Risk Factors for CVD in Type 1 Diabetes Marian Rewers, MD, PhD Professor & Clinical Director, BDC
Duality of Interest Declaration I have no conflict of interest in the field covered by my lecture but I d rather be there today
Type 1 diabetes = a disease of adults 1.4 million of adults with T1D in the U.S. 150,000 Number of patients, 2005 125,000 100,000 75,000 50,000 25,000 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 Age [yrs]
Survival among T1 D patients is improving Allegheny County IDDM Registry 1965-1999 1 0.9 0.8 0.7 0.6 General Population SMR =100 1975-79 SMR =235 1970-74 SMR =367 1965-69 SMR =497 0.5 0 5 10 15 20 25 30 35 Nishmura R, et al. Diabetes Care 2001 Duration of diabetes (yrs)
The incidence of microvascular complications in T1D is declining Steno Clinic, Denmark, 600 Patients diagnosed 1965-84 Proliferative diabetic retinopathy 1965-69 1961-65 Diabetic nephropathy 1965-69 40 1970-74 1966-70 1970-74 30 1975-79 1975-79 1971-75 20 1971-75 1966-70 1980-84 1980-84 10 1976-80 1976-80 Hovind P, et al. Diabetes Care 2003
The incidence of coronary artery disease in T1D is increasing 684 Patients diagnosed 1950-1980 100 % 90 80 1960-69 1950-59 70 60 1970-80 50 40 30 20 10 0 20 yrs` 25 yrs 30 yrs 35 yrs 40 yrs 45 yrs 50 yrs Orchard T, Pittsburgh EDC Study Diabetes duration
Incidence of CAD /100 p-yr 4 Coronary Artery Disease in T1D EDC T1D Patients vs. General Population 3 DM Men 2 DM Women 1 non-dm Men 0 20-29 30-39 40-49 50+ Age non-dm Women
Summary 1 Vast majority of the U.S. T1D patients are middle-aged Survival has improved, due to prevention of acute complications and nephropathy CAD is the leading cause of death in people with T1D and poorly responds to prevention efforts Women with T1D have 10-30 times higher risk of CAD, and men have 4-10 times higher risk, compared to the general population.
Standards of Medical Care, ADA 2010 Non-pregnant adults (T1D and T2D) A1c: <7% (eag <154 mg/dl) pre-prandial BG 70-130 mg/dl post-prandial peak BG <180 mg/dl avoid severe hypoglycemia BP: 130/80 mm/hg antihypertensives if micro-/macroalbuminuria LDL-Ch: <100 mg/dl (non-hdl-ch<130, apob<90) TG <150 mg/dl, HDL-ch >40(M) >50(F) No smoking BMI <25 Aspirin M>50, F>60 and high risk CVD
Standards of Medical Care, ADA 2010 Adults with T1D A1c: <7% (eag <154 mg/dl) pre-prandial BG 70-130 mg/dl post-prandial peak BG <180 mg/dl avoid severe hypoglycemia BP: 130/80 mm/hg antihypertensives if micro-/macroalbuminuria LDL-Ch: <100 mg/dl (non-hdl-ch<130, apob<90) TG <150 mg/dl, HDL-ch >40(M) >50(F) No smoking BMI <25 Aspirin M>50, F>60 and high risk CVD
<10% of T1D patients meet the ABC goals: A1c<7%, LDL<100 mg/dl, BP<130/80 CACTI, N=652 age 20-55, duration 23 ± 8 yr % P=0.001 Snell-Bergeon J et al 2011
% 6-yr cumulative incidence [%] Meeting the ADA ABC goals helps to prevent microvascular complications: CACTI, N=459 age 20-55, duration 23 ± 8 yr 100 90 80 70 60 50 40 30 20 10 0 p<0.0001 p=0.008 p=0.032 p=0.009 DN DR PDR Neuropathy Met all goals Met some goals Met no goals Snell-Bergeon J et al 2011 A1c<7%, LDL<100 mg/dl, BP<130/80
Figure 2. Compliance CACTI, N=459 with age ADA 20-55, Goals duration and CAC 23 Progression ± 8 yr in T1D CAC progresses regardless of meeting the ADA goals: % CAC progressed in 6 yrs Snell-Bergeon J et al 2011 A1c<7%, LDL<100 mg/dl, BP<130/80
Angiography & IVUS EBT CAC Increased calcium in the LAD and CFX Each magnified image demonstrates focal regions of LAD intimal artery architecture viewed by IVUS.
