Rationale for ADA Treatment Guidelines for CVD Prevention. Robert E. Ratner, MD American Diabetes Association

Transcription

1 Rationale for ADA Treatment Guidelines for CVD Prevention Robert E. Ratner, MD American Diabetes Association 1

2 No Financial Disclosures 2

3 Trends in age-standardized rates of diabetes-related complications among U.S. adults with diabetes, Gregg et al. N Engl J Med 370: , 2014

4 The ability to show a difference in a clinical trial depends upon: The Hazard Rate of the outcome The Effect Size of the intervention The Exposure to the intervention The Confounding therapies provided to the participants 6

5 UKPDS Myocardial Infarction Fatal or Non-fatal MI, Sudden Death 573 of 3867 Patients (15%) % of Patients With an Event Conventional Intensive Risk Reduction 16% (0%-29%) P= Years From Randomization UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352(9131):

6 STENO-2 - Composite Cardiovascular Endpoint Cumulative Incidence of any Cardiovascular event (%) p < Conventional therapy Intensive therapy 0 Gaede P, et al. N Engl J Med 2008;358: No. at risk Follow-up time (years) Intensive Conventional

7 Myocardial Infarction Hazard Ratio (fatal or non-fatal MI or sudden death) Intensive (SU/Ins) vs Conventional Glucose Control MI HR=0.84 p=0.052 HR=0.85 p= HR (95%CI) HR Number of Events Con: Int: UKPDS 80. N Eng J Med 2008;359:

8 UKPDS - Intensive Therapy Significantly Reduced the Incidence of Myocardial Infarction 1.0 Proportion with event P=0.01 Risk reduction 15% (3-26%) p=0.014 Conventional therapy Intensive Years since randomization No. at risk Conventional Intensive UKPDS 80. N Eng J Med 2008;359:

9 DCCT/EDIC: Cumulative Incidence of the First of Any of the Predefined CVD Outcomes Cumulative Incidence of Any Predefined CV Outcome No. at Risk Risk reduction 42% 95% CI: 9 63 Log-rank P=0.016 Years Since Entry Conventional Treatment Intensive Treatment Intensive Conventional Nathan DM, et al. N Engl J Med. 2005;353(25); Copyright 2005 Massachusetts Medical Society.

10 2014 ADA Treatment Recommendations for Glycemic Control Lowering A1c to below or around 7% has been shown to reduce microvascular complication of diabetes and, if implemented soon after the diagnosis of diabetes, is associated with long term reduction in macrovascular disease. Therefore a reasonable goal for many nonpregnant adults is < 7% (B) More stringent A1c goals (< 6.5%) if this can be achieved without significant hypoglycemia or adverse effects. (C) Less stringent goals (>8%) may be appropriate for patients with severe hypoglycemia, comorbidities, etc. (B) Standards of Medical Care in Diabetes Diabetes Care 37 (Suppl 1): S14-S

11 ACCORD: Treatment Effect on Primary Outcome Non-fatal MI, Non-fatal Stroke, CVD Death 25 Patients with Events (%) HR 0.90 ( ) p=0.16 Standard therapy Intensive therapy 2.29%/yr 2.11%/yr Time (Years) MI = myocardial infarction ACCORD Study Group. N Engl J Med 2008;358:

12 ACCORD: Treatment Effect on All-Cause Mortality 25 Patients with Events (%) HR 1.22 ( ) P=0.04 Intensive Therapy Standard Therapy %/yr 1.14%/yr Time (Years) HR = hazard ratio Gerstein HC, et al. N Engl J Med. 2008;358(24): Copyright 2008 Massachusetts Medical Society.

13 Risk of Death Over a Range of Average A1c Adjusted log (HR) by Treatment Strategy Relative to standard at A1c of 6% Steady increase of risk from 6% to 9% A1c with intensive strategy 1 Intensive strategy 0 1 Standard strategy Average A1c % Excess risk with intensive strategy vs standard occurred above A1c 7% Riddle MC, et al. Diabetes Care. 2010;33(5): Copyright 2010 by the American Diabetes Association.

