47 Year Old Male with Hyperlipidemia and Metabolic Syndrome

1. 47 Year Old Male with Hyperlipidemia and Metabolic Syndrome Case Categories Primary Prevention Secondary Prevention Pediatric Case Familial Hypertriglyceridemia Diabetes Metabolic Syndrome Low HDL Familial Combined Hyperlipidemia Familial Hypercholesterolemia Elevated Lipoprotein (a) Statin Intolerance Case category: Familial Combined Hyperlipidemia, Metabolic Syndrome History of present illness: 47 year old Male with premature family history of heart disease and stroke, hyperlipidemia, metabolic syndromeand hypertension. Currently on Crestor 40, Zetia 10, Niaspan 1000, Lovaza 4 and vitamin D3 3000. No tolerance issues with medications. Here for follow-up.

2. Patient Information

3. Patient History

4. Current Medications

5. Labs Worth Noting on Crestor 40, Zetia 10, Niaspan 1000, Lovaza 4 and Vitamin D3 3000

6. Questions to Consider • Question 1 • Question 2 • Question 3 • Question 4

7. NMR LipoProfile • Insert NMR LipoProfile

8. Other Labs Worth Noting on Crestor 40, Zetia 10, Niaspan 1000, Lovaza 4 and Vitamin D3 3000

9. Initial Treatment & Management • For familial combined hyperlipidemia, stop taking Zetia 10 and increase Niaspan to 1500 mg/day. Continue Crestor 40 mg/day. • Vitamin D3 levels are normal. Continue supplements.

10. Discussion

11. Discussion

12. Discussion

13. 6 Month Follow UpOn Crestor 40, Niaspan 1500, Lovaza 4 and Vitamin D3 3000 (1 of 3) • Familial Combined Hyperlipidemia – Deteriorated. • Last visit, stopped Zetia and increased Niaspan to1500. Experiencing flushing on higher dose of Niaspan. Also taking Crestor 40 and Lovaza 4. • LDL-P increased from 782 to 1318. Small dense LDL-P increased from 458 to 1073. LDL-C is up to 65 from 36. Triglycerides are now 217 from 92. HDL decreased from 51 to 47. Non-HDL-C also increased to 106 from 54. Sterol markers of absorption are not high, but the ratio to cholesterol is high. Patient may be experiencing hyperabsorption. • Will continue current therapy for now. May need to restart Zetia. Work on diet modification and increasing exercise. • Insulin resistance syndrome – Unchanged. • IR-score is now 67 compared to 33. HbA1c did lower from 6.0 to 5.5. Fasting glucose lowered from 127 to 100. • Focus on low carb diet and increase exercise.

14. 6 Month Follow Up On Crestor 40, Niaspan 1500, Lovaza 4 and Vitamin D3 3000 (2 of 3) • Vitamin D Deficiency – Unchanged. • Vitamin D levels remain stable. • Continue supplements. • Homocystinemia – New. • Homocysteine is 16. Optimal is <10. • Higher level may be due to taking a higher dose of Niaspan. • Homocystinemia is an Independent risk factor for premature CVD caused by deficiencies in folate, B12, and B6. Increased risk for CVD is >10. • Will work up secondary causes before discussing treatment which typically involves folic acid supplementation. • We do not know that treatment of elevated homocysteine will be able to reduce risk of future events. • Start Vitamin B12 500-1000 mg/day.

15. 6 Month Follow Up On Crestor 40, Niaspan 1500, Lovaza 4 and Vitamin D3 3000 (3 of 3) • Vitamin B12 Deficiency – New. • Vitamin B12 level in low at 385. Optimal is >400. • Causes of B12 deficiency include use of certain drugs such as metformin, methotrexate and antacids, bacterial flora changes that may induce food cobalaminmalabsorption, poor dietary intake of foods high in B12 and some chronic diseases. Treatment of B12 deficiency is important to avoid health changes. • Foods high in B12 that are also heart healthy include Sockeye salmon, plain yogurt, milk and roasted chicken. • Starting vitamin B12 for homocystinemia. • Apo E3E4 Genotype • Abnormal E4 gene is associated with high CVD risk (42%). • High dose statin therapy may not be as effective as combination therapy. • Individuals with this E4 genotype should avoid drinking alcohol as alcohol will increase LDL and potentially decrease HDL. • Soluble fiber may help decrease LDL. Plant sterols can also decrease LDL and Apo B but not recommended because if absorbed, sterols can cause more plaque and is more atherogenic than own cholesterol. • Plant stanols (Benecol) could be an option as never absorbed.

