Sitagliptin/Metformin Clinical Slide Kit · Ramadan fasting. Salti I, Benard E, Detournay B et al. A population-based study of diabetes and its characteristics during the fasting

Sitagliptin:

A component of incretin based therapy

Rezvan Salehidoost, M.D., Endocrinologist

Agenda

Mode of Action

Evidences for sitagliptine

cardiovascular safety of sitagliptin

Ramadan study

Impact of Hypoglycemia

Summary

Agenda

Mode of Action



Ramadan study


Summary

Sitagliptin Enhances Active Incretin Levels

Through Inhibition of DPP-41–4

By increasing and prolonging active incretin levels, sitagliptin increases insulin release

and decreases glucagon levels in the circulation in a glucose-dependent manner.

Release of

active incretins

GLP-1 and GIPa

Blood glucose in

fasting and

postprandial states

Ingestion

of food

Glucagon

from alpha cells

(GLP-1)

Hepatic

glucose

production

GI tract

DPP-4

enzyme

Inactive

GLP-1

X Sitagliptin

(DPP-4

inhibitor)

Insulin from

beta cells

(GLP-1 and GIP)

Glucose-dependent

Glucose-dependent

Pancreas

Inactive

GIP

Beta cells

Alpha cells

Peripheral

glucose

uptake

DPP-4=dipeptidyl peptidase 4; GI=gastrointestinal; GIP=glucose-dependent insulinotropic peptide; GLP-1=glucagon-like peptide-1. aIncretin hormones GLP-1 and GIP are released by the intestine throughout the day, and their levels increase in response to a meal. 1. Kieffer TJ et al. Endocr Rev. 1999;20(6):876–913. 2. Ahrén B. Curr Diab Rep. 2003;3(5):365–372. 3. Drucker DJ. Diabetes Care. 2003;26(10):2929–2940, 4. Holst JJ. Diabetes Metab Res Rev. 2002;18(6):430–441.

Sitagliptin improves

beta-cell function

and increases insulin

synthesis and

release.1

Sitagliptin reduces HGO through

suppression of glucagon from alpha

cells.2 Metformin decreases HGO by

targeting the liver to decrease

gluconeogenesis and

glycogenolysis.4

Metformin has insulin-

sensitizing properties.3–5

(Liver > Muscle, fat)

Beta-Cell Dysfunction

Hepatic Glucose Overproduction (HGO)

Insulin Resistance

1. Aschner P et al. Diabetes Care. 2006;29(12):2632–2637. 2. Data on file. 3. Abbasi F et al. Diabetes Care. 1998;21(8):1301–1305. 4. Kirpichnikov D et al. Ann Intern Med. 2002;137(1):25–33. 5. Zhou G et al. J Clin Invest. 2001;108(8):1167–1174.

Sitagliptin and Metformin Target the Core

Metabolic Defects of Type 2 Diabetes

Dosing

Adult ,Diabetes mellitus, type 2: Oral: 100 mg once daily

Concomitant use with insulin and/or insulin secretagogues (eg, sulfonylureas): Reduced dose of insulin and/or insulin secretagogues

may be needed.

Administration Oral: Administer without regard to meals.

Dosing

Renal Impairment CrCl ≥50 mL/minute: No dosage adjustment

necessary.

CrCl ≥30 to <50 mL/minute (approximate SCr of >1.7 to ≤3 mg/dL

[males] or >1.5 to ≤2.5 mg/dL [females]): 50 mg once daily

CrCl <30 mL/minute (approximate SCr of >3 mg/dL [males] or >2.5

mg/dL [females]): 25 mg once daily

ESRD requiring hemodialysis or peritoneal dialysis: 25 mg once

daily; administer without regard to timing of hemodialysis

Dosing

Hepatic Impairment Mild to moderate impairment (Child-Pugh

classes A and B): No dosage adjustment necessary.

Severe impairment (Child-Pugh class C): There are no dosage

adjustments provided in the manufacturer’s labeling (has not been

studied).

