Diabetes updates, DPP4 inhitors and Ramadan and DM

• Respected audience
• Warm Welcome to you all

• Dr. Rajat SR Biswas, MD
• Resident Physician
• CMSOGH, Agrabad
• Chittagong

Type 2 Diabetes - Its
Managements &
Use of DPP-4 inhibitor:
Sitagliptin

History of Diabetes Mellitus
• Coined phrase ‘diabetes mellitus’ from Greek and Latin origins
• 1552 B.C. - Earliest known record of diabetes mentioned on 3rd
Dynasty Egyptian papyrus by physician Hesy-Ra; mentions polyuria
(frequent urination) as a symptom
• 1869 - Paul Langerhans, a German medical student, announces that
the pancreas contains contains two systems of cells. One set
secretes the normal pancreatic juice, the function of the other was
unknown. These cells are identified as the 'islets of Langerhans.'
• 1921 – Frederick Banting and Charles Best find insulin is secreted
from the ‘islets of Langerhans’ of the pancreas.
• 1959 - Two major types of diabetes are recognized: type 1 (insulin-

The Diabetes Epidemic: Global
Projections, 2010–2030
IDF. Diabetes Atlas 5th
Ed. 2011

In Matlab 5% of the
young adults (27-50
years) are affected by
diabetes
Ref: ICDDR’B annual report 2008
In Bangladesh 5.6 million
peoples are diagnosed as
diabetic patients, which
is 6.1% of total
population (age group
20-79 years).

•But only 2% are aware of it.
•This means that two-thirds of diabetic people in the
community are unaware of their condition, and this lack
of awareness can often lead to complications and end
organ damage such as kidney failure , blindness and also
may precipitate cardiovascular disease.
Ref: ICDDR’B annual report 2008

Type 2 Diabetes is the main cause of
untreated complications, severe
disabilities and death for an estimated
3 millon people.

Type 2 diabetes increases theType 2 diabetes increases the
risk of serious morbidityrisk of serious morbidity
4.9
3.6
3.2
2.8 3
11
7
0
2
4
6
8
10
12
Angina Cardiac
failure
Myocardial
infarction
Stroke Renal
failure
Amputation
(minor)
Amputation
(major)
Relativeincreaseinrisk
Adapted from The Information Centre. National Diabetes Audit, Abridged report for the audit period
2004/2005. London: The Information Centre, 2006.

CARBOHYDRATE METABOLISM
Homeostatic mechanisms maintain plasma
glucose concentration between 55 - 140 mg/dL
(3.1 to 7.8 mmol/L).
A minimum concentration of 40 - 60 mg/dL
(2.2 to 3.3 mmol/L) is required to provide
adequate fuel for (CNS), which uses glucose as its
primary energy source.
CNS: Central Nervous System.

Blood glucose concentration exceed the
Re-absorptive capacity of the kidneys( 180
mg/dL ), glucose spills into the urine resulting
in a loss of calories and water.
Muscle and fat use glucose as major source of
energy, but these tissues require insulin for
glucose uptake.
If glucose is unavailable, these tissues are able
to use amino acids and fatty acids for fuel.
CARBOHYDRATE METABOLISM – Cont’d

Postprandial Glucose Metabolism
in the Nondiabetic Individual
In muscle, insulin promotes the uptake of glucose
and its storage as glycogen.
It also stimulate the uptake of amino acid and their
conversion to protein.
In adipose tissue, glucose is converted to free fatty
acids and stored as triglycerides.
Insulin prevents a breakdown of these
triglycerides to free fatty acids.
The liver doesn't require insulin for glucose
transport, but insulin facilitates the conversion of
glucose to glycogen and free fatty acids.

Fasting Glucose Metabolism
in Nondiabetic Individual
As blood glucose concentrations drop toward
normal during the fasting state, insulin release is
inhibited .
A number of counter regulatory hormones
that promote an increase in blood sugar are
released (e.g., glucagon, epinephrine, growth
hormone, glucocorticoides).
Several processes maintain a minimum blood
glucose concentration for the CNS.
CNS: Central Nervous System.