14 Mortality HRs for Post-Randomization Prescription of Glycemia Medications (Adjusted for Baseline Participant Characteristics) HR Decreased Risk Increased Risk

15 ADVANCE: Treatment Effect on Primary Macrovascular Outcome Non-fatal MI, Non-fatal Stroke, CVD Death 25 Cumulative Incidence (%) HR 0.94 ( ) p= Standard control Intensive control Follow-up (Months) ADVANCE Collaborative Group. N Engl J Med 2008;358:

16 VADT Primary Outcome Non-fatal MI, Non-fatal Stroke, CVD Death, Hospitalisation for CHF, Revascularisation Proportion Free of Primary Outcome HR 0.88 ( ) p=0.14 Intensive Standard Follow-up Time (Years) VADT Study Group. N Engl J Med 2009;360:129 39

17 Comparison of Studies Standard Group Event Rates ACCORD ADVANCE VADT Primary Outcome Macrovascular Outcome Primary Outcome Predicted 2.9% per yr 3.0% per yr 6.7% per yr Observed 2.3% per yr 2.2% per yr 5.6% per yr % Reduction 21% 27% 16%

18 Effect of Intensive Glucose Lowering on Macrovascular Complications in T2DM Primary outcome HR for primary outcome (95% CI) HR for mortality (95% CI) ACCORD ADVANCE VADT Non-fatal MI Non-fatal stroke CVD death Non-fatal MI Non-fatal stroke CVD death Non-fatal MI Non-fatal stroke CVD death Hospitalization for CHF Revascularization 0.90 ( ) 0.94 ( ) 0.87 ( ) 1.22 ( )* 0.93 ( ) ( ) *p=0.04 VADT = Veterans Affairs Diabetes Trial ADVANCE Collaborative Group. N Engl J Med 2008;358: ACCORD Study Group. N Engl J Med 2008;358: VADT Study Group. N Engl J Med 2009;360:129 39

19 Effect of more vs less intensive control of glucose on CHD Study Odds Ratio (95% CI) Weight (%) UKPDS PROactive* ADVANCE VADT ACCORD Overall I-squared = 0% (95% CI 0% to 53%), p = (0.54, 1.04) 0.81 (0.65, 1.00) 0.92 (0.78, 1.07) 0.85 (0.62, 1.17) 0.82 (0.68, 0.99) 0.85 (0.77, 0.93) Odds Ratio Intensive therapy better Standard therapy better Ray KK, et al. Lancet. 2009;373:

20 Effect of more vs less intensive control of glucose on NF-MI Study Odds Ratio (95% CI) Weight (%) UKPDS PROactive ADVANCE VADT ACCORD Overall I-squared = 0% (95% CI 0% to 69.3%), p = (0.62, 0.98) 0.83 (0.64, 1.06) 0.98 (0.78, 1.23) 0.81 (0.58, 1.15) 0.78 (0.64, 0.95) 0.83 (0.75, 0.93) Odds Ratio Intensive therapy better Standard therapy better Ray KK, et al. Lancet. 2009;373:

21 Why Can t We Prove Glycemic Control Reduces CVD? Absolute Risk of CVD events is falling, therefore We need large numbers of subjects We need to follow them for a long period of time, and therapies change We start too late in the course of disease We don t have the appropriate therapies, yet!

