Approach to Dyslipidemia among diabetic patients Farzad Hadaegh, MD, Professor of Internal Medicine & Endocrinology Prevention of Metabolic Disorders Research Center, Research Institute for Endocrine Sciences Shahid Beheshti University of Medical Sciences Tehran, Nov 2017 11/28/2017 2
CV events 5 0 Per 4 mmhg lower SBP Per 1 mmol/l lower LDL-C Per 0.9% lower HbA1c 5 2.9 10 8.2 15 12.5 20 11/28/2017 Ray KK, et al. Lancet. 2009;373:1765 72 3
11/28/2017 Cholesterol, 2012, doi:10.1155/2012/861924 4
8 Significant Residual Risk Remains Untreated Residual risk: Due to increased triglycerides, elevated Lp(a), other untreated risk factors 11/28/2017 Cannon et al NEJM 2015 5
VLDL LDL HDL Normal Insulin resistance VLDL triglycerides VLDL apo B VLDL: very low-density lipoprotein; LDL: low-density lipoprotein HDL: high-density lipoprotein; Apo B: apolipoprotein B LDL apo B particle number particle size (small, dense) HDL cholesterol particle number particle size (small, dense) 11/28/2017 Watts G. Diapedia 2014. Available at: http://www.diapedia.org/61040851150/rev/5. Last accessed September 2016 6
LDL cholesterol (LDL-C) is the traditional measure of LDL, chosen for historical, not analytic or clinical reasons. Alternatively, LDL can be measured by particle number (LDL-P), or estimated by apolipoprotein B. Due to differences in the amount of cholesterol contained in LDL, alternate LDL measures (LDL-C vs. LDL-P) frequently disagree (discordance). 1-7 Triglycerides LDL Particle LDL-P LDL Particle LDL-P LDL-C LDL-C Cholesterol 1. Otvos JD, et al. Am J Cardiol. 2002;90(8A):22i-29i. 4. Otvos JD, et al. J Clin Lipidol. 2011;5(2):105-113. 2. Cromwell WC, Otvos JD. Am J Cardiol. 2006;98(12):1599-1602. 5. Sniderman AD, et al. Am J Cardiol. 2003;91(10):1173-1177. 3. Cromwell WC, et al.. J Clin Lipidol. 2007;1(6):583-592. 6. Sniderman AD, et al. Am J Cardiol. 2001;87(6):792-793, A798. 11/28/2017 7. Sniderman AD. J Clin Lipidol. 2008;2(1):36-42. 7
Cardiovascular risk tracks with LDL particle number When alternate LDL measures (LDL-C vs LDL particle number) agree (concordance) each measure is equally associated with CVD risk. When alternate measures are discordant (e.g., diabetes, metabolic syndrome, statin therapy), risk tracks with LDL-P, not LDL-C. The majority of atherogenic lipoproteins in individuals with insulin resistance, metabolic syndrome or T2D are smaller, cholesterol-depleted LDL particles. These compositional changes in LDL particles may lead to a disagreement between measures of LDL-C and LDL-P resulting in discordance 11/28/2017 8
Reduce LDL Particle Production (make less) Diet Exercise Weight Loss Glycemic Control Co-Morbidity Management (up to 30-50% 6 LDL-P) Marine Omega-3 o DHA + EPA (no 6 LDL-P) o EPA Only (4-15 % 6 LDL-P) LDL-P Target Improve LDL Particle Clearance (remove more) Statins (35-55% 6 LDL-P) Gut agents o Ezetimibe (15-30% 6 LDL-P) o Resins / Bile Acid Sequestrates (15-30% 6 LDL-P) Statin + Gut (50-70% 6 LDL-P) Statin + Gut + Niacin (> 60% 6 LDL-P) PCSK9 inhibitors 11/28/2017 Lipid and lipoprotein disorders: Current clinical solutions. Baltimore: International Guideline Center; 2012. 9
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Aim: assess the effects on vascular mortality and morbidity of a substantial LDL-C reduction maintained for several years in a large cohort of diabetic individuals Methods : 5963 UK adults (aged 40 80 years) known to have DM, and an additional 14 573 with occlusive arterial disease (but no diagnosed DM), were randomly allocated to receive 40 mg simvastatin daily or matching placebo 11/28/2017 Lancet 2003; 361: 2005-16 11
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Allocation to 40 mg simvastatin daily reduced the rate of first major vascular events by about a quarter in a wide range of diabetic patients studied. Statin therapy should now be considered routinely for all diabetic patients at sufficiently high risk of major vascular events, irrespective of their initial cholesterol concentrations. 11/28/2017 Lancet 2003; 361: 2005-16 13
n = 2838 Age 40-75, no history of CVD T2DM plus one or more: Retinopathy Albuminuria Hypertension Smoking Intervention: Atorvastatin 10 mg vs. Placebo Outcome: ACS, revascularization, stroke 11/28/2017 Colhoun HM, et al. Lancet 2004;364:685. 14
11/28/2017 Colhoun HM, et al. Lancet 2004;364:685. 15
Aim of study: Although statin therapy reduces the risk of occlusive vascular events in people with DM There is uncertainty about the effects on particular outcomes and whether such effects depend on the type of diabetes, lipid profile, or other factors. Methods: Data from 18686 individuals with diabetes (1466 type 1 and 17,220 type 2) in the context of a further 71,370 without diabetes in 14 randomised trials of statin therapy. Estimates effects on clinical outcomes per 1.0 mmol/l reduction in LDL cholesterol. 11/28/2017 Lancet 2008, Jan 12;371(9607):117-25 16
Result in Diabetic patients: All cause mortality MI or Coronary Death Coronary Revasculari sation Stroke Risk Reduction %9 RR= 0.87 P<0.0001 22% RR=0.78 P<0.0001 25% RR=0.75 P<0.0001 21% RR=79 P=0.0002 11/28/2017 Lancet 2008, Jan 12;371(9607):117-25 17
After 5 years, 42 (95% CI 30 55) fewer people with diabetes had major vascular events per 1000 allocated statin therapy. 11/28/2017 18
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Among diabetic patients the proportional effects of statin therapy were similar irrespective of whether there was a : Prior history of vascular disease Other baseline characteristics. Conclusion: Statin therapy should be considered for all diabetic individuals who are at sufficiently high risk of vascular events. 11/28/2017 Lancet 2008, Jan 12;371(9607):117-25 21
Cumulative incidence of major cardiovascular events* 0.20 0.15 HR = 0.75 (95% CI: 0.58, 0.97) P = 0.026 Atorvastatin 10 mg Atorvastatin 80 mg 0.10 0.05 0 Relative risk reduction = 25% 0 1 2 3 4 5 6 Years 1501 patients with diabetes and CHD, primary end point: time to first major cardiovascular event* *CHD death, nonfatal non procedure-related MI, resuscitated cardiac arrest, fatal or nonfatal stroke TNT: Treating to New Target study 11/28/2017 Shepherd J, et al. Diabetes Care 2006;29:1220 6 22
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The Risk Calculator. The American College of Cardiology/American Heart Association ASCVD risk calculator may be a useful tool to estimate 10-year ASCVD (http://my.americanheart.org). 11/28/2017 25
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Reduce LDL-C 18 55% & TG 7 30% Raise HDL-C 5 15% Major side effects Myopathy Increased liver enzymes Contraindications Absolute: liver disease Relative: use with certain drugs 11/28/2017 31
Fibric acid derivatives, especially Gemfibrozil Niacin Cyclosporine Azole antifungals Macrolide antibiotics HIV protease inhibitors Nefazodone Verapamil and diltiazem Amiodarone Grapefruit juice, >1 qt/d 11/28/2017 32
A meta-analysis of 13 randomized statin trials with 91,140 participants showed an odds ratio of 1.09 (9%) for a new diagnosis of diabetes, On average,treatment of 255 patients with statins for 4 years resulted in 1 additional case of diabetes, while simultaneously preventing 5.4 vascular events among those 255 patients 11/28/2017 33
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Hypertriglyceridemia should be addressed with dietary and lifestyle changes including abstinence from alcohol Severe hypertriglyceridemia (>1,000 mg/dl) may warrant pharmacologic therapy (fibric acid derivatives and/or fish oil) to reduce the risk of acute pancreatitis. Low levels of HDL cholesterol, often associated with elevated triglyceride levels, are the most prevalent pattern of dyslipidemia in individuals with type 2 diabetes. 11/28/2017 35
Drug Gemfibrozil Fenofibrate Clofibrate Dose 600 mg BID 200 mg QD 1000 mg BID 11/28/2017 36
Major actions Lower LDL-C 5 20% (with normal TG) May raise LDL-C (with high TG) Lower TG 20 50% Raise HDL-C 10 20% Side effects: dyspepsia, gallstones, myopathy Contraindications: Severe renal or hepatic disease 11/28/2017 37
Combination therapy (statin/fibrate) has not been shown to improve atherosclerotic cardiovascular disease outcomes and is generally not recommended. However, therapy with statin and fenofibrate may be considered for men with both triglyceride level 204 mg/dl (2.3 mmol/l) and HDL cholesterol level 34 mg/dl (0.9 mmol/l). Combination therapy (statin/niacin) has not been shown to provide additional cardiovascular benefit above statin therapy alone and may increase the risk of stroke and is not generally recommended. 11/28/2017 38
Clinicians should attempt to find a dose or alternative statin that is tolerable, if side effects occur. There is evidence for benefit from even extremely low, less than daily, statin doses. The addition of Ezetimibe to moderate-intensity statin therapy has been shown to provide additional cardiovascular benefit compared with moderate-intensity statin therapy alone and may be considered for patients : with a Recent ACS with LDL C >50 mg/dl or for those patients who cannot tolerate high intensity statin therapy. A 11/28/2017 39
Individuals were 50 years of age who experienced an ACS within the preceding 10 days and had an LDL C level> 50 mg/dl. In those with diabetes (27%), the combination of moderate intensity simvastatin (40mg) and ezetimibe (10 mg) showed a significant reduction of major adverse cardiovascular events with an absolute risk reduction of 5% (40% vs. 45%) and RR reduction of 14% (RR 0.86 [95% CI 0.78 0.94]) over moderate-intensity simvastatin (40 mg) alone. 11/28/2017 40
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Simvastatin EZ/Simvastatin Male 34.9 33.3 Female 34.0 31.0 Age <65 years 30.8 29.9 Age 65 years 39.9 36.4 No diabetes 30.8 30.2 Diabetes * 45.5 40.0 Prior LLT 43.4 40.7 No prior LLT 30.0 28.6 LDL-C >95 31.2 29.6 LDL-C 95 38.4 36.0 *p-interaction = 0.023, otherwise >0.05 7-year event rates LLT: lipid-lowering therapy 0.7 Ezetimibe/Simvastatin 1.0 Simvastatin 1.3 better better 11/28/2017 Cannon et al NEJM 2015 42
The addition of the novel PCSK9 inhibitors, Evolocumab and Alirocumab, To maximally tolerated doses of statin therapy in participants who were at high risk for ASCVD Decrese the LDL cholesterol ranging from 36% to 59%. 11/28/2017 43
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LAPLACE-2: LDL-C Assessment with PCSK9 Monoclonal Antibody Inhibition Combined With Statin Therapy. RUTHERFORD-2: Reduction of LDL-C With PCSK9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder Study. GAUSS-2: Goal Achievement after Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects. 11/28/2017 45
Treatment of T2DM patients with evolocumab led to a: reduction of ~60% in LDL-C vs placebo and ~39% vs ezetimibe 1 reduction of ~55% in non-hdl-c vs placebo and ~34% vs ezetimibe 1 Evolocumab has no measurable effect on glycaemic parameters in patients with or at high- or low-risk of diabetes 2 0.0 10.0 20.0 30.0 40.0 50.0 60.0 70.0 80.0 Mean change in LDL-C concentration (%) from baseline to week 12 Evolocumab vs. placebo 60.2 65.9 Evolocumab vs. ezetimibe 39.3 40.4 T2DM (n=413) No T2DM (n=2119) Mean change in non-hdl-c concentration (%) from baseline to week 12 Evolocumab vs. placebo Evolocumab vs.ezetimibe 0.0 1. Sattar N, et al. Lancet Diab Endocrin 2016;4:403 10 2. Sattar N, et al. Presented at EASD, 2015 11/28/2017 46-10.0-20.0-30.0-40.0-50.0-60.0-70.0 54.9 58.2 33.8 35.4
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Evolocumab markedly reduces atherogenic lipoproteins in patients with type 2 diabetes, an effect that is consistent across subgroups and similar to that seen in patients without type 2 diabetes 11/28/2017 48
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Patients aged 40-75, without ASCVD, with DM and baseline LDLc 70-189 mg/dl on statin for primary prevention 11/28/2017 54
Patients with clinical ASCVD with comorbidities on statin for secondary prevention 11/28/2017 55
Patients with diabetes need to look beyond LDL C for better cardiovascular risk factor stratification as they often have elevated triglycerides, non-hdl cholesterol/ldl P PCSK9 inhibitors reduce LDL cholesterol and have favorable safety profile LDL-C reductions in those with diabetes were similar to those without diabetes PCSK9 inhibitors lower non HDL cholesterol, Lp(a) and may be an important tool in reducing residual risk All trials of PCKS9 inhibitors have been conducted on top of baseline statin therapy PCSK9 inhibitors do not yet have CV outcome data to support their use in diabetes for primary prevention 11/28/2017 56
Thanks for your patience, dear colleagues! 11/28/2017 57