Glycogen in the liver  glucose.
Amino acids are transported from muscle to
liver  glucose.
Uptake of glucose by insulin dependent tissues
is diminished to conserve glucose for the
brain.
Triglycerides are broken down into free fatty
acids, which are used as alternative fuel
sources.
Fasting Glucose Metabolism
in Nondiabetic Individual – Cont’d

(5) Excess glucose accumulation
in the circulation
(2) Resistance to action of insulin
(1) impaired
Insulin secretion
(4)↑ Glucose
output
Hepatic
Peripheral
(3) ↓ Glucose
utilization
(6) Hyperglycemia
Stimulates the pancreas
to produce more insulin
Pathogenesis

Overweight/Obesity - Inactivity.
Hypertension.
A first degree relative with DM
Previous Gestational DM
Coronary Heart Disease
Dyslipidemia
Previously identified impaired
fasting glucose (IFG) OR
impaired glucose tolerance (IGT).
RISK FACTORS FOR DIABETES INCLUDE:

CLINICAL PRESENTATION OF
HYPERGLYCEMIA

Screening of asymptomatic individuals at
high risk for Type 2 DM should be carried out
on an opportunistic basis.
Screening should begin at age 40 years,
and be considered at an earlier
age (e.g. 30 years) if risk factors for diabetes
are present.
Screening should be carried out every 3
years for those with normal glucose
tolerance and annually for those with
impaired fasting glucose (IFG) or impaired
glucose tolerance (IGT).
SCREENING OF ASYMPTOMATIC INDIVIDUALS.

DIAGNOSTIC CRITERIA OF TYPE
2 DM
Casual plasma glucose > 200 mg/dl and symptoms of diabetes
OR
Fasting Plasma Glucose (FPG)
>126 mg/dl OR
Results of a 2-hour 75-g Oral Glucose
Tolerance Test (OGTT) > 200 mg/dl
(Non-Pregnant Adults)

Flowchart For The Diagnosis Of Diabetes Mellitus
No typical symptoms
Casual plasma glucose >11.1 mmol/l
OR
Fasting plasma glucose >7.0 mmol/l
NO YES
Repeat FPG
FPG
>7.0 mmol/l
YES
DM
NO
Go to
figure 2
Typical symptoms and/or
acute metabolic
decompensation
Unequivocal hyperglycemia
Casual PG >11.1 mmol/l
OR
FPG >7.0 mmol/l

Flowchart For Individuals Suspected To Have Diabetes But Whose
FPG <7.0 Mmol/L
FPG
< 6.0 mmol/l 6.1- 6.9 mmol/l
Oral Glucose
Tolerance Test
2- hour post -
challenge glucose
<7.8
mmol/l
7.8 - 11.0
mmol/l
>11.1
mmol/l
Impaired
Fasting
Glycaemia
Impaired
Glucose
Tolerance
Diabetes
Mellitus
Normal
Fasting
Glucose

ADA-EASD Position Statement: Management of
Hyperglycemia in T2DM
•Glycemic targets
- HbA1c < 7.0% (mean PG ∼150-160 mg/dl [8.3-8.9
mmol/l])
- Pre-prandial PG <130 mg/dl (7.2 mmol/l)
- Post-prandial PG <180 mg/dl (10.0 mmol/l)
- Individualization is key:
 Tighter targets (6.0 - 6.5%) - younger, healthier
 Looser targets (7.5 - 8.0%+) - older, comorbidities,
hypoglycemia prone, etc.
- Avoidance of hypoglycemia
PG = plasma glucose Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of prin

Figure 1 Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]
(Adapted with permission from: Ismail-Beigi F, et al. Ann Intern Med 2011;154:554)

ANTI-HYPERGLYCEMIC THERAPY-
•Therapeutic options: Lifestyle
-Weight optimization
-Healthy diet
- Increased activity level
Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of prin

ANTI-HYPERGLYCEMIC THERAPY
• Therapeutic options:
Oral agents & non-insulin injectables
- Metformin
- Sulfonylureas
- Thiazolidinediones
- DPP-4 inhibitors
- GLP-1 receptor agonists
- Meglitinides
- α-glucosidase inhibitors
- Bile acid sequestrants
- Dopamine-2 agonists
- Amylin mimetics
Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

•Therapeutic options: Insulin
- Neutral protamine Hagedorn (NPH)
- Regular
- Basal analogues (glargine, detemir)
- Rapid analogues (lispro, aspart, glulisine)
- Pre-mixed varieties

Long (Detemir)
Rapid (Lispro, Aspart, Glulisine)
Hours
Long (Glargine)
0 2 4 6 8 10 12 14 16 18 20 22 24
Short (Regular)
Hours after injection
Insulinlevel
•Therapeutic options: Insulin
Intermediate (NPH)

•Implementation strategies:
-Initial therapy
-Advancing to dual combination therapy
-Advancing to triple combination therapy
-Transitions to & titrations of insulin

