Diabetes & macrovascular disease

Prevalence of Diabetes: Males Prevalence of raised blood glucose (%) ages 25+, age standardized, ≥ 7 mmol/l or on medication for raised blood glucose World Health Organization 2011

ages 25+, age standardized, ≥ 7 mmol/l or on medication for raised blood glucose Prevalence of Diabetes: Females Prevalence of raised blood glucose (%) World Health Organization 2011

UKPDS: 25% decrease in microvascular complications for ~ 1% reduction in HbA1c Each 0.9% fall in HbA 1c means a risk reduction in 12 years of: 12%for any diabetes-related endpointp = %for microvascular endpointsp = %for cataract extractionp = % for retinopathy at 12 yearsp = % for albuminuria at 12 yearsp = %for MIp = % for stroke p = NS Newly diagnosed T2DM; prior vasc ds 2%; mean age 53y; UKPDS Group. UKPDS 33. Lancet 1998; 352: 837–53.

Current Treatment Targets ADA2013 IDF2012 HbA 1c * < 7% < 7% Blood pressure < 140/80 mmHg< 130/80 LDL cholesterol < 2.6 mmol/l**< 2.0** HDL cholesterol Men> 1.1 mmol/l> 1.0 Women > 1.3 mmol/l> 1.0 Triglycerides < 1.7 mmol/l< 2.3 * Individualisation of HbA1c target advocated; ** <1.8 mmol/L if CAD

VADT 1 (n=1700) ACCORD 2 (n=10,250) ADVANCE 3 (n=11,140) HbA1c at end of follow up: standard vs intensive 8.4 vs vs vs 6.5 Primary endpoint Non-fatal MI Non-fatal stroke CVD death Hospitalisation for CHF Revascularisation Non-fatal MI Non-fatal stroke CVD death Non-fatal MI Non-fatal stroke CVD death Hazard ratio for primary outcome (95% CI) 0.87 (0.730 – 1.04) 0.90 (0.78 – 1.04) 0.94 (0.84 – 1.06) Hazard ratio for mortality (95% CI) (0.801 – 1.416)1.22 (1.01 – 1.46)0.93 (0.83 – 1.06) 1 Duckworth W et al for the VADT Investigators. N Engl J Med 2009; 360: 129–39. 2 The ACCORD Study Group N Engl J Med 2008;358: ; 3 The ADVANCE Collaborative Group N Engl J Med 2008,358: * Mean age:62.2/65.8/60.4y; DM duration:10/7/10/10y; prior vascular disease:53/43/55%; follow-up:5.6/3.4/5y; *p=0.04 Intensive glycaemic control does not reduce cardiovascular diseases in patients with long-standing T2DM

. Relative risk (95% CI) for intensive group versus conventional group (n at baseline = 80 in each group) T2 DM with microalbuminuria. Average follow up = 7.8 years; Gliclazide/Met/Insulin (NHP/regular) Conventional: according to national guidelines. Intensive: stepwise implementation of behaviour modification and pharmacological therapy that targeted hyperglycaemia, hypertension, dyslipidaemia and microalbuminuria, along with secondary prevention of CVD with aspirin. Steno-2: Intensive Multi-factorial Management vs Conventional Rx: 50% reduction in DM Complications Intensive therapy better Conventional therapy better Variable p Nephropathy Retinopathy 0.02 Autonomic neuropathy Peripheral neuropathy 0.66 Gaede P et al. N Engl J Med 2003; 348: 383–93

Gaede P et al. N Engl J Med 2003; 348: 383–93. *Primary composite endpoint of death from cardiovascular causes, non-fatal MI, CABG, percutaneous coronary intervention, non-fatal stroke, amputation or surgery for peripheral atherosclerotic artery disease n Conventional Intensive Steno-2: Intensive Multifactorial Management vs Conventional Therapy on CV Complications ~50% reduction Conventional therapy Primary composite endpoint* (%) Months of follow-up Intensive therapy

Dyslipidaemia in Type 2 Diabetes Lipid AbnormalitiesPathogenetic Mechanisms  Triglyceride  lipoprotein lipase activity Insulin resistance (  FFA + hepatic overproduction)  HDL cholesterol  lipoprotein lipase;  CETP;  hepatic lipase activity  Small dense LDL  triglyceride;  CETP;  hepatic lipase activity  LDL cholesterolLDL glycation CETP, cholesterol ester transfer protein activity FFA, free fatty acids Lam KS, Diabetes in the New Millenium,1999; p327-35

LDL Subfractions “Control” vs Patient with Insulin Resistance Increasing density Decreasing size I II III DJB-TG 0.9 mmol/l DM-TG 2.95 mmol/l

Large, buoyant particles Small, dense particles Apo BMore apo B The Absolute Concentration of LDL-C Can be Misleading in Subjects with Small, Dense LDL? At the same LDL-C level, the number of LDL particles is increased, if small and dense Each LDL particle contains one molecule of apo B Apo B concentration increases in direct relation to number of LDL particles Sniderman AD et al Ann Intern Med 2001

CVD Prevention Trials with Statins in DM Subgroup Analyses: Consistent Clinical Benefit CAREPravastatin (p=0.05) 4SSimvastatin (p=0.002) LIPIDPravastatin (NS) 4S reanalysisSimvastatin (p=0.001) HPSSimvastatin (p<0.0001) CVD % Risk Reduction Overall Diabetes Secondary prevention GREACE Atorvastatin (p<0.0001)

CARDS: Collaborative AtoRvastatin Diabetes Study Atorvastatin 10 mg Placebo High-risk patients with type 2 diabetes (N=2838) No known CVD but at least one other CV risk factor (current smoking; hypertension; retinopathy; micro- or macroalbuminuria; age y Primary outcome: reduction in composite of major coronary events, revascularisation, unstable angina, resuscitated cardiac arrest, and stroke. Randomisation complete June 2001 Early termination June 2003 Results announced June 2004 Planned completion 2005 Colhoun et al. Diabet Med 2002;19(3):

CARDS Median Lipid Levels by Treatment LDL cholesterol (mmol/L) Years of Study PlaceboAtorvastatin Total Cholesterol (mmol/L) Average difference 26% 1.40 mmol/L; p< Average difference 40% 1.20 mmol/L p<0.0001

CARDS Median Lipid Levels by Treatment HDL cholesterol (mmol/L) Triglycerides (mmol/L) Years of Study PlaceboAtorvastatin Average difference 1% 0.02 mmol/L; p= Average difference 19% 0.39 mmol/L; p<0.0001

Colhoun et al. Lancet 2004;364(9435): Cumulative Hazard (%) Placebo Atorvastatin Number at Risk CARDS=Collaborative AtoRvastatin Diabetes Study. Years Placebo 127 events Atorvastatin 83 events 37% risk reduction P=.001 Placebo (127 events) Atorvastatin (83 events) CARDS Statin Reduces Primary Outcome Cumulative Hazard of Major Cardiovascular Events

Population: 978 ACS patients with DM LDL 101mg/dl. 734 clinical history; 219 fasting glucose >126mg/dl (7mmol/l); 25 HbA1c>7% without diabetes LDL 108mg/dl Diabetic patients older, more often female, more CVD morbidity, hypertension, PVD but less smokers Design: RCT: standard (pravastatin 40mg; vs intensive statin (atorvastatin 80mg; therapy in patients treated early (10 d) after ACS. Median LDL-C over 2 year: 2.46 mM (n=2063) vs 1.6mM (n=2099). Acute Coronary Syndromes and Diabetes. Is Intensive Lipid Lowering Therapy Beneficial? Results of the PROVE IT-TIMI 22 Trial Non Diabetes Event Rate Diabetes n=978 n=978 No Diabetes n=3184 n=3184 HR 0.75 p= 0.03 HR 0.76 p= Ahmed S et al Eur Heart J 2006; 27: Riker PM et al NEJM 2005; 352: 20-8

TNT Study: Time to First Major Cardiovascular Event Patients With Diabetes and CHD HR = 0.75 (95% CI 0.58, 0.97) P= Time (years) Cumulative incidence of major cardiovascular events* Atorvastatin 80mg Atorvastatin 10mg Shepherd J et al Diabetes Care 2006 Relative risk reduction = 25% Study end LDL 2 mM (A 80mg) vs 2.5 mM (A 10mg) 1501 diabetic patients (total: 10001)

Prognosis of Patients with New-Onset T2DM Waters DD et al. Am Coll Cardiol. 2011;57(14): ; TNT, IDEAL and SPARCL TNT, IDEAL and SPARCL Atorvastatin 80 mg groups With new-onset T2DM Without new-onset T2DM Diabetes at baseline* With new-onset T2DM Without new-onset T2DM Diabetes at baseline* Incidence of MCVE n / N (%) 157 / 1,387 (11.3%) 1,884/ 17,472 (10.8%) 832 / 4,761 (17.5%) 76 / 756 (10.1%) 867 / 8,684 (10.0%) 358 / 2,359 (15.2%) Univariate analysis** (HR=1.03, 95% CI , p=0.83) ––(HR=0.90, 95% CI , p=0.59) –– Multivariate analysis** (HR=1.02, 95% CI , p=0.69) ––(HR=0.87, 95% CI , p=0.49) –– *Patients were excluded from the new-onset T2DM study **MCVEs in patients with and without new-onset T2DM were assessed with an extensive time-dependent Cox proportional hazard analysis Although any potential increased risk of new-onset T2DM with atorvastatin might warrant careful monitoring, the benefits of atorvastatin clearly outweigh the risks in patients with coronary or cerebrovascular disease

Is intensive LDL-cholesterol lowering beneficial and safe? PROVE IT-TIMI 22 substudy: No safety issues with 4m LDL-C <40mg-<80mg/dl (n=1428); <40-60mg/dl significantly less major CV events than ≥80-100mg/dl (n=233) SPARCL: Atorvastatin 80mg vs placebo 1-6m after stroke or TIA- HR 0.8 for major CV event in 5y (p=0.002); HR 0.78 ( ) for ischaemic stroke but HR1.66 ( ; 55/2365 vs 33/2366) for haemorrhagic stroke; LDL-C 1.89 vs 3.3 mM No ↑ in haemorrhagic stroke in PROVE IT-TIMI and TNT (2099 and 4995 on A 80mg ; median 2y and 4.9y; mainly no previous stroke) SPARCL: ↑ ALT 3x UNR (2.2% vs 0.5%; p<0.001) Meta-analysis of 13 statin trials: ↑ incident DM (OR1.09; 95% CI ) Cheung BM & Lam KS. Lancet 2010; 376: SPARCL Investigators. NEJM 2006; 355: ; Wiviott SD et al. JACC 2006; 46: ; Sattaar N et al. Lancet. 2010:735-42