherapy: Adverse Experience
Summary Over 18 Weeks1
APaT Population

Sitagliptin/metformin
FDC 50/1,000 mg bid
(n=625)
n (%)

Metformin
(n=621)
n (%)

With one or more AEs

271 (43.4)

301 (48.5)

With no AEs

354 (56.6)

320 (51.5)

With drug-related AEs

109 (17.4)

116 (18.7)

With serious AEs

13 (2.1)

20 (3.2)

With serious drug-related AEs

1 (0.2)

1 (0.2)

Who died

1 (0.2)

1 (0.2)

Who were discontinued due to AEs

25 (4.0)

25 (4.0)

Who were discontinued due to drug-related AEs

18 (2.9)

16 (2.6)

Who were discontinued due to serious AEs

6 (1.0)

5 (0.8)

Who were discontinued due to serious drug-related

AEs

1 (0.2)

1 (0.2)

Clinical AEsa

AE=adverse experience; APaT=all patients as treated; bid=twice a day; FDC=fixed-dose combination.

a
Excluding data after initiation of an additional antihyperglycemic agent.
1. Adapted with permission from Reasner C et al. Diabetes Obes Metab. 2011;13:644-652.

29

Initial Therapy With Sitagliptin/Metformin FDC vs

Metformin Monotherapy: Prespecified Gastrointestinal
AEs Over 18 Weeks1
Prespecified Gastrointestinal AEs, %

APaT Population
20

P<0.05

16.6

Sitagliptin/metformin
50/1,000 mg FDC bid (n=625)
Metformin 1,000 mg bid (n=621)

15
12.0
10
5.6

P<0.05

6.3

2.9

3.9

2.6
1.1

0
Diarrhea

Nausea

Vomiting

Abdominal
paina

AE=adverse experience; APaT=all patients as treated; bid=twice a day; FDC=fixed-dose combination.

a
Includes lower abdominal pain, upper abdominal pain, abdominal pain, abdominal discomfort, and epigastric pain.
1. Reasner C et al. Diabetes Obes Metab. 2011;13:644-652.

30

Addition of Sitagliptin or Glimepiride in Patients

Inadequately Controlled on Metformin: Study Design1

Patients 18 years of
age with T2DM on
stable dose of
metformin (1500
mg/day) for
12 weeks and HbA1c
6.5% 9.0%

Sitagliptin 100 mg qd

R
Glimepiride

(started at 1 mg qd and up-titrated until week

18 as needed up to maximum dose of 6 mg qd)
Continue stable dose of metformin

Screening
Period

Week 4

Single-blind
Placebo Run-in

Week 2

Day 1

qd=once daily; R=randomization; T2DM=type 2 diabetes mellitus.

1. Adapted with permission from Arechavaleta R et al. Diabetes Obes Metab. 2011;13:160168.

Double-blind
Treatment Period

Week 30

31

Sitagliptin Was Noninferior to Glimepiride in Reducing

HbA1c at Week 30 (Primary End Point)1
Per-Protocol Population
LS mean change from baseline
at 30 weeks (for both groups): 0.5%

8.0

From Baseline (SE), %

LS Mean Change in HbA1c

7.8
7.6

Sitagliptin 100 mg + metformin (n=443)

7.4

Glimepiridea + metformin (n=436)

7.2

0.47

7.0

(95% CI)
0.07% (0.03, 0.16)

0.54

6.8

Achieved primary
hypothesis of
noninferiority to
sulfonylurea

6.6
6.4
6.2
6.0

12

18

24

30

Week
LS=least squares; SE=standard error.
a
Mean dose of glimepiride (following the 18-week titration period) was 2.1 mg per day.
1. Used with permission from Merck Sharp and Dohme Corp 2010. Arechavaleta R et al. Diabetes Obes Metab. 2011;13:160168. Copyright 2010 Merck
Sharp and Dohme Corp.