CAC strongly predicts future coronary events in asymptomatic subjects OR=2.1 (1.6-2.9) OR=5.4 (2.2-13) OR=10.0 (3.1-34) Pletcher MJ, Arch Intern Med 2004
Summary 2 Few T1D patients meet the ADA ABC goals those who do, lower their risk of microvascular disease, but remain at high risk of CVD We need to find additional important risk factors and interventions Non-invasive monitoring of progression of subclinical CVD and effects of treatment will help
Risk factors for CVD in T1D
Non-modifiable predictors of CVD in T1D Age Duration of diabetes Male gender (less than in the general population) Lack of residual insulin secretion Genetic markers, e.g.: family history of MI in parents apolipoprotein A-IV Gln360His hepatic lipase (LIPC-480C>T) ACE I/D, angiotensin type 1 receptor (1166A), angiotensinogen (235M>T) VDR Matrix metalloproteinase-3 (MMP3-5A/6A)
Hypertension Renal dysfunction Risk factors for CVD in T1D tubular markers, MA, GFR
Independent Baseline Predictors of CAD Events Both Sexes, Cox PH Model Orchard TJ. EDC 2004 Type of CAD Variables HR (95% CI) p Total CAD Duration 2.18 (1.74-2.73) <0.001 Hypertension 2.16 (1.40-3.32) <0.001 WBC 1.35 (1.11-1.59) 0.002 HDLc 0.72 (0.58-0.91) 0.005 non-hdlc 1.33 (1.08-1.59) 0.007 Ever Smoke 1.58 (1.05-2.38) 0.028 HR yes/no or change per standard deviation (SD): WBC=1.92x10 3, Duration=7.5 y, HDLc=12.4 mg/dl, non-hdlc=43.0 mg/dl
Baseline DCCT Predictors of CVD in T1D Nathan DM et al. DCCT/EDIC 2006 With CVD N=83 No CVD N=1358 p-value Intensive insulinotherapy (%) 37 50 0.02 HbA1c (%) 9.5 9.0 0.014 Current smoking (%) 33 18 <0.001 Albuminuria (mg/24h) 19 16 0.02 LDL (mg/dl) 127 109 <0.001 Triglicerides (mg/dl) 88 81 0.04
Coronary Artery Calcification in Type 1 Diabetes Baseline examination (N=1,416) 652 T1D patients + 764 non-diabetic controls 20-55 yr old, 10+ yr diabetes duration N=559 (86%) 3-yr follow-up exam (N=1,215) N=543 (83%) 6-yr follow-up exam (N=1,173)
Baseline characteristics of T1D participants with CAC progression from baseline to 6 years CACTI 2000-08 Progressors (n = 192) Sex (%male) 57.8** 37.8 Age (yrs) 40.6±8.3** 34.3±8.4 Duration of Diabetes (yrs) 26.7±8.8** 20.3±7.9 Hypertension (%) 57.8** 27.42 Systolic Blood Pressure 121±14** 113±12 Diastolic Blood Pressure 78±9* 76±8 Non-Progressors (n = 249) Means ± SD, percent, or median. ŧsquare root transformed. *p<0.05, **p<001
Maahs, CACTI. J Diab Comp, 2006 62% lower risk of CAC progression with ACE/ARB Tx
Hypertension Renal dysfunction Risk factors for CVD in T1D tubular markers, MA, GFR Hyperglycemia and glycemic variability
Cumulative Incidence Cardiovascular Events Non-Fatal MI, Stroke or CVD Death 0.12 0.10 0.08 0.06 0.04 Risk reduction 57% 95% CI: (12-79%) Log-rank P = 0.018 Conventional 0.02 0.00 Intensive 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 Years from Study Entry Number at Risk Intensive: 705 686 640 118 Conventional: 721 694 637 96 DCCT/EDIC
OR for progression of CAC A1c predicts progression of coronary calcium in T1D CACTI participants Adjusted 100.0 for age, gender, duration of diabetes and baseline CAC 10.0 1.0 RR 7.1 p=0.02 0.1 <6.0% 6-6.8% 6.8-7.5% >7.5% HbA1c HbA1c Snell-Bergeon et al. Diabetes Care 2003 0.0
Mixed-effects models for 6-yr progression of CAC, best models in T1D patients Estimate (95% CI) p-value Age (yrs) 0.97 (0.50, 1.44 ).0001 Baseline CAC>0 3.39 (2.53, 4.25 ).0000 Diabetes Duration (yrs) 1.10 (0.63, 1.57 ).0000 Hypertension 1.74 (0.94, 2.53 ).0000 HbA1c 0.54 (0.08, 1.01 ).0224 Estimates per SD: age 9 yr, duration 9 yr, HbA1c 1.5% CACTI 2010
Glucose (mg/dl) Good glycemic control & low variability CGM CACTI ID 2013; 3443 observations in 15 days 400 300 Grand mean Overall standard deviation % within 70 180 96% MODD_ave 117 mg/dl 33 mg/dl 31 mg/dl HbA1c 6.4% 200 100 0 12:00 AM 6:00 AM 12:00 PM 6:00 PM 12:00 AM Time of Day
Glucose (mg/dl) Good glycemic control & high variability CGM CACTI ID 1049; 2805 observations in 15 days Grand mean SD 131 mg/dl 72 mg/dl 400 % within 70 180 78% MODD_ave 67 mg/dl HbA1c 5.8% 300 200 100 0 12:00 AM 6:00 AM 12:00 PM 6:00 PM 12:00 AM Time of Day
Glycemic variability is associated with CAC in men with T1D Odds Ratios (95% CI) Men (n=29) Women (n=40) p-value interaction by sex Mean glucose 5.0 (1.1-21.6) 1.2 (0.6-2.2) 0.07 SD T 7.2 (1.6-32.6) 1.2 (0.6-2.4) 0.04 % of time <70 mg/dl 1.3 (0.4-3.7) 0.9 (0.4-1.7) 0.52 % of time >180 mg/dl 9.0 (1.5 54.5) 1.1 (0.6 2.2) 0.03 Snell-Bergeon J et al Diabet Med 2010
Hypertension Renal dysfunction Risk factors for CVD in T1D tubular markers, MA, GFR Hyperglycemia and glycemic variability Insulin resistance central obesity HDL, triglycerides, impaired FFA suppression
Glucose Disposal mg/kg/min T1D Subjects are Insulin Resistant CACTI N=87 16 14 12 10 8 6 4 2 0 p<0.0001 T1D Women Control Women p<0.005 T1D Men Control Men LS Mean ± SE, adjusted for age, BMI, fasting glucose, final clamp glucose and insulin
Interventions to improve insulin sensitivity Optimal timing of insulin delivery Weight loss if BMI>23; no gain in those with BMI<23 Aerobic exercise intervention Metformin?? TZD, acipimox??