T2DM Antihyperglycemic Therapy: General Recommendations
Diabetes Care, Diabetologia. 19 April 201
[Epub ahead of print]

Diabetes Care, Diabetologia.
19 April 2012 [Epub ahead of print]

equential Insulin Strategies in T2DM Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of prin

4. OTHER CONSIDERATIONS
•Age
•Weight
•Sex / racial / ethnic / genetic differences
•Comorbidities
-Coronary artery disease
-Heart Failure
-Chronic kidney disease
-Liver dysfunction
-Hypoglycemia

OTHER CONSIDERATIONS
•Age: Older adults
-Reduced life expectancy
-Higher CVD burden
-Reduced GFR
-At risk for adverse events from polypharmacy
-More likely to be compromised from hypoglycemia
Less ambitious targets
HbA1c <7.5–8.0% if tighter
targets not easily achieved
Focus on drug safety
Less ambitious targets
HbA1c <7.5–8.0% if tighter
targets not easily achieved
Focus on drug safety

•Weight
-Majority of T2DM patients overweight / obese
-Intensive lifestyle program
-Metformin
-GLP-1 receptor agonists
-? Bariatric surgery

T2DM Anti-hyperglycemic Therapy: General Recommendations
Diabetes Care, Diabetologia. 19 April
2012 [Epub ahead of print]

Adapted Recommendations: When Goal is to Avoid Weight Gain
Diabetes Care, Diabetologia. 19 April
2012 [Epub ahead of print]

•Sex/ethnic/racial/genetic differences
-Little is known
-MODY & other monogenic forms of diabetes
-Latinos: more insulin resistance
-East Asians: more beta cell dysfunction
-Gender may drive concerns about adverse effects
(e.g., bone loss from TZDs)

•Comorbidities
-Coronary Disease
-Heart Failure
-Renal disease
-Liver dysfunction
-Hypoglycemia
 Metformin: CVD benefit
(UKPDS)
 Avoid hypoglycemia
 ? SUs & ischemic
preconditioning
 ? Pioglitazone & ↓ CVD
events
 ? Effects of incretin-based
therapies
 Metformin: CVD benefit
(UKPDS)
 Avoid hypoglycemia
 ? SUs & ischemic
preconditioning
 ? Pioglitazone & ↓ CVD
events
therapies

•Comorbidities
-Coronary Disease
-Heart Failure
-Renal disease
-Liver dysfunction
-Hypoglycemia
 Metformin: May use unless
condition is unstable or severe
 Avoid TZDs
therapies
 Metformin: May use unless
condition is unstable or severe
 Avoid TZDs
therapies

•Comorbidities
-Coronary Disease
-Heart Failure
-Renal disease
-Liver dysfunction
-Hypoglycemia
 Increased risk of hypoglycemia
 Metformin & lactic acidosis
US: stop @SCr ≥ 1.5 (1.4
women)
UK: ↓ dose @GFR <45 &
stop @GFR <30
 Caution with SUs (esp.
glyburide)
 DPP-4-i’s – dose adjust for
most
 Increased risk of hypoglycemia
 Metformin & lactic acidosis
US: stop @SCr ≥ 1.5 (1.4
women)
UK: ↓ dose @GFR <45 &
stop @GFR <30
 Caution with SUs (esp.
glyburide)
 DPP-4-i’s – dose adjust for
mostDiabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

•Comorbidities
-Coronary Disease
-Heart Failure
-Renal disease
-Liver dysfunction
-Hypoglycemia
 Most drugs not tested in
advanced liver disease
 Pioglitazone may help steatosis
 Insulin best option if disease
severe
 Most drugs not tested in
advanced liver disease
 Pioglitazone may help steatosis
 Insulin best option if disease
severe

•Comorbidities
-Coronary Disease
-Heart Failure
-Renal disease
-Liver dysfunction
-Hypoglycemia
 Emerging concerns regarding
association with increased
mortality
 Proper drug selection in the
hypoglycemia prone
 Emerging concerns regarding
association with increased
mortality
 Proper drug selection in the
hypoglycemia prone

T2DM Anti-hyperglycemic Therapy: General Recommendations

Adapted Recommendations: When Goal is to Avoid Hypoglycemia

Adapted Recommendations: When Goal is to Minimize Costs

Guidelines for Glycemic, BP, & Lipid Control
American Diabetes Assoc. Goals
HbA1C < 7.0% (individualization)
Preprandial
glucose 70-130 mg/dL (3.9-7.2 mmol/l)
Postprandial
glucose < 180 mg/dL
Blood pressure < 140/90 mmHg
Lipids
LDL: < 100 mg/dL (2.59 mmol/l)
< 70 mg/dL (1.81 mmol/l) (with overt
CVD)
HDL: > 40 mg/dL (1.04 mmol/l)
> 50 mg/dL (1.30 mmol/l)
TG: < 150 mg/dL (1.69 mmol/l)

FUTURE DIRECTIONS / RESEARCH NEEDS
•Comparative effectiveness research
 Focus on important clinical outcomes
•Contributions of genomic research
•Perpetual need for clinical judgment!