32

Sitagliptin Was Associated With a Lower Incidence of

Hypoglycemia and Reduced Body Weight vs Glimepiride1
All patients inadequately controlled on metformin monotherapy (1500 mg/day)
(APaT Population)

(95% CI)
15.0% (19.3, 10.9)
(P<0.001)

n=516

n=518

Body Weight Change at Week 30

LS Mean (95% CI) Change in

Body Weight From Baseline, kg

Patients With 1
Hypoglycemic Episode, %

Hypoglycemia Over 30 Weeks

APaT=all patients as treated; CI=confidence interval; LS=least-squares.

a
Mean dose of glimepiride (following the 18-week titration period) was 2.1 mg per day.
1. Arechavaleta R et al. Diabetes Obes Metab. 2011;13:160168.
2. Data on file, MSD.

= 2.0 kg
(P<0.001)

n=461
n=465

Sitagliptin 100 mg + metformin

Glimepiridea + metformin

Before Initiation please consult the full prescription

information
MSD does not recommend the use of any product
in any different manner than as described in the
prescription information.

44

Summary: A Case for Use of Sitagliptin as

Add-on to Metformin in Place of Sulfonylureas
Risk for hypoglycemia is a consideration when managing
hyperglycemia, according to the ADA/EASD Consensus Algorithm1
Addition of a DPP-4 inhibitor after metformin is a treatment option for those who
do not achieve individualized HbA1c target after ~3 months

Hypoglycemia is a barrier to glycemic control2,3

In comparison to sulfonylureas, sitagliptin provided similar efficacy in
reducing HbA1c in patients uncontrolled on metformin, but with no
weight gain and fewer reported hypoglycemic episodes.47
1. Inzucchi SE et al. Diabetes Care. 2012;35:13641379.
2. Pollack MF et al. Diabetes Res Clin Pract. 2010;87: 204210.
3. lvarez Guisasola F et al. Diabetes Obes Metab. 2008;10(suppl 1):2532.
4. Nauck MA et al. Diabetes Obes Metab. 2007;9(2):194205.
5. Seck T et al. Int J Clin Pract. 2010;64(5):562576.
6. Seck TL et al. Diab Res Clin Pract. 2011;doi:10.1016/j.diabres.2011.03.006.
7. Arechavaleta R et al. Diabetes Obes Metab. 2011;13:160168.

The Incidence of Hypoglycemia in Muslim

Patients With Type 2 Diabetes Treated With
Sitagliptin or a Sulfonylurea During Ramadan

46

Potential Increased Risk of Hypoglycemia of Fasting in

Muslim Patients With Type 2 Diabetes: Introduction
Decreased food intake is a well-known risk factor for the development of
hypoglycemia1
The majority of Muslims fast from dawn until dusk during the annual Islamic holy
month of Ramadan2
Treatment guidelines recommend that most patients with T2DM refrain from fasting
during Ramadan1,2
Many Muslims with T2DM, however, insist on observing the fasting during Ramadan2,3
The ADA recommendsa that sulfonylureas be used with caution in Muslim patients with
T2DM during Ramadan because of their increased risk of hypoglycemia1,2

Fasting increases the risk of hypoglycemia in patients with T2DM who are on
certain oral or injectable diabetes medications2,4
In a population-based study, the incidence of severe hypoglycemic events was
increased 7.5-fold (0.03 vs 0.004 episodes/month) during Ramadan compared with
the preceding year in patients with T2DM2,3

=American Diabetes Association; T2DM=type 2 diabetes mellitus.

s report represents the collective analysis, evaluation, and opinion of the authors at the time of publication and does not represent the official position of the ADA.
-Arouj M et al. Diabetes Care. 2010;33(8):18951902.
avind SR et al. Curr Med Res Opin. 2011;27(6):12371242.
alti I et al. Diabetes Care. 2004;27(10):23062311.
arnett AH et al. Int J Clin Pract. 2010;64(8):11211129.

47

The Incidence of Hypoglycemia in Muslim

Patients With Type 2 Diabetes Treated
With Sitagliptin or a Sulfonylurea During
Ramadan: A Randomized Trial
Al Sifri S et al. Int J Clin Pract. 2011;65:11321140.