Agenda

Mode of Action

Evidences for sitagliptine cardiovascular safety of sitagliptin

Ramadan study


Summary

Initial Fixed-Dose Combination Therapy With Sitagliptin

+ Metformin vs Metformin Monotherapy: Study Design

Day 1

Randomization Week 44

Screening

period Phase A Phase B

Screening

1 week 18 weeks

aMetformin was initiated at 500 mg bid and titrated up to 1000 mg bid over 4 weeks. Patients who were unable to tolerate the

maximum dose of sitagliptin/metformin FDC or metformin were allowed to be down-titrated to a minimum dose of

sitagliptin/metformin FDC 50/500 mg bid or metformin 500 mg bid.

bid=twice daily; FDC=fixed-dose combination; OHA=oral antihyperglycemic agent; qd=once daily; R=randomization; T2DM=type 2

diabetes mellitus.

1. Reasner C et al. Poster presented at: American Diabetes Association 69th Scientific Sessions. New Orleans, LA. June 5–9, 2009.

2. Data on file, MSD.

R

26 weeks

Week 18

T2DM, aged

18–78 yrs,

Off OHA

≥4 months,

HbA1c ≥7.5%

Sitagliptin 50 mg bid + metformin 1000 bida (n=626)

Metformin 1000 mg bida (n=624)

Initial Fixed-Dose Combination Therapy With Sitagliptin

+ Metformin vs Metformin Monotherapy: HbA1c Results

Over 18 Weeks H

bA

1c L

S M

ean

(±

SE

)

Ch

an

ge F

rom

Baseli

ne,

%

Week

Sitagliptin/metformin FDC (n=560)

Mean baseline HbA1c=9.9%

Metformin (n=566)

Mean baseline HbA1c=9.8%

LS means

difference

–0.6; P<0.001

7

8

9

10

0 6 12 18

FAS=full analysis set; FDC=fixed-dose combination; LS=least-squares; SE=standard error.

1. Reasner C et al. Poster presented at: American Diabetes Association 69th Scientific Sessions. New Orleans, LA. June 5–9, 2009.

2. Data on file, MSD.

FAS Population

Published Online in Nov. 2010

Week 30

Addition of Sitagliptin or Glimepiride in Patients Inadequately Controlled on Metformin:

Study Design1

Continue stable dose of metformin

Single-blind Placebo Run-in

Double-blind Treatment Period

Week –2 Day 1

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

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

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

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

1. Arechavaleta R et al. Diabetes Obes Metab. 2011;13(2):160–168.

Sitagliptin 100 mg qd

Week –4

R

Screening Period

HbA1c-Lowering Efficacy of Sitagliptin at Week 30 Was Noninferior to That of Glimepiride in Patients

Inadequately Controlled on Metformin1

LS=least squares; SE=standard error.

aMean dose of glimepiride (following the 18-week titration period) was 2.1 mg per day.


Week

LS

Mean

(±

SE

) H

bA

1c,

%

Per-Protocol Population

6.0

6.2

6.4

6.6

6.8

7.0

7.2

7.4

7.6

7.8

8.0

0 6 12 18 24 30

(95% CI)

0.07% (–0.03, 0.16)

Sitagliptin 100 mg + metformin (n=443)

Glimepiridea + metformin (n=436)

–0.47

–0.54

Prespecified

noninferiority

margin =

0.40%

Addition of Sitagliptin or Glimepiride in Patients Inadequately Controlled on Metformin: Clinical Assessment of Hypoglycemia Over 30 Weeks1

APaT Population

APaT=all patients as treated; CI=confidence interval.

aMean dose of glimepiride (following the 18-week titration period) was 2.1 mg per day.


7

22

0

5

10

15

20

25

Patients

With ≥

1

Hypogly

cem

ic E

pis

ode,

%

(95% CI)

–15.0% (–19.3, –10.9)

(P<0.001)

Sitagliptin 100 mg + metformin (n=516)

Glimepiridea + metformin (n=518)

Addition of Sitagliptin or Glimepiride in Patients Inadequately Controlled on Metformin: Body Weight Change from Baseline1

LS

Mean C

hange (±

SE

) in

Bo

dy

Weig

ht

Fro

m B

aselin

e,

kg

Week

0 6 12 18 24 30

–1

0

1

2

APaT Population

Sitagliptin 100 mg + metformin

Glimepiridea + metformin

= –2.0 kg

(P<0.001)

–0.8 kgb

1.2 kgb

APaT=all patients as treated; LS=least squares; SE=standard error.

aMean dose of glimepiride (following the 18-week titration period) was 2.1 mg per day. bLS mean body weight change at 30 weeks.


