Learning Objectives. Outline 4/3/2018. Treatment Strategies to Maximize the Value of Diabetes Medications

Transcription

1 Treatment Strategies to Maximize the Value of Diabetes Medications Presenters: Jennifer Toy, PharmD, BCACP and Crystal Zhou, PharmD, APh AHSCP, BCACP Learning Objectives 1. Discuss which patients may benefit from lowdose pioglitazone therapy. 2. Identify which patients are candidates for NPH vs long-acting analog insulins. 3. Describe the appropriate patient population to use GLP-1 analogs and SGLT-2 inhibitors. 4. Determine when to use c-peptide testing to guide therapeutic options. Outline I. Low-dose pioglitazone II. NPH vs long-acting insulin analogs III. GLP-1 analogs and SGLT-2 inhibitors IV. C-peptide testing 1

2 LOW-DOSE PIOGLITAZONE MS is a 48 yo female referred to the clinical pharmacist for diabetes management. Medical History: Type 2 diabetes, ASCVD 12% Essential hypertension Dyslipidemia Major depressive disorder Gastroesophageal reflux disease Tension type headache Labs Date A1C TC LDL HDL TG 11/18/ /15/ /4/ /4/ /6/ /12/ Vitals BP HR Wt (kg) 146/ / / / / /

3 Medication list 1. Amlodipine 5 mg po twice daily 2. Aspirin 81 mg po daily 3. Atorvastatin 80 mg po daily 4. Chlorthalidone 25 mg po daily 5. Citalopram 40 mg po daily 6. Humalog Kwikpen 55 units subcut with meals 7. Ibuprofen 600 mg po q6h prn pain 8. Toujeo Solostar 75 units subcut twice daily 9. Losartan 100 mg po daily 10. Metformin 1000 mg po twice daily 11. Omeprazole 20 mg po daily 12. Ondansetron 4 mg po q8h prn nausea 13. Pioglitazone 45 mg po daily 14. Liraglutide 1.8 mg subcut daily Diabetes medications 1. Metformin 1000 mg po twice daily 2. Toujeo Solostar 75 units subcut twice daily 3. Humalog Kwikpen 55 units subcut with meals 4. Pioglitazone 45 mg po daily 5. Liraglutide 1.8 mg subcut daily Theory Pioglitazone causes weight gain, exacerbates heart failure, and increases a patient s risk for bladder cancer. 3

4 Diabetes medications 1. Metformin 1000 mg po twice daily 2. Toujeo Solostar 75 units subcut twice daily 3. Humalog Kwikpen 55 units subcut with meals 4. Pioglitazone 45 mg po daily 5. Liraglutide 1.8 mg subcut daily Randomized Controlled Trial Majima et al. 2006, f/u for 6 months, Japanese women N=84, Age 58 yo, newly diagnosed T2DM, A1C ~7.6%, BMI ~24, no previous diabetes therapy Intervention: randomized to pioglitazone 7.5 mg vs 15 mg and encouraged lifestyle modifications Outcomes: metabolic control, weight gain, and incidence of edema Results * p<0.05, p< Majima, T. et al. Endocr. J. 53, (2006). 4

5 = pioglitazone 7.5 mg/day = pioglitazone 15 mg/day Results Peripheral Edema Group A: 2 Group B: 11 p= Majima, T. et al. Endocr. J. 53, (2006). Randomized Controlled Trial Rajagopalan et al. 2015, f/u for 12 weeks, Southeast Asian patients N=90, Age 50 yo, 3.5 years of T2DM, A1C ~8.4%, BMI 26, already on metformin +/- sulfonylurea for >3 months Intervention: randomized to pioglitazone 7.5 mg vs 15 mg vs 30 mg and encouraged lifestyle modifications Outcomes: glycemic and safety parameters Results B. DECREASING THE INSULIN REQUIREMENT Table 2 Efficacy Parameters Pioglitazone 7.5 mg Pioglitazone 15 mg Pioglitazone 30 mg Baseline 12 week Baseline 12 week Baseline 12 week A1C (%) 8.2 ± ± 1.2* 8.4 ± ± 1.2* 8.5 ± ± 0.9* TC (mg/dl) 178 ± ± ± ± ± ± 33.2 LDL (mg/dl) ± ± ± ± ± ± 39.5 HDL (mg/dl) 44.9 ± ± 10.6* 41.7 ± ± 8.6* 43.2 ± ± 8.3* Weight (kg) 70.1 ± ± ± ± 11.2* 69.2 ± ± 10.5* BMI 26.4 ± ± ± ± 4.5* 25.9 ± ± 3.8* * = p<0.05 Rajagopalan, S. et al. Diabetes Research and Clinical Practice 109, e32 e35 (2015). 5

6 Panikar et al. 2015, f/u for 6 months, Asian Indian patients N=237, Age 56 yo, <2 years of T2DM, A1C ~7.6%, BMI 26.7, on oral therapy including pioglitazone Intervention: patients taking pioglitazone 7.5 mg or 15 mg or 30 mg and instructed to follow lifestyle changes Outcomes: doses of pioglitazone on glycemic control and weight gain Results Group A= 7.5 mg pioglitazone/day Group B= 15 mg pioglitazone/day Group C= 30 mg pioglitazone/day Panikar, V. et al. Journal of the Association of Physicians of India 63, (2015). Patient MS 1. Metformin 1000 mg po twice daily 2. Toujeo Solostar 75 units subcut twice daily 3. Humalog Kwikpen 55 units subcut with meals 4. Pioglitazone 45 mg po daily 5. Liraglutide 1.8 mg subcut daily Plan: Decrease to half a tablet of pioglitazone (22.5 mg) po daily 6

7 Conclusions 1. Low-dose (7.5 mg) is as effective as the initial dose (15 mg) of pioglitazone in terms of A1C reduction 2. There is significantly less weight gain with lowdose pioglitazone 3. The maximum effective dose of pioglitazone is 15 mg per day NPH VS LONG-ACTING INSULIN ANALOGS CG is a 70 yo female who presents to clinic today for a DM visit. She brings her medications but says she has been out of insulin for the last week. She recently hit the Medicare Part D gap and has to pay out of pocket for her Lantus. She said she can t afford the $600 cost at this time (needs Lantus 2 vials per month). The medical resident asks for your help. He says he has heard Lantus is the safest option because it causes less nocturnal hypoglycemia and is more effective than the other long-acting insulins such as NPH. 7

8 What are your other therapeutic insulin options? What is your recommendation taking into account and addressing the resident s concerns? Theory Lantus (glargine) causes less nocturnal hypoglycemia than NPH. No peak? No danger? 8

9 Study Name Eliaschewitz (24 weeks) Fritsche (24 weeks) Rosenstock (28 weeks) Riddle (24 weeks) Hypoglycemia Defined? Yes No Yes Yes Types of Hypoglycemia Symptomatic Nocturnal symptomatic Confirmed nocturnal symptomatic Severe symptomatic All episodes All episodes of symptomatic Nocturnal Severe Symptomatic Nocturnal Severe Events per patient year All Symptomatic Confirmed (BG <72 mg/dl) Confirmed