Case Category: Metabolic Syndrome

1. 32 Year Old Male with High Triglycerides, Low HDL on Fibrate Therapy, and Family History of Premature CAD Case Category: Metabolic Syndrome History of present illness: 32 year old male with high triglycerides currently on fibrate, persistently low HDL and family history of CVD.

2. Patient Information

3. Patient History

4. Current Medications

5. Labs Worth Noting on Gemfibrozil

6. Labs on Gemfibrozil

7. Labs on Gemfibrozil

8. Labs on Gemfibrozil

9. NMR LipoProfile • Insert NMR LipoProfile 05132010 ML77 Insert • Insert NMR LipoProfile 05132010 ML77 Insert Page 2

10. Questions to Consider • Question 1: Always in setting of high triglycerides, need to rule out secondary causes, in this case pre-diabetes noted. Any other secondary causes? • Question 2: BP is abnormal, so it’s important to carefully choose BP medications that will not impact triglycerides. Need to avoid beta blockers other than Carvedilol (Coreg) or Nebivolol(Bystolic), which do not raise triglycerides. May want to minimize high use of high dose HCTZ which can also raise triglycerides. Which medication options? • Question 3: CRP is borderline elevated. Does a normal LpPLA2 level change opinion of elevated CRP? If both are high consider higher risk for CVD and stroke.

11. Questions to Consider • Question 4: Always ask details about diet. Alcohol use elevates triglycerides significantly. How much? Also carb and sugar intake? Ask what the patient is drinking(fruit juice, soda, etc). These highly concentrated sugar beverages should be avoided. • Question 5: Assess compliance with twice daily Gemfibrozil. In this case the patient was regularly not able to remember to take second dose.

12. Initial Treatment & Management • Stop Gemfibrozil (temporarily). BID dosing an issue with compliance. • Start Lovaza 4g/day (prescription omega 3) all at once daily • Continue Zestoretic (HCTZ/ lisinopril) • Advise home blood pressure meter • Start metformin ER 750 mg 1-2 tablets daily with slow titration as tolerated over the next few weeks • Advise diet modification (low carb) and daily exercise • Start Vitamin D3 5000 IU/day

13. Discussion

14. Discussion

15. Follow Up – 1 Month • Mixed Hyperlipidemia / Elevated triglycerides with low HDL – Improved; Triglycerides decreased from 550 to 177 with lifestyle changes (exercise and low carbs), Metformin 1500 mg and Lovaza 4 g; Continue lifestyle changes as well as decrease alcohol to no more than 1-2 drinks/day; Avoid fruit juice and refined carbs to further lower triglycerides and diabetes risk; HDL is now <15 and likely transient and will increase over time with current treatment; Continue Metformin and Lovaza. Consider Niaspan if needed. • Metabolic Syndrome/Insulin Resistance – Initial HbA1c was 6.1 prior to starting Metformin 1 month ago; too soon to recheck HgAIC. • Hypertension – Improved; BP is 122/74. • Vitamin D Deficiency – Unchanged; Continue Vitamin D3 5000 mg/day; • Elevated Transaminases – Unchanged; It is likely that he has a fatty liver; may recommend additional labs if does not improve. • CIMT – normal.

16. Follow Up – 4 Months • Mixed Hyperlipidemia / Elevated triglycerides with low HDL – Improved; On Metformin 1500 mg and Lovaza 4 g; triglycerides dropped from 550 to 155; HDL increased from 15 to 32 and most likely due to exercise, weight loss and Lovaza increasing HDL; Total cholesterol and LDL-P have increased which is not uncommon when trying to lower triglycerides; LDL-P is still too high at 2098; Start Simvastatin 40 mg/day and Niaspan; Statin will give anticlotting and anti-inflammatory benefit which will help stabilize plaque and help prevent rupture; Recommend CO Q-10 300-600 mg/day supplement with oil if muscle aching occurs; If side effects occur, may try Crestor. • Metabolic Syndrome / Insulin Resistance – Improved; HbA1c lowered from 6.1 to 5.5; Continue Metformin 1500 mg; Weight loss of >30 pounds is exceptional; • Vitamin D Deficiency – Improved; On Vitamin D 5000 IU/day; Levels are now up to 42 from 16; Continue therapy. • Elevated Transaminases – Improved; Normalized with treatment of lipids.

17. Follow-Up Labs on Lovaza 4 and Metformin 1500

18. Follow-Up Labs on Lovaza4 and Metformin 1500

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20. Case Summary

21. Clinical Pearls Bothfibrates and high dose omega 3 are the most effective therapies for triglyceride reduction (>30-45 if triglycerides >500). Both therapies have the potential to raise LDL cholesterol due to conversion of VLDL particles to LDL particles. Some patients will have an increase in LDL-P, Apo B and others not. Certain genetic conditions such as pure type IV hypertrigylceridemia may not be associated with high cardiovascular risk only risk for pancreatitis, if they have normal Apo B/LDL-P in the setting of the very high triglycerides. NCEP guidelines have suggested we address triglycerides as primary goal of therapy if triglycerides >500. After we treat triglycerides we are able to determine if there is residual Apo B, LDL-P elevation. This is more suggestive of not a pure type IV but actually type Iib which is associated with CV risk and goal needs to be to lower Apo B/LDL-P. These patients will likely need addition of statin or other Apo B reducing agent. Gemfibrozil is very appropriate as monotherapy. When used in combination with statin there is potential drug-drug interaction so should be avoided (exception Fluvastatin). The reason initially this patient was switched to Lovaza was recognition that statin will likely be needed to control high LDL-P and due to fact triglycerides were still elevated despite therapy with fibrate. Fenofibrate is another option to use in combination with statin which would be much safer than Gemfibrozil. Also complicating this case is the underlying insulin resistance and prediabetes. Metformin response was excellent as far as glucose control but other agents may be more effective for beta cell preservation function and other add ons or alternatives (Pioglitazone, GLP-1 agonists, or Cycloset(quick release bromocriptine).

22. References • Implications of Recent Clinical Trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. Circulation. July 13, 2004;110:227-239. • National Cholesterol Education Program. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA. May 16 2001;285(19):2486-97. • Kolovou GD, Anagnostopoulou KK, Kostakou PM, et al. Primary and secondary hypertriglyceridaemia. Curr Drug Targets. Apr 2009;10(4):336-43. • Haffner SM. Secondary prevention of coronary heart disease: the role of fibric acids [editorial; comment]. Circulation. Jul 4 2000;102(1):2-4. • Roth EM, Bays HE, Forker AD, et al. Prescription omega-3 fatty acid as an adjunct to fenofibrate therapy in hypertriglyceridemic subjects. J CardiovascPharmacol. Jul 10 2009; • McKenney JM, McCormick LS, Weiss S. A randomized trial of the effects of atorvastatin and niacin in patients with combined hyperlipidemia or isolated hypertriglyceridemia. Collaborative Atorvastatin Study Group. Am J Med. Feb 1998;104(2):137-43. • 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, Hamman RF, Lachin JM, Walker EA, Nathan DM. Reduction in the incident of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346:393-403. • Gerstein HC, Yusuf S, Bosch J, Pogue J, Sheridan P, Dinccag N, Hanefeld M, Hoogwerf B, Laakso M, Mohan V, Shaw J, Zinman B, Holman RR. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomized controlled trial. Lancet 2006;368:1096-1105. • Orchard TJ, Temprosa M, Goldberg R, Haffner S, Ratner R, Marcovina S, Fowler S: 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. • GISSI-P Investigators. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzion trial. Lancet. 1999;354(9177):447-455.