incretin based therapy in diabetes mellitus type 2 josephine carlos-raboca,m.d.,f.p.s.e.m....

Incretin Based Therapy in Diabetes Mellitus Type 2

JOSEPHINE CARLOS-RABOCA,M.D.,F.P.S.E.M. ENDOCRINOLOGY,DIABETES AND METABOLISM

DIABETES CARE CENTERWEIGHT WELLNESS CENTER

MAKATI MEDICAL CENTER

Outline Review of Incretins and Diabetes Goals of Treatment for Diabetes Treatment OptionsSitagliptin Studies(Case/Clinical trials)

Monotherapy UseCombination UseCardiovascular Benefits

After food ingestion

GLP-1 is secreted from theL-cells of the jejunum

& ileum

That in turn…

• Stimulates glucose-dependent insulin secretion

• Suppresses glucagon secretion

• Slows gastric emptying

• Leads to reduction of food intake

• Improves insulin sensitivity

Longtime effects in animal models:

• Increase of β-cell mass and improved β-cell function

Drucker. Curr Pharm Des. 2001Drukcer. Mol. Endocrinol. 2003

GLP-1: effects in humans

GLP-1: Biological Activity

LL Baggio and DJ Drucker. Gastroenterology 2007; 132: 2131-2157.

CVD

Fastinghyperglycemia

Postprandial hyperglycemia /hypertriglyceridemia

Obesity

InsulinResistance

Impaired insulin secretionHyperglucagonemiab-cell mass i

GLP-1 Enhancenent

GLP-1 Secretion is impaired in Type 2 DiabetesNatural 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-1Drucker. Curr. Pharm. Des. 200; Drucker. Mol. Endocrinol. 2003

Incretin Mimetics and DPP-4 Inhibitors: Major Differences

Gallwitz. European Endocrine Diseases. 2003

Outline

Incretins and DiabetesGoals of Treatment for Diabetes Treatment OptionsRole of incretins in diabetes treatmentSitagliptin Studies

Monotherapy UseCombination 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 DiabetesGoals of Treatment for Diabetes Treatment OptionsRole of incretins in diabetes treatmentSitagliptin Studies

Monotherapy UseCombination Use

Efficacy and tolerability of existing anti-diabetic agents

Class

Primary therapeutic

effect LimitationsSulfonylureas HbA1c

Hypoglycemia, weight gain

Meglitinides PPG Hypoglycemia, weight gain

Biguanides (metformin) HbA1cGI adverse effects, lactic acidosis (rare)

PPARs HbA1cWeight gain, edema, anemia, potential for liver toxicity

Alpha-glucosidase inhibitors PPG GI adverse effects

Insulin HbA1cInjectable 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

• 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

N

ONH2

NN

CF3

F

F

F

N

ADA 2006 Late Breaking Clinical Presentation (Stein).

N

ONH2

NN

CF3

F

F

F

N

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 >100,000ADA 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


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

Lifestyle + Metformin+

Basal Insulin


Sulfonylurea


Intensive Insulin


PioglitazoneNo hypoglycemiaWeight lossNausea/Vomiting


Basal Insulin Lifestyle + Metformin

+ GLP-1 agonistNo hypoglycemiaWeight lossNausea/Vomiting

STEP 1 STEP 2 STEP 3

Tier 1 : Well-validated core therapies

Tier 2 : Less well-validated therapies

At diagnosis:

Lifestyle+

Metformin


Pioglitazone+

Sulfonylurea

Nathan, D et al. Diabetes Care 2009; 32(1): 1-11

ADA-EASD –Algorithm for Control of Type 2 Diabetes (2008)

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


26

• 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 normalLab 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

CASE # 1

26

What would be your initial treatment plan?a. Insulinb. Sitagliptinc. Exenatided. TZDe. Sulfonylureaf. Metformin

7.2

7.6

8.0

8.4

Placebo (n=244)

Sitagliptin 100 mg (n=229)

24-week Study

Time (weeks)

0 5 10 15 20 25

-0.79%(p<0.001)

Japanese Study

-1.05%(p<0.001)

Placebo (n=75)


Time (weeks)

0 4 8 12

A1C

(%

)

7.6

8.0

8.4

7.2

6.8

D change vs placebo*

18-week Study

Placebo (n=74)


Time (weeks)

0 6 12 18

A1C

(%

)

7.2

7.6

8.0

8.4

-0.6%(p<0.001)

A1C

(%

)

=

Sitagliptin Consistently and Significantly Lowers A1C With Once-Daily Dosing in Monotherapy

Redu

ction

in A

1C (%

)

Baseline A1C (%)

Mean (%)

Redu

ction

in A

1C (%

)

<8% 8–<9% ≥9%

7.37 8.40 9.48

<8% 8–<9% ≥9%

7.39 8.36 9.58

Sitagliptin 100 mg Once-daily Provides Significant and Progressively Greater Reductions in A1C With Progressively

Higher Baseline A1C Inclusion Criteria: 7%–10%+

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).

