Management of Metabolic Syndrome in a 51-Year-Old Female with Premature Family History of Heart Disease

1. 51 Year Old Female with Premature Family History of Heart Disease and Metabolic Syndrome Case Category: Metabolic Syndrome History of present illness: 51 year old female with premature family history of heart disease and personal history of metabolic syndrome. At her initial visit more than 2 years ago, on no medications, her LDL-cholesterol was 113 and LDL-particle was 1814. Small LDL-particle was 1431. While her total cholesterol was under 200, her triglycerides were elevated at 178. Her HDL was low at 42 and she had a vitamin D deficiency. She is now returning for follow up and taking metformin 2250, Pravachol 80 and Niaspan 500 (unable to tolerate higher dose). She started Victoza but has not taken for 6 weeks due to insurance coverage issues. With lifestyle changes and metformin she has lost over 25 lbs.

2. Patient Information

3. Patient History

4. Current Medications

5. Labs Worth Noting on Metformin 2250, Niaspan 500 and Pravachol 80

6. Questions to Consider • Question 1: Assess willingness to continue current therapy. Are there any intolerance issues? (She would like to stop Niaspan as only on 500 and not tolerant) • Question 2: Rule out secondary cause of dyslipidemia, high triglycerides and also several lipoprotein markers of insulin resistance. IR score above optimal <45 currently 82. Treatment needs to be directed at this root cause as she is already on a maximum dose of metformin. • Question 3: Is she motivated to make lifestyle changes?

7. Labs on Metformin 2250, Niaspan 500 and Pravachol 80 (1 of 5)

8. Labs on Metformin 2250, Niaspan 500 and Pravachol 80 (2 of 5)

9. Labs on Metformin 2250, Niaspan 500 and Pravachol 80 (3 of 5)

10. Labs on Metformin 2250, Niaspan 500 and Pravachol 80 (4 of 5)

11. Labs on Metformin 2250, Niaspan 500 and Pravachol 80 (5 of 5)

12. NMR LipoProfile • Insert NMR Lipoprofile 08242011 SR60 Insert

13. Other Labs on Metformin 2250, Niaspan 500 and Pravachol 80

14. Initial Treatment & Management • Dyslipidemia is stable on Pravachol 80 and Niaspan 500. Only taking 500 mg/day due to intolerance. Recommend trying 2/day. • Restart Victoza 0.6 mg/day increasing to 1.2 in 1 week (GLP-1 agonist for diabetes) for dyslipidemia and metabolic syndrome. • Continue metformin 2250 mg/day. • Recommend taking a higher dose of omega 3 fatty acids to improve profile. • Consume less carbs and sugar. Increase exercise. • Advise home blood pressure meter.

15. Discussion (1 of 3)

16. Discussion (2 of 3)

17. Discussion (3 of 3)

18. Follow Up on Metformin 2250, Pravachol 80 and Victoza 1.8 (1 of 2) • Dyslipidemia – Improved. • On Pravachol 80 mg and metformin 2250 mg. Stopped Niaspan 500 mg due to intolerance. • Restarted Victoza 1.8. • LDL-P lowered to 780 from 1172 (despite being off Niaspan). Two years ago, LDL-P was >1800. • Metabolic Syndrome – Improved. • Restarted Victoza 1.8. On metformin 2250 mg. LDL-P and underlying insulin resistance improved. • HbA1c lowered from 5.9 to 5.3. • Insulin is still elevated at 18. There is still evidence of insulin resistance on NMR despite high dose of metformin (2250 mg) and Victoza. • Treatment of insulin resistance with lifestyle changes and medications is important to reduce progression to diabetes. The medications used to control insulin resistance and improve metabolism need to not produce hypoglycemia. Neither Victoza nor metformin cause low glucose. • Will not restart Niaspan due to side effects.

