Transcript GLP-1 Therapy – Beyond Glucose Control

Incretin Based Therapy in
Diabetes Mellitus Type 2
JOSEPHINE CARLOS-RABOCA,M.D.,F.P.S.E.M.
ENDOCRINOLOGY,DIABETES AND METABOLISM
DIABETES CARE CENTER
WEIGHT WELLNESS CENTER
MAKATI MEDICAL CENTER
Outline
•
•
•
•
Review of Incretins and Diabetes
Goals of Treatment for Diabetes
Treatment Options
Sitagliptin Studies(Case/Clinical trials)
– Monotherapy Use
– Combination Use
– Cardiovascular Benefits
GLP-1: effects in humans
•Stimulates glucose-dependent
insulin secretion
After food ingestion
GLP-1 is secreted from the
L-cells of the jejunum
& ileum
•Suppresses glucagon
secretion
•Slows gastric emptying
•Leads to reduction of food
intake
• Improves insulin sensitivity
That in turn…
Drucker. Curr Pharm Des. 2001
Drukcer. Mol. Endocrinol. 2003
Longtime effects in animal
models:
•Increase of β-cell mass and
improved β-cell function
GLP-1: Biological Activity
Obesity
CVD
Postprandial hyperglycemia /
hypertriglyceridemia
Fasting
hyperglycemia
Insulin
Resistance
Impaired insulin secretion
Hyperglucagonemia
b-cell mass i
LL Baggio and DJ Drucker. Gastroenterology 2007; 132: 2131-2157.
GLP-1 Enhancenent
GLP-1 Secretion is impaired in Type 2 Diabetes
Natural GLP-1 has extremely short half-life
Add GLP-1 analogues
with longer half-life:
•exenatide
•liraglutide
Block DPP-4, the enzyme
that degrades GLP-1:
•sitagliptin
•vildgaliptin
Injectables
Oral agents
DPP-4= Dipeptidyl Peptidase-4 ; GLP=Glucagpn like peptide-1
Drucker. Curr. Pharm. Des. 200; Drucker. Mol. Endocrinol. 2003
Incretin Mimetics and
DPP-4 Inhibitors: Major Differences
Gallwitz. European Endocrine Diseases. 2003
Outline
•
•
•
•
•
Incretins and Diabetes
Goals of Treatment for Diabetes
Treatment Options
Role of incretins in diabetes treatment
Sitagliptin Studies
– Monotherapy Use
– Combination Use
Goals of Therapy in Type 2 Diabetes
• To lower the incidence of microvascular
disease
• To reduce the excess of cardiovascular disease
• To improve the quality of life
• To limit the burden of treatment
Treatment Guidelines for
Type 2 Diabetes
*Capillary glucose
† May not be achievable with as manyt as 5 anytihypertensive drugs in some individuals; use higher targets
where there is a risk of postural hypertension
‡With statin treatment for patients>40 y.o. or with evidence of cardiovascular disease
§Consider use of fibrates to achieve thee goals once LDL-C is controlled
Outline
•
•
•
•
•
Incretins and Diabetes
Goals of Treatment for Diabetes
Treatment Options
Role of incretins in diabetes treatment
Sitagliptin Studies
– Monotherapy Use
– Combination Use
Efficacy and tolerability of existing
anti-diabetic agents
Class
Primary
therapeutic
effect
Limitations
Sulfonylureas
 HbA1c
Hypoglycemia, weight gain
Meglitinides
 PPG
Hypoglycemia, weight gain
Biguanides (metformin)
 HbA1c
GI adverse effects, lactic acidosis (rare)
PPARs
 HbA1c
Weight gain, edema, anemia, potential for liver
toxicity
Alpha-glucosidase inhibitors
 PPG
GI adverse effects
Insulin
 HbA1c
Injectable route, hypoglycemia, weight gain
Adapted from DeFronzo RA Ann Intern Med 1999;131:281–303; Williams G, Pickup JC, eds. Handbook of Diabetes. 3rd ed. Malden, MA:
Blackwell Publishing, 2004; Holz GG, Chepurny OG Curr Med Chem 2003;10(22):2471–2483; Meneilly GS Diabetes Care 2003;26(10):
2835–2841; Ahrén B et al Diabetes Care 2002;25(5):869–875; Moller DE Nature 2001;414:821–828.