18-week Study

-0.44

-0.61

-1.2-1.8

-1.6

-1.4

-1.2

-1.0

-0.8

-0.6

-0.4

-0.2

0.0

24-week Study

-0.57

-0.8

-1.52-1.8

-1.6

-1.4

-1.2

-1.0

-0.8

-0.6

-0.4

-0.2

0.0

Sitagliptin Once Daily Significantly Improves Both Fasting and Post-meal Glucose In Monotherapy

* LS mean difference from placebo after 24 weeks.Aschner P, et al. Protocol 021. Abstract presented at American Diabetes Association; June 10, 2006; Washington, DC.ADA 2006 Late Breaking Clinical Presentation (Stein).

Fasting Glucose

FPG* = –17.1 mg/dL (p<0.001)

Weeks0 3 12 18 24

Fasti

ng G

luco

se (m

g/dL

)

140

150

160

170

180


Post-meal Glucose

Time (minutes)

Plas

ma

Glu

cose

(mg/

dL)

D in 2-hr PPG* = –46.7 mg/dL (p<0.001)

144

180

216

252

288

0 60 120 0 60 120

Placebo (N=204)Sitagliptin 100 mg (n=201)

Baseline24 Weeks

Baseline24 Weeks

Placebo (n=247)

6

0

10

20

30

40

50

0

10

20

30

40

50

0

10

20

30

40

50

SitagliptinPlacebo

Monotherapy Study Add-On to Metformin Study

Add-On to TZD Study

Perc

enta

ge

Perc

enta

ge

Perc

enta

ge

P<0.001

P<0.001

P<0.001

17%

41%

18%

47%

23%

45%

Sitagliptin Once Daily Significantly Increases Proportion of Patients Achieving Goal in Monotherapy or Combination Therapy

Goal A1C <7%

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

• 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

Pooled Phase III Population Analysis: no statistically significant difference in incidence for either dose vs. placebo

Hypoglycemia

Weight Changes

0.9

Placebo

1.2

Sitagliptin100 mg

0.9

Sitagliptin200 mg

Hypoglycemia

Proportion of patients with (%)

34

Sitagliptin Once Daily Shows Consistent Glycemic Efficacy, Safety and Tolerability Profile > 1 Year

PN 020: Extended Study of Add-on to Ongoing Metformin Therapy

Sitagliptin 100 mg qd

Placebo/glipizide

Efficacy

∆H

bA1c

(%)

Weeks

0 6 12 18 24 30 38 46 54

-0.1

-0.3

-0.5

-0.7

-0.9

-1.1

Placebo Glipizide

Phase A Phase BSitagliptin

-1

-2

Sitagliptin 100 mg qd

Placebo/glipizide

Safety

1

0

0

Phase A Phase B

2.4 kg

12 24 38 54

Body Weight Gain

Weeks

Placebo Glipizide

Sitagliptin

Glipizide

Placebo

Sitagliptin

Hypoglycemia

2.10%

18.30%

1.30% 0.80%

24-Week 26-Week

Glipizide

Placebo

Sitagliptin

Hypoglycemia

2.10%

18.30%

1.30% 0.80%

24-Week 26-Week

Meininge

Not sure what "26-week" means for hypoglycemia histiogram. Please clarify since base study was a 24-week study and 1 year analysis was performed on 54 weeks of data.

Meininge

Not sure what "26-week" means for hypoglycemia histiogram. Please clarify since base study was a 24-week study and 1 year analysis was performed on 54 weeks of data.Changed Hypoglycemia label on bottom of figure to Phase A and Phase B, from 24-week and 26-week

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

26

• 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

CASE # 2

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

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

* 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).

Add-on to Metformin in A1C vs. Placebo* = –0.65% (p<0.001)

Weeks

0 6 12 18 24

A1C

(%)

7.0

7.2

7.4

7.6

7.8

8.0

8.2

Weeks

Add-on to Pioglitazone in A1C vs. Placebo* = –0.70% (p<0.001)

0 6 12 18 24A1

C (%

)7.0

7.2

7.4

7.6

7.8

8.0

8.2

Placebo Sitagliptin 100 mg

Co-administration of Sitagliptin and Metformin in Healthy Adults Increased Active GLP-1 Greater Than Either Agent Alone

Values represent geometric mean±SE.