The Role of Incretins inThe Role of Incretins in
Type 2 DiabetesType 2 Diabetes

IncretinsIncretins
Peptides secreted by the intestinalPeptides secreted by the intestinal
mucosa in response to food intakemucosa in response to food intake
– Glucagon-like peptide-1 (GLP-1)Glucagon-like peptide-1 (GLP-1)
– Glucose-dependent insulinotrophicGlucose-dependent insulinotrophic
polypeptide (GIP)polypeptide (GIP)

The incretinsThe incretins
Y
A
E
G
T
F
I
S
D
Y
S
I
A
M
D
K
I
H
Q
Q
DFVN
WLLA
QKGK
KNDW
K
H N Q
TI
GIP: glucose-dependent insulinotropic peptide
H
A
E
G
T
F
T
S
D
V
S
S
Y
L
E
G
Q
A
A
K
EFIA
WLVK
GR
G
GLP-1: glucagon-like peptide-1
Amino acids shown in gold are homologous with the structure of glucagon

L-Cell
(ileum)
Proglucagon
GLP-1 [7–37]
GLP-1 [7–36 NH2]
K-Cell
(jejunum)
ProGIP
GIP [1–42]
GIP=glucose-dependent insulinotropic peptide; GLP-1=glucagon-like peptide-1
Adapted from Drucker DJ. Diabetes Care. 2003; 26: 2929–2940.
GLP-1 and GIP are synthesized and secretedGLP-1 and GIP are synthesized and secreted
from the Gut in Response to food intakefrom the Gut in Response to food intake

59
GLP-1 Effects in Humans
Understanding the Natural Role of Incretins
Adapted from Flint A, et al. J Clin Invest. 1998;101:515-520
Adapted from Larsson H, et al. Acta Physiol Scand. 1997;160:413-422
Adapted from Nauck MA, et al. Diabetologia. 1996;39:1546-1553
Adapted from Drucker DJ. Diabetes. 1998;47:159-169
Stomach:Stomach:
Helps regulateHelps regulate
gastric emptyinggastric emptying
Promotes satiety andPromotes satiety and
reduces appetitereduces appetite
Liver:Liver:
↓↓ Glucagon reducesGlucagon reduces
hepatic glucose outputhepatic glucose outputBeta cells:Beta cells:
Enhances glucose-Enhances glucose-
dependent insulin secretiondependent insulin secretion
Decreased apoptosisDecreased apoptosis
Beta cell regenerationBeta cell regeneration
Alpha cells:Alpha cells:
↓↓ PostprandialPostprandial
glucagon secretionglucagon secretion
GLP-1 secreted upon
the ingestion of food
↓↓ Beta-cell
workload
↓↓ Beta-cell
workload
↑↑ Beta-cell
response
↑↑ Beta-cell
response
GLP-1 levels are decreased in DM 2

Pancreatic Islet Cells are Targets for IncretinPancreatic Islet Cells are Targets for Incretin
HormonesHormones
GLP-1=Glucagon-Like Peptide-1
Adapted from Drucker D. Diabetes Care. 2003;26:2929-2940. Wang Q, et al. Diabetologia. 2004;47:478-487.
Incretin Response
Food
intake
-Cellα
-β
Cell
Pancreatic Islet
cells
Incretin

DPP 4
 GLP-1 and GIP are inactivated by dipeptidyl peptidase-
4 (DPP-4) - this enzyme inactivates the incretin molecules
by removing two amino acids from the N-terminal ends of
the GLP-1 and GIP peptide chains.
As a result of DPP-4 activity, intact, biologically active
GLP-1 represents only 10-20% of total plasma GLP-1.
GLP-1 Inactive
metabolites
Dipeptidyl peptidase-IV
(DPP-IV)

