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Diabetes and Lipids

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With respect to (LDL) cholesterol. Should we be checking LDL (or other lipid fractions)? What is the normal range? Is there an upper limit to the range? Is there a lower limit to the range? What are the targets in people with diabetes? What should the targets be? Is the cholesterol hypothesis proven? Hypothesis or fact?

Learning objectives: Review the importance of statins to lower CV risk in diabetes To review lipid guidelines (Canadian and American) as they pertain to diabetes Is lower better (at least for diabetes)? To review results with Ezetemibe and PCSK9 inhibitors Are studies with these drugs going to impact guidelines? Does glycemic control matter wrt lipids/targets? To review where triglyceride management might fit in Is statin intolerance real? Does it matter? Do statins cause diabetes? Does it matter? Small interfering RNA Etc..

Proportion without Major CHD Event Major Coronary Events in 4S Patients with or without Diabetes by History (n=202) 1.0 0.9 0.8 0.7 0.6 0.5 0 Diabetes by Hx, simvastatin Diabetes by Hx, placebo No diabetes by Hx, simvastatin No diabetes by Hx, placebo P=0.002 P=0.0001 0 1 2 3 4 5 6 Years Since Randomization Adapted from Pyörälä et al. Diabetes Care 1997;20:614-620. Slide Source: Lipids Online www.lipidsonline.org

CARDS placebo Atorva 10

TNT: Diabetes Subgroup

With DM There is no question that treating diabetics with statins lowers CV risk.

With DM The resulting lower risk achieved still exceeds non-diabetics

With DM There does not seem to be a LDL below which risk does not continue to drop

Should every diabetic be treated with a statin?

USA guidelines: how do they compare?

Who Should Receive Statins? 2013 40 yrs old or Macrovascular disease or Microvascular disease or DM >15 yrs duration and age >30 yrs or Warrant therapy based on (other) Canadian Cardiovascular Society lipid guidelines guidelines.diabetes.ca 1-800-BANTING (226-8464) diabetes.ca Copyright 2013 Canadian Diabetes Association

If on therapy, target LDL 2.0 mmol/l (77.2 mg/dl)

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USA guidelines: how do they compare?

A New Perspective on LDL-C and Non-HDL-C goals The expert panel was unable to find RCT evidence to support continued use of specific LDL-C and/or non-hdl-c treatment targets 25

placebo Atorva 10 CARDS

NEJM 350;15 April 8 2004

TNT: Diabetes Subgroup

A New Perspective on LDL-C and Non-HDL-C goals The expert panel was unable to find RCT evidence to support continued use of specific LDL-C and/or non-hdl-c treatment targets 4 major statin benefit groups were identified for whom the ASCVD risk reduction clearly outweighs the risk of adverse events.3) diabetes aged 40-75 years with LDL-C 70-189 mg/dl and without ASCVD 30

The difficulty of giving up the treat to goal paradigm was deliberated extensively over a 3-year period Use of LDL-C targets may result in under-treatment with evidence based statin therapy

Scenario 1 Mr. M. S., age 58, diabetic Meds include Metformin 1 gm bid, Ramipril 10 mg, Metoprolol 50 mg bid and Atorvastatin 10 mg TC: 4.0 mmol/l (155 mg/dl) HDL: 1.1 mmol/l (42 mg/dl) LDL: 2.4 (96 mg/dl) Triglyceride: 2.2 mmol/l (200 mg/dl) A1c: 6.9% Are his lipids optimally controlled? Should you add more statin? Would more information help?