Agenda

• Mode of Action

• Evidences for sitagliptine

• cardiovascular safety of sitagliptin

• Ramadan study

• Impact of Hypoglycemia

• Summary

• Objective: To assess the long-term

cardiovascular safety of adding sitagliptin to

usual care, as compared with usual care alone, in

patients with type 2 diabetes and established

cardiovascular disease

N Engl J Med 2015;373:232-42.

aMono- or dual therapy with metformin, sulfonylurea, or pioglitazone, or insulin alone or in combination with metformin. bIf eGFR is ≥50 mL/min/1.73 m2, dose of sitagliptin or placebo will be 100 mg/day; if eGFR is 30 to <50 mL/min/1.73 m2 at screening, dose of sitagliptin or placebo will be 50 mg/day; if

eGFR is <30 mL/min/1.73 m2 during the study, dose will be reduced to 25 mg/day.

TECOS = Trial Evaluating Cardiovascular Outcomes With Sitagliptin; CV = cardiovascular; T2DM = type 2 diabetes mellitus; CVD = cardiovascular disease; AHA = antihyperglycemic

agent;DPP-4 = dipeptidyl peptidase-4; GLP-1 = glucagon-like peptide-1; ADA = American Diabetes Association; eGFR = estimated glomerular filtration rate.

1. Green JB et al. Am Heart J. 2013;166:983–989.e7. 2. Green JB et al. [published online ahead of print June 8, 2015] N Engl J Med. doi: 10.1056/NEJMoa1501352.

TECOS CV Safety Trial: Study Design1,2

Patients aged ≥50 years with T2DM, and established CVD

HbA1c 6.5%–8.0% and dose-stable for ≥3 months on other AHA therapya

Sitagliptin dose was 100 mg, or 50 mg if

eGFR was ≥30 and <50 mL/min/1.73 m2.

Adjusted during trial based on eGFR as

needed. b

Sitagliptin (n=7,332)

Continue metformin and/or pioglitazone and/or sulfonylurea, and/or insulin

Placebo (n=7,339)

Randomized 1:1 treatment assignment

Additional AHA or insulin (other than GLP-1 receptor agonists and DPP-4 inhibitors)

added according to usual care to target HbA1c, according to current guidelines (eg, ADA)

Study continued until 1300 patients with a confirmed event in the primary composite

outcome were reached

80

20

Key message

• Among patients with type 2 diabetes and

established cardiovascular disease, adding

sitagliptin to usual care did not appear to

increase the risk of major adverse

cardiovascular events, hospitalization for

heart failure, or other adverse events

11/21/2017 21

Agenda

Mode of Action



Ramadan Study Impact of Hypoglycemia

ADA/EASD Guideline

Summary

Background

78.8% of patients with type 2 diabetes fast during Ramadan, with a 7.5-fold increase in the incidence of severe hypoglycaemia.

There is no consensus about the most appropriate oral antihyperglycaemic agent(s) for patients with type 2 diabetes to use during Ramadan.

SU is typically recommended in combination with metformin because of broad clinical experience and lower cost. The ADA recommends caution when using SU during Ramadan because they are associated with an increased risk of hypoglycaemia.

Sitagliptin when added to ongoing metformin monotherapy was shown to reduce the incidence of symptomatic hypoglycaemia 3- to 6-fold compared with the addition of a SU in patients with type 2 diabetes.

Given the low risk of hypoglycaemia demonstrated in previous sitagliptin trials in non-fasting patients with type 2 diabetes, it was of interest to evaluate the incidence of hypoglycaemia with sitagliptin during Ramadan fasting.

Salti I, Benard E, Detournay B et al. A population-based study of diabetes and its characteristics during the fasting month of Ramadan in 13 countries: results of the epidemiology of diabetes and Ramadan 1422/2001 (EPIDIAR) study. Diabetes Care 2004; 27: 2306-11. Inzucchi SE. Oral antihyperglycemic therapy for type 2 diabetes: scientific review. JAMA 2002; 287: 360-72. Malik S, Lopez V, Chen R, Wu W, Wong ND. Undertreatment of cardiovascular risk factors among persons with diabetes in the United States. Diabetes Res Clin Pract 2007; 77: 126-33. Nauck MA, Meininger G, Sheng D, Terranella L, Stein PP. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trial. Diabetes Obes Metab 2007; 9: 194-205. Arechavaleta R, Seck T, Chen Y et al. Efficacy and safety of treatment with sitagliptin or glimepiride in patients with type 2 diabetes inadequately controlled on metformin monotherapy: a randomized, double-blind, non-inferiority trial. Diabetes Obes Metab 2011; 13: 160-8. Data on file, MSD

