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Dm medications cv safety

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DM medications and Cardiovascular Safety

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Dm medications cv safety

  1. 1. 1 DM and CVD Cardiovascular Outcome Trials Does it matter? Dr. Mohammad Daoud Consultant Endocrinologist KAMC/ NGHA - Jeddah –Saudi Arabia
  2. 2. Objectives To Understand : DM and CV Risk Glycemic Control and CV outcomes The evidence ? DM Medications and CVD ? Medications CV Safety
  3. 3. Questions -Does lowering A1c below a target (<7.0 % - 6.5% ) translate in reduction in CVD Risk ? -Does it matter which intervention /treatment is used to achieve this objective ? ( target A1c / CVD risk reduction ?) -Could a medication cause more harm then benefit ? The target The intervention
  4. 4. HbA1c Is Associated With Outcomes  Increases in HbA1c are correlated with both microvascular and macrovascular disease complications1,2  However, in clinical trials, interventions to lower HbA1c have only reduced microvascular complications1,3,4 UKPDS = United Kingdom Prospective Diabetes Study. 1. Stratton IM et al. BMJ. 2000;321:405–412. 2. Gerstein HC et al. Diabetologia. 2010;53:2509–2517. 3. ADVANCE Collaborative Group et al. N Engl J Med. 2008;358:2560–2572. 4. Ismail-Beigi F et al. Lancet. 2010;376:419–430. HazardRatio Updated Mean HbA1c UKPDS: Fatal and Nonfatal Myocardial Infarction1 0.5 1 5 0 5 6 7 8 9 10 14% increase per 1% increase in HbA1c P<0.0001 11 1 10 15 0 5 6 7 8 9 10 11 UKPDS: Microvascular End Points1 37% increase per 1% increase in HbA1c P<0.0001 0.5
  5. 5. Compared with subjects without diabetes, people with diabetes* have… Diabetes increases CV risk > 2  risk of heart disease1 > 2  risk of stroke1 *Type 1 or Type 2. 1. NIDDK. http://diabetes.niddk.nih.gov/dm/pubs/stroke/ accessed May 2013. 2. Inzucchi SE, et al. Diabetes Care. 2012;35:1364–1379. Reducing CV risk is a major focus of diabetes management2
  6. 6. Diabetes → Increased Risk of Heart Failure Independent of Ischemia  Diabetic cardiomyopathy  2 to 4-fold increase incidence of heart failure in DM  Asymptomatic abnormalities of ventricular systolic and diastolic function, independent of ischemic heart disease or systemic hypertension  Independent risk factors for CHF  Elevated A1C  Micro-albuminuria Nichols G A et al. Dia Care 2004;27:1879-1884
  7. 7. Lower HbA1c levels are associated with reduced micro- and macrovascular risk Risk reduction with 1% decline in annual mean HbA1c 1 All, p < 0.0001 p = 0.035 p = 0.016 p = 0.0001 Microvascular disease 37% PVD 43% Stroke 14% 12% Heart failure Cataract extraction 16% 19% 0% 15% 30% 45% Myocardial infarction PVD, peripheral vascular disease (lower extremity amputation or fatal peripheral vascular disease); UKPDS, UK Prospective Diabetes Study 1. Stratton IM, et al. BMJ. 2000;321:405–412. UKPDS observational study
  8. 8. 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.
  9. 9. Submission with NDA • Meta-analysis of important CV events across controlled Phase II and III studies to calculate the risk ratio • If the upper bound of the 2-sided 95% CI for the estimated risk ratio is: – > 1.8, inadequate data to support approval – 1.3–1.8,* postmarketing CV trial(s) needed to show definitively < 1.3 – < 1.3,* postmarketing CV trial(s) generally not necessary (*With a reassuring point estimate.) • Studies included in the meta-analysis must be appropriately designed, and include patients at higher CV risk so that sufficient endpoints are obtained to allow a meaningful estimate of risk Regulatory requirements for CV outcome data FDA: Guidance for industry (Dec 2008) Diabetes Mellitus: Evaluating Cardiovascular Risk in New Antidiabetic Therapies in Type 2 Diabetes1 1. FDA Guidance for Industry. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071627.pdf. 2. EMA Guidelines. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC500129256.pdf.
