Diabetes Mellitus: Implications of New Clinical Trials and New Medications

Transcription

1 Diabetes Mellitus: Implications of New Clinical Trials and New Medications Estimates of Diagnosed Diabetes in Adults, 2005 Alka M. Kanaya, MD Asst. Professor of Medicine UCSF, Primary Care CME October 30, 2008 CDC, 2005 Roadmap CHD Risk Factors 1. Glycemic control Cardiovascular/mortality outcomes Microvascular outcomes Critically ill patients 2. Diabetes Medications 3. Other treatment targets Lipid goals BP goals Multifactorial Intervention for diabetes Kannel,

2 Life Expectancy Case 1 Life Expectancy, years Men: -7.5 years Women: -8.2 years CVD No CVD Ms. EH is a 68 y.o. woman with type 2 diabetes, hypertension, and coronary heart disease (s/p MI in 2002). Meds: Metformin, glipizide, aspirin, lisinopril, metoprolol, and simvastatin Exam: BP 145/89, HR 72, BMI 29 kg/m 2 Normal heart, lungs, extremities 0 No DM DM No DM DM MEN WOMEN Arch Int Med, 2007 Question ADA Position Statement What should her glycemic goal be? A.HbA1c <6.0% B.HbA1c <6.5% C.HbA1c <7.0% D.HbA1c <7.5% A level: A1c~7.0% reduces microvascular and neuropathic complications; Goal A1c < 7.0% B level: A1c goal to normal level (<6%) E level: less stringent goals appropriate for some (very young, very old, limited life-expectancy, multiple comorbidities, long-term DM with minimum microvascular complications) Diabetes Care, Jan

3 Glycemic control and CVD 3 new trials ADVANCE ACCORD VA Diabetes Trial Older studies (UKPDS, VA, UGDP) Ongoing studies ADVANCE trial 11,140 type 2 diabetes patients Intervention: standard vs. intensive control (A1c 6.5%) Gliclazide-based regimen for intensive group Outcomes: composite macrovascular and/or major microvascular events 5 years of f/u NEJM, 2008 Outcomes Outcomes Intensive n=5,571 Standard n=5,569 HR (95% CI) Intensive n=5,571 Standard n=5,569 HR (95% CI) A1c achieved: 6.5% 7.3% A1c achieved: 6.5% 7.3% Combined: 18.1% 20.0% 0.90 ( ) Combined: 18.1% 20.0% 0.90 ( ) Macrovascular: CVD death Total mortality 10.0% 4.5% 8.9% 10.6% 5.2% 9.6% 0.94 ( ) 0.88 ( ) 0.93 ( ) Macrovascular: CVD death Total mortality 10.0% 4.5% 8.9% 10.6% 5.2% 9.6% 0.94 ( ) 0.88 ( ) 0.93 ( ) Microvascular: Nephropathy 9.4% 4.1% 10.9% 5.2% 0.86 ( ) 0.79 ( ) Microvascular Nephropathy 9.4% 4.1% 10.9% 5.2% 0.86 ( ) 0.79 ( ) Hypoglycemia: 2.7% 1.5% 1.86 ( ) Hypoglycemia: 2.7% 1.5% 1.86 ( ) NEJM, 2008 NEJM,

4 Combined Events p=0.01 Microvascular Events p=0.01 Macrovascular Events p=0.32 Total Mortality p=0.28 ACCORD trial 10,251 patients with T2DM, mean A1c 8.1% Patients had known CVD or CVD risk factors Goal A1c <6.0% intensive vs std group 1 outcome: CVE; 2 : microvascular, QOL, Lipids: Fenofibrate Placebo Glucose control Hba1c<6 Hba1c Glucose control Hba1c<6 Hba1c SBP 120 SBP 140 n=5,518 n=4,733 ACCORD trial Intensive therapy arm halted at 3.5 years due to higher mortality Prior CVD A1c base Primary Outcome subgroups: A1c achieved: Intensive n=5, % Standard n=5, % HR (95% CI) - Mortality Subgroups: 1 outcome: ( ) Total mortality 5.0% 3.1% 1.22 ( ) CVD mortality 2.6% 1.8% 1.35 ( ) Hypoglycemia 10.5% 3.5% - Wt. gain>10 kg 27.8% 14.1% - NEJM,