62
Incretins in Glucose Homeostasis & negative
activity of DPP-4 (Dipeptidyl peptidase- 4) enzyme
1. Kieffer TJ, Habener JF. Endocr Rev. 1999;20:876–913.
2. Ahrén B. Curr Diab Rep. 2003;2:365–372.
3. Drucker DJ. Diabetes Care. 2003;26:2929–2940.
4. Holst JJ. Diabetes Metab Res Rev. 2002;18:430–441.
 Insulin from beta cells
(GLP-1 and GIP)
 Glucagon from
alpha cells
(GLP-1)
Release of gut
hormones—
Incretins1,2
Pancreas2,3
Glucose DependentGlucose Dependent
Active
GLP-1 & GIP
DPP-4
enzyme
Inactive
GIP
Inactive
GLP-1
Glucose DependentGlucose Dependent
↓↓ BloodBlood
glucoseglucose
GI tractGI tract
↓↓GlucoseGlucose
productionproduction
by liverby liver
Food ingestionFood ingestion
↑↑GlucoseGlucose
uptake byuptake by
peripheralperipheral
tissuetissue2,42,4
Beta cellsBeta cells
Alpha cellsAlpha cells

63
New treatment options for Type 2 Diabetes
1) Amylin analog
2) GLP-1 analogs
3) DPP-IV inhibitors
Clinical Diabetes. VA Fonseca. Saunders, 2006, p.395-416.

64
New oral hypoglycaemic
DPP 4 Inhibitors

65
Inhibition of DPP-4 increases active GLP-1
GLP-1
inactive
(>80% of pool)
Active
GLP-1
Meal
DPP-4
Intestinal
GLP-1
release
GLP-1 t½=1–2 min
DPP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1
Adapted from Rothenberg P, et al. Diabetes 2000; 49 (suppl 1): A39. Abstract 160-OR.
Adapted from Deacon CF, et al. Diabetes 1995; 44: 1126-1131.

DPP-4=dipeptidyl peptidase-4; T2DM=type 2 diabetes mellitus
Adapted from Unger RH. Metabolism 1974; 23: 581–593. Ahrén B. Curr Enzyme Inhib 2005; 1: 65–73.
↑ Insulin
↓ Glucagon
Improved
glycaemic control
Incretin
activity
prolonged
Improved islet
function
DPP-4 inhibitor
↓ Insulin
↑ Glucagon
Hyperglycaemia
Incretin
response
diminished
Further impaired
islet function
T2DM
Blocking DPP-4 can improve incretin activity andBlocking DPP-4 can improve incretin activity and
correct the insulin:glucagon ratio in T2DMcorrect the insulin:glucagon ratio in T2DM

Beyond insulin targeted therapyBeyond insulin targeted therapy
 Most therapeutic options for diabetes are focused on
abnormal insulinsecretion and action and do not address the
role of other glucoregulatory hormones.
 Also current intensive treatment of diabetes have some
shortcomings, like weight gain, oedema, increased risk of
hypoglycemia and inability to suppress marked day to day
glucose fluctuation.

New treatment options for Type 2New treatment options for Type 2
DiabetesDiabetes
1) Amylin analog
2) GLP-1 analogs
3) DPP-IV inhibitors

DPP-4 inhibitor:
sitagliptin (GLIPITA)

DPP-IV inhibitor: SitagliptinDPP-IV inhibitor: Sitagliptin
(GLIPITA)
Sitagliptin (Glipita): tab 50, 100
mg
FDA approved in Oct 2006.

Pharmacokinetic studyPharmacokinetic study
Following a single oral 100 mg dose to healtly volunteers:
 AUC: 8.52 µM.hr; it increased in a dose-proportional manner.
 Cmax: 950 nM.
 Bioavailability: 87 %
 Absorbed within 1-4 hours of oral intake
Because coadministration of a high-fat meal with Sitagliptin had no effect
on the pharmacokinetics, it may be administered with or without food.

Pharmacokinetic dataPharmacokinetic data
 Protein binding: 38%
 T1/2: 12.4 hours
 Duration of action 18-24 hrs
 Metabolism: Hepatic (CYP3A4 and CYP2C8) , nominal.
 Excretion: Renal (80%)
Elimination occours primarily unchanged via active tubular
secretion by OAT3
 Renal clearanceRenal clearance: 350 ml/min

DoseDose
100 mg orally once daily in the morning
Not influenced by food.
 If CCR <30 ml/min/1.73m2
then 25 mg
daily
If CCR 30-50 ml/min/1.73m2
then 50 mg
daily
Can be used in mild to moderate
impairment of liver function.

IndicationIndication
Used as monotherapy or add-on with MTF
/TZD in inadequately controlled T2DM.
Can be used with any other class of oral agent
or insulin.
Not to be used in T1DM and DKA
Suitable for obese and overweight patients.