  10. 10. 11 Superiority Noninferiority Approvable; CV safety study postapproval may not be required Noninferiority Boundary HR 1.3 Noninferiority Boundary HR 1.8 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 2.2 Hazard ratio HR = hazard ratio; CV = cardiovascular; CI = confidence interval. 1. Hirshberg B et al. Diabetes Care. 2011:34;S101–S106. FDA Statistical Hurdles for Approval1 Hypothetical examples of possible HRs, and regulatory consequences If the upper bound of two-sided 95% CI for HR is <1.3, a postmarketing CV trial may not be required under normal conditions.
  11. 11. 12 Non-inferiority Boundary HR 1.3 Non-inferiority Boundary HR 1.8 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 2.2 FDA Statistical Hurdles for Approval1 Hypothetical examples of possible HRs, and regulatory consequences Non-inferiority Inferiority Underpowered Approvable; need for full postapproval CV safety study (~600 events) Not approvable If upper bound of two-sided 95% CI for HR is between 1.3 and 1.8, a postmarketing full CV safety trial will be required to definitively assess whether upper bound is <1.3. HR = hazard ratio; CV = cardiovascular; CI = confidence interval. 1. Hirshberg B et al. Diabetes Care. 2011:34;S101–S106. Hazard ratio
  12. 12. 13 Non-inferiority Boundary HR 1.3 Non-inferiority Boundary HR 1.8 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 2.2 Hazard ratio FDA Statistical Hurdles for Approval1 Hypothetical examples of possible HRs, and regulatory consequences Non-inferiority Inferiority Underpowered Approvable; need for full postapproval CV safety study (~600 events) Not approvable If the upper bound of the two-sided 95% CI for HR is >1.8, the drug is not approvable and a full safety trial is required prior to approval. HR = hazard ratio; CV = cardiovascular; CI = confidence interval. 1. Hirshberg B et al. Diabetes Care. 2011:34;S101–S106.
  13. 13. 14 CI = confidence interval; HR = hazard ratio; CV = cardiovascular. 1. Hirshberg B et al. Diabetes Care. 2011:34;S101–S106. FDA Statistical Hurdles for Approval1  If the upper bound of the two-sided 95% CI for HR is <1.3 (after interim analysis) and the overall risk-benefit analysis supports approval, a postmarketing CV trial may not be needed  If the upper bound of the two-sided 95% CI for HR is between 1.3 and 1.8, a postmarketing trial will be required to definitively assess whether upper bound is <1.3 before obtaining approval  If the upper bound of the two-sided 95% CI for HR is >1.8, the drug is not approvable
  14. 14. Impact of Intensive DM Control
  15. 15. STUDY POPULATION GLUCOSETARGET PRIMARY ENDPOINT RESULT HYPOGLYCEMIA Van den Berghe—1 SICU (n = 1548) 80-110 versus 180-200 ICU death 42% RRR 7.2% (<40 mg/dL) Van den Berghe—2 MICU (n = 1200) 80-110 versus 180-215 Hospital death No difference 18.7% (mean 32 mg/dL) VISEP* MICU, sepsis (n = 488) 80-110 versus 180-200 28-day death ↑ Mortality trend 17.0% (<40 mg/dL) GIST-UK* Stroke ICU (n = 933) 72-126 versus usual care 90-day death No difference 15.7% (<70 mg/dL) European Glucontrol* MICU (n = 1101) 80-110 versus 140-180 Hospital death ↑ Mortality trend 8.6% (<40 mg/dL) NICE-SUGAR MICU 81-108 versus <180 90-day death 14% ↑ Mortality 6.8% (<40 mg/dL) RandomizedTrials Comparing Normalization of Blood Glucose Concentration with Insulin Infusion, Compared with Standard of Care in aVariety of ICU Settings