16. 6 Month Follow-Up Labs on Crestor 40, Niaspan 1500, Lovaza 4 and Vitamin D3 3000 (1 of 7)

17. 6 Month Follow-Up Labs on Crestor 40, Niaspan 1500, Lovaza 4 and Vitamin D3 3000 (2 of 7)

18. 6 Month Follow-Up Labs on Crestor 40, Niaspan 1500, Lovaza 4 and Vitamin D3 3000 (3 of 7)

19. 6 Month Follow-Up Labs on Crestor 40, Niaspan 1500, Lovaza 4 and Vitamin D3 3000 (4 of 7)

20. 6 Month Follow-Up Labs on Crestor 40, Niaspan 1500, Lovaza 4 and Vitamin D3 3000 (5 of 7)

21. 6 Month Follow-Up Labs on Crestor 40, Niaspan 1500, Lovaza 4 and Vitamin D3 3000 (6 of 7)

22. 6 Month Follow-Up Labs on Crestor 40, Niaspan 1500, Lovaza 4 and Vitamin D3 3000 (7 of 7)

23. NMR LipoProfile • Insert NMR Lipoprofile 092011 EC63 Insert

24. 9Month Follow Up On Crestor 40, Niaspan 1500, Lovaza 4, Vitamin D3 3000, B12 1000 and 20 lb weight loss (1 of 3) • Familial Combined Hyperlipidemia – Improved. • Off Zetia and increased Niaspan to1500. Also taking Crestor 40 and Lovaza 4. • Excellent changes in weight of 20 lb loss. • LDL-P decreased from 1318 to <300. Small dense LDL-P decreased 1073 to <90. LDL-C lowered from 65 to 28. Triglycerides are now 71 down from 92. HDL is 44. Non-HDL-C also decreased to 48 from 106. • CRP is elevated at 4. CRP is a nonspecific inflammatory marker associated with vascular inflammation. A CRP level greater than 2, regardless of LDL-C level, is associated with increased CVD risk (2 to 3 times) and is a useful test for identifying higher risk individuals. The extent to which CRP testing provides additional benefit in terms of CHD risk screening and CHD prevention is uncertain. • Continue therapy.

25. 9 Month Follow Up On Crestor 40, Niaspan 1500, Lovaza 4, Vitamin D3 3000, B12 1000 and 20 lbweight loss (2 of 3) • Insulin resistance syndrome – Improved. • IR-score is now 34 compared to 67. HbA1c did lower from 5.5 to 5.0. Fasting glucose lowered from 100 to 77. • Free fatty acids are normalized. • 20 lb weight loss and low carb diet has improved significantly. No need to add metformin. • Vitamin D Deficiency – Improved. • Vitamin D levels are now high at 111. • Reduce dose of vitamin D3 to 2000 IU/day. • Homocystinemia – Improved. • Last visit, started vitamin B12 500-1000 mg/day. • Homocysteine decreased from 16 to 12. Optimal is <10. • Continue therapy.

26. 9 Month Follow Up On Crestor 40, Niaspan 1500, Lovaza 4, Vitamin D3 3000, B12 1000 and 20 lbweight loss (3 of 3) • Vitamin B12 Deficiency – Improved. • At last visit started vitamin B12 for homocystinemia. • Vitamin B12 level in low at 625. Optimal is >400. • Continue therapy.

27. 9 Month Follow-Up Labs on Crestor 40, Niaspan 1500, Lovaza 4, Vitamin D3 3000, B12 1000 and 20 lbweight loss (1 of 6)

28. 9 Month Follow-Up Labs on Crestor 40, Niaspan 1500, Lovaza 4, Vitamin D3 3000, B12 1000 and 20 lbweight loss (2 of 6)

29. 9 Month Follow-Up Labs on Crestor 40, Niaspan 1500, Lovaza 4, Vitamin D3 3000, B12 1000 and 20 lbweight loss (3 of 6)

30. 9 Month Follow-Up Labs on Crestor 40, Niaspan 1500, Lovaza 4, Vitamin D3 3000, B12 1000 and 20 lbweight loss (4 of 6)

31. 9 Month Follow-Up Labs on Crestor 40, Niaspan 1500, Vitamin D3 3000, B12 1000 and 20 lbweight loss (5 of 6)