Side EffectsSide Effects
Nasopharyngitis and upper RTI
Headache
Nausea, stomach pain, diarrhoea ( less
common)
Allergy including anaphylaxis (rarely)
Exfoliative skin lesion (rarely)

PrecautionsPrecautions
Before starting sitagliptin, take history of
Allergy
Pancreatitis
CKD
Heart disease

Stop the drugStop the drug
In case of
Pancreatitis
Fever, sore throat, headache
Severe blistering, peeling, red skin rash
Allergic reactions

Drug InteractionsDrug Interactions
No significant interactions
Dose adjustment required with digoxin

Use in Special situationsUse in Special situations
Pregnancy- Category B drug in all
trimesters. No harm to fetus in animal
studies. Inadequate studies in pregnant
women.
Breastfeeding- No studies
Paediatrics- Use not established

Clinical trial:phase IIIClinical trial:phase III
Following a single oral 100 mg dose to healtly volunteers:
 AUC: 8.52 µM.hr; it increased in a dose-proportional manner.
 Cmax: 950 nM.
 T1/2: 12.4 hours.
 Bioavailability: 87 %
Because coadministration of a high-fat meal with Sitagliptin had no effect
on the pharmacokinetics, it may be administered with or without food.
Aims/hypothesis:
1. to assess the efficacy and safety of sitagliptin as monotherapy.
2. to assess the inadequate glycaemic control (HbA1c ≥7% and ≤10%) on
exercise and diet.
• Methods: a total of 521 patients aged 27-76 years with main baseline
HbA1c of 8.1% were randomised in a 1:2:2 ratio to treatment with:
1. Placebo
2. Sitagliptin 100mg once daily
For 18 weeks.
Aims/hypothesis:
1. to assess the efficacy and safety of sitagliptin as monotherapy.
2. to assess the inadequate glycaemic control (HbA1c ≥7% and ≤10%) on
exercise and diet.
• Methods: a total of 521 patients aged 27-76 years with main baseline
HbA1c of 8.1% were randomised in a 1:2:2 ratio to treatment with:
1. Placebo
For 18 weeks.
The American Journal of Medicine (2010) 123. S38-S48

Clinical trial:phase IIIClinical trial:phase IIIClinical trial:phase IIIClinical trial:phase III
HbA1c was
significantly
reduced with
Sitagliptin 100 mg
and 200 mg
compared with
placebo.
HbA1c was
significantly
reduced with
Sitagliptin 100 mg
and 200 mg
compared with
placebo.
Results:: after 18 weeksResults:: after 18 weeks
Mean HbA1c over time for placebo, once-daily sitagliptin 100mg and once-
daily sitagliptin 200mg groups.
Mean HbA1c over time for placebo, once-daily sitagliptin 100mg and once-
daily sitagliptin 200mg groups.

Fasting glucose over time placebo,once daily sitagliptin 100 mg and once daily sitagliptin
200 mg groups.
Fasting glucose over time placebo,once daily sitagliptin 100 mg and once daily sitagliptin
200 mg groups.
Sitagliptin also significantly decreased fasting plasma
glucose relative to placebo

 Insulin:glucagon ratio, markers of insulin secretion and
beta cell function, were significantly improved with
sitaglipin.
 HbA1c was reduced by 0.7 to 0.8 % over 24-52 wks.
 Fasting blood sugar was reduced by 1-1.5mmole/L.
 Postprandial blood sugar was reduced by 3 mmole/L.
 Insulin:glucagon ratio, markers of insulin secretion and
beta cell function, were significantly improved with
sitaglipin.
 HbA1c was reduced by 0.7 to 0.8 % over 24-52 wks.
 Fasting blood sugar was reduced by 1-1.5mmole/L.
 Postprandial blood sugar was reduced by 3 mmole/L.

 The incidence of hypoglycaemia and
gastrointestinal adverse experiences was not
signicantly different between sitagliptin and
placebo.
 Sitagliptin had a neutral effect on body weight.

