Your SlideShare is downloading. ×
Type 2 DM ; Metformin Best Partner
Upcoming SlideShare
Loading in...5
×

Thanks for flagging this SlideShare!

Oops! An error has occurred.

×
Saving this for later? Get the SlideShare app to save on your phone or tablet. Read anywhere, anytime – even offline.
Text the download link to your phone
Standard text messaging rates apply

Type 2 DM ; Metformin Best Partner

1,100

Published on

Slide Presentation …

Slide Presentation
Diabetes Melliuts Type 2 management basics are life style modifications followed by use of Metformin
What is the best and safest next pharmacologic choice

Published in: Health & Medicine
0 Comments
2 Likes
Statistics
Notes
  • Be the first to comment

No Downloads
Views
Total Views
1,100
On Slideshare
0
From Embeds
0
Number of Embeds
0
Actions
Shares
0
Downloads
105
Comments
0
Likes
2
Embeds 0
No embeds

Report content
Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
No notes for slide

Transcript

  • 1. JAN-2009-WS-4046-ST DM-Type 2 Treatment Best-Partners Mohammad Daoud, MD Consultant Endocrinologist KAMC – Jeddah
  • 2. Objectives Introduction Barriers and Safety Incretins Based Rx Take home messages
  • 3. Case A 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.
  • 4. Case What is your best intervention to get this patient to adequate DM control ? A- Maximize her Metformin 1 gmTID B- Add a DPP4 inhibitor once daily C- Maximize glimepiride to 8 mg once daily D- Add GLP-1 injection once daily or once weekly E- Add NPH insulin 10 u at dinner time
  • 5. Aims of Mx of DM Improve quality of life Reduce acute symptoms Achieve euglycemia Avoid Acute & Chronic Complications
  • 6. 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
  • 7. ???
  • 8. Prevalence (%) estimates of DM (20-79 years), 2030
  • 9. 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.
  • 10. Current and Projected Global Prevalence of DM 2007 2025 Patients (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 AtlasThird Edition. International Diabetes Federation (IDF) - 2006
  • 11. Today…. c
  • 12. Type 2 diabetes is NOT a mild disease Diabetic Retinopathy Leading cause of blindness in working age adults1 Diabetic Nephropathy Leading cause of end-stage renal disease2 Cardiovascular Disease Stroke 2 to 4 fold increase in cardiovascular mortality and stroke3 Diabetic Neuropathy Leading 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 ?
  • 13. 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.
  • 14. 0 5 10 15 20 25 30 35 40 45 50 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.
  • 15. 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 %
  • 16. 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 Relative Risk N=3642
  • 17. DM Management Obstacles Weight gain Hypoglycemia Cardiovascular safety Limitations by co-morbidities ( Renal , Cardiac…) Others
  • 18. Effect of Antidiabetic Agents on Weight C
  • 19. 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.
  • 20. Intensive Control ACCORD- Negative Impact Conventional Intensive PValue 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
  • 21. 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
  • 22. 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
  • 23. Impact of Intensive Therapyfor Diabetes: Summary of Major Clinical Trials Study Microvasc CVD Mortality UKPDS       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)
  • 24. Goals should be individualized based on Duration of diabetes Age/life expectancy Comorbid conditions : CRF , CHF … Known CVD or advanced microvascular complications Hypoglycemia unawareness Individual patient considerations Glycemic Recommendations for Nonpregnant Adults with Diabetes ADA. V. Diabetes Care. Diabetes Care 2014;37(suppl 1):S26; Table 9
  • 25. (C) (B)
  • 26. 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
  • 27. Diabetes in Elderly < 7.5 % <8.0% < 8.5% Healthy Intermediate Poor
  • 28. IDF 2012 _______________ < 7% FPG/ Premals < 6.5 mmol/L (115 mg/dl) Postmeals < 9 mmol/L (160 mg /dl) EASD 2013 ADA 2014 2013
  • 29. Therapy for Type 2 Diabetes
  • 30. Pharmacologic Targets of Current Drugs Used in the Treatment of T2DM -glucosidase inhibitors Delay intestinal carbohydrate absorption Thiazolidinediones Decrease lipolysis in adipose tissue, increase glucose uptake in skeletal muscle and decrease glucose production in liver Sulfonylureas Increase insulin secretion from pancreatic -cells GLP-1 analogues Improve pancreatic islet glucose sensing, slow gastric emptying, improve satiety Glinides Increase insulin secretion from pancreatic -cells DPP-4 inhibitors Prolong GLP-1 action leading to improved pancreatic islet glucose sensing, increase glucose uptake SGLT-2 inhibitors Bromocriptine (Cycloset) Colesevelam
  • 31. S S
  • 32. √ Weight √ Hypo √ CVD