  16. 16. NICE-SUGAR Normoglycemia in Intensive Care Evaluation Survival Using Glucose Algorithm Regulation 6104 patients ; 1/3 (surgical) and 2/3( medical) Only 20% had known diabetes Intensive-Rx Group Conventional Group Subjects received IV insulin 97% 69% Mean BG achieved 115 mg/dL. 144 mg/dL. Mortality rate at 90 days 27.5% 14% higher mortality rate OR 1.14 (85% CI, 0.4 to 4.8) 24.9% Severe hypoglycemia 6.8% 0.5% (P<0.001) (BG ≤40 mg/dL)
  17. 17. Steno-2 Study Multifactorial Intervention for Type 2 DM Gaede P, et al. N Engl J Med. 2008;358:580–591. Copyright © 2008 Massachusetts Medical Society. All rights reserved. 0 10 20 30 40 50 60 70 80 CumulativeIncidence CardiovascularEvent(%) Years of Follow-up 0 1 2 3 5 7 8 11 13 Intensive Therapy No. at Risk Intensive Therapy Conventional Therapy 80 80 72 70 65 60 61 46 56 38 50 29 47 25 31 14 4 6 9 1210 Conventional Therapy P<0.001 Lower risk of death from CV causes (HR 0.43; 95% CI, 0.19 to 0.94; P = 0.04) Lower CV events (HR, 0.41; 95% CI, 0.25 to 0.67; P<0.001) 160 patients …Rx for 7.8 Follow up 5.5 yrs Total 13.3 yrs
  18. 18. Aa Aa
  19. 19. Study Number of events (annual event rate, %) Difference in HbA1c (%) Favours intensive therapy Favours less intensive therapy Hazard ratio (95% CI) More intensive Less intensive ACCORD 198 (1.18) 245 (1.51) –1.01 0.77 (0.64, 0.93) ADVANCE 310 (1.18) 337 (1.28) –0.72 0.92 (0.79, 1.07) UKPDS 150 (1.20) 76 (1.40) –0.66 0.81 (0.62, 1.07) VADT 72 (16.5) 87 (1.99) –1.16 0.83 (0.61, 1.13) Overall 730 745 –0.88 0.85 (0.76, 0.94) Intensive glycaemic control may reduce risk of myocardial infarction Meta-analysis of ACCORD, ADVANCE, VADT and UKPDS suggests intensive glucose control reduces the risk of myocardial infarction by 15% Turnbull FR, et al. Diabetologia. 2009;52:2288–2298. 00.5 2.0
  20. 20. 21 Impact of Intensive vs Conventional Glycemic-Lowering Strategies on Risk of CV Outcomes Is Unclear Study Diabetes Duration (mean) Antihyperglycemic Medicationa Follow-up (median) HbA1c: Baseline, Between-arm Difference Microvascular CVD Mortality UKPDS1 Newly diagnosed SU/insulin or metformina vs dietary restriction 10 years 7.1% (all patients)b, –0.9%c ↓ ↔ ↔ UKPDS Long-term follow-up2 10 years post intervention No difference in HbA1c between treatment armsd ↓ ↓ ↓ ADVANCE3 8 years Intensive glucose control including gliclazide vs standard treatment 5 years 7.5% (both arms)b, –0.8%d ↓ ↔ ↔ ACCORD4 ,5 10 years Multiple drugs in both arms 3.4 years 8.1% (both arms)e, –1.1%c ↓ ↔ ↑ VADT6 11.5 years Multiple drugs in both arms 5.6 years 9.4% (both arms)b, –1.5%d ↔ ↔ ↔ aObese patients; bMean baseline HbA1c; cMedian between-arm difference; dMean between-arm difference; eMedian baseline HbA1c. CV = cardiovascular; UKPDS = United Kingdom Prospective Diabetes Study (UKPDS); ADVANCE = Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation; ACCORD = Action to Control Cardiovascular Risk in Diabetes; VADT = Veterans Affairs Diabetes Trial. 