• Conclusion/interpretation:
Sitagliptin significantly improved glycaemic control and was well
tolerated in patients with type 2 diabetes mellitus who had inadequate
glycaemic control on exercise and diet.
• Conclusion/interpretation:
Sitagliptin significantly improved glycaemic control and was well
tolerated in patients with type 2 diabetes mellitus who had inadequate
glycaemic control on exercise and diet.
Sitagliptin is also well-tolerated at doses of 100 mg once
daily in combination with metformin or pioglitazone,
without significant hypoglicemia or weight gain.
Clinical Trial

Sitagliptin Vs Vildagliptin
• Efficacy: Comparable
• Safety: Non comparable
• Efficacy: Comparable
• Safety: Non comparable
Sitagliptin is USFDA approved.
But Vildagliptin is not.
US FDA has required another clinical
data on renal impaired patients
regarding vildagliptin.
Rather Sitagliptin has US FDA approved Dosage guideline on impaired
renal function of patients
Rather Sitagliptin has US FDA approved Dosage guideline on impaired
renal function of patients

Sitagliptin can be used in mild to moderate
impairment of liver function.
Vildagliptin is contraindicated when ALT or
AST >3times the upper limit of normal.
Vildagliptin also requires monitoring of
LFT during treatment.

• Sitagliptin 100 mg/day was found well tolerated in clinical trials
up to 2 years in duration.
• Insignificant side effects such as Nausea/Vomiting, Nasal/Sinus
Congestion, and Headache were observed.
• Treatment with Sitagliptin does not cause hypoglycemia
• Treatment with Sitagliptin does not cause weight gain
• An effective choice in diabetic with renal insufficiency
• Sitagliptin 100 mg/day was found well tolerated in clinical trials
up to 2 years in duration.
• Insignificant side effects such as Nausea/Vomiting, Nasal/Sinus
Congestion, and Headache were observed.
• Treatment with Sitagliptin does not cause hypoglycemia
• Treatment with Sitagliptin does not cause weight gain
• An effective choice in diabetic with renal insufficiency
Summary of clinical trial

Risks associated with FASTING inRisks associated with FASTING in
patients with diabetespatients with diabetes
Hypoglycemia
HyperglycemiaHyperglycemia
Diabetic ketoacidosisDiabetic ketoacidosis
Dehydration and thrombosisDehydration and thrombosis

Patient Queries
•Should I fast?
•What dose adjustment to be done?
•How often should I monitor blood glucose?
•What to do if I develop hypoglycemia?

Physician Queries
•Is fasting safe in diabetics?
•How should fasting patients with type 2 DM be
managed?
• How should fasting patients with type 1DM be
managed?
•Is it safe for pregnant women with DM?
•Absolute contraindications of fasting ?

Physician Queries
•Which OHA is safe and superior?
•Is insulin safe? If yes, which insulin and which
regimen?
•What are the dose adjustment in Ramadan?

Pre-Ramadan medical assessment &
educational counseling

• Plan at least 3 months before
• Education of diabetic patients and their families
• Must focus on:
- The situations contraindicating fasting
- Treatment of diabetes and it’s modification:
Meal planning
physical activities
medication

• Importance and tool of self monitoring skills and
adjustment
• Must insist on:
- The risk of acute complication and means to
prevent them

Dietary guidelines
Divide your food in to 2-3 meal –
- Iftaar, Dinner & Sahur/predawn.
Limit the amount of sweet food taken at iftaar –
- Jelapi, Laddoo, burfi, Sweets, sugar containing
sarbat
Limit fried food-
- Samosas , Pakoras, puri, parata, fried kababs
Choose sugar free type drinks and drink plenty water

• Slow energy release foods ( such as wheat,
semolina, beans, rice) should be taken before
fasting, whereas foods high in saturated fat ( such as
ghee, samosas, pakoras) should be minimized
• Advise to use small amount of monounsaturated
oils in cooking
• Before and after fasting include high fibre foods
such as whole grain cereals, brown rice, beans and
pulses, fruits vegetables and salad

Exercise
-Maintain normal level of physical activity
-Excessive physical activity: increased risk of
hypoglycemia (especially before Iftaar)
-Physical exercise can be performed about one hour
after Iftaar.
-Taraweih are to be considered as part of the daily
exercise

Management of patients with type 2
diabetes
The choice of treatment options should be
individualizedindividualized

Recommended changes to treatment
regimen in patients with type 2 DM who
fast during Ramadan
(ADA Position Statement on Ramadan )
Before Ramadan During Ramadan
Patients controled on
diet and exercise
No change needed
(modify time and
intensity of exercise),
ensure adequate fluid
intake

Patients on oral agents
Biguanide, metformin 500
mg three times a day, or
sustained release
metformin
Metformin, 1,000 mg at the
sunset meal (Iftaar), 500
mg at the predawn meal
(Sahur)
TZDs
Acarbose
No change needed

Sulfonylureas once daily dose
Glimepiride, gliclazide MR,
Dose should be given at Iftaar
Sulfonylureas BID dose
Gliclazide, Glipizide
Full morning dose at the
Iftaar and half of the usual
evening dose at Sahur/Pre-
dawn

Glinides: Prandial regulators :
Repaglinide, Nateglinide
These are quick acting tablet
might be more suitable for
taking when fasting
DPP-4 inhibitors Keep same dose as before
Liraglutide keep the same dose anytime
but preferably during iftaar.

