sitagliptin/metformin clinical slide kit · ramadan fasting. salti i, benard e, detournay b et al....
TRANSCRIPT
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
Evidences for sitagliptine
cardiovascular safety of sitagliptin
Ramadan study
Impact of Hypoglycemia
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
Impact of Hypoglycemia
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.
1. Arechavaleta R et al. Diabetes Obes Metab. 2011;13(2):160–168.
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.
1. Arechavaleta R et al. Diabetes Obes Metab. 2011;13(2):160–168.
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.
1. Arechavaleta R et al. Diabetes Obes Metab. 2011;13(2):160–168.
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
Evidences for sitagliptine
cardiovascular safety of sitagliptin
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
Evidences for sitagliptine
cardiovascular safety of sitagliptin
Ramadan Study
Impact of Hypoglycemia
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