Scenario 2 Mr. M. S., age 58, diabetic Meds include Metformin 1 gm bid, Ramipril 10 mg, Metoprolol 50 mg bid and Atorvastatin 20 mg. TC: 3.75 mmol/l (150 mg/dl) HDL: 1.24 mmol/l (49.6 mg/dl) LDL: 1.7 mmol/l (68 mg/dl) Triglyceride: 1.55 mmol/l (141 mg/dl) A1c: 6.9% Are his lipids optimally controlled? 41

Scenario 3 Mr. M. S., age 58, diabetic Meds include Metformin 1 gm bid, Ramipril 10 mg, Metoprolol 50 mg bid and Atorvastatin 20 mg. Had an MI 6 mos ago TC: 3.75 mmol/l (150 mg/dl) HDL: 1.24 mmol/l (49.6 mg/dl) LDL: 1.7 mmol/l (68 mg/dl) Triglyceride: 1.55 mmol/l (141 mg/dl) A1c: 6.9% Are his lipids optimally controlled? 42

Scenario 4 Mr. M. S., age 58, diabetic Meds include Metformin 1 gm bid, Ramipril 10 mg, Metoprolol 50 mg bid and Atorvastatin 80 mg. Had MI 6 mos ago TC: 2.4 mmol/l (95 mg/dl) HDL:.9 mmol/l (35 mg/dl) LDL: 1.0 mmol/l (39 mg/dl) Triglyceride: 1.1 mmol/l (100 mg/dl) A1c: 6.9% Are his lipids optimally controlled? 43

Scenario 4 Mr. M. S., age 58, diabetic Meds include Metformin 1 gm bid, Ramipril 10 mg, Metoprolol 50 mg bid and Atorvastatin 80 mg. Had MI 6 mos ago TC: 2.4 mmol/l (96mg/dl) HDL:.9 mmol/l (36 mg/dl) LDL: 1.0 mmol/l (40mg/dl) Triglyceride: 1.1 mmol/l (100 mg/dl) A1c: 6.9% Are his lipids optimally controlled? Would you decrease the statin? Would LESS information help? 46

The difficulty of giving up the treat to goal paradigm was deliberated extensively over a 3-year period Use of LDL-C targets may result in under-treatment with evidence based statin therapy

Media, internet, print, etc

IMProved Reduction of Outcomes: Vytorin Efficacy International Trial A Multicenter, Double-Blind, Randomized Study to Establish the Clinical Benefit and Safety of Vytorin (Ezetimibe/Simvastatin Tablet) vs Simvastatin Monotherapy in High-Risk Subjects Presenting With Acute Coronary Syndrome

Study Design Patients stabilized post ACS 10 days: LDL-C 1.3-3.2 mmol/l (1.3 2.6 mmol/l if prior lipid-lowering Rx) N=18,144 Standard Medical & Interventional Therapy Simvastatin 40 mg Uptitrated to Simva 80 mg if LDL-C > 2.05 (adapted per FDA label 2011) Ezetimibe / Simvastatin 10 / 40 mg Follow-up Visit Day 30, every 4 months 90% power to detect ~9% difference Duration: Minimum 2 ½-year follow-up (at least 5250 events) Primary Endpoint: CV death, MI, hospital admission for UA, coronary revascularization ( 30 days after randomization), or stroke Cannon CP AHJ 2008;156:826-32; Califf RM NEJM 2009;361:712-7; Blazing MA AHJ 2014;168:205-12 53

Mean LDL-C (mmol/l) LDL-C and Lipid Changes 1 Yr Mean LDL-C TC TG HDL hscrp 2.5 Simva 1.81 3.75 1.55 1.24 3.8 mg/dl EZ/Simva 1.38 3.25 1.36 1.26 3.3 mg/dl 2.25 Δ in mmol/l -0.43-0.50-0.19 +0.2-0.5mg/dl 2.0 1.75 1.5 1.25 1.0 Number at risk: QE R 1 4 8 12 16 24 36 48 60 72 84 96 Time since randomization (months) 54

Mean LDL-C (mmol/l) LDL-C and Lipid Changes 1 Yr Mean LDL-C TC TG HDL hscrp 2.5 Simva 70 145 1.55 1.24 3.8 mg/dl EZ/Simva 53 126 1.36 1.26 3.3 mg/dl 2.25 Δ in mg/dl -17-19 -0.19 +0.2-0.5mg/dl 2.0 1.75 1.5 1.25 1.0 Number at risk: QE R 1 4 8 12 16 24 36 48 60 72 84 96 Time since randomization (months) 55