Estimation of insulin sensitivity using clinical parameters Equations derived from clamp studies in 40 adults with T1D Validated in CACTI cohort (n=652) Group Equation Mean egdr± SD T1D Men T1D Women 23.91 +(adiponectin*0.139) (triglycerides*0.003) - (insulin dose/kg/day*4.29) - (waist*0.184) 6.92 + (adiponectin*0.139) - (triglycerides * 0.003) - (insulin dose/kg/day*4.29) 6.0 ± 2.8 6.7 ± 1.8 Snell-Bergeon J, CACTI 2010
Risk factors for CVD in T1D Hypertension Renal dysfunction tubular markers, MA, GFR Hyperglycemia and glycemic variability Insulin resistance central obesity HDL, triglycerides, impaired FFA suppression LDL-cholesterol smoking
Baseline characteristics of T1D participants with CAC progression from baseline to 6 years CACTI 2000-08 Progressors (n = 192) Sex (%male) 57.8** 37.8 Age (yrs) 40.6±8.3** 34.3±8.4 Duration of Diabetes (yrs) 26.7±8.8** 20.3±7.9 Non-Progressors (n = 249) LDL Cholesterol 101.8±27.6* 96.1±28.0 HDL Cholesterol 53.9±15.7* 57.7±16.7 Log Triglycerides 4.5±0.5** 4.3±0.5 Means ± SD, percent, or median. ŧsquare root transformed. *p<0.05, **p<001 CACTI 2010
Effects of Simvastatin on First Major CVD Event in Diabetes HPS Collaborative Group, Lancet 361:2010, 2003
Practical implications Take care of the ABCs: A1c, Blood pressure, LDL-Cholesterol Screen all asymptomatic diabetic patients older than 30 for increased plaque burden = high or rapidly increasing CAC score Patients with high or rapidly increasing CAC score -> myocardial perfusion tests, angiography, IVUS Intensive interventions
Emerging CVD risk factors in T1D Dysfunctional (high/normal) HDL Inflammation (markers of response to injury?) adiponectin sil-2r, WBC, hscrp, IL-1, IL-1ra, IL-6, IL-6r, TNF- TNF-rII, IL18, ICAM-1, VCAM-1, E-selectin, P-selectin, Lp-PLA2, CD40L Hypovitaminosis Vitamin E in subjects with haptoglobin 1/1? Vitamin D in subjects with VDR Fok I T allele? Folate in subjects with MTHFR-677 C>T? Impaired fibrinolysis fibrynogen, PAI-1 Rewers M. 4/2010
University of Colorado Barbara Davis Center: Marian Rewers, P.I., Janet Snell-Bergeon David Maahs, Franziska Bishop Greg Kinney, Paul Wadwa Ram Naik, Satish Garg Nicole Gendelman, Katherine Pratte Colorado School of Public Health: John Hokanson, Lorri Ogden Dana Dabelea, Kim McFann Medicine: Robert Eckel Robert Quaife, Marcus Chen Irene Schauer, Bryan Bergman Colorado Heart Imaging: James Ehrlich Roche Molecular Systems: Suzanne Cheng, Henry Erlich Univ. Bialystok: Adam Kretowski Univ. Vermont: Russell Tracy Wake Forest Univ. Ronald Prineas Porto Alegre Univ. Ticiana Rodirigues Univ. de Chile: Rossana Roman UCLA: Matthew Budoff Univ. Pittsburgh: Trevor Orchard Tina Costacou
The Bad and the Good Cholesterol ApoB ApoAI LDL HDL Can HDL become dysfunctional so as not to be atheroprotective or anti-inflammatory? Alan Chait, ADA 2011
Altered HDL composition and function Inflammatory HDL bind avidly to vascular proteoglycans Oxidized HDL functions poorly in reverse cholesterol transport CE HDL level CE HDL INFLAMMATION CE ApoA-I PON1 SAA1/2 cholesterol efflux anti-oxidant activity Khovidhunkit J Lipid Res 2004; Navab J Lipid Res 2009; Han ATVB 2006; Shao J Lipid Res2010