  • 33. Limiting factors Weight Gain and Hypoglycemia Hypoglycemia risk Linked more to treatment strategies than to achieved lower A1C Now Before
  • 34. Antihyperglycemic Therapy in Type 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
  • 35. Incretins Based Therapy
  • 36. 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.
  • 37. 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. placebo Adapted 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 hyperglycemia GLP-1 stimulated insulin and suppressed glucagon. Glucose (mmol/L) Glucagon (pmol/L) Time (minutes) 250 200 150 100 50 15.0 12.5 10.0 7.5 5.0 20 15 10 5 0 60 120 180 240 Placebo GLP-1 infusion Insulin (pmol/L) * * * * * * * * * * * * * * * * * * * When glucose levels approached normal, insulin levels declined and glucagon was no longer suppressed. Infusion
  • 38. 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 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 XDPP-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.
  • 39. 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
  • 40. Pharmacokinetic of DPP-4 Inhibitors 46 Sitagliptin (Merck)1 Vildagliptin (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 h Terminal 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% metabolized 69% 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.
  • 41. 47 Sitagliptin vs Metformin in Type 2 DM Sitagliptin Is Non-Inferior to Metformin1 Per-Protocol Population (Week 24) Between-groups difference=0.14 (0.06, 0.21)a HbA1cLSMean ChangeFromBaseline,% 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
  • 42. 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.
  • 43. Sitagliptin + Metformin Improves 24-Hour Glycemic Control
  • 44. Vildagliptin vs Metformin: A1C
  • 45. Vildagliptin Monotherapy Improves Glycemic Control in Type 2 Diabetes
  • 46. Alogliptin Added to Metformin: A1C
  • 47. Initial Fixed-Dose Combination Therapy With Sitagliptin + Metformin vs Metformin Monotherapy Change 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 DiabetesAssociation 69th Scientific Sessions. New Orleans, LA. June 5–9, 2009. 2. Data on file, MSD. HbA1cLSMeanChangefrom Baseline,% 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
  • 48. Sitagliptin Improves Glycemic Control in Patients With Type 2 Diabetes Not Controlled With Pioglitazone
  • 49. HbA1c With Sitagliptin or Glipizide as Add-on Combination With Metformin: Comparable Efficacy Per-protocol Population LSM 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) HbA1c,%±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.
  • 50. 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 Week52 = –2.5kg Least squares mean change from baseline BodyWeight,kg±SE Sulfonylureaa + metformin (n=416) Sitagliptinb + metformin (n=389) −3 −2 −1 0 1 2 3 Weeks 0 12 24 38 52 P<0.001 Hypoglycemia P<0.001 32% 5% 0 10 20 30 40 50 Week 52 PatientsWith≥1Episode Over52Weeks,% 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
  • 51. Exenatide: Proportion of Patients Achieving A1C ≤7%
  • 52. Incretins Based Therapy Safety
  • 53. Reductions in MI (15% Su/ InsulinVs 33% MFN) All-cause mortality (13% and 27%, respectively) N Engl J Med 2008;359:1577–1589
  • 54. Veterans Affairs • 6,185 with CHF & DM • Oral antihyperglycemic: - With metformin (n=1,561) - Without metformin • Statistically adjusted for co-variables Death: 0.76 (0.63-0.92) p < 0.01 CHF hospitalization: 0.93 (0.74-1.18) p = 0.56 Total hospitalization: 0.94 (0.83-1.07) p = 0.35 Survivalestimates 1.00 0.95 0.90 0.75 0.85 0.80 Time (days) 0 700100 200 300 600400 500 Metformin No metformin p = 0.01 Aguilar D, et al. Circ Heart Fail 2011;4:53-8. Metformin Use in Heart Failure Patients 24 % RRR in MORTALITY
  • 55. Drug Study Dose Primary Outcome Pts (N) GLP-1 RAs Exenatide 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 inhibitors Vildagliptin 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
  • 56.  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
  • 57. To Conclude…
  • 58. 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
  • 59. Achieve DM proper control …using the safest tools
  • 60. Get the maximum benefit  Avoid hypoglycemia and Wight gain  Cardiovascular safety  Proper Agent andTargets  Tailor therapy /targets Individualize Treat safely Conclusions
  • 61. Conclusions The older agents, possibly reduce CV events inT2DM 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
  • 62. Safety Patient Disease Comorbidities Treatment Do It Right
  • 63. Case A 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.
  • 64. Case What is your best intervention to get this patient to adequate DM control ? A- Maximize her Metformin 1 gmTID B- Add a DPP4 inhibitor once daily C- Maximize glimepiride to 8 mg once daily D- Add GLP-1 injection once daily or once weekly E-Add NPH insulin 10 u at dinner time

×