48

Sitagliptin vs Sulfonylurea in Muslim Patients With

Type 2 Diabetes Treated During Ramadan: Study Design1

Muslim patients
18 years of age with T2DM
on stable dose of SU for
3 months with or without
metformin before enrollment
HbA1c 10% at screening
Intended to fast during
Ramadan

Sitagliptin 100 mg qd Metformin (n=529)

R
Sulfonylureaa Metformin (n=537)

Screening Period
Screening Visit
(5 weeks prior to start of
Ramadan)

qd=once daily; R=randomization; SU=sulfonylurea; T2DM=type 2 diabetes mellitus.

a
Sulfonylureas used by patients in the study included glibenclamide (glyburide), glimepiride, and gliclazide.
1. Al Sifri S et al. Int J Clin Pract. 2011;65:11321140.

Open Label
Treatment Period
(Ramadan 2010)

49

Sitagliptin vs Sulfonylurea in Muslim Patients With

Type 2 Diabetes Treated During Ramadan: Objective and
End Points1
Objective
To assess the incidence of hypoglycemia with sitagliptin vs SU treatment (with
or without metformin in either group) in adult Muslim patients with T2DM who
fasted during Ramadan in 2010

Primary End Point

Overall proportion of patients with 1 symptomatic hypoglycemica event based
on patient-reported symptoms recorded during Ramadan

Secondary End Point

Proportion of patients with 1 symptomatic or asymptomatic hypoglycemic
event based on patient-reported symptoms and/or recorded blood glucose
level 3.9 mmol/L (70 mg/dL)

SU=sulfonylurea; T2DM=type 2 diabetes mellitus.

a
Without regard to glucose level.
1. Al Sifri S et al. Int J Clin Pract. 2011;65:11321140.

50

Sitagliptin vs Sulfonylurea in Muslim Patients With

Type 2 Diabetes Treated During Ramadan: Select Baseline
Characteristics1
Sitagliptin
metformin
(N=507)

Sulfonylurea
metformin
(N=514)

Age at baseline, years

Mean SD

55 11

55 10

Gender Male

n (%)

269 (53)

255 (50)

BMI, kg/m2

Mean SD

30.5 5.7

30.5 5.6

HbA1c, %

Mean SD

7.5 1.3

7.6 1.2

FPG, mmol/L

Mean SD

8.3 2.9

8.5 2.8

Duration of diabetes, years

Median

5.0

6.0

BMI=body mass index; FPG=fasting plasma glucose; SD=standard deviation.

1. Reprinted with permission from Al Sifri S et al. Int J Clin Pract. 2011;65:11321140.

51

Switching to Sitagliptin Treatment Was Associated With a

Significantly Lower Incidence of Symptomatic Hypoglycemia
Compared With Remaining on Sulfonylurea Treatment1
Primary End Point (APaT Population):
Incidence of Symptomatic Hypoglycemia (Proportion of Patients With 1 Events)
RRR (95% CI) = 0.51 (0.34, 0.75); P < 0.001
50% Risk
Reduction

195 symptomatic hypoglycemic events were reported by 68 patients in the SU group

compared with 128 events in 34 patients for the sitagliptin group in the APaT population
Most common symptoms were headache, sweating, dizziness, hunger, and tremor

APaT=all patients as treated; CI=confidence interval; qd=once daily; RRR=relative risk ratio; SU=sulfonylurea.
1. Al Sifri S et al. Int J Clin Pract. 2011;65:11321140.

52

Switching to Sitagliptin Treatment Was Associated With a Significantly Lower

Risk of Symptomatic or Asymptomatic Hypoglycemia Compared With Remaining
on Sulfonylurea Treatment1
The relative risk of symptomatic or asymptomatic hypoglycemic events was
significantly lower with sitagliptin treatment compared with sulfonylurea treatment
RRR (95% CI) = 0.50 (0.36, 0.69); P < 0.001
APaT Population

Number of Patients Experiencing

Event of Hypoglycemia, n (%)
Symptomatic or asymptomatic
Severea
Requiring nonmedical assistance
Requiring medical assistanceb

Sitagliptin
metformin
(n=507)

Sulfonylurea
metformin
(n=514)

43 (8.5)

92 (17.9)

0 (0)

0 (0)

1 (0.2)

4 (0.8)

0 (0)

0 (0)

APaT=all patients as treated; CI=confidence interval; RRR=relative risk ratio.

a
Events that caused loss of consciousness, seizure, coma, or physical injury. bEg, visits to physician, emergency department admission, or hospitalization.
1. Reprinted with permission from Al Sifri S et al. Int J Clin Pract. 2011;65:11321140.