Placebo

Metformin 1000 mg Sitagliptin 100 mg

Co-administration of sitagliptin 100 mg plus metformin 1000 mg

Mean AUC ratioSita + Met: 4.12

Mean AUC ratiosSita: 1.95 Met: 1.76

–20

10

20

30

40

50

–1 0 1 2 3 4

Act

ive

GL

P-1

C

on

cen

trat

ion

s, p

M

MealMorning Dose Day 2 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%

Achieved primary hypothesis of non-

inferiority to sulfonylurea

Sulfonylureaa + metformin (n=411)

Sitagliptinb + metformin (n=382)

Hb

A1

c,

% ±

SE

Weeks

6.2

6.4

6.6

6.8

7.0

7.2

7.4

7.6

7.8

0 6 12 18 24 30 38 46 52

8.0

8.2

aSpecifically glipizide ≤20 mg/day; bSitagliptin 100 mg/day with metformin (≥1500 mg/day).

Per-protocol population; LSM=least squares mean.SE=standard error.

27

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.

Greater Reductions in HbA1c Associated With Higher Baseline HbA1c – 52-Week Post Hoc Analysis

n=117

Baseline HbA1c Category

Mea

n C

han

ge

Fro

m B

asel

ine

in H

bA

1c, %

<7% ≥7 to <8% ≥8 to <9% ³9%

− 0.1

− 0.6

−1.1

−1.8

− 0.3

−0.5

−1.1

−1.7

−2.0

−1.8

−1.6

−1.4

−1.2

−1.0

−0.8

−0.6

−0.4

−0.2

0.0

Sitagliptinb plus metformin

Sulfonylureaa plus metformin

n=33 n=21n=82 n=82n=179 n=167n=112

aSpecifically glipizide ≤20 mg/day.bSitagliptin 100 mg/day with metformin (≥1500 mg/day);

Per-protocol population. Add-on sitagliptin with metformin vs sulfonylurea

with metformin study.28


Sitagliptin With Metformin Provided Weight Reduction (vs Weight Gain) and a Much Lower Incidence of Hypoglycaemia

aSpecifically glipizide ≤20 mg/day; bSitagliptin (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.

between groups = –2.5 kg

Least squares mean change over timec

Bo

dy

Wei

gh

t, k

g ±

SE

Sulfonylureaa plus metformin (n=416)

Sitagliptinb plus metformin (n=389)

−3

−2

−1

0

1

2

3

Weeks

0 12 24 38 52

Hypoglycaemiac

P<0.001

32%

5%

0

10

20

30

40

50

Week 52P

atie

nts

Wit

h ≥

1 E

pis

od

e, %

P<0.001

Sulfonylureaa plus metformin (n=584)

Sitagliptinb plus metformin (n=588)

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

Nauck MA et al. Diabetes Obes Metab. 2007;9:194–205.30

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

• 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

Summary: A Case for Earlier Use of Combination Therapy in the Management of Type 2 Diabetes

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

Hermansen K et al. Diabetes Obes Metab. 2007;9:733–745. 40

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

Regional wall LV motion (septal, lateral, anterior, inferior, anteroseptal and posterior )Global LV function – mitral annular systolic velocity – 6 sitesPeak systolic tissue velocity (Vs)Strain and strain rateA diameter of >50% stenosis on CA was considered hemodynamically significant

Global LV function assessed by LV ejection fraction (mean ± SEM) at baseline, peal stress and 30 minute recovery.

P A Read et al. Circ Cardiovasc Imaging 2010; DOI: 10.1161/CIRCIMAGING.109.899377

63.9 ± 7.9%

72.6 ± 7.2%

Conclusions

In patients with CAD, metabolic manipulation with DPP4-inhibition to prevent degradation of GLP-1 can protect the heart from ischemic LV dysfunction during dobutamine stress and mitigate post- ischemic stunning. Global and regional wall LV performance was greater following sitaglipitin at peak stress and at 30 minutes into recovery compared to control .

Conclusions

The rise in plasma insulin was also reduced by sitagliptin which suggests that the beneficial effect on the heart was due to GLP-1 and not to insulin. At peak stress, sitagliptin improved both global function assessed by ejection fraction and mitral annular Vs, and regional wall function assessed by Vs, strain and strain rate. This was primarily driven by increasing the performance of the ischemic segments.

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

incretin based therapy in diabetes mellitus type 2 josephine carlos-raboca,m.d.,f.p.s.e.m....

Documents