CV Death, Non-fatal MI, or Non-fatal Stroke HR 0.90 CI (0.84, 0.97) p=0.003 NNT= 56 Simva 22.2% 1704 events EZ/Simva 20.4% 1544 events 7-year event rates 56

Giugliano et al. Hotline sessions, ESC2015, London, UK, August 30thth 2015

Cannon CP, et al. N Engl J Med. 2015;372:2387-2397. Supplementary Appendix. Unpublished Giugliano et al. Hotline sessions, ESC2015, London, UK, August 30thth 2015

Cannon CP, et al. N Engl J Med. 2015;372:2387-2397. Supplementary Appendix. Giugliano et al. Hotline sessions, ESC2015, London, UK, August 30thth 2015

LDL Receptor Function and Life Cycle For illustration purposes only 61 61

The Role of PCSK9 in the Regulation of LDL Receptor Expression 62 For illustration purposes only

Impact of PCSK9 inhibitors on LDL Receptor Expression For illustration purposes only 63 63

LS mean (SE) % change in LDL-C Level at week 8/12 LOCF Pooled Results: % Change from Baseline in LDL-C at Week 8/12 by Baseline LDL-C, non-hdl-c and Apo B Placebo Alirocumab 150 mg Q2W 0% Baseline LDL-C subgroup Baseline non-hdl-c subgroup 3.36 mmol/l >3.36 mmol/l <4.3 mmol/l 4.3 mmol/l n=43 n=66 n=32 n=38 n=49 n=77 n=26 n=27 Baseline Apo B subgroup <1.1 g/l 1.1 g/l 130 mg/dl >130 mg/dl <166 mg/dl 166 mg/dl <110 mg/dl 110 mg/dl n=46 n=59 n=28 n=44-10% -20% -8.5% (2.9) -13.5% (3.2) -8.6% (2.9) -14.0% (4.2) -7.4% (2.8) -14.7% (3.8) -30% -40% -50% -60% -70% -69.7% (2.4) -66.4% (2.9) -68.4% (2.5) -68.1% (4.2) -69.2% (2.7) Cut-offs for LDL-C (3.36 mmol/l, 130 mg/dl) and non-hdl-c (4.3 mmol/l, 166 mg/dl) based on thresholds for starting therapy in patients at, respectively, moderate/moderately high cardiovascular (CV) risk in the most recent US cholesterol management (ATP III) guidelines -80% 1 and intermediate CV risk in the 2012 Canadian dyslipidemia guidelines 2. Cut-off for Apo B (1.1 g/l, 110 mg/dl) based on value derived by regression analysis from consensus target LDL-C and non-hdl-c values 3 and threshold for initiatiing therapy in intermediate-risk patients in the 2012 Canadian guidelines 2. 1. Grundy et al. Circulation. 2004;110:227-239. 2. Anderson et al. Can J Cardiol. 2013;29151-167. 3. Soran et al. Ann Clin Biochem 2011;48[Pt6]:566-571. Data pooled from mitt population of studies 1003 (NCT01266876), 11565 (NCT01288443), and 11566 (NCT01288469). -66.9% (3.0) 64

i.e., MACE

Adverse events were NOT more common if LDL was VERY low Unpublished data

1.42 2.07 1.81 2.58 2.58 3.37

Does glycemic control affect the function of lipids? If it does, then should the degree of glycemic control affect our recommendations for treating the lipids?