5 Differences between ACCORD and ADVANCE Differences between ACCORD and ADVANCE ACCORD ADVANCE ACCORD ADVANCE Mean age Mean age Duration DM 10 8 Duration DM 10 8 Target A1c < Target A1c < Statin use in trial 88 vs vs. 48 Statin use in trial 88 vs vs. 48 TZD use in trial 92 vs vs. 11 TZD use in trial 92 vs vs. 11 ASA use in trial 76 vs vs. 55 ASA use in trial 76 vs vs. 55 Death (any cause) 5.0 vs vs. 9.6 Death (any cause) 5.0 vs vs. 9.6 Weight gain in trial (kg) 3.5 vs vs Weight gain in trial (kg) 3.5 vs vs Major hypoglycemia 3.1 vs vs. 0.4 Major hypoglycemia 3.1 vs vs. 0.4 Dluhy, NEJM, 2008 Dluhy, NEJM, 2008 VA Diabetes Trial VADT: HbA1c achieved 20 VA centers; n=1,791; started in 2000 Intervention: intensive glycemic Rx (goal A1c<6.0%) vs. improved treatment (goal A1c 8-9.0%) A1c separation goal of 1.5% Protocol-based intervention (metformin, rosiglitazone, glimepiride, then insulin) BP and lipid treatment goals equal Outcomes: CV events (CV deaths, MI, CVA, CHF, cardiac revascularization, ischemic amputation) Abraira, DM, Obes, Met, % 6.9% Abraira,

6 Results No significant reduction in CVD with intensive glycemic control (HR 0.87, , p=0.12) Subgroups: Advanced subclinical disease: CAC 100: no benefit CAC<100: benefit from intensive control Duration of diabetes: shortest time period had the most benefit years had neutral effect >16 years had increased risk of CV events ADA meeting, 2008 Study UKPDS-33 Older Trials N Intervention Outcome 3,867 Diet, Chlorpropramide, Glibenclamide, Insulin UKPDS Metformin vs. diet VA-CSDM 153 Insulin Std. vs. intensive UGDP 823 Insulin vs. Tolbutamide vs. Placebo 16% RRR MI (NS) (p=0.054) 39% RRR MI 30% RRR agg. 1.6x increased risk (NS) 2x increased risk with Tol. HbA1c (%) Type 1 Diabetes and CVD Glucose Lowering to Prevent CVD Ongoing Trials in People with Dysglycemia Yrs from Diagnosis ACCORD NAVIGATOR VADT ACE ADVANCE Cum. Incid. NFMI, CVA, CVD High IFG &/or IGT ORIGIN HEART 2D RECORD BARI 2D Eye, Kidney, Nerve Disease CVD Type 2 Diabetes (T2DM) NEJM, 1993; Jama, 2002; NEJM, 2005 Dysglycemia Gerstein,

7 Microvascular Complications Type 1: reduced complications Study N A1c Achieved UKPDS 3, vs. 7.9% Ohkubo vs. 9.4% RRR 25% microvasc. 2% ARR, NNT=50 83% retinopathy 24% ARR, NNT=4 Kawamori vs. 11% retinopathy & microalbuminuria Lebovitz, 2008 Critically Ill patients? Meta-analysis of 29 RCTs (n=8,432 patients) Overall Very tight, 110 mg/dl Moderate, <150 mg/dl Medical ICU Surgical ICU Med-Surg ICU Mortality Rates Tight Usual 21.6% 23.3% 23.0% 25.2% 17.3% 18.0% 26.9% 29.7% 8.8% 10.8% 26.1% 27.0% RR (95% CI) 0.93 ( ) 0.90 ( ) 0.99 ( ) 0.92 ( ) 0.88 ( ) 0.95 ( ) Wiener, Jama,

8 Subgroups Wiener, Jama, 2008 Glycemic Control Summary No consistent evidence that tight glycemic control reduces risk of CVD Possible subgroups with benefit: shorter diabetes duration less CAC (no prior CVD) Strong evidence to support decrease in microvascular disease outcomes with more intensive glucose control More hypoglycemia and weight gain with most intensive regimens No consistent evidence that tight glucose control improves mortality in hospitalized patients. Case 1 Question 1 Ms. EH is a 68 y.o. woman with type 2 diabetes, hypertension, and coronary heart disease (s/p MI in 2002). Meds: Metformin, glipizide, aspirin, lisinopril, metoprolol, and simvastatin Exam: BP 145/89, HR 72, BMI 29 kg/m 2 Normal heart, lungs, extremities What should her glycemic goal be? A.HbA1c <6.0% B.HbA1c <6.5% C.HbA1c <7.0% D.HbA1c <7.5% 8