1. UKPDS Group. Lancet. 1998;352:837–853. 2. Holman RR et al. N Engl J Med. 2008;359:1577–1589. 3. ADVANCE Collaborative Group et al. N Engl J Med. 2008;358:2560–2572. 4. Gerstein HC et al. N Engl J Med. 2008;358:2545–2559. 5. Ismail-Beigi F et al. Lancet. 2010;376:419–430. 6. Duckworth W et al. N Engl J Med. 2009;360:129–139. Lowering HbA1c may prevent macrovascular disease if started early, but the effects may not be apparent for a very long time
  21. 21. The Look AHEAD Research Group > 5000 Patients
  22. 22. The Look AHEAD Research Group Stopped early on the basis of futility analysis at about 9.6 yrs (was scheduled for 13 + yrs )
  23. 23. Reductions in MI (15% Su/ InsulinVs 33% MFN) All-cause mortality (13% and 27%, respectively) N Engl J Med 2008;359:1577–1589
  24. 24. 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
  25. 25. Aim: the impact of the use different insulin secretagouges (ISs) on long-term major clinical outcomes (Mortality & CV risk) in type 2 diabetes. Method : 107,806 diabetic patients with or without MI (Danish residents)  Initiating single (IS) agent or Metformin  between 1997 and 2006 followed up for 9 years Schramm study
  26. 26. Schramm study Agent W/O prior MI W prior MI Glimepiride 1.32 (1.24-1.40) 1.30 (1.11-1.44) Glibenclamide 1.19 (1.11-1.28) 1.47 (1.22-1.76) Glipizide 1.27 (1.17-1.38) 1.53 (1.23-1.89) Tolbutamide 1.28 (1.17-1.39) 1.47 (1.17–1.84) Gliclazide 1.05 (0.94–1.16) 0.90 (0.68–1.20) Repaglinide 0.97 (0.81–1.15) 1.29 (0.86–1.94) Compared with Metformin (H.R/ 95% confidence intervals)
  27. 27. Schramm Study :Results Schramm study Conclusion Most used ISs, including Glimepiride, Glibenclamide, Glipizide, and Tolbutamide, seems to be associated with increased mortality and cardiovascular risk Metformin ,Gliclazide and Repaglinide appear to be asso. with a lower risk than other ISS
  28. 28. Cardiovascular safety of sulfonylureas: Meta-Analysis of randomized clinical trials. Diabetes Obes Metab. 2013 Oct;15(10):938-53. 115 selected trials Mortality was significantly increased with SUs (OR: 1.22 [1.01-1.49], p = 0.047) CONCLUSIONS SU .. increased mortality and a higher risk of stroke Safety of SU cannot be considered established unless it is evaluated in long-term CV outcomes trials.
  29. 29. Risk of acute coronary events associated with Glyburide Vs. Gliclazide use in patients with type 2 DM a nested case-control study. . Diabetes Obes Metab 2014 Jan;16(1):22-9. observational study , over 5.5 yrs > 21, 000 patients 4239 patients had an ACS-related admission / death (adjusted OR 1.14; 95% CI 1.06-1.23) (N.N.Harm: 50). CONCLUSION Glyburide Vs. Gliclazide a 14% higher risk of ACS events.