Sitagliptin - Overview
F
F
F
F
NH2 O
NH2 O
N
N
F
N
F
N
N N
N
N
CFCF
3 3
• DPP-4 inhibitor for the treatment of patients
with type 2 diabetes
• Provides potent and highly selective inhibition
of the DPP-4 enzyme
• Fully reversible and competitive inhibitor
ADA 2006 Late Breaking Clinical Presentation (Stein).
Sitagliptin Is Potent and Highly Selective
(>2500x) for the DPP-4 Enzyme
Enzyme
IC50 (nM)
DPP-4
18
DPP-8
48,000
DPP-9
>100,000
DPP-2, DPP-7
>100,000
FAP
>100,000
PEP
>100,000
APP
>100,000
ADA 2006 Late Breaking Clinical Presentation (Stein).
Pharmacokinetics of Sitagliptin
Supports Once-Daily Dosing
• With once-daily administration, trough (at 24 hrs) DPP-4 inhibition
is ~80%
– ≥80% inhibition provides full enhancement of active incretin
levels
• No effect of food on pharmacokinetics
• Well absorbed following oral dosing
• Low protein binding
• Primarily renal excretion as parent drug
– Approximately 80% of a dose recovered as intact drug in urine
• No clinically important drug-drug interactions
– No meaningful P450 system inhibition or activation
ADA 2006 Late Breaking Clinical Presentation (Stein).
Incretin based therapy in diabetes
• Incretin hormone secretion and actions are impaired
in type 2 diabetes.
• Although β-cell responsiveness to GLP-1 is reduced,
exogenous GLP-1 can still restore β-cell sensitivity to
glucose and improve glucose-induced insulin
secretion.
• A GLP-1 based therapy of type 2 diabetes may
therefore be expected to
–
–
–
–
Reduce hyperglycaemia and HbA1c levels
Improve β-cell function
Improve insulin sensitivity
Improve metabolism
ADA-EASD –Algorithm for Control of Type 2 Diabetes (2008)
Tier 1 : Well-validated core therapies
At diagnosis:
Lifestyle
+
Metformin
STEP 1
Lifestyle + Metformin
+
Basal Insulin
Lifestyle + Metformin
+
Intensive Insulin
Lifestyle + Metformin
+
Sulfonylurea
STEP 2
STEP 3
Tier 2 : Less well-validated therapies
Lifestyle + Metformin
+
Pioglitazone
No hypoglycemia
Weight loss
Nausea/Vomiting
Lifestyle + Metformin
+
GLP-1 agonist
No hypoglycemia
Weight loss
Nausea/Vomiting
Lifestyle + Metformin
+
Pioglitazone
+
Sulfonylurea
Lifestyle + Metformin
+
Basal Insulin
Nathan, D et al. Diabetes Care 2009; 32(1): 1-11
Recent Clinical Studies of Sitagliptin
• Monotherapy use
• Combination use with metformin or a PPAR
agent
• Combination use with sulfonylurea with /
without metformin
• With adjusted doses in patients with diabetes
and renal insufficiency
ADA 2006 Late Breaking Clinical Presentation (Stein).
CASE # 1
• R.M. 43 year old Filipino saw you because he wanted to know if he had
diabetes because his parents are diabetic. He had no polyuria, polydipisia,
no weight loss.
He didn’t smoke but had no exercise. Past medical history was unremarkable.
Physical Examination was normal
Lab exams: FBS 116 2h post 75 gm ,OGTT 283 HBa1c 7.6 %
Creatinine 1.0 SGOT 71 SGPT 146 cholesterol 226 triglyceride 213 HDL 45
LDL 139
Hb 15.7 HCT 45 WBC 12.75 Seg 51 Lympho 40 Mono 6 platelet 277000
Urine wbc 5-10/hpf rbc 0-1 protein trace sugar negative
26
What would be your initial treatment plan?