19. Follow Up on Metformin 2250, Pravachol 80 and Victoza 1.8 (2 of 2) • Elevated CRP – Deteriorated. • Levels high due to possible kidney infection. CBC was normal. • Hypertension – Improved. • Blood pressure is stable on medications. • Check urine microalbumin to see if an ACE inhibitor is appropriate. • Check aspirin works to determine whether she has activated platelets. • Vitamin D Deficiency – Deteriorated. • Vitamin D levels decreased from 58 to 37. Optimal is >60-90. • Currently taking vitamin D3 1000 IU/day. • Increase vitamin D3 to 4000 IU/day. Take D3, not D2. Choose an oil based capsule rather than a tablet for better absorption. • Low Omega 3 Index – Unchanged. • Omega 3 index is low at 4.2%. Optimal is >8-10%. • Joint aches and arthritis may improve with higher dose of omega 3 fish oil. • Recommend starting Lovaza 3-4 g/day and all at once. • To lower triglycerides and raise HDL, take 4 g/day. For cardiovascular protection, lower doses may be beneficial, but will not impact triglycerides.

20. Follow-Up Labs on Metformin 2250 ER, Pravachol 80 and Victoza 1.8 (1 of 5)

21. Follow-Up Labs on Metformin ER 2250, Pravachol 80 and Victoza 1.8 (2 of 5)

22. Follow-Up Labs on Metformin ER 2250, Pravachol 80 and Victoza 1.8 (3 of 5)

23. Follow-Up Labs on Metformin ER 2250, Pravachol 80 and Victoza 1.8 (4 of 5)

24. Follow-Up Labs on Metformin ER 2250, Pravachol 80 and Victoza 1.8 (5 of 5)

25. NMR LipoProfile • Insert NMR Lipoprofile 02012012 SR60 Insert

26. Clinical PearlsGLP 1 Agonists • Victoza and other GLP 1 agonists do not cause hypoglycemia so can be used in the prediabetic setting. Note there are no medications approved for prediabetes. We restarted Victoza 0.6 pen injection once daily with titration to higher dose of 1.8 as tolerated. Byetta BID was not chosen, which was preferred per her insurance, due to her history of pancreatitis. • Victoza signals the pancreas to make the right amount of insulin after meals (i.e. glucose dependent). It stops the liver from producing glucose when the body does not need it and slows the breakdown of how quickly glucose leaves the stomach. Victoza will likely decrease appetite. Side effects include nausea and vomiting especially if high glycemic starchy carbs are over consumed. Limit calories to 1500/day. Keep carbs at <30-50 g/meal to avoid nausea associated with Victoza. Nausea will lessen after a few weeks. Successful weight loss and weight maintenance will require regular exercise (at least 30 min/day – goal of 60-90 min/day). Not exercising and decreasing calories may cause the metabolism to slow down.

27. Potential Candidates for Incretin Therapy • Need to avoid hypoglycemia • Need to avoid weight gain and promote weight loss • Intolerant of/contraindications of other agents • Relatively close to HbA1c goal

28. Avoid or Use Incretins Cautiously • Caution in history of pancreatitis • Caution in renal insufficiency • Liraglutide contraindicated in medullary thyroid cancer or MEN2 syndrome

29. Liraglutide (Victoza) • Liraglutide vs exenatide (Byetta) • Once daily vs BID dosing • Nausea less frequent, abates faster • Reduces HbA1c 0.1-1.5% vs 0.7-0.9% • Caution with renal dysfunction and pancreatitis • Exenatide approved in October 2011 for use as an adjunct to insulin glargine with or without oral agents, Only GLP 1 receptor agonist approved for use with insulin

30. Exenatide QW (Bydureon) • Approved January 27,2012 • Bydureon is a long-acting form of the medication in Byetta (exenatide) injection so both drugs should not be used together • Bydureon is not for people with type 1 diabetes or people with diabetic ketoacidosis • Bydureon is not recommended for use in children. It is not known if Bydureon is safe and effective in people with a history of pancreatitis or severe kidney problems

31. Exenatide (Byetta) • Efficacy and safety of exenatide once weekly versus sitagliptin or pioglitazone as an adjunct to metformin for treatment of type 2 diabetes (DURATION-2): a randomised trial • Bergenstal RB et al. Lancet. 2010 Aug 7;376(9739):431-9.

32. Case Summary

33. References • 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. • 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. • 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 Feb 7;346(6):393-403. • Nathan DM, Davidson M, DeFronzo RA, et al. Impaired fasting glucose and impaired glucose tolerance: implications for care. A consensus statement from the American Diabetes Association. Diabetes Care. 2007;30:753-759. • 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. • 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 Infarction in Men. Arch Intern Med. 2008;168(11):1174-1180.