9 Diabetes Medications Category Sulfonylurea Biguanides α Glucosidase inhibitors Thiazolidenediones Meglitinides DPP-4 inhibitors Incretin mimetics Antihyperglycemic synthetic analogs Action Stimulates insulin secretion hepatic glucose production Delay conversion of CHO to glucose in digestion Insulin sensitizers (muscle/fat) Stimulates insulin production Blocks enzyme that deactivates GLP-1 Stimulates insulin; slows digestion (GLP-1 agonists) Analog of amylin hormone Safety Issues with all Classes SU: hypoglycemia, weight gain, increased CVD mortality? Metformin: GI symptoms, lactic acidosis (with impaired renal function) TZD: CHF, edema, weight gain, fractures, increased CVD mortality? DPP-4 inhibitors: HA, URI, nasopharyngitis Incretin mimetics: N/V, acute pancreatitis? Insulin: weight gain, severe hypoglycemia TZD and CHD MA of 42 trials of rosiglitazone vs. other MI: OR 1.43 ( ), p=0.03 CVD death: OR 1.64 ( ), p=0.06 Nissen, NEJM,

10 What about Pioglitazone? PRO-active trial: 5,238 DM with macrovascular disease Pio vs. placebo Primary endpoint: HR 0.90, 95% CI , p=0.095 Composite endpoint: HR 0.84, , p=0.027 CHICAGO trial: effect of Pioglitazone vs. glimepiride on CIMT Less change in CIMT in pio group ( mm difference between groups), p<0.02 PERISCOPE trial: 543 patients with DM and CHD Pio vs. glimepiride for 18 months on IVUS 0.16% in Pio vs. 0.73% in glim. (p=0.002) Normal weight Medication Strategy Lifestyle + insulin secretagogue + Metformin Or + TZD Or + DPP-4 inhibitor First Level of Treatment Second Level of Treatment Third Level of Treatment Insulin or Incretin mimetic Overweight/obese Lifestyle + metformin + DPP-4 inhibitor Or + insulin secretagogue Or + TZD Lebovitz, CEU, 2007 Roadmap 1. Glycemic control Cardiovascular/mortality outcomes Microvascular outcomes Critically ill patients 2. Diabetes Medications 3. Other treatment targets Lipid goals BP goals Multifactorial Intervention for diabetes Case 1 Ms. EH is a 68 y.o. woman with type 2 diabetes, hypertension, and coronary heart disease (s/p MI in 2002). Meds: Metformin, glipizide, aspirin, lisinopril, metoprolol, and simvastatin Exam: BP 145/89, HR 72, BMI 29 kg/m 2 Normal heart, lungs, extremities Labs: HbA1c: 7.5% Total Chol 166; TG:105; HDL 32; LDL

11 Question 2 Would you make any changes to her lipid control? A. Increase her statin dose B. Add a fibrate C. Add niacin D. No change now Lipid Goals LDL <100 mg/dl (without overt CVD) LDL <70 mg/dl is an option (overt CVD) Secondary goals: HDL>40 (men), >50 mg/dl (women) Triglycerides < 150 mg/dl ADA, 2008 Question 3 Would you make any changes to her blood pressure regimen? BP 145/89 mmhg BP Meds: Lisinopril + Metoprolol A. Increase one of her meds B. Add another BP med C. No change now Blood Pressure Goals Systolic BP < 130 mmhg (grade C) Diastolic BP < 80 mmhg (grade B) Pharmacologic therapy should include either an ACEI or ARB 11

12 Steno 2: Multifactorial Intervention Steno 2: 13 year follow-up Gaede, NEJM, 2003 Gaede, NEJM, 2008 Steno 2: 13- year outcomes Total Mortality Any Cardiovascular Event Gaede, NEJM, 2008 Gaede, NEJM,

13 12-year Outcomes Time Course Effectiveness? Gaede, NEJM, 2008 Lebovitz, 2008 Conclusions Tight glycemic control not effective in lowering CHD or CVD outcomes. Many newer diabetes agents available, all with some side effects few with hard outcome data Glucose control may be more important early in diabetes Good BP and lipid control is important throughout the diabetes life course 13