53

Sulfonylurea Treatment Was Associated With a Higher

Incidence of Adverse Events Compared With Sitagliptin
Treatment1
Excluding hypoglycemia, 9 patients in the sulfonylurea
group reported 16 adverse events during Ramadan
compared with 3 patients in the sitagliptin group who
reported 3 adverse events
There were 3 serious adverse events in the sulfonylurea group
(ischemic stroke, acute pancreatitis, and urinary tract infection)
that resulted in hospitalization
No serious adverse events were reported in the sitagliptin group
No deaths were reported in the study

1. Al Sifri S et al. Int J Clin Pract. 2011;65:11321140.

54

Hypoglycemia in Patients With Type 2

Diabetes From India and Malaysia Treated
with Sitagliptin or a Sulfonylurea During
Ramadan: A Randomized, Pragmatic
Study
Aravind SR et al. Curr Med Res Opin. 2012; 28(8):12891296.

55

Sitagliptin vs Sulfonylurea in Muslim Patients From India and

Malaysia With Type 2 Diabetes Treated During Ramadan:
Study Design1

Muslim patients at 18 years

of age with T2D treated with a
stable dose of SU with or
without metformin for at least
3 months
HbA1c <10% at screening
Intended to fast during
Ramadan

Sitagliptin 100 mg qd Metformin (n=436)

R
Sulfonylureaa Metformin (n=434)

Screening Period
Screening Visit
(5 weeks prior to start of
Ramadan)

qd=once daily; R=randomization; SU=sulfonylurea; T2DM=type 2 diabetes mellitus.

a
Sulfonylureas used by patients in the study included glibenclamide, glimepiride, and gliclazide.
1. Aravind SR et al. Curr Med Res Opin. 2012; 28:1289-1296.

Treatment Period
(Malaysia, Ramadan 2010)
(India, Ramadan 2011)

56

Switching to Sitagliptin Treatment Was Associated With a

Significantly Lower Risk of Symptomatic Hypoglycemia Compared
With Remaining on Sulfonylurea Treatment1
Primary End Point
APaT Population
RRR (95% CI) = 0.52 (0.29, 0.94); P=0.028
48% Risk
Reduction

N=421

N=427

63 symptomatic hypoglycemic events were reported by 31 patients in the SU group compared with 22 events
in 16 patients for the sitagliptin group
In the overall study population, switching to sitagliptin was associated with a nearly 50% reduction of risk of
symptomatic hypoglycemia
APaT=all patients as treated; CI=confidence interval; RRR=relative risk ratio; SU=sulfonylurea.
1. Aravind SR et al. Curr Med Res Opin. 2012; 28:1289-1296.

57

Switching to Sitagliptin Treatment Was Associated With a Significantly Lower

Risk of Symptomatica and Asymptomaticb Hypoglycemia Compared With
Remaining on Sulfonylurea Treatment1,2
APaT Population
RRR (95% CI) = 0.49 (0.29, 0.83); P = 0.006

Sitagliptin 100 mg daily

metformin (n=421)

Symptomatica or
asymptomaticb

Severec

Requiring nonmedical assistanced

SU metformin (n=427)

Requiring medical
assistancee

Proportion of patients reporting hypoglcemia during Ramadan, %

APaT=all patients as treated; CI=confidence interval; RRR=relative risk ratio; SU=sulfonylurea.

a
Without regard to glucose level. bNo reported symptoms but a recorded blood glucose level 3.9 mmol/L (70 mg/dL). cEvents that caused loss of consciousness, seizure, coma, or physical
injury. dEg, family member or friend. eEg, visits to physicians office, emergency department admission, or hospitalization.
1. Aravind SR et al. Curr Med Res Opin. 2012; 28:1289-1296. 2. Data on file, MSD.