Patients on insulin
Basal-Bolus
Bolus
-Morning Insulin Dose –Full dose at Iftaar
-Lunch dose – keep same dose if dinner is taken
-Evening Insulin Dose – reduce 50% at Sahur
Basal
-If on intermediate acting -reduce 50% of
intermediate acting Insulin at sahur
-If on analogue - keep same dose at same time as
before.

Patients on premixed Insulin
Before Rramadan During Ramadan
70/30 premixed insulin
twice daily.
e.g. 30 U in morning and
20 U at evening
Use the usual morning
dose at iftaar and half the
usual evening dose at
sahur. e.g ; 70/30 premixed
insulin
30 U at iftaar and 10 U at
suhur

On premixed insulin + Metformin
Give Iftaar as same as for breakfast premixed dose
but
Take Metformin at Sahur and Iftaar and patient may
be okay and may not require premixed at Sahur
But if midday blood sugar control not good, add
premixed 50% of normal evening dose at Sahur

Before Ramadan
Short Acting +
Intermediate
R + R + R
+ NPH
During Ramadan
Short Acting +
Intermediate
R + 0 + R
NPH + 0+ NPH
Iftaar Dinner Sahur
R + 0 + ½ R
NPH + 0 + ½ NPH
Iftaar Dinner Sahur
M-R + L-R + N- ½ R
+ ½ NPH
Patient on Split regimen

Patients on combination of OHA and
GLP-1 analogue
• Keep same dose of Liraglutide preferably during
iftaar.
• Keep same dose of Metformin and
• Dose and time schedule of secretagogues should be
reduced according to the treatment guideline of OHA
during Ramadan.

Patients on combination basal insulin
and GLP-1 analogue
• Keep the same dose of Liraglutide preferably during
iftaar
• Basal insulin dose should be same at bed time

Monitoring during Ramadan
To recognize subclinical hypo and hyperglycemia
2hour post Suhur and one/half hour pre Iftaar
- to pick subclinical hypoglycemia
2 hour post Iftar/ Dinner
- to pick sub clinical hyperglycemia
Adjust insulin dose 3 days interval
Pre-iftaar- Adjust Detemir/Glargin
Mid day-Adjust NPH
2 h Post iftaar-Adjust iftaar bolus dose
2 h Post dinner- Adjust dinner bolus dose
2 h Post sahur-Adjust sahur bolus dose

Breaking the fast
- Immediately if hypoglycemia occurs
(BG<60mg/dL, 3.3 mmol/L)
- If BG<70mg/dL, 3.9 mmol/L in the few hours
after the start of the fast
- If BG exceeds 300 mg/dL (16.7 mmol/L) ketones
in urine should be checked, medical advice
sought
- Sick days

Pregnancy and fasting during RAMADAN
• Pregnancy is a state of increased insulin resistance
• Elevated BG & HbA1c levels are associated with increased
risk of major congenital malformations
• Should be strongly advised not to fast
• Ideally, patients should be managed by a team -Obstetrician,
Endocrinologist, a Nutritionist and Diabetes Nurse Educators
• The management of pregnant patients during RAMADAN is
based on appropriate diet and intensive insulin therapy

CONCLUSION
• Type 2 diabetes is largely asymptomatic and the
treatments are inconvenient, impose on daily life
and employment
• Lifestyle change is the most important but the
most difficult to achieve
• In insulin-treated patients, hypoglycaemia is a
major risk, especially in the young, elderly and
long-standing Type 1 patients
• Monitor diabetes complications
• Ensure older people are actively involved in
setting goals for their diabetes management

-Majority of uncomplicated type 2 diabetic patients can fast during
Ramadan safely though fasting during Ramadan for patients with
diabetes carries a risk of complications
-Type 1 diabetic patients should be strongly advised not to fast
(hypo- hyperglycemia)
-Type 2 diabetic patients, who fast during Ramadan, are at
relatively lower risk of hypo- hyperglycemia
-Pre-Ramadan medical assessment, education and motivation are
very important to prevent diabetes related complication
-Management plan must be highly individualized
Conclusion(Contd.)

Diabetes updates, DPP4 inhitors and Ramadan and DM

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