HDL and Anti-Atherosclerosis Inhibition of Adhesion Molecules Monocyte LDL Vessel Lumen Adhesion Molecules MCP-1 LDL Endothelium Cytokines Modified LDL Macrophage Foam Cell Intima Cockerill GW et al. Arterioscler Thromb Vasc Biol 1995;15:1987-1994. Slide Source: Lipids Online www.lipidsonline.org

HDL and Anti-Atherosclerosis Inhibition of Adhesion Molecules Monocyte HDL Inhibits Chemotaxis and inhibits Adhesion Molecule Expression LDL Vessel Lumen Adhesion Molecules Cytokines MCP-1 LDL Modified LDL Endothelium HDL Inhibit Oxidation of LDL Macrophage Foam Cell HDL Promote Cholesterol Efflux Intima Cockerill GW et al. Arterioscler Thromb Vasc Biol 1995;15:1987-1994. Slide Source: Lipids Online www.lipidsonline.org

Presented at ADA San Diego 2011 91

Mean A1c 7.6% 95

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Glycated LDL and HDL Glycemic control may play a role in how atherogenic the lipoproteins may be Guidelines don t specifically recommend it, but if you have someone with an A1c of 6.5% vs A1c of 8.5%, you might choose to be more aggressive treating the lipids of the latter. Some Type 1 s have HDL of 2 or more. If their A1c is 10%, do we care? Is the HDL doing anything? At what point are we assured?

Summary and conclusions Statins lower CV risk in essentially all diabetics. The use of statins should be guided by perceived CV risk, as per guidelines (which guidelines???) Lifetime risk should also be considered Correct LDL first In people in whom you cannot decide, measuring an apob, non-hdl might provide further information

Summary and conclusions: cont d The addition of Ezetemibe to statin with subsequent lowering of LDL does lower risk more (at least in diabetics) Targets are changing (at least in the US) in view of IMPROVE-IT and FOURIER PCSK9 inhibitors..

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Mr. M. S., age 58, diabetic Meds include Metformin 1 gm bid, Ramipril 10 mg, Metoprolol 50 mg bid and Atorvastatin 10 mg TC: 4.22 mmol/l (163 mg/dl) HDL:.99 mmol/l (38 mg/dl) LDL: 1.42mmol/L (55 mg/dl) Triglyceride: 3.98 mmol/l (349 mg/dl) A1c: 6.9% Are his lipids optimally controlled? Should you add more statin? Should you add a fibrate?

Mr. M. S., age 58, diabetic Meds include Metformin 1 gm bid, Ramipril 10 mg, Metoprolol 50 mg bid and Atorvastatin 10 mg TC: 4.22 mmol/l (163 mg/dl) HDL:.99 mmol/l (38 mg/dl) LDL: 1.42mmol/L (54 mg/dl) Triglyceride: 3.98 mmol/l (349 mg/dl) A1c: 6.9% Are his lipids optimally controlled? Should you add more statin? Should you add a fibrate?

Mr. M. S., age 58, diabetic Meds include Metformin 1 gm bid, Ramipril 10 mg, Metoprolol 50 mg bid and Atorvastatin 10 mg TC: 4.22 mmol/l (163 mg/dl) HDL:.99 mmol/l (38 mg/dl) LDL: 1.42mmol/L (54 mg/dl) Triglyceride: 3.98 mmol/l (349 mg/dl) apob:.94 Are his lipids optimally controlled? Should you add more statin? Should you add a fibrate?

Mr. M. S., age 58, diabetic Meds include Metformin 1 gm bid, Ramipril 10 mg, Metoprolol 50 mg bid and Atorvastatin 80 mg TC: 3.52 mmol/l (136 mg/dl) HDL:.89 mmol/l (34 mg/dl) LDL: 1.07 mmol/l (41 mg/dl) Triglyceride: 3.5 mmol/l (310 mg/dl) apob.79 Are his lipids optimally controlled? Should you add more statin? Should you add a fibrate?

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BIP: Effects of baseline Triglycerides on response to treatment Circulation, 2000;102:21-27

Baseline Characteristics Characteristic Placebo (n = 4900) Fenofibrate (n = 4895) Male, % 63 63 No Prior CVD, % 78 78 Lipid parameters, mg/dl (mmol/l) TC 194 195 LDL-C 119 (3.07) 119 (3.07) HDL-C 42 (1.1) 42 (1.1) TG 153 (1.73) 154 (1.74) Dyslipidemic*, % 37 39 *TG >150 (1.7) and HDL <40 mg/dl (1.03) for men or <50 mg/dl (1.29) for women The FIELD Study Investigators. Lancet [Early Online Publication]. November 14, 2005.

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Lipid Goals for Individuals at Risk for ASCVD Lipid parameter Goal (mg/dl) TC <200 LDL-C Non HDL-C TG <150 Apo B <130 (low risk) <100 (moderate risk) <100 (high risk) <70 (very high risk) <55 (extreme risk) 30 above LDL-C goal; 25 above LDL-C goal (extreme risk individuals) <90 (individuals at high risk of ASCVD, including those with diabetes) <80 (individuals at very high risk with established ASCVD or diabetes plus 1 additional risk factor) <70 (individuals at extreme risk) Abbreviations: apo, apolipoprotein; ASCVD, atherosclerotic cardiovascular disease; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TC, total cholesterol; TG, triglycerides. AACE/ACE 2017;epub ahead of print; Baigent C, et al. Lancet. 2010;376:1670-1681; Boekholdt SM, et al. J Am Coll Cardiol. 2014;64(5):485-494; Brunzell JD, et al. Diabetes Care. 2008;31:811-822; Cannon CP, et al. N Engl J Med. 2015;372(25):2387-2397; Heart Protection Study Collaborative Group. Lancet. 2002;360:7-22; Jellinger P, Handelsman Y, Rosenblit P, et al. Endocr Practice. 2017;23(4):479-497; Ridker PM, J Am Coll Cardiol. 2005;45:1644-1648; Sever PS, et al. Lancet. 2003;361:1149-1158; Shepherd J, et al. Lancet. 2002;360:1623-1630; Weiner DE, et al. J Am Soc Nephrol. 2004;15(5):1307-1315.

Recommendations associated with this question: Question: How are different drugs used to treat dyslipidemia? Statins, Fibrates R55. In individuals at risk for ASCVD, aggressive lipid-modifying therapy is recommended to achieve appropriate LDL-C goals (Grade A, BEL 1). Statins R56. Statin therapy is recommended as the primary pharmacologic agent to achieve target LDL-C goals on the basis of morbidity and mortality outcome trials (Grade A; BEL 1). R57. For clinical decision making, mild elevations in blood glucose levels and/or an increased risk of newonset T2DM associated with intensive statin therapy do not outweigh the benefits of statin therapy for ASCVD risk reduction (Grade A, BEL 1). R58. In individuals within high-risk and very high-risk categories, further lowering of LDL-C beyond established targets with statins results in additional ASCVD event reduction and may be considered (Grade A, BEL 1). R59. Very high-risk individuals with established coronary, carotid, and peripheral vascular disease, or diabetes, who also have at least 1 additional risk factor, should be treated with statins to target a reduced LDL-C treatment goal of <70 mg/dl (Grade A, BEL 1). R60. Extreme risk individuals should be treated with statins or with combination therapy to target an even lower LDL-C treatment goal of <55 mg/dl (Grade A, BEL 1). Fibrates R61. Fibrates should be used to treat severe hypertriglyceridemia (TG >500 mg/dl) (Grade A; BEL 1). R62. Fibrates may improve ASCVD outcomes in primary and secondary prevention when TG concentrations are 200 mg/dl and HDL-C concentrations <40 mg/dl (Grade A; BEL 1). Abbreviations: ASCVD, atherosclerotic cardiovascular disease; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TG, triglycerides. Jellinger P, Handelsman Y, Rosenblit P, et al. Endocr Practice. 2017;23(4):479-497.

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Summary and conclusions: cont d Most guidelines around the world are coming around to the same conclusion, i.e., that in the presence of atherogenic dyslipidemia, there is reasonable evidence that fibrates decrease CV risk (Gemfibrozil should not be used with a statin)