a. Insulin
b. Sitagliptin
c. Exenatide
d. TZD
e. Sulfonylurea
f. Metformin
26
Sitagliptin Consistently and Significantly Lowers A1C
With Once-Daily Dosing in Monotherapy
18-week Study
change vs
=
placebo*
Japanese Study
24-week Study
-0.6%
-0.79%
(p<0.001)
(p<0.001)
8.4
-1.05%
(p<0.001)
8.4
8.4
8.0
8.0
8.0
7.6
A1C (%)
A1C (%)
A1C (%)
7.6
7.6
Placebo (n=74)
7.2
Sitagliptin 100 mg (n=168)
0
6
12
Time (weeks)
18
7.2
Placebo (n=244)
7.2
Placebo (n=75)
6.8
Sitagliptin 100 mg (n=229)
0
5
10
15
20
Time (weeks)
25
Sitagliptin 100 mg (n=75)
0
4
8
Time (weeks)
12
Sitagliptin 100 mg Once-daily Provides Significant and
Progressively Greater Reductions in A1C With Progressively
Higher Baseline A1C
Inclusion Criteria: 7%–10%+
18-week Study
24-week Study
<8%
8–<9%
≥9%
<8%
8–<9%
≥9%
Mean (%)
7.37
8.40
9.48
7.39
8.36
9.58
0.0
0.0
-0.2
-0.2
-0.4
-0.4
Reduction in A1C (%)
Reduction in A1C (%)
Baseline A1C (%)
-0.6
-0.8
-1.0
-0.44
-0.61
-1.2
-1.4
-1.6
-1.8
-1.2
-0.6
-0.8
-1.0
-1.2
-0.57
-0.8
-1.4
-1.6
-1.8
Reductions are placebo-subtracted.
Adapted from Raz I, et al. Protocol 023; Aschner P, et al. Protocol 021. Abstracts presented at ADA2006.
ADA 2006 Late Breaking Clinical Presentation (Stein).
-1.52
Sitagliptin Once Daily Significantly Improves
Both Fasting and Post-meal Glucose In Monotherapy
Fasting Glucose
Post-meal Glucose
 in 2-hr PPG* = –46.7 mg/dL (p<0.001)
180
288
170
252
160
150
Placebo (n=247)
Sitagliptin 100 mg (n=234)
140
Plasma Glucose (mg/dL)
Fasting Glucose (mg/dL)
 FPG* = –17.1 mg/dL (p<0.001)
216
180
Baseline
24 Weeks
Placebo (N=204)
Baseline
24 Weeks
Sitagliptin 100 mg
(n=201)
144
0
3
6
1224 weeks.18
24
0 60 120
0 60 120
* LS mean difference
from
placebo
after
Aschner P, et al. Protocol
10, 2006; Washington, DC.
TimeJune
(minutes)
Weeks 021. Abstract presented at American Diabetes Association;
ADA 2006 Late Breaking Clinical Presentation (Stein).
Sitagliptin Once Daily Significantly Increases Proportion of Patients
Achieving Goal in Monotherapy or Combination Therapy
Goal A1C <7%
P<0.001
50
41%
17%
Percentage
Percentage
20
50
47%
45%
40
40
30
P<0.001
40
Percentage
50
P<0.001
30
20
18%
30
23%
20
10
10
10
0
0
0
Monotherapy Study
Add-On to Metformin Study
Placebo
Add-On to TZD Study
Sitagliptin
Aschner P, et al. Protocol 021. Rosenstock J, et al. Protocol 019. Karacik A, et al. Protocol 020. ADA 2006.
ADA 2006 Late Breaking Clinical Presentation (Stein).
Sitagliptin Once-daily Lowers A1C Without Increasing the
Incidence of Hypoglycemia or Leading to Weight Gain
Hypoglycemia
Proportion of patients with (%)
Placebo
Sitagliptin
100 mg
Hypoglycemia
0.9
1.2
Sitagliptin
200 mg
0.9
Pooled Phase III Population Analysis: no statistically significant
difference in incidence for either dose vs. placebo
Weight Changes
•
Neutral effect on body weight
– In monotherapy studies, small decreases from baseline (~0.1 to 0.7 kg) with sitagliptin;
slightly greater reductions with placebo (~0.7 to 1.1 kg)
– In combination studies, weight changes with sitagliptin similar to placebo-treated patients
Sitagliptin Once Daily Shows Consistent Glycemic
Efficacy, Safety and Tolerability Profile > 1 Year
Efficacy
Safety
Body Weight Gain
Phase A
Phase A
Phase B
Phase B
18.30%
Sitagliptin
Sitagliptin
Placebo
Hypoglycemia
Placebo
Glipizide
-0.1
Glipizide
1
∆ HbA1c (%)
-0.3
-0.5
0
2.4 kg
-0.7
-1
-0.9
2.10%
1.30%
0.80%
24-Week
26-Week
-1.1
-2
0
6
12 18 24 30 38
46
Weeks
54
0
12
24
38
54
Weeks
Placebo
Placebo/glipizide
Placebo/glipizide
Sitagliptin
Sitagliptin 100 mg qd
Sitagliptin 100 mg qd
Glipizide
