Type 2 DM ; Metformin Best Partner

JAN-2009-WS-4046-ST

DM-Type 2 TreatmentBest-Partners

Mohammad Daoud, MDConsultant

Endocrinologist KAMC – Jeddah

Objectives

Introduction

Barriers and Safety

Incretins Based Rx

Take home messages

CaseA 48-year-old, obese woman with a 5-year history of (T2DM), HTN, and (CAD) presents for follow-up complaining of weight gain and frequent episodes of hypoglycemia

Medications : Metformin 1000 mg twice daily, glimepiride 6 mg once daily, ramipril 10 mg once daily, and aspirin 81 mg

Laboratory : HbA1c 8.3% ;didn’t improve since her last visit 9 months ago despite adherence to her therapeutic regimen with diet, and exercise.

CaseWhat is your best intervention to get this patient to adequate DM control ?

A- Maximize her Metformin 1 gm TIDB- Add a DPP4 inhibitor once dailyC- Maximize glimepiride to 8 mg once daily D- Add GLP-1 injection once daily or once weeklyE- Add NPH insulin 10 u at dinner time

Aims of Mx of DM

Improve quality of life Reduce acute symptoms Achieve euglycemia Avoid Acute & Chronic

Complications

Burden of Disease

Number of diabetic adults more than doubled in less than 3 decades

Vascular disease ( remains the leading cause of morbidity and mortality in people with diabetes)

Macrovascular complications, chiefly cardiovascular (CV) disease and stroke, are fatal in 50% of people with diabetes

???

Prevalence (%) estimates of DM (20-79 years), 2030

Diabetes Mellitus in Saudi Arabia; Al Nozha et al.

M.M. Al Nozha; Diabetes mellitus in Saudi Arabia; Saudi Med J 2004; Vol. 25 (11): 1603-1610.

Current and Projected Global Prevalence of DM

2007 2025Patients (Millions) Prevalence (%) Patients (Millions Prevalence (%)

1 India (40.9) Nauru (30.7) India (69.9) Nauru (32.3)

2 China (39.8) UAE (19.5) China (59.3) UAE (21.9)

3 USA (19.2) Saudi Arabia (16.7) USA (25.4) Saudi Arabia

(18.4)4 Russia (9.6) Bahrain (15.2) Brazil (17.6) Bahrain (17.0)

5 Germany (7.4) Kuwait (14.4) Pakistan (11.5) Kuwait (16.4)

6 Japan (7.0) Oman (13.1) Mexico (10.8) Tonga (15.2)

7 Pakistan (6.9) Tonga (12.9) Russia (10.3) Oman (14.2)

8 Brazil (6.9) Mauritius (11.1) Germany (8.1) Mauritius (13.4)

9 Mexico (6.1) Egypt (11.0) Egypt (7.6) Egypt (13.4)

10 Egypt (4.4) Mexico (10.6) Bangladesh (7.4) Mexico (12.4)Ref 4: Diabetes Atlas Third Edition. International Diabetes

Federation (IDF) - 2006

Today….

c

Type 2 diabetes is NOT a mild diseaseDiabeticRetinopathyLeading causeof blindnessin working ageadults1

DiabeticNephropathyLeading cause of end-stage renal disease2

CardiovascularDisease

Stroke2 to 4 fold increase in cardiovascular mortality and stroke3

DiabeticNeuropathyLeading cause of non-traumatic lower extremity amputations5

8/10 diabetic patients die from CV events4

1 Fong DS, et al. Diabetes Care 2003; 26 (Suppl. 1):S99–S102. 2Molitch ME, et al. Diabetes Care 2003; 26 (Suppl. 1):S94–S98. 3 Kannel WB, et al. Am Heart J 1990; 120:672–676. 4Gray RP & Yudkin JS. In Textbook of Diabetes 1997.5Mayfield JA, et al. Diabetes Care 2003; 26 (Suppl. 1):S78–S79.

Mild Type 2 Diabetes ?