R

wk 3 wk 1 wk 2 wk 4

4 weeks

Start of

Ramadan

Screen patient

according to

inclusion and

exclusion

criteria

SU stable-doseSU (glimepiride, gliclazide or glibenclamide [glyburide]

± Metformin

1ry E.P: overall incidence of symptomatic

hypoglycaemia recorded during Ramadan

Mean age: 55 yrs Mean HbA1c: 7.5% Mean disease duration: 5-6 yrs

Sitagliptin 100 mg/day

± Metformin

Continue stable dose SU

± Metformin

Study Design

1066 patients ≥ 18 yrs HbA1c <10% Fasting during Ramadan

Data on file, MSD

Results

The proportion of patients who recorded ≥1 symptomatic hypoglycaemic events during Ramadan was 4.8% in the sitagliptin group and 14.3% in the SU group.

The proportion of patients with hypoglycaemic events (symptomatic or asymptomatic) was 8.5% in the sitagliptin group and 17.9% in the SU group

Data on file, MSD

Conclusion

In Muslim patients with type 2 diabetes who observed the fast during Ramadan, switching to a sitagliptin-based regimen decreased the incidence of hypoglycaemia compared to remaining on a SU-based regimen.

Data on file, MSD

Agenda

• Mode of Action

• Evidences for sitagliptine

• cardiovascular safety of sitagliptin

• Impact of Hypoglycemia

• Summary

Hypoglycemia May Be a Barrier to Glycemic Control in

Patients With Type 2 Diabetes

Hypoglycemia is an important limiting factor in glycemic management and

may be a significant barrier to treatment adherence.

Fear of hypoglycemia is an additional barrier to control.

– A study in patients with type 2 diabetes showed

increased fear of hypoglycemia as the number of

mild/moderate and severe hypoglycemic events

increased.

Amiel SA et al. Diabet Med. 2008;25(3):245–254.

Vicious circle of hypoglycemia awareness

Hypoglycemic

events

lead

hypoglycaemic

events

Frequent hypoglycemias

<60 mg/dl

Adapted from Hermanns et al. Diabetologie 2009; 4: R 93-R112

Symptoms of hypoglycemia:

- weaker

- appear later

- change

Awareness of hypoglycemia:

- more difficult

- less reliable

Complications and Effects of Severe

Hypoglycemia

Plasma glucose level

10

20

30

40

50

60

70

80

90

100

110

1

2

3

4

5

6

mg/dL

mmol/L

1. Landstedt-Hallin L et al. J Intern Med. 1999;246:299–307.

2. Cryer PE. J Clin Invest. 2007;117(4):868–870.

Increased Risk of Cardiac

Arrhythmia1

Progressive

Neuroglycopenia2

Abnormal prolonged cardiac

repolarization—

↑ QTc and QTd

Sudden death

Cognitive impairment

Unusual behavior

Seizure

Coma

Brain death

Sitagliptin & Hypoglycemic events

Most previous studies of sitagliptin as monotherapy or in combination with

metformin or a PPARγ agonist showed:

– Incidence of hypoglycemia generally similar to placebo

– Low rate of hypoglycemia observed with sitagliptin

consistent with glucose-dependent mechanism of

insulin secretion and glucagon suppression

PPARγ=peroxisome proliferator-activated receptor gamma.

T. Vilsbøll et al. Diabetes, Obesity and Metabolism 12: 167–177, 2010.

Agenda

Mode of Action



Ramadan Study


Summary

Summary

Sitagliptin therapy has been shown to be effective in lowering blood glucose when

administered as monotherapy or when used in combination with metformin in

appropriate patients with type 2 diabetes

Combination therapy with sitagliptin and metformin improves glycemic control in

appropriate patients with type 2 diabetes, with a low risk of hypoglycemia and

no weight gain

Sitagliptin/Metformin Clinical Slide Kit · Ramadan fasting. Salti I, Benard E, Detournay B et al. A population-based study of diabetes and its characteristics during the fasting

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