PN 020: Extended Study of Add-on to Ongoing Metformin Therapy
34
Safety laboratory mean changes
•
•
Small rise in WBC – largely due to slight increase in absolute neutrophil count (ANC)
–
~ 0.2 K/mm3 maximum difference from placebo in WBC with baseline mean of
6.7 K/mm3
–
No increase in patients meeting PDLC (> 20% increase and > ULN) for WBC or
ANC; no increase in bands/earlier WBC forms
–
No associated laboratory AEs of increased WBC
Slight increase in uric acid ~ 0.2 mg/dL (baseline ~ 5.3 mg/dL)
–
•
No increase in gout AEs
Decrease in alk phosphatase – ~ 4-5 IU/mL (baseline of ~ 55 IU/mL)
–
Small decrease ALT (-1 mIU/mL), small/variable decrease in bili
–
In Phase II studies – similar reduction in total AP with metformin (-6.4 IUI/mL)
and glipizide (-2.4 IU/mL) comparator groups
–
Literature suggests decrease AP occurs with improved glycemic control
Combination Treatment
CASE # 2
• R. C. M 61 y/o consulted for diabetes mellitus of 8 years. Medications
include glimepiride 2 mg BID, Metformin 100 mg BID.
FPG 154 mg/dl
His mother, brother and sister are diabetic. He does not smoke nor drink
alcohol. His past medical history was unremarkable.
Physical examination: Height 176.6 cm weight 88.5 kg BP 140/80 BMI 29.8.
WC 38 inches. He had no retinopathy on funduscopy. The rest of the
physical examination was normal.
Lab work up: 2hour PPBS 240 Hba1c of 7.8%. uric acid 5.51 cholesterol 294
triglyceride 387 VLDL 32.21 LDL 145 SGPT 36 Serum creatinine 1.22, urine
microalbumin 64mg/dl; urine creatinine 118 mgdl ; UAC 54
ECG, sinus bradycardia incomplete RBBB, Treadmill stress test: Exaggerated
BP response to exercise
26
Diagnosis: Diabetes Mellitus Type 2
Diabetic nephropathy , stage 2
Dyslipidemia
Hypertension
How will modify treatment to reach target goals for his diabetes?
a. Insulin
b. Sitagliptin 100 mg OD
c. Sulfonylurea
d. Pioglitazone
26
Other treatment?
a. Fenofibrate
b. Statin
c. Aspirin
d. ARB
e. Vaccination
26
Summary: Mechanism of Action of the Co-administration of
Sitagliptin Plus Metformin
• Co-administration of sitagliptin and metformin addresses the 3 core
defects of type 2 diabetes in a complementary manner
• Sitagliptin and metformin have different but complementary
mechanisms of action
– Metformin increases total GLP-1 → likely by enhancing GLP-1 release
– By inhibition of DPP-4, sitagliptin increases levels of active GLP-1
• Co-administration of these drugs results in higher GLP-1 levels than
when either drug is administered alone
• Co-administration of sitagliptin and metformin results in a more
than additive effect on both pre- and post-prandial active GLP-1
concentrations
25
Sitagliptin Once Daily Significantly
Lowers A1C When Added on to Metformin or Pioglitazone
Add-on to Metformin
 in A1C vs. Placebo* = –0.65%
(p<0.001)
8.0
8.0
7.8
7.8
7.6
7.6
7.4
7.4
7.2
7.2
7.0
0
6
12
18
Weeks
Add-on to Pioglitazone
 in A1C vs. Placebo* = –0.70%
(p<0.001)
8.2
A1C (%)
A1C (%)
8.2
24
7.0
0
6
12
Weeks
Placebo
Sitagliptin 100 mg
* Placebo Subtracted Difference in LS Means.
Rosenstock J, et al. Protocol 019. Karasik A, et al. Protocol 020. Abstracts presented at ADA 2006.
ADA 2006 Late Breaking Clinical Presentation (Stein).
18
24
Co-administration of Sitagliptin and Metformin in Healthy
Adults Increased Active GLP-1 Greater Than Either Agent Alone
Sitagliptin 100 mg
Placebo
Metformin 1000 mg
Co-administration of sitagliptin 100 mg plus metformin 1000 mg
Active GLP-1
Concentrations, pM
50
Mean AUC ratio
Sita + Met: 4.12
40
30
Mean AUC ratios
Sita: 1.95
Met: 1.76
20
10
Values represent geometric mean±SE.
