Embed Size (px)
Citation preview
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