58

Selected Summary of Clinical AEs Other Than

Hypoglycemia1
APaT Population

Sitagliptin
metformin
(n=421)

Sulfonylurea
metformin
(n=427)

42 (10.0)

30 (7.0)

9 (2.1)

7 (1.6)

Serious drug-related AEsa

0 (0)

0 (0)

Discontinued due to an AE

5 (1.2)

0 (0)

Discontinued due to a drug-related AEa

3 (0.7)

0 (0)

Blood glucose decreased

1 (0.6)

6 (1.4)

Hyperglycemia

11 (2.6)

7 (1.6)

Pyrexia

5 (1.2)

6 (1.4)

Number of Patients With Adverse

Events Other Than Hypoglycemia,
n (%)
1 AE
Drug-related AEsa

AEs with an incidence 1% in either group

AE=adverse event; APaT=all patients as treated.

a
Determined by the investigator to be drug-related.
1. Reprinted with permission from Aravind SR et al. Curr Med Res Opin. 2012; 28:1289-1296.

59

The Incidence of Hypoglycemia in Adult Muslim Patients

With Type 2 Diabetes Treated With Sitagliptin or a
Sulfonylurea During Ramadan: Summary
In a 5-country observational study, nearly 20% of SU-treated Muslim patients with type 2
diabetes experienced symptomatic hypoglycemia during Ramadan fasting1
6.7% experienced severe hypoglycemia during Ramadan fasting 1

In Muslim patients with T2DM who fasted during Ramadan, treatment with sitagliptin vs
SU with or without metformin resulted in significantly lower
incidences of2,3
Symptomatic hypoglycemia (P<0.0012; P=0.0283)
Asymptomatic or symptomatic hypoglycemia (P<0.0012;P = 0.0063)

There were no recorded severe hypoglycemic events in either treatment group in either of
the 2 sitagliptin vs SU studies2,4

The authors concluded that switching antihyperglycemic therapy is an appropriate

therapeutic option for physicians to consider for management of patients with T2DM who
choose
to mellitus.
observe the daytime fast during Ramadan3
=sulfonylurea; T2DM=type
2 diabetes

ravind SR et al. Curr Med Res Opin. 2011;27(6):12371242.

l Sifri S et al. Int J Clin Pract. 2011;65:11321140.
ravind SR et al. Curr Med Res Opin. 2012; 28:1289-1296.
ata on File MSD.

Recommendations for management of

diabetes during Ramadan: update 2015
Dipeptidyl peptidase-4 (DPP4) inhibitors have been increasingly used during the
past decade for the treatment of patients with type 2 diabetes during Ramadan.
These agents work by increasing insulin secretion in a glucose-dependent
mechanism; therefore, they are not associated with increased risk of
hypoglycemia when used as monotherapy. DPP4 inhibitors also reduce glucagon
concentration and delay gastric emptying. These agents are attractive during
Ramadan because of the low rate of hypoglycemia. The results of these studies
indicate that DPP4 inhibitors are effective in improving glycemic control with low
rates of hypoglycemia and less weight gain compared with insulin
secretagogues.
BMJ Open Diab Res Care 2015;3:e000108 doi:10.1136/bmjdrc-2015-000108

Recommendations for management of

diabetes during Ramadan: update 2015
Sulfonylureas and insulin secretagogues are widely used during
Ramadan. Recent studies, however, have highlighted an increased
risk of hypoglycemia during fasting in patients treated with insulin
secretagogues.The risk of hypoglycemia increases exponentially in
elderly patients and patients with renal failure and medical illnesses
treated with sulfonylureas. In general, it is recommended that insulin
secretagogues should be avoided during periods of prolonged fasting
due to the increased risk of hypoglycemia.
BMJ Open Diab Res Care 2015;3:e000108 doi:10.1136/bmjdrc-2015-000108

Recommendations for management of

diabetes during Ramadan: update 2015
Metformin is the preferred agent for the management of patients with
type 2 diabetes. Metformin is associated with a reduction in HbA1c of
12% and carries a low risk of hypoglycemia.These properties make
metformin an attractive therapy for the majority of patients who will
undergo prolonged fasting.
BMJ Open Diab Res Care 2015;3:e000108 doi:10.1136/bmjdrc-2015-000108

63

64