0
–2
Morning
Dose Day 2
–1
0
1
2
3
4
Meal
Time (hours pre/post meal)
N=16 healthy subjects.
AUC=area under the curve
24
HbA1c With Sitagliptin or Glipizide as Add-on
Combination With Metformin: Comparable Efficacy
LSM change from baseline
(for both groups): –0.7%
8.2
8.0
Sulfonylureaa + metformin (n=411)
7.8
Sitagliptinb + metformin (n=382)
HbA1c, % ±SE
7.6
Achieved primary
hypothesis of noninferiority to
sulfonylurea
7.4
7.2
7.0
6.8
6.6
6.4
6.2
0
6
12
18
24
30
38
46
52
Weeks
Adapted from Nauck MA, Meininger G, Sheng D, et al, for the Sitagliptin Study 024
Group. 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 with permission from Blackwell Publishing Ltd., Boston, MA.
glipizide ≤20 mg/day;
100 mg/day with metformin (≥1500 mg/day).
Per-protocol population; LSM=least squares mean.
SE=standard error.
aSpecifically
bSitagliptin
27
Greater Reductions in HbA1c Associated With
Higher Baseline HbA1c – 52-Week Post Hoc Analysis
Baseline HbA1c Category
<7%
Mean Change From Baseline
in HbA1c, %
0.0
−0.2
−0.4
−0.6
−0.8
n=117
n=112
≥7 to <8%
n=179
n=167
≥8 to <9%
n=82
n=82
−1.1
−1.1
9%
n=33
n=21
− 0.1
− 0.3
− 0.6
−0.5
−1.0
−1.2
−1.4
−1.6
−1.8
Sulfonylureaa plus metformin
Sitagliptinb plus metformin
−1.8
−2.0
Adapted from Nauck MA, Meininger G, Sheng D, et al, for the Sitagliptin Study 024
Group. 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 with permission from Blackwell Publishing Ltd., Boston, MA.
−1.7
aSpecifically glipizide ≤20 mg/day.
100 mg/day with metformin (≥1500 mg/day);
Per-protocol population.
Add-on sitagliptin with metformin vs sulfonylurea
with metformin study.
bSitagliptin
28
Sitagliptin With Metformin Provided Weight Reduction
(vs Weight Gain) and a Much Lower Incidence of Hypoglycaemia
Least squares mean change over timec
Hypoglycaemiac
Sulfonylureaa plus metformin (n=416)
Sitagliptinb plus metformin (n=389)
2
1
 between groups = –2.5 kg
0
P<0.001
−1
−2
−3
Patients With ≥1 Episode, %
Body Weight, kg ± SE
3
Sulfonylureaa plus metformin (n=584)
50
Sitagliptinb plus metformin (n=588)
40
32%
P<0.001
30
20
10
5%
0
0
12
24
38
Week 52
52
Weeks
Adapted from Nauck MA, Meininger G, Sheng D, et al, for the Sitagliptin Study 024
Group. 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 with permission from Blackwell Publishing Ltd., Boston, MA.
aSpecifically glipizide ≤20 mg/day;
(100 mg/day) with metformin (≥1500 mg/day);
cAll-patients-as-treated population.
Least squares mean between-group difference at week 52 (95% CI):
change in body weight = –2.5 kg [–3.1, –2.0] (P<0.001);
Least squares mean change from baseline at week 52:
glipizide: +1.1 kg; sitagliptin: –1.5 kg (P<0.001).
Add-on sitagliptin with metformin vs sulfonylurea
with metformin study.
bSitagliptin
29
Summary: Sitagliptin or Glipizide as
Add-on Combination With Metformin
Efficacy profile
– Comparable efficacy in lowering HbA1c
– Both provided greater HbA1c reductions in patients with the highest
baseline HbA1c
Safety profile
– Both were generally well tolerated
– Adverse event profiles (ie, serious and GI-related adverse events,
those leading to discontinuation) were similar, with the exception of
hypoglycaemia
• Significantly lower incidence of hypoglycaemic episodes associated with
sitagliptin with metformin
– Body weight significantly decreased for sitagliptin with metformin, but
increased for glipizide with metformin
30
Nauck MA et al. Diabetes Obes Metab. 2007;9:194–205.