  30. 30. Aa Aa
  31. 31. Aa Aa
  32. 32. Secondary endpoints
  33. 33. SELECTED OUTCOMES TRIALS DPP-4 INHIBITORS
  34. 34. 39 Vildagliptin does not have an ongoing CV outcomes trial Linagliptin CARMELINA (N=8,300)4 Pre-existing CVD + albuminuria or impaired renal function End Jan 2018 Risk Factors Stable CAD-CVD-PAD Post ACS patients Sitagliptin TECOS (N=~14,000)3 Pre-existing CVD End Dec 2014 Alogliptin EXAMINE (N=5,380)1 ACS within 15–90 days Presented Sept 2013 Saxagliptin SAVOR-TIMI (N=16,492)2 Pre-existing CVD or multiple risk factors for CVD Presented Sept 2013 CV = cardiovascular; DPP-4 = dipeptidyl peptidase-4; CAD = coronary artery disease; CVD = cardiovascular disease; PAD = peripheral artery disease; ACS = acute coronary syndrome; ACS = acute coronary syndrome; EXAMINE = Examination of Cardiovascular Outcomes: Alogliptin vs Standard of Care in Patients With Type 2 Diabetes Mellitus and Acute Coronary Syndrome; SAVOR-TIMI = Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus Trial-Thrombolysis in Myocardial Infarction; TECOS = Trial Evaluating Cardiovascular Outcomes With Sitagliptin; CARMELINA = Cardiovascular and Renal Microvascular Outcome Study With Linagliptin in Patients With Type 2 Diabetes Mellitus at High Vascular Risk. 1. White W et al. N Engl J Med. 2013;369:1327–1335. 2. Scirica BM et al. N Engl J Med. 2013;369:1317–1326. 3. Green JB et al. Am Heart J 2013;166:983–989.e7. 4. CARMELINA: Cardiovascular and renal microvascular outcome study with linagliptin in patients with type 2 diabetes mellitus at high vascular risk. ClinicalTrials.gov web site. http://clinicaltrials.gov/ct2/show/ NCT01703298. Accessed September 12, 2014. Baseline Risk of Patient Populations Enrolled in CV Outcome Trials of DPP-4 Inhibitors
  35. 35. FOR INTERNAL USE No. at risk Placebo 2679 2299 1891 1375 805 286 Alogliptin 2701 2316 1899 1394 821 269 CI, confidence interval; CV, cardiovascular; CVD, CV disease; HR, hazard ratio; MI, myocardial infarction. †The primary endpoint occurred in 11.3% of alogliptin patients and 11.8% of placebo patients; HR = 0.96 (1-sided repeated CI bound, 1.16). Source: White WB, et al. N Engl J Med. 2013;369:1327–1335. Placebo 246 12 18 100 90 80 70 60 50 40 30 20 10 0 24 18 12 0 30 Months Cumulativeincidenceofprimary endpointevents(%) 6 0 0 6 12 18 24 30 Alogliptin HR = 0.96 (upper boundary of the 1-sided repeated CI, 1.16) EXAMINE: Alogliptin was non-inferior versus placebo for the composite primary endpoint†(death from CVD, non-fatal MI, non-fatal stroke)
  36. 36. 42 EXAMINE and SAVOR-TIMI: Primary Safety End Point (Composite of CV Death, Nonfatal MI, Nonfatal Stroke) SAVOR-TIMI2 Saxagliptin n=8,280 Placebo n=8,212 HR (95% CI) 1° Endpt 7.3% 7.2% 1.00 (0.89–1.12) EXAMINE1 Alogliptin n=2,701 Placebo n=2,679 HR (upper limit of 95% CI) 1° Endpt 11.3% 11.8% 0.96 (1.16) Alogliptin and saxagliptin were non-inferior for the primary composite end point1,2 CV = cardiovascular; MI = myocardial infarction; EXAMINE = Examination of Cardiovascular Outcomes: Alogliptin vs Standard of Care in Patients With Type 2 Diabetes Mellitus and Acute Coronary Syndrome; SAVOR-TIMI = Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus Trial-Thrombolysis in Myocardial Infarction; HR = hazard ratio; CI = confidence interval. 1. White WB et al. N Engl J Med. 2013;369:1327–1335; 2. Scirica BM et al. N Engl J Med. 2013;369:1317–1326.