22 FDA Regulatory Requirements for CV Safety in Type 2 DM CV Outcome Trials Primary Endpoints Agent Trial Patient Population CV Death Saxagliptin SAVOR-TIMI 53 CVD and/or Risk Factors A 1C 6.5%, n=16,500 MI Stroke Alogliptin EXAMINE ACS, A 1C %, n=5,400 Sitagliptin TECOS Pre-existing CVD, A 1C 6.5 8%, n=14,000 Linagliptin CAROLINA CVD or End-organ Damage or RFs A 1C %, n=6,000 Linagliptin CARMELINA CVD+Albuminuria; Renal Dysfunction A 1C %, n=8,300 Liraglutide LEADER CVD Risk or Age/RFs, A 1C 7%, n=9,341 UA Hospitalization Lixisenatide ELIXA ACS, A 1C % n=6,000 Dulaglutide REWIND High CV Risk, A 1C 9.5%, n=9,622 Exenatide ER EXSCEL A 1C % and CV Risk n=9,500 Canagliflozin CANVAS High CV Risk, A 1C %, n=4,385 Dapagliflozin DECLARE-TIMI 58 High CV Risk, n=17,150 Empagliflozin EMPA-REG OUTCOME Pre-existing CVD n=7,000

23 2014 ADA Treatment Recommendations for Blood Pressure People with diabetes and hypertension should be treated to a blood pressure target of < 140/80. (Evidence level B) Lower systolic targets, such as < 130, may be appropriate for certain individuals (C) Standards of Medical Care in Diabetes Diabetes Care 37 (Suppl 1): S14-S

24 Major outcomes of the HOT trial Events/1000 patient-yrs Diabetes subgroup 18.8 P < Major CV events Goal of therapy: Target diastolic pressure < 90 mmhg (n = 501) 85 mmhg (n = 501) 80 mmhg (n = 499) Achieved < mm Hg mm Hg mm Hg Hansson L, et al. Lancet. 1998;351:

25 ACCORD: Systolic Pressures (Mean + 95% CI) Mean # Meds Intensive: Standard: SBP (mm Hg) Average : Standard vs Intensive, Delta = N = Years Post-Randomization ACCORD Study Group. Intensive N Engl J Med Standard 2010; On-Line March 14

26 Effects of Intensive Blood Pressure Control on CV Events in Type 2 Diabetes in ACCORD Patients with Events (%) Primary Outcome Nonfatal MI, Nonfatal Stroke or CVD Death HR = % CI ( ) Patients with Events (%) Total Mortality HR = % CI ( ) Years Post-Randomization Years Post-Randomization ACCORD Study Group. N Engl J Med 2010; On-Line March 14

27 2014 ADA Treatment Recommendations for Lipids Statin therapy should be added to lifestyle therapy, regardless of baseline lipid levels for people with diabetes: With overt CVD (A) > 40 years with > 1 risk factor for CVD (A) Lower risk patients with LDL-c > 100mg/dl (C) In overt CVD, the goal is LDL-c < 100mg/dl, but < 70mg/dl with a high dose statin is an option (B) Standards of Medical Care in Diabetes Diabetes Care 37 (Suppl 1): S14-S

28 2014 ADA Treatment Recommendations for Lipids Triglyceride levels < 150 mg/dl and HDL-c > 40 in men, and > 50 in women are desireable (C) LDL-c targeted statin therapy remains the preferred strategy (A) Combination therapy has been shown not to provide additional CVD benefit above statin therapy alone and is not generally recommended (A) Standards of Medical Care in Diabetes Diabetes Care 37 (Suppl 1): S14-S

29 Effects of Combination Lipid Therapy on CV Events in Type 2 Diabetes in ACCORD Primary Outcome Nonfatal MI, Nonfatal Stroke or CVD Death Total Mortality Patients with Events (%) HR = % CI ( ) p = 0.32 Patients with Events (%) HR = % CI ( ) p = Years Post-Randomization Years Post-Randomization Placebo Fenofibrate ACCORD Study Group. N Engl J Med 2010; On-Line March 14

30 Ray KK, et al. Lancet. 2009;373: Benefit of different interventions per 200 diabetic pts treated for 5 years Per 4mmHg lower SBP Per 1mmol/L lower LDL-C Per 0.9% lower HbA1c