Summary: Initial Combination Therapy With
Sitagliptin Plus Metformin Through 54 Weeks
Efficacy profile
–
–
–
–
Marked reductions in HbA1c for up to 54 weeks
Continued and substantial reductions in FPG and 2-hour PPG concentrations
Improved measures of β-cell function (HOMA-β; proinsulin-to-insulin ratio)
Provided greater HbA1c reductions in patients with the highest baseline HbA1c
Safety profile
– Generally well tolerated
– Discontinuation due to adverse events was low across treatment
groups
– Adverse event profile similar to that observed with metformin
monotherapy, including gastrointestinal adverse events
– Weight loss similar to that observed with metformin monotherapy
– Low incidences of hypoglycaemia
Goldstein BJ et al. Diabetes Care. 2007;30:1979–1987; Williams-Herman D et al. Poster presentation at ADA 67th Annual Scientific
Sessions in Chicago, Illinois, USA, 22–26 June 2007. Late Breaker (04-LB).
38
Summary: A Case for Earlier Use of Combination
Therapy in the Management of Type 2 Diabetes
• Sitagliptin and metformin have complementary mechanisms of action that
address all 3 core defects of type 2 diabetes
– Improves HbA1c, fasting plasma glucose and post-prandial glucose
• As initial therapy, compared with metformin monotherapy,
co-administration of sitagliptin with metformin provides improved efficacy
without increased incidence of weight gain or hypoglycaemia
– Provides an additive effect on the reduction of HbA1c
– Improves the markers of β-cell function
– Has similar adverse event profile to metformin monotherapy
• Combination of therapy of sitagliptin as an add-on to sulfonylurea or as an add-on
to sulfonylurea plus metformin resulted in a reduction in HbA1c and was generally
well-tolerated
Nauck MA et al. Diabetes Obes Metab. 2007;9:194–205;; Goldstein BJ et al. Diabetes Care. 2007;30:1979–1987; Hermansen K et al. Diabetes
Obes Metab. 2007;9:733–745.
42
Clinical data overview of combination therapy of sitagliptin
and sulfonylurea (as add-on to sulfonylurea alone or
sulfonylurea plus metformin)
26
Summary: Sitagliptin Add-on to
Glimepiride With or Without Metformin Study
Efficacy profile
– Provided sustained reduction in HbA1c for 24 weeks
Safety profile
– Was generally well tolerated
– No differences were observed in the incidence of clinical adverse events,
serious adverse events, or adverse events leading to treatment discontinuation
between groups
– Provided modest increase in mean body weight in the overall cohort
• Weight gain observed when added to glimepiride alone
• Small numerical increase when added to the combination of glimepiride
and metformin
– As expected, the incidence of hypoglycaemia increased when glimepiride,
a sulfonylurea, was co-administered with sitagliptin
40
Hermansen K et al. Diabetes Obes Metab. 2007;9:733–745.
DPP-4 Inhibition by Sitagliptin Improves the
Myocardial Response to Dobutamine
Stress and Mitigates Stunning in a Pilot Study
of Patients with Coronary Artery Disease
• Read PA et al, Circ Cardiovasc Imaging
published online Jan 14, 2010;
Echocardiographic Analysis
Global LV function assessed by LV ejection fraction (mean
± SEM) at baseline, peal stress and 30 minute recovery.
72.6 ± 7.2%
63.9 ± 7.9%
P A Read et al. Circ Cardiovasc Imaging 2010; DOI:
10.1161/CIRCIMAGING.109.899377
Conclusions
Conclusions
Conclusions
• In the recovery period, there was evidence
of post- ischemic stunning in the control
scans with reduced global and regional
wall function compared to baseline.
• However, sitagliptin protected the heart
from ischemia and mitigated this effect.
Conclusions
• The inhibition of DPP-4 augmented
plasma levels of GLP-1 (7-36) which
improved global and regional wall LV
function during dobutamine stress and
mitigated post-ischemic stunning in the
recovery period.
• This was predominantly driven by a
cardioprotective effect on ischemic
segments and was independent of insulin.
Conclusion
• Incretin Based therapy in diabetes
• can be used as monotherapy or in combination
therapy with other hypoglycemic agents
• Safe, effective, provides long term glucose control
• Benefits beyond glucose control
•
weight neutral or weight loss
•
probable CV benefits and beta cell mass
enhancement
•Thank you