  37. 37. 43 EXAMINE and SAVOR-TIMI: Hospitalization for Heart Failure SAVOR-TIMI3 Saxagliptin n=8,280 Placebo n=8,212 HR (95% CI) HHF 3.5% 2.8% 1.27 (1.07–1.51) EXAMINE1,2 Alogliptin n=2,701 Placebo n=2,679 HR (95% CI) HHFa 3.9% 3.3% 1.19 (0.89–1.58) SAVOR-TIMI: Hospitalization for HF was significantly increased with saxagliptin compared with placebo3 – Mortality due to HF was not significantly different between saxagliptin and placebo (0.5% for both)3 aPost-hoc analysis. EXAMINE = Examination of Cardiovascular Outcomes: Alogliptin vs Standard of Care in Patients With Type 2 Diabetes Mellitus and Acute Coronary Syndrome; SAVOR-TIMI = Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus Trial-Thrombolysis in Myocardial Infarction; HHF = hospitalization for heart failure; HR = hazard ratio; CI = confidence interval; HF = heart failure. 1. White WB et al. N Engl J Med 2013;369:1327–1335. 2. Sanon VP et al. Clin Diabetes. 2014;32:121–126. 3. Scirica BM et al. N Engl J Med 2013;369:1317–1326. EXAMINE: In a post-hoc analysis, there was a trend (P=NS) for increased hospitalization for HF with alogliptin compared with placebo2
  38. 38. 44 TECOS: Analysis1  Primary outcome analysis is designed to demonstrate noninferiority of usual care with sitagliptin vs usual care without sitagliptin for the primary composite end point of time from randomization to the first adjudicated CV-related death, nonfatal MI, nonfatal stroke, or unstable angina requiring hospitalization – If sitagliptin is found noninferior to placebo, an assessment of superiority will be performed  Median follow-up of up to 4 years is anticipated – Study achieved 1,300 confirmed CV events TECOS = Trial Evaluating Cardiovascular Outcomes With Sitagliptin; CV = cardiovascular; MI = myocardial infarction. 1. Green JB et al. Am Heart J. 2013;166:983–989.e7.
  39. 39. FOR INTERNAL USE TECOS: Study design + Standard of care for Type 2 Diabetes N = 14,724; expected median follow-up ~ 4 years Main inclusion criteria 1. Patients aged ≥ 50 years with Type 2 Diabetes 2. HbA1c 6.5–8.0% receiving stable oral glucose-lowering therapy* and/or insulin 3. Cardiovascular disease Primary endpoint: time to first occurrence of 1 of the following: 1. CV-related death 2. Unstable angina requiring hospitalisation 3. Non-fatal stroke 4. Non-fatal MI PlaceboSitagliptin 100 mg daily versus *Monotherapy or dual combination therapy with metformin, pioglitazone or a sulphonylurea; or insulin monotherapy or in combination with metformin for  3 months prior to enrolment. Regulatory requirement for recruitment of ≥ 2000 patients receiving metformin monotherapy at baseline Source: Green JB, et al. Am Heart J. 2013;166:983–989; Bethel MA, et al. IDF Congress 2013. Poster P-700; ClinicalTrials.gov NCT00790205.
  40. 40. 46 TECOS: Secondary and Other Prespecified Outcomes1  Secondary outcomes – Composite end point of time to first adjudicateda confirmed CV-related death, nonfatal MI, nonfatal stroke – Time to the occurrence of the individual components of the primary end point – Time to all-cause mortality – Time to hospital admission for adjudicated congestive heart failure  Other prespecified outcomes include: – Changes from baseline in urinary albumin:creatinine ratio, eGFR, HbA1c, body weight – Time to initiation of additional antihyperglycemic medications and/or initiation of chronic insulin – Counts of outpatient visits and hospitalizations aCV events will be adjudicated by an independent committee, blinded to study therapy. TECOS = Trial Evaluating Cardiovascular Outcomes With Sitagliptin; CV = cardiovascular; MI = myocardial infarction; eGFR = estimated glomerular filtration rate. 1. Green JB et al. Am Heart J. 2013;166:983–989.e7.