Microvascular and Macrovascular Complications of Diabetes Are

Serious1

2- to 4-fold increased risk of CV death and stroke

Diabetes is the leading cause of kidney failure More than 60% of nontraumatic lower-limb

amputations occur in people with diabetes Diabetes is the leading cause of new cases of

blindness among adults ages 20 to 74 years 60% to 70% of patients have mild to severe

forms of nervous system damage

Macrovascular complications

Microvascular complications

CV = cardiovascular. 1. Centers for Disease Control and Prevention. National diabetes fact sheet: national estimates and general information on diabetes and

prediabetes in the United States, 2011. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, 2011.

05

101520253035404550

Inc id

e nce

Rat

e (%

)

Myocardial Infarction Stroke CV Death

Nondiabetic –MI (n=1,304)

Diabetic +MI (169)

Nondiabetic +MI (n=69)

Diabetic –MI (n=890)

P<0.001*

P<0.001*P<0.001*

CV = cardiovascular; -MI = no prior myocardial infarction; +MI = prior myocardial infarction *For diabetes vs. no diabetes and prior MI vs. no prior MI

Increased Risk of Cardiovascular Events Over 7 Years in Patients With Type 2 Diabetes

Haffner SM, et al. N Engl J Med. 1998;339:229–234.

Diabetes =

“CHD Risk Equivalent.”

Study Name

DDCT UKPDS Kumamoto Steno-2

HbA1c 2 % 0.9 % 2 % 0.5 %

Retinopathy 63 % 17-21% 69 % 58 %

Nephropathy 54 % 24-33 % 70 % 61 %

Autonomic Neuropathy

60 % --------- ---------- 63 %

Macro-Vascular Dis

41 % 16 % P value 0.052

---------- 53 %

18

UKPDS: Improving HbA1c Control Reduced Diabetes-Related

Complications

UKPDS=United Kingdom Prospective Diabetes Study. Data adjusted for age, sex, and ethnic group, expressed for white men aged 50–54 years at diagnosis and with mean duration of diabetes of 10 years. Stratton IM et al. UKPDS 35. BMJ 2000;321:405–412.

EVERY 1% reduction in HbA1c

REDUCED RISK(P<.0001)

1%

Diabetes-related deaths

Myocardial infarctions

Microvascular complications

Amputations or deaths from peripheral

vascular disorders

21%

14%

37%

43%

Relative RiskN=3642

DM Management Obstacles Weight gain

Hypoglycemia

Cardiovascular safety

Limitations by co-morbidities ( Renal , Cardiac…)

Others

Effect of Antidiabetic Agents on Weight

C

Hypoglycemia in Recent Major Clinical Trials

After the results became available, hypoglycemia was identified as an area of concern in 3 recent major clinical trials in which intensive glucose control was compared with standard glucose control: ACCORD1

VADT2

ADVANCE3

22

ACCORD=Action to Control Cardiovascular Risk in Diabetes; ADVANCE=Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation; VADT=Veterans Affairs Diabetes Trial. 1. ACCORD Study Group et al. N Engl J Med. 2008;358:2545–2559.2. Duckworth W et al. N Engl J Med. 2009;360:129–139.3. ADVANCE Collaborative Group et al. N Engl J Med. 2008;358:2560–2572.

Intensive ControlACCORD- Negative Impact

Conventional Intensive P Value

HbA1C 7.5% 6.4%

Morbidity(Primary outcome)

371 352 0.16

Mortality 203 257 0.04(HR 1.22;

CI 1.01-1.46)Severe-

Hypoglycemia,

Wt Gain > 10 kg

Less More <0.001

Increased Mortality without significant

effect on Cardiovascular events

ACCORD: The Action to Control Cardiovascular Risk in Diabetes Study Group

Potential Complications and Effects of

Severe Hypoglycemia

24

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;117:868–870.

Arrythmia1 Neuroglycopenia2

Abnormal prolonged cardiac repolarization — ↑ QTc and QT dispersion

Sudden death

Cognitive impairment

Unusual behavior Seizure Coma Brain death

History of Severe Hypoglycemia Greater Risk of Dementia

25

The clinical significance of minor glycemic episodes with dementia risk is unknown.

aAttributable risk calculated as difference between rate in group and rate in reference group (0 hypoglycemic events).1. Whitmer RA et al. JAMA. 2009;301:1565–1572.

