Case Category: Diabetes

1. 48 Year Old Female with Elevated Cholesterol, Abnormal LFTs, Hypothyroidism, and Undiagnosed Diabetes Case Category: Diabetes History of present illness: 48 year old female with fatigue, difficulty sleeping and concentrating. History of elevated cholesterol (no prior treatment) and hypothyroidism (briefly treated with Synthroid).

2. Patient Information

3. Patient History

4. Current Medications

5. Labs Worth Noting on No Medications

6. Questions to Consider • Question 1: Multiple untreated conditions? Assess motivation to start several therapies. New diabetes diagnosis is a very important secondary cause for abnormal lipids/lipoproteins/triglycerides. This should be focus of initial treatment. • Question 2: Diet review is critical. Avoid simple sugars, carbohydrates, and alcohol. • Question 3: Any evidence of end organ disease from diabetes? Has patient ever had any renal issues? Is creatinine normal? Seeing an ophthalmologist regularly?

7. Criteria for the Diagnosis of Diabetes ADA. I. Classification and Diagnosis. Diabetes Care 2012;35(suppl 1):S12. Table 2.

8. Labs on No Medications (1 of 3)

9. Labs on No Medications (2 of 3)

10. Labs on No Medications (3 of 3)

11. NMR Lipoprofile • Insert NMR LipoProfile 03112010 TP61 Insert • Insert NMR LipoProfile 03112010 TP61 Insert Page 2

12. Initial Treatment & Management • Advised low glycemic, low saturated fat diet and daily exercise. • Start metformin ER 750 mg 2-3 tablets daily with slow titration as tolerated. • Start Byetta10 mcg injectable twice daily. (Start with 5 mcg BID x 1 month and then increase to 10) • Start Crestor 5 mg/day due to >60 % reduction LDL needed. • Start Fish Oil OTC 2000 mg with EPA and DHA at meal. • Increase Vitamin D3 to 5000 IU daily and 50,000 IU/weekly for vitamin D deficiency. • Follow-up with PCP regarding elevated TSH.

13. Discussion (1 of 3)

14. Discussion (2 of 3)

15. Discussion (3 of 3)

16. Follow Up – 1 on Crestor 5, Byetta 10 BID, Metformin 1500 • Type II Diabetes – Improved. • HbA1c lowered to 7.5. • As Byetta is hard to dose with meals and she is skipping on occasion, switch to Victoza once daily injectable. She is an excellent candidate for GLP 1 agonist as glucose is on average at 180. • Increase metformin to 2250 mg/day. • Dyslipidemia – Improved. • On Crestor 5 mg/day. • LDL-P is down to 1140 from 2098. LDL-C was 167 and is now 67. Triglycerides are down to 131 from 222. Continue low dose for now as tolerating. • Vitamin D Deficiency – Improved. • Levels increased at 2400 IU/day from 7 to 41. • Increase to 5000 IU/day. • Continue therapy. • Elevated TSH – Unchanged. • Consulted specialist. Thyroid ultrasound showed nondescript, nodules left lobe. • Referred to endocrinologist.

17. Follow Up Labs on Crestor 5, Byetta 10, Metformin 1500

18. Follow-Up 2 on Crestor 5, Victoza 1.8 and Metformin 2250 (1 of 2) • Vitamin B12 Deficiency • Vitamin B12 is low at 304. • Cause of B12 deficiency may be due to metformin, bacterial flora changes that 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. • Start sublingal 1000 mcg/day and recheck. • Foods high in B12 that are also heart healthy include sockeye salmon, plain yogurt, milk and roasted chicken. • Type II Diabetes – Improved. • HbA1c is now 5.7. • On Victoza but having issues with injection. • Try Cycloset 0.8 mg/day as a new option of diabetes management as it does not lower glucose to the extent of causing hypoglycemia and works well to treat insulin resistance. Also beneficial on lipids and has been shown to reduce CVD eventsin the safety/efficacy trial.

19. Follow-Up 2 on Crestor 5, Victoza 1.8 and Metformin 2250 (2 of 2) • Vitamin D Deficiency – Suspect Improved. • Levels not checked today. • Dyslipidemia – Deteriorated. • Very high stress likely contributing to symptoms and labs worsening. • On Crestor 5 mg, Metformin 2250 mg, Victoza 1.8 mg and OTC fish oil 4 g/day. • LDL-P is up to 1181 from 661. • Advise higher dose of Crestor to 10 mg/day. • Meet with dietitian to improve diet. • Elevated TSH – Unchanged. • Seeing endocrinologist. No treatment indicated. • Elevated ALT – Improved. • Improved as expected with lipid and diabetes treatment. • Sleep Apnea • Advise work-up for sleep apnea due to disturbed sleep and increased cardiovascular risk. • May not respond well to Cycloset if sleep pattern not normal.

20. Follow-Up Labs on Crestor 5, Victoza 1.8 and Metformin 2250

21. Follow-Up 3 On Crestor 10, Cycloset 0.8 and Metformin 2250 • Diabetes Type 2 – Improved. • HbA1c is normal at 5.6. • Tolerating Cycloset. • Continue therapy. • Vitamin D Deficiency – Deteriorated. • Taking Vitamin D3 10,000 IU/day. • Consider using name brand and restarting 50,000 IU/weekly. • Dyslipidemia – Improved. • LDL-P is now 486 compared to 1181 on Crestor 10 mg, Cycloset 0.8 mg, and Omega 3. • B12 Deficiency – Improved. • Improved on supplement. • Continue due to ongoing use of high dose metformin. • Elevated CRP – Improved. • Fatigue – Improved. • Improved with treatment of vitamin D deficiency, vitamin B12 deficiency, and diabetes.

22. Follow-Up Labs on Crestor 10, Cycloset 0.8, and Metformin 2250

23. Clinical Pearls • Aggressive treatment of diabetes with medications that also help lipoprotein abnormalities is key. Here we have example of appropriate use of GLP-1 agonist in addition to metformin at initial visit when diabetes first diagnosed as HbA1C >10. • Twice daily therapy is often associated with lack of compliance. There are several options now for either once daily GLP-1 agonists or now once weekly Byetta (Bydureon) 2/2012. • Cycloset is an excellent option for diabetes management when injectable is either not desired or not effective. Use of these above combination therapies may be very effective and avoid need for starting insulin. Cycloset is weight neutral and GLP-1 agonists cause weight loss vs. the weight gain that may occur with insulin.

24. Case Summary

25. Diabetes Care: Initial Evaluation • A complete medical evaluation should be performed to • Classify the diabetes • Detect presence of diabetes complications • Review previous treatment, glycemic control in patients with established diabetes • Assist in formulating a management plan • Provide a basis for continuing care • Perform laboratory tests necessary to evaluate each patient’s medical condition ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S16.

26. Components of the Comprehensive Diabetes Evaluation (1) ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S17. Table 7.

27. Components of the Comprehensive Diabetes Evaluation (2) ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S17. Table 7.

28. Components of the Comprehensive Diabetes Evaluation (3) *See appropriate referrals for these categories. ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S17. Table 7.

29. Components of the Comprehensive Diabetes Evaluation (4) *See appropriate referrals for these categories. ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S17. Table 7.

30. Components of the Comprehensive Diabetes Evaluation (5) ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S17. Table 7.

31. Components of the Comprehensive Diabetes Evaluation (6) ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S17. Table 7.

32. Components of the Comprehensive Diabetes Evaluation (7) ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S17. Table 7.

33. 2009 ADA/EASD Revised Diabetes Treatment Algorithm STEP 1 STEP 2 STEP 3 Tier 1: Lifestyle + Metformin + Intensive Insulin Lifestyle + Metformin + Basal Insulin At Diagnosis: Lifestyle + Metformin Lifestyle + Metformin + Sulfonylurea Tier 2: Lifestyle + Metformin + Pioglitazone + Sulfonylurea Lifestyle + Metformin + Pioglitazone Lifestyle + Metformin + GLP-1 agonist Lifestyle + Metformin + Basal Insulin Reinforce lifestyle interventions at every visit. Check A1C every 3 months until A1C < 7.0%, then at least every 6 months thereafter. Change interventions whenever A1C ≥ 7.0%. GLP-1: glucagon-like peptide-1 Adapted from Nathan DM, et al. Diabetes Care. 2009;32:193-203.

34. 13 “Classes” of Agents Currently Available for Controlling Hyperglycemia Adapted from Nathan DM, et al. Diabetes Care. 2006;29:1963-1972. Nathan DM, et al. Diabetes Care. 2009;32:193-203. American Diabetes Association. Diabetes Care. 2008;31(suppl 1):S12-S54. U.S. Food and Drug Administration Center for Drug Evaluation and Research Web site. http://www.accessdata.fda.gov/Scripts/cder/DrugsatFDA. Accessed August 11, 2009. PPG: postprandial glucose

35. 13 “Classes” of Agents Currently Available for Controlling Hyperglycemia (Cont.) Adapted from Nathan DM, et al. Diabetes Care. 2006;29:1963-1972. Nathan DM, et al. Diabetes Care. 2009;32:193-203. American Diabetes Association. Diabetes Care. 2008;31(suppl 1):S12-S54. U.S. Food and Drug Administration Center for Drug Evaluation and Research Web site. http://www.accessdata.fda.gov/Scripts/cder/DrugsatFDA. Accessed August 11, 2009. DPP-4: dipeptidyl peptidase-4

36. Tier 1 Agents When metformin is not tolerated or is contraindicated: Glomerular filtration rate < 30 mL/min, Creatinine >1.5 When a large reduction in A1C is needed: A1C reduction ≥ 1.5% When medication cost is a hardship Tier 2 Agents When avoidance of hypoglycemia is important: Certain occupations (eg, drivers, heavy equipment operators, using power tools, public safety jobs) Certain populations (eg, history of hypoglycemia, alcohol use, elderly patients, renal insufficiency) When promotion of weight loss is important Selecting an Individualized Glycemic Regimen From Tier 1 or Tier 2 Adapted from Nathan DM, et al. Diabetes Care. 2009;32:193-203. Lassmann-Vague V. Diabetes Metab. 2005;31:5S53-5S57.

37. Quick Release Bromocriptine (Cycloset™) A Novel Treatment for Type 2 Diabetes also Demonstrates Improvements in Blood Pressure Improvement in Systolic and Diastolic Blood Pressure at Week 52 in Bromocriptine-QR vs. Placebo treated Subjects Hypertension Adverse Events N=1951 N=1786 N= 1536 N=814 N=662 All differences in Systolic Blood Pressure between Bromocriptine-QR and placebo groups are significant Baseline Fewer subjects randomized to Bromocriptine-QR reported adverse events of hypertension compared to placebo-treated subjects in the overall (N=3070) study population (p = 0.01) Scranton RE, et al. World Diabetes Congress Montreal 2009

38. Effect of 24 Weeks Treatment with Cycloset or Placebo on Diurnal Plasma Triglyceride and FFA levels in Subjects with Type 2 Diabetes Failing Sulfonylurea Therapy Cycloset significantly reduced plasma triglycerides by 29% and free fatty acid levels by 19% throughout the diurnal period of the day (pre- and post-meals; 7am to 7 pm) compared to placebo. †A two-way repeated measures (ANOVA) analysis of treatment and hour indicates a significant treatment effect over the entire diurnal test period for plasma triglycerides and FFA levels (P<0.0001 and P<0.02. respectively) Scranton R, Cincotta A. Expert Opin Pharmacother. 2010;11(2):269-79.

39. Time to Composite Endpoint of Non-Fatal Myocardial infarction (excluding silent MI) or Stroke or Cardiovascular Death (MACE) (ITT Population) for Bromocriptine-QR and Placebo Groups • Bromocriptine-QR + Standard of diabetes care, solid line • Placebo + Standard of diabetes care, dotted line Log Rank P < 0.05 52% RRR Number at risk Bromocriptine-QR 2054 1830 1702 1469 Placebo 1016 956 908 804 VeroScience Data on file

40. References (1 of 2) • 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. • Gerstein HC, Yusuf S, Bosch J, et al. 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, 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. • Gaziano JM, Cincotta AH, O’Connor CM, et al. Randomized clinical trial of quick-release bromocriptine among patients with type 2 diabetes on overall safety and cardiovascular outcomes. Diabetes Care. 2010 Jul;33(7):1503-8. • Pili H, Ohashi S, Matsuda M, et al. Bromocriptine: a novel approach to the treatment of type 2 diabetes. Diabetes Care 2000 Aug;23(8):1154-61. • Nathan DM, Buse JB, Davidson MB, et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2006 Aug;29(8):1963-72.

41. References (2 of 2) • Nathan DM, Buse JB, Davidson MB, et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2009 Jan;32(1):193-203. • Bolen S, Feldman L, Vassy J, et al. Systematic review: comparative effectiveness and safety of oral medications for type 2 diabetes. Ann Intern Med. 2007 Dec 18;147(12):887. • Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008 Nov 20;359(21):2195-207.