C ase Category: Familial Combined Hyperlipidemia, Metabolic Syndrome, Elevated Lipoprotein(a)

1. 38 Year Old Male with Familial Combined Hyperlipidemia, Metabolic Syndrome and Elevated Lipoprotein(a) Case Category: Familial Combined Hyperlipidemia, Metabolic Syndrome, Elevated Lipoprotein(a) History of present illness: 38 year old male with high cholesterol and no prior treatment. Tries to exercise regularly and has a reasonable diet. He is having fatigue, muscle aches and headaches, as well as struggling with inability to lose weight.

2. Patient Information

3. Patient History

4. Current Medications

5. Labs Worth Noting on No Medications

6. Questions to Consider • Question 1: Assess diet. Any room to improve? Pattern of lipids (high triglycerides, low HDL, and high small dense LDL) suggests high carb diet may be contributing. What about alcohol intake? • Question 2: Why is sleep apnea untreated? Still symptomatic?

7. Labs on No Medications Note discordance between LDL-C and LDL-P. Pattern is typical of insulin resistance/ metabolic syndrome. Small dense LDL-P predominates causing disconnect between LDL-C and LDL-P.

8. Labs on No Medications

9. LDL-P and LDL-C Discordance in MESA CVD Event Rates in Subgroups with Low LDL Discorcordant High LDL-P Residual Risk Concordant Discorcordant Low LDL-P Need Additional LDL-C Lowering? Otvos et al. J Clin Lipidol 2011;5:105-13

10. Population Equivalent Cut Points for Alternate LDL Measures. Patient has discordance. Disease tracks with LDL-P. (LDL-C, Measured Apo B and NMR LDL-P) LDL-C LDL-P 1 Contois, et al. Clinical Chemistry 2009;55:407-419 2 Cromwell WC. Clinical Challenges in Lipid Disorders. Oxford:Clinical Publishing, 2008:249-259.

11. NMR Lipoprofile – IR Score • Insulin resistance score is 66 (IR-Score 66/100 with optimal <45/100). • This pattern of lipoproteins are what is typically seen in insulin resistance. The lipoproteins begin to shift in such a way that is predictive of insulin resistance. These lipoprotein changes provide a “window into diabetes” possibly years before the HbA1C and glucose tell this same story. • This is important clinically as it is one secondary cause of high LDL-P and may be very appropriate to direct therapy to addressing this first versus just targeting dyslipidemia (high triglycerides/low HDL) with lipid therapy. • Low carb diet, exercise and weight loss will be of great benefit and should be first step in therapy. We use metformin often in these patients as it helps address root cause and helps aid in weight loss. It is inexpensive, generic, and safe and will improve triglycerides and HDL too. There are no drugs approved for prediabetes or metabolic syndrome but metformin is recognized as safe to use in this setting.

12. Labs on No Medications Always rule out additional secondary cause of high triglyceride and high LDL with TSH.

13. Labs on No Medications We consider vitamin D <50 to be abnormal especially in the setting of myalgias.

14. Initial Treatment & Management • Advise a low carb diet and increased exercise. • For familial combined hyperlipidemia and metabolic syndrome, start metformin ER 750 mg 1-2 tablets daily with slow titration as tolerated. This is off label use of metformin but may be very helpful due to insulin resistance being present based on lipoprotein analysis. • Start vitamin D3 3000-4000 IU/day for vitamin D deficiency. • Consider a CIMT to assess for underlying plaque formation and help guide aggressiveness of therapy. • Advised formal work up for sleep apnea and treatment if indicated as this is another potential cause of his fatigue.

15. Discussion (1 of 3)

16. Discussion (2 of 3)

17. Discussion (3 of 3)

18. One Year Follow-Up on Metformin 750 (1 of 2) • Familial Combined Hyperlipidemia and Metabolic Syndrome – Improved. • On metformin 750 mg/day only one daily • LDL-P lowered from 1950 to 1244. Triglycerides dropped to 111 from 357. Total cholesterol at 150. HDL-C increased to 38 from 29. IR-score lowered to 54 from 66. Optimal is <45. • Elevated Lipoprotein(a) – Improved. • Levels improved to 42 mg/dL, but still high. • Reassuring that lipoprotein(a) cholesterol is normal (<2 mg/dL). Lipoprotein cholesterol estimates false positives that result from the Lp(a) mass immunoassay. • Additional less well proven strategies to lower Lp(a) include aspirin 81-150 mg/day, omega 3 fish oil 3000/day, low carb diet, ground flax 2 tbsp/day, raw almonds ¼ cup/day, CO Q 10 150 mg/day. • Metformin and normalizing thyroid may also reduce Lp(a). No indication for thyroid treatment. • Recommend aggressively lowering LDL-P with statin or niacin therapy.