Attributable risk of dementia with any hypoglycemia: 2.39% (1.72–3.01)a

n=1,002 n=258 n=205

1.64

4.34 4.28

Impact of Intensive Therapy for Diabetes: Summary of Major Clinical Trials

Study Microvasc CVD MortalityUKPDS DCCT / EDIC* ACCORD ADVANCE VADT

Long Term Follow-up

Initial Trial

* in T1DM

Kendall DM, Bergenstal RM. © International Diabetes Center 2009

UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:854.

Holman RR et al. N Engl J Med. 2008;359:1577. DCCT Research Group. N Engl J Med 1993;329;977.

Nathan DM et al. N Engl J Med. 2005;353:2643. Gerstein HC et al. N Engl J Med. 2008;358:2545.

Patel A et al. N Engl J Med 2008;358:2560. Duckworth W et al. N Engl J Med 2009;360:129. (erratum:

Moritz T. N Engl J Med 2009;361:1024)

Goals should be individualized based on

Duration of diabetesAge/life expectancyComorbid conditions : CRF , CHF …Known CVD or advanced microvascular complicationsHypoglycemia unawarenessIndividual patient considerations

Glycemic Recommendations forNonpregnant Adults with Diabetes

ADA. V. Diabetes Care. Diabetes Care 2014;37(suppl 1):S26; Table 9

(C)

(B)

ADA – EASD Consensus:(June 2012)

ADA. V. Diabetes Care. Diabetes Care 2014;37(suppl 1):S25. Figure 1; adapted with permission from Ismail-Beigi F, et al. Ann Intern Med 2011;154:554-559

Diabetes in Elderly

< 7.5 %

<8.0%

< 8.5%

Healthy

Intermediate

Poor

IDF 2012_______________

< 7%FPG/ Premals< 6.5 mmol/L(115 mg/dl)

Postmeals < 9 mmol/L(160 mg /dl)

EASD 2013

ADA 2014

2013

Therapy for Type 2 Diabetes

Pharmacologic Targets of Current Drugs Used in the Treatment of T2DM

-glucosidase inhibitorsDelay intestinal carbohydrate absorption

ThiazolidinedionesDecrease lipolysis in adipose tissue, increase glucose uptake in skeletal muscle and decrease glucose production in liver

SulfonylureasIncrease insulin secretion from pancreatic -cells

GLP-1 analoguesImprove pancreatic islet glucose sensing, slow gastric emptying, improve satiety

BiguanidesIncrease glucose uptakeand decreases hepatic glucose production

GlinidesIncrease insulin secretion from pancreatic -cells

DPP-4 inhibitorsProlong GLP-1 action leading to improved pancreatic islet glucose sensing, increase glucose uptake

Know the Pros /

Cons

SGLT-2 inhibitorsBromocriptine (Cycloset)Colesevelam

SS

√ Weight

√ Hypo

√ CVD

Limiting factorsWeight Gain and Hypoglycemia

Hypoglycemia risk Linked more to treatment strategies

than to achieved lower A1C

Now Befor

e

Antihyperglycemic Therapy inType 2 Diabetes

ADA. V. Diabetes Care. Diabetes Care 2014;37(suppl 1):S27. Figure 2;adapted with permission from Inzucchi SE, et al. Diabetes Care 2012;35:1364–1369

Incretins Based Therapy

Therapeutic Strategies to Enhance Incretin Action1,2

GLP-1 agonists(GLP-1 receptor activators; incretin mimetics)

Purpose: Raise agonist plasma concentrations into the pharmacologic range

DPP-4-resistant GLP-1 mimetics GLP-1 analogues with delayed absorption

DPP-4 inhibitors (Incretin enhancers)Purpose: Prevent degradation of endogenously released incretin hormones to elevate plasma levels of the active incretins

DPP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1.1. Deacon C et al. Diabetes. 1995;44:1126–1131.2. Brubaker PL. Trends Endocrinol Metab. 2007;18(6):240–245.

N=10 patients with type 2 diabetes. Patients were studied on two occasions. A regular meal and drug schedule was allowed for one day between the experiments with GLP-1 and placebo. *p<0.05 GLP-1 vs. placeboAdapted from Nauck MA et al Diabetologia 1993;36:741–744.