  41. 41. 47 TECOS The Good News  Objectives achieved  No excess CV Risk  No higher risk of congestive heart failure Assuring …. It is not a class effect
  42. 42. 48 Linagliptin Outcome Trial Programme Comparator PlaceboGlimepiride Endpoint measures 1. Change from baseline in HbA1c at Week 24 2. Time weighted average of percentage change from baseline in UACR at Week 24 Time to first occurrence of primary CV composite endpoint* Population T2DM patients with albuminuria on ACEi or ARB T2DM patients at high CV risk Trial type EfficacyCV outcome *CV composite endpoint: CV death (including fatal stroke and fatal MI); nonfatal MI; nonfatal stroke; hospitalization for unstable angina pectoris. **Renal composite endpoint: renal death; sustained ESRD; sustained decrease of ≥ 50% eGFR. Source: 1. ClinicalTrials.gov CT01897532; 2. ClinicalTrials.gov NCT01243424; 3. ClinicalTrials.gov NCT01792518. 1 2 3 Placebo 1. Time to first occurrence of primary CV composite endpoint* 2. Time to first occurrence of renal composite endpoint** T2DM patients with vascular complications and albuminuria or renal-related end- organ damage CV and renal microvascular outcome
  43. 43. The Legacy Effect …The Earlier …The Better
  44. 44. 51 Impact of Intensive vs Conventional Glycemic-Lowering Strategies on Risk of CV Outcomes Is Unclear Study Diabetes Duration (mean) Antihyperglycemic Medicationa Follow-up (median) HbA1c: Baseline, Between-arm Difference Microvascular CVD Mortality UKPDS1 Newly diagnosed SU/insulin or metformina vs dietary restriction 10 years 7.1% (all patients)b, –0.9%c ↓ ↔ ↔ UKPDS Long-term follow-up2 10 years post intervention No difference in HbA1c between treatment armsd ↓ ↓ ↓ ADVANCE3 8 years Intensive glucose control including gliclazide vs standard treatment 5 years 7.5% (both arms)b, –0.8%d ↓ ↔ ↔ ACCORD4 ,5 10 years Multiple drugs in both arms 3.4 years 8.1% (both arms)e, –1.1%c ↓ ↔ ↑ VADT6 11.5 years Multiple drugs in both arms 5.6 years 9.4% (both arms)b, –1.5%d ↔ ↔ ↔ aObese patients; bMean baseline HbA1c; cMedian between-arm difference; dMean between-arm difference; eMedian baseline HbA1c. CV = cardiovascular; UKPDS = United Kingdom Prospective Diabetes Study (UKPDS); ADVANCE = Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation; ACCORD = Action to Control Cardiovascular Risk in Diabetes; VADT = Veterans Affairs Diabetes Trial. 1. UKPDS Group. Lancet. 1998;352:837–853. 2. Holman RR et al. N Engl J Med. 2008;359:1577–1589. 3. ADVANCE Collaborative Group et al. N Engl J Med. 2008;358:2560–2572. 4. Gerstein HC et al. N Engl J Med. 2008;358:2545–2559. 5. Ismail-Beigi F et al. Lancet. 2010;376:419–430. 6. Duckworth W et al. N Engl J Med. 2009;360:129–139. Lowering HbA1c may prevent macrovascular disease if started early, but the effects may not be apparent for a very long time
  45. 45. VADT Mortality correlated well with Duration of DM at study enrollment. Diabetes duration less than 15 years = Mortality benefit (Vs. Diabetes duration of ≥20 years ) DuckworthWC, Abraira C, MoritzTE, et al.; Investigators of theVADT.The duration ofdiabetes affects the response to intensive glucose control in type 2 subjects: theVA DiabetesTrial. J DiabetesComplications 2011;25:355–361
  46. 46. Conclusions  “Gluco -centric” approach targeting (HbA1C ) doesn’t tell the whole story Reducing CV risk in DM patients = Aggressive management of the standard CV risk factors rather than intensive glycemic control alone Apply the ABCs
  47. 47.  Uncontrolled DM correlates well with both macro-vascular ( MI , HF , CVA & PAD and -associated mortality) and micro-vascular diseases and outcomes  The impact of DM medications on HbA1c may not reflect the full effect on overall risk of CV events  Strict control has less robust impact on macro-vascular (Vs. microvascular) outcomes  It takes longer duration of strict control to cash out significant macro-vascular benefits …but with legacy effect

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