19. One Year Follow-Up on Metformin 750 (2 of 2) • Vitamin D Deficiency – Improved. • Not taking any vitamin D supplements. • Levels improved from 30 to 38. Optimal is >60-90. • Start vitamin D3 2000-4000 IU/day. Take D3, not D2. Choose an oil based capsule rather than a tablet for better absorption.

20. One Year Follow-Up Labs on Metformin 750 (1 of 5)

21. One Year Follow-Up Labs on Metformin 750 (2 of 5)

22. One Year Follow-Up Labs on Metformin 750 (3 of 5) THIS TESTING OPTIONAL: Platelet genetics obtained here but not needed as he is not on Plavix therapy. Reassuring Factor V and prothrombin normal as he has other risks for hypercoagulable state.

23. One Year Follow-Up Labs on Metformin 750 (4 of 5)

24. One Year Follow-Up Labs on Metformin 750 (5 of 5)

25. NMR LipoProfile • Insert NMR Lipoprofile 06212011 JW71 Insert

26. Clinical Pearls • The lipoprotein changes we see in insulin resistance are early markers that may help determine if a patient is on the path toward diabetes years before any glucose abnormality is seen. This patient has small dense LDL-P, large VLDL-P increase, large HDL-P decrease with normal HbA1C. The lipoprotein shifts are summarized in the abnormal IR score (normal is <45/100). • See data from IRAS and WHS on the next 2 slides. This additional information obtained from the NMR lipoprofile changed our plan for management with this patient. This type of pattern is also more likely to respond to aggressive diet and exercise changes.

27. Results From the Insulin Resistance Atherosclerosis Study NMR lipoprotein particle concentrations in normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and diabetes (DM) subjects. Goff, Metabolism 2005;54:264-70

28. Women’s Health Study Adjusted hazard ratios for the association of lipoprotein measure with incident type 2 diabetes in quintiles 1 through 5 Mora et al. 2010. Diabetes

29. Case Summary Note Lp(a) was done with 2 different assays and cannot be compared between 2 visits.

30. References • Otvos JD, Mora S, Shalaurova I, et al. Clinical implications of discordance between low-density lipoprotein cholesterol and particle number. J ClinLipidol. 2011 Mar-Apr 5(2):105-13. • Contois JH, McConnell JP, Sethi AA, et al. Apolipoprotein B and cardiovascular disease risk: position statement from the AACC Lipoproteins and Vascular Diseases Division Working Group on Best Practices. Clin Chem. 2009 Mar;55(3):407-19. • Taddei S, Caraccio N, Virdis A. et al. Impaired endothelium-dependent vasodilation in subclinical hypothyroidism: beneficial effect of levothyroxine therapy. J ClinEndocrinolMetab 2003 Aug;88(8):3731-7. • Diagnosis and classification of diabetes mellitus. Diabetes Care. Jan 2010;33 Suppl 1:S62-9. • Standards of medical care in diabetes. Diabetes Care. Jan 2012;35 Suppl S20. • Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet. Sep 12 1998;352(9131):854-65. • KnowlerWC,Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393-403. • Orchard TJ, Temprosa M, Goldberg R, et al. The effect of metformin and intensive lifestyle intervention on the metabolic syndrome: the Diabetes Prevention Program randomized trial. Ann Intern Med 2005; 142:611-619.

31. References • 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. • 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. 2007 J ClinLipidol. Dec;1(6):583-92 • 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. • Mora S, Otvos JD, Rosenson RS, et al. Lipoprotein particle size and concentration by nuclear magnetic resonance and incident type 2 diabetes in women. Diabetes. 2010 May;59(5):1153-60. • Nordestgaard B, Chapman M, Ray K, et al. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J. 2010 Dec;31(23):2844-53. • 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. • Giovannucci E, Liu Y, Hollis B, Rimm E. 25-hydroxyvitamin d and risk of myocardial infar • Holick M. Vitamin D Deficiency. N Engl J Med. 2007;357:266-81.ction in men. Arch Intern Med. 2008;168(11):1174-1180. • Jockers B. Vitamin D sufficiency: An approach to disease prevention. The American Journal for Nurse Practitioners. 2007;11(10):43-50.