Effects of GLP-1 on Insulin and Glucagon Shown to Be Glucose Dependent in Type 2 Diabetes

With hyperglycemiaGLP-1 stimulated insulin and suppressed glucagon.

Glu

cose

(mm

ol/L

)G

luca

gon

(pm

ol/L

)

Time (minutes)

25020015010050

15.012.510.07.55.0

2015105

0 60 120 180 240

PlaceboGLP-1 infusion

Insu

lin(p

mol

/L)

*

*

* * *

* * *

* *

* * **

* * * *

*

When glucose levels approached normal,insulin levels declinedand glucagon was no longer suppressed.

Infusion

DPP4-I Enhances Active Incretin Levels Through Inhibition of DPP-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 ofactive incretinsGLP-1 and GIPa

Blood glucose in fasting and

postprandial states

Ingestion of food

Glucagonfrom alpha cells

(GLP-1)

Hepatic glucose

production

GI tract

DPP-4 enzyme

InactiveGLP-1

XDPP-4 inhibitor

Insulin from beta cells

(GLP-1 and GIP)

Glucose-dependent

Glucose-dependent

Pancreas

InactiveGIP

Beta cellsAlpha 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.

DPP4-I improves beta-cell function and increases insulin synthesis and release.1

DPP4-I 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.

DPP4-I and Metformin Target the Core Metabolic Defects of Type 2 Diabetes

Pharmacokinetic of DPP-4 Inhibitors

46

Sitagliptin

(Merck)1Vildagliptin (Novartis)2

Saxagliptin (BMS/AZ)3

Alogliptin (Takeda)5

Linagliptin(BI)6,7

Absorption tmax (median) 1–4 h 1.7 h 2 h (4 h for active

metabolite) 1–2 h 1.5 h

Bioavailability ~87% 85% >75 %4 N/A ~30%

Half-life (t1/2) at clinically relevant dose

12.4 h ~2–3 h 2.5 h (parent)3.1 h (metabolite)

12.4–21.4 h(25–800 mg)

Effective t1/2 ~12 hTerminal t1/2 >100 h

Distribution 38% protein bound 9.3% protein bound Low protein binding N/A

Concentration-dependent protein

binding:1 nM: 99% (DPP-4)≥30 nM: 75%–89%

Metabolism ~16% metabolized69% metabolized

mainly renal(inactive metabolite)

Hepatic (active metabolite)

CYP3A4/5 <8% metabolized ~13% metabolized

Elimination Renal 87%(79% unchanged)

Renal 85%(23% unchanged)

Renal 75%(24% as parent; 36% as

active metabolite)

Renal(60%–71%

unchanged)

Feces 80%(90% unchanged)

Renal 5%

DPP-4=dipeptidyl peptidase-4. aPharmacokinetic studies were performed in different assay systems and should not be compared. 1. Data on file, MSD. 2. EUSPC for Galvus. 3. EUSPC for Onglyza. 4. EPAR for Onglyza. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/001039/WC500044319.pdf. Accessed May 4, 2011. 5. Christopher R et al. Clin Ther. 2008;30:513–527. 6. EUSPC for Trajenta. 7. Blech S et al. Drug Metab Dispos.2010;38:667–678.

47

Sitagliptin vs Metformin in Type 2 DM Sitagliptin Is Non-Inferior to

Metformin1Per-Protocol Population (Week 24)

Between-groups difference=0.14 (0.06, 0.21)a

HbA 1c

LS

Mea

n Ch

ange

Fro

m B

asel

ine,

%

aPrespecified noninferiority margin=0.40%.

LS=least-squares. 1. Aschner P et al. Diabetes Obes Metab. 2010;12(3):252–261.

–0.43

–0.57

–0.8

–0.6

–0.4

–0.2

0.0

Sitagliptin (n=455) Metformin (n=439)

Mean baseline HbA1c, % = 7.2 7.2

Effects of Sitagliptin and Metformin on Incretin Hormone Concentrations in Healthy

Adult Subjects: Summary of Study Results

Total GLP-1 Active GLP-1

Active GIP Observations in Healthy Subjects

Sitagliptin Increases active GLP-1 and GIP

Metformin No effect

Increases total GLP-1 and increases active GLP-1

Does not increase active GIP

Sitagliptin +

Metformin Additive effect on active GLP-1;

increases active GIP

GIP=glucose-dependent insulinotropic peptide; GLP-1=glucagon-like peptide-1.Data available on request from Merck. Please specify 20752937(2)-JMT.