32. 9 Month Follow-Up Labs on Crestor 40, Niaspan 1500, Vitamin D3 3000, B12 1000 and 20 lb weight loss (6 of 6)

33. NMR LipoProfile • Insert NMR Lipoprofile 121511 EC63 Insert

34. Clinical Pearls • Was taking Zetia long term (over 5 years as prescribed by PCP). No need to keep patients on medications long term if no benefit. Option is to trial off or consider sterol testing. • Niaspan may transiently increase insulin resistance. Over time, this resolves. • Benefit of weight loss

35. Clinical Pearls • Comparison of sterol testing results – No need for Zetia

36. Case Summary

37. References Familial Combined Hyperlipidemia • Cromwell WC, Otvos JD, Keyes MJ, et al. LDL particle number and risk of future cardiovascular disease in the Framingham offspring study – implications for LDL management. J ClinLipidol. 2007 Dec;1(6):583-92. • Brunzell JD, Davidson M, Furberg CD, et al. Lipoprotein management in patients with cardiometabolic risk: consensus statement from the American Diabetes Association and the American College of Cardiology Foundation. Diabetes Care. 2008 Apr;31(4):811-22. • Nicholls SJ, Ballantyne CM, Barter PJ, et al. Effect of two intensive statin regimens on progression of coronary disease. N Engl J Med. 2011 Dec 1;365(22):2078-87. Metabolic Syndrome • Rosenson RS, Otvos JD and Hsia J. Effects of rosuvastatin and atovastatin on LDL and HDL particle concentrations in patients with metabolic syndrome: a randomized, double-blind, controlled study. Diabetes Care. 2009 Jun;32(6):1087-91. • ADA Standards of Medical Care in Diabetes - 2012. Diabetes Care. Jan 2012 35(1)11-63. • DeFronzo RA, Abdul-Ghani M. Assessment and treatment of cardiovascular risk in prediabetes: impaired glucose tolerance and impaired fasting glucose. Am J Cardiol. 2011 Aug 2;108(3 Suppl):3B-24B. • Goff DC Jr, D'Agostino RB Jr, Haffner SM. Insulin resistance and adiposity influence lipoprotein size and subclass concentrations. Results from the Insulin Resistance Atherosclerosis Study. Metabolism. 2005 Feb;54(2):264-70.

38. References Vitamin D Deficiency • Dobnig H, Pilz S, Scharnagl H, et al. Independent association of low serum 25-hydroxyvitamin d and 1,25-dihydroxyvitamin d levels with all-cause and cardiovascular mortality. Arch Intern Med. 2008;168(12):1340-1349. • Cannell J, Hollis B, Zasloff M, et al. Diagnosis and treatment of vitamin D deficiency. Pharmacotherapy. 2008;9(1):1-12. • Giovannucci E, Liu Y, Hollis B, Rimm E. 25-hydroxyvitamin d and risk of myocardial infarction in men. Arch Intern Med. 2008;168(11):1174-1180. • Holick M. Vitamin D Deficiency. N Engl J Med. 2007;357:266-81. • Michos E and Blumenthal R. Vitamin D Supplementation and Cardiovascular Disease Risk. Circulation. 2007;115(7):827-828. • Hathcock J, Shao A, Vieth R, et al. Risk assessment for vitamin D. Am J ClinNutr. 2007;85:6-18. • Jockers B. Vitamin D sufficiency: An approach to disease prevention. The American Journal for Nurse Practitioners. 2007;11(10):43-50. • Perez-Castrillon J, Vega G, Abad L, et al. Effects of atorvastatin on vitamin D levels in patients with acute ischemic heart disease. Am J Cardiol. 2007;99(7):903-4.

39. References Homocystinemia • BosMJ, Heijer M, Willems H, et al. Homocysteine lowering by B vitamins and the secondary prevention of deep vein thrombosis and pulmonary embolism: a first randomized, placebo-controlled, double-blind trial. Blood. 2004; 104: 142a. • Toole JF, Malinow MR, Chambless LE, et al. Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death. JAMA. 2004; 291: 565–575. • Wald DS, Law M, Morris JK. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. BMJ. 2002 Nov23;325(7374):1202. • Saposnik G, Ray JG, Sheridan P, et al. Homocysteine-lowering therapy and stroke risk, severity, and disability: additional findings from the HOPE 2 trial. Stroke. 2009 Apr;40(4):1365-72.