Consensus and Controversy in Diabetes and Dyslipidemia

Consensus and Controversy inDiabetes and DyslipidemiaOm Ganda MDDirector, Lipid clinicJoslin Diabetes Ctr.Boston, MA

DisclosuresDr. Ganda does not have any financialrelationships relevant to thispresentation to disclose.

CVD Outcomes in DM vs non- DM102 Prospective studies; 698, 782 people, 8.5 million person-yr of follow-upThe Emerging Risk Factors Collaboration, Lancet 2010; 375: 2215-22Multivariate adjusted

Supremacy of Statins inCVD Risk Reduction

HPS: Major Vascular Events by LDLCholesterolRisk ratio and 95% CILipid Levelsat EntrySimvastatin(10,269)Placebo(10,267)STATINBetterPLACEBOBetterLDL cholesterol (mg/dl)< 100 282 (16.4%) 358 (21.0%) 100 < 130 668 (18.9%) 871 (24.7%) 130 1083 (21.6%) 1356 (26.9%)ALL PATIENTS 2033 (19.8%)2585(25.2%)0.424% SE 3reduction(2P

LDL-C : Less is More3.72.9Relative Riskfor CoronaryHeart Disease(Log Scale)2.21.71.31.0Grundy, S. et al., Circulation 2004;110:227-39.40 70 100 130 160 190LDL-Cholesterol (mg/dL)

CTT: Meta-analysis of 26 Statin Trialsn= 129, 526n= 39612CTT Trialists. Lancet 2010; 376: 167-181CV mortality: - 20 %; Total mortality - 10%

Is there a point of No-Return?

23 % had diabetes: same outcome

Statin-induced Myalgia / Myopathy:Underlying Mechanism?

AHA, 2008Simvastatin and Myopathy

Myopathy Associated with 80 mg of Simvastatin Daily, According toSLCO1B1 rs4149056 GenotypeSLCO1B1 encodes theorganic anion transportingpolypeptide OATP1B1 thatregulates hepatic uptake ofstatins.

06-08-2011FDA Drug Safety Communication: New restrictions,contraindications, and dose limitations for Zocor(simvastatin) to reduce the risk of muscle injury

Statin-induced Diabetes?

Intensive vs Moderate Dose Statin:New Onset DiabetesPreiss, D et al JAMA 2011; 305: 2556-2564

Lipid Changes with Statin alone orStatin +EZEPooled analyses, 27 studies, 4-24 wk , n= 15253 (non-DM), and 6541 (DM)Leiter, LA et al, Diab, Ob, Metab 2011; on- lineDM vs NDM , p= 0-04 or less, foe each

Potential LDL Lowering Agents• Thyromimetic (Eprotirome)Mean reductions in LDL,a po-B, ~ 30%,TG, ~ 40%, and LP(a), ~ 40%• Anti-sense apoB synthesis inhibitor~ 30% reduction in LDL-C in patients with FH(Baseline LDL-C: 420 mg/dl)• PCSK-9 Inhibitors

Effects of Eprotirome (KB 2115) on Serum LipidsMean age ~60 yr, BMI 27.5, LDL-C ~ 140 mg/dl on Statin Rx, n= 44-47 eachNo change in TSHNo adverse effectson Heart, BonePutative mechanisms: ↑ SRB-1, Chol 7 α–hydroxylase, liver/gut ABCG 5/8 activity, ↓SREBP-1cLadenson PW et al. N Engl J Med 2010;362:906-916

Effect of PCSK9 antibody (REGN 727) onLDL-C with or without Statins/c injection on Day 1, 29, 43Stein, EA et al NEJM 2012; 366: 1108-118

Diabetes Patients Have High Residual CVDRisk After Statin TreatmentEvent Rate(No Diabetes)Event Rate(Diabetes)On Statin On Placebo On Statin On PlaceboHPS* (CHDpatients)19.8% 25.7% 33.4% 37.8 %CARE † 19.4% 24.6% 28.7% 36.8%LIPID ‡ 11.7% 15.2% 19.2% 22.8%PROSPER § 13.1% 16.0% 23.1% 18.4%ASCOT-LLA ‡ 4.9% 8.7% 9.6% 11.4%TNT ║ 7.8% 9.7% 13.8% 17.9%HPS Collaborative Group. Lancet. 2003;361:2005-2016.Sacks FM, et al. N Engl J Med. 1996;335:1001-1009.LIPID Study Group. N Engl J Med. 1998;339:1349-1357.Shepherd J, et al. Lancet. 2002;360:1623-1630.Sever PS, et al. Lancet. 2003;361:1149-1158.Shepherd J, et al. Diabetes Care. 2006;:29:1220-1226.* CHD death, nonfatal MI, stroke, revascularizations†CHD death, nonfatal MI, CABG, PTCA‡CHD death and nonfatal MICHD death, nonfatal MI, stroke║CHD death, nonfatal MI, resuscitated cardiac arrest, stroke(80 mg vs 10 mg atorvastatin)

ADA/ACC Consensus Statement“…In patients with Cardio-metabolic Risk, we recommend guidingtherapy with apo-B measurements, and treatment to apo-B goals, inaddition to LDL-C and non-HDL-C assessment.”TREATMENT GOALSHighest-risk patientsIncluding those with1) Known CVD or2) Diabetes plus one or more additionalCVD risk factor*High-risk patientsIncluding those with1) No diabetes or known clinical CVD but2 or more additional major CVD riskfactors or2) Diabetes but no other CVD risk factorsLDL-C(mg/dL)Non–HDL-C(mg/dL)ApoB(mg/dL)< 70 < 100 < 80< 100 < 130 < 90*Smoking, HBP, f/h premature CHD Brunzell JD et al. Diabetes Care. 2008;31:811-822.

Objective:Joslin Apo-B studyTo compare the prevalence of at-goal levels of LDL-C,non-HDL-C, and Apo-B in a cohort of patients withDiabetes and TG> 200 mg/ml, according to therecommended targets by ADA/ACC ConsensusStatement

Discordance between LDL-C, non-HDL-C,and Apo-Bn Apo-B < 90 mg/dl (%) Apo-B ≥ 90 mg/dl (%) DiscordanceLDL-C

Discordance between LDL-C, non-HDL-C,and Apo-BnApo-B < 80 mg/dl(%)Apo-B ≥ 80 mg/dl(%)DiscordanceLDL-C

Effect of Lowering Triglycerides(with Fibrates) in Reducing Residual Risk?

ACCORD- Lipid Resultsn=5518Mean Age; 62 yrMean f/u: 4.7 yrAdherence ~80%No Rhabdomyolysis.CK> 10x: 0.4 vs 0.3%ALT> 3x: 1.9 vs 1.5%The ACCORD Study Group. N Engl J Med 2010;10.1056/NEJMoa1001282

ACCORD Lipid: Primary Outcome,Expanded Outcome, and DeathHR 0.92 (0.79-1.08)HR 0.94 (0.85-1.05)HR 0.91 (0.75-1.10)HR 0.83 (0.66-1.12)The ACCORD Study Group. N Engl J Med 2010;10.1056/NEJMoa1001282

ACCORD Lipid: Primary Outcome inPre-specified SubgroupsThe ACCORD Study Group. N Engl J Med 2010;10.1056/NEJMoa1001282

Circ 2011;123: 2292-2333NHANESTG > 200 mg/dl:~35% Prevalence inAdults with DiabetesNHANES, 1999-2002Recommendation…Up to 50% reduction in TG levels by intensive lifestylemeasures, including reduction in sucrose and fructose.

Effect of Raising HDL-C inReducing Residual Risk?

ARIC: CHD Risk within HDL and LDL Categoriesn=13,615F/M (%): 57/43Age 45-64 yr14-yr follow-upMuntner,P et alAm J Med Sci 2011;341: 173-180

Does HDL-C matter if LDL-C is < 70mg/dl?

AIM-HIGH: Primary Composite EndpointBoden, W et al NEJM 2011; Nov 15:on- line

AIM-HIGH: Primary EndpointsBoden,W et al NEJM 2011; Nov 15:on- line

Cholesterol Efflux Capacity andAngiographic Coronary Atherosclerosisn= 442 patients with, and 351 without, angiographic CADKhera AV et al NEJM 2011; 364: 127-135

Potential HDL Therapies‣ Cholesterol ester transfer protein (CETP)inhibitors (Torcetrapib withdrawn); Dalcetrapib,Anacetrapib‣ APO A-1 mimetic agents‣ PPAR g /a - dual agonists(Muraglitazar, Tesaglitazar withdrawn); Aleglitazar‣ MK-0524A: ER Niacin + DP-1 receptorantagonist (Laropiprant)- available in EU (Tredaptive)