It is unclear what these findings mean for changes in glycemic control in patients with type 2 diabetes.

Sitagliptin + Metformin Improves24-Hour Glycemic Control

Vildagliptin vs Metformin: A1C

Vildagliptin Monotherapy Improves Glycemic Control in Type 2 Diabetes

Alogliptin Added to Metformin: A1C

Initial Fixed-Dose Combination Therapy With Sitagliptin + Metformin vs Metformin MonotherapyChange from Baseline in HbA1c by Baseline HbA1c

at Week 18

FAS=full analysis set; FDC=fixed-dose combination. 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.

HbA

1c L

S M

ean

Chan

ge

from

Bas

elin

e, %

Baseline HbA1c,% <8 ≥8 and <9 ≥9 and <10 ≥10 and <11 ≥11

P=0.009

P<0.001

P<0.001

Mean HbA1c,% 7.6 8.4 9.5 9.4 10.4 12.2

n=

–1.1

–1.6

–2.0

–2.9

–3.6

–2.7

–2.1

–1.7

–1.1–0.8

–4.0

–3.5

–3.0

–2.5

–2.0

–1.5

–1.0

–0.5

0

Sitagliptin/metformin FDC Metformin

99 95 99 11187 101 124 109 150 148

P=0.158

P=0.111

Sitagliptin Improves Glycemic Control

in Patients With Type 2 Diabetes Not Controlled With Pioglitazone

HbA1c With Sitagliptin or Glipizide as Add-on Combination With Metformin: Comparable Efficacy

Per-protocol PopulationLSM change from baseline

at 52 weeks (for both groups): –0.7%

Achieved primary

hypothesis of noninferiority to

sulfonylurea

Sulfonylureaa + metformin (n=411)Sitagliptinb + metformin (n=382)

HbA

1c, %

±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).

LSM=least squares mean.SE=standard error.

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.

Sitagliptin With Metformin Vs SU Weight / Incidence of Hypoglycemia

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

Least squares mean between-group difference at week 52 (95% CI):

change in body weight at Week 52 = –2.5 kg [–3.1, –2.0] (P<.001);Least squares mean change from baseline at week 52:

glipizide: +1.1 kg; sitagliptin: –1.5 kg (P<.001).Add-on sitagliptin with metformin vs sulfonylurea

with metformin study.

between groups at Week 52 = –2.5 kg

Least squares mean change from baseline

Body

Wei

ght,

kg

± S

E

Sulfonylureaa + metformin (n=416)Sitagliptinb + metformin (n=389)

−3

−2

−1

0

1

2

3

Weeks0 12 24 38 52

P<0.001

Hypoglycemia

P<0.00132%

5%

0

10

20

30

40

50

Week 52

Pati

ents

Wit

h ≥

1 Ep

isod

e O

ver

52 W

eeks

, %

Sulfonylureaa + metformin (n=584)Sitagliptinb + metformin (n=588)

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.

All-patients-as-treated Population

Exenatide: Proportion of Patients Achieving A1C ≤7%

Incretins Based Therapy

Safety

Reductions in MI (15% Su/ Insulin Vs 33% MFN)

All-cause mortality (13% and 27%,

respectively)

N Engl J Med 2008;359:1577–1589

Veterans Affairs• 6,185 with CHF & DM• Oral antihyperglycemic:

- With metformin (n=1,561)

- Without metformin• Statistically adjusted for

co-variablesDeath: 0.76 (0.63-0.92) p < 0.01CHF hospitalization: 0.93 (0.74-1.18) p = 0.56Total hospitalization: 0.94 (0.83-1.07) p = 0.35

Surv

ival

est

imat

es

1.00

0.95

0.90

0.75

0.85

0.80

Time (days)0 700100 200 300 600400 500

Metformin

No metforminp = 0.01

Aguilar D, et al. Circ Heart Fail 2011;4:53-8.

Metformin Use in Heart Failure Patients

24 % RRR in MORTALITY

Drug Study Dose Primary Outcome Pts (N)GLP-1 RAsExenatide EXSCEL 2.0 mg SC qw Time to first confirmed CV

event~9,500

Liraglutide LEADER 1.8 mg SC qd Time to first nonfatal MI, nonfatal stroke or CV death

~8,750

Lixisenatide ELIXA 20 mcg SC qd Time to first nonfatal MI, nonfatal stroke, hospitalization for UA, or CV death

~6,000

Dulaglutide REWIND 1.5 mg SQ qw Time to first nonfatal MI, nonfatal stroke, or CV death

~9,600

DPP-4 inhibitorsVildagliptin   50 mg bid LV function as determined

via changes in ejection fraction

~490

Sitagliptin TECOS 50-100 mg qd Time to first CV event (nonfatal MI, nonfatal stroke, or hospitalization for UA)

~14,000

Alogliptin EXAMINE* 6.25-25 mg qd Time to first primary MACE (nonfatal MI, nonfatal stroke, or CV death)

5,380

Saxagliptin SAVOR-TIMI 53* 2.5-5 mg qd Time to first CV event (nonfatal MI, nonfatal ischemic stroke, or CV death)

16,492

Linagliptin CAROLINA 5 mg qd Time to first nonfatal MI, nonfatal stroke, hospitalization for UA, or CV death

~6,000

 Cardiovascular Outcomes Trials With Use of Incretin-Based Therapies in Patients With T2DM

SAVOR-TIMI 53 and EXAMINE: Conclusions

Meta-analysis performed including all randomized clinical trials (N=53) with a duration of ≥24 weeks, enrolling patients with type 2 diabetes, comparing DPP-4 inhibitors with either placebo or active drugs

The primary outcome measured in this study was the incidence of cancer

Secondary outcomes examined include pancreatitis reported as a serious AE, all-cause and CV mortality, and incidence of MACE

In the 13 trials reporting at least one case of pancreatitis among serious adverse events, the MH-OR of DPP-4 inhibitors was 0.786 [0.357–1.734], P=0.55

Meta-analysis of Clinical Trials With DPP-4 I

No Evidence of Increased Risk of Pancreatitis Associated With Treatment1

AE=adverse event; CV=cardiovascular; DPP-4=dipeptidyl peptidase-4; MACE=major adverse cardiovascular events; MH-OR= Mantel–Haenszel odds ratio.

aComparators were: acarbose, GLP-1R agonists, metformin, sulfonylureas, thiazolidinediones, and placebo.

Monami M et al. Curr Med Res Opin. 2011; 27:57–64.66

To Conclude…

Incretins-Based Rx + MFN DPP4-Inhibitors & MFN

Monotherapy and combination therapy with metformin provided

substantial and statistically significant glucose-lowering efficacy

Favorable risk-to-benefit profile

Achieve DM proper control …using the safest tools

Get the maximum benefit

Avoid hypoglycemia and Wight gain

Cardiovascular safety

Proper Agent and Targets

Tailor therapy /targetsIndividualizeTreat safely

Conclusions

Conclusions

The older agents, possibly reduce CV events in T2DM patients, but with a price of hypoglycemic risk and weight gain

Incretins –based therapies, are noteworthy for their association with low hypoglycemic risk and neutral weight/ loss while effectively controlling blood glucose

Large-scale clinical trials are in progress to clarify the CV safety and efficacy of the incretin-based therapies in T2DM patients

Safety

Patient

Disease

Comorbidities

Treatment

Do It Right

CaseA 48-year-old, obese woman with a 5-year history of (T2DM), HTN, and (CAD) presents for follow-up complaining of weight gain and frequent episodes of hypoglycemia

Medications : Metformin 1000 mg twice daily, glimepiride 6 mg once daily, ramipril 10 mg once daily, and aspirin 81 mg

Laboratory : HbA1c 8.3% ;didn’t improve since her last visit 9 months ago despite adherence to her therapeutic regimen with diet, and exercise.

CaseWhat is your best intervention to get this patient to adequate DM control ?

A- Maximize her Metformin 1 gm TIDB- Add a DPP4 inhibitor once dailyC- Maximize glimepiride to 8 mg once daily D- Add GLP-1 injection once daily or once weeklyE-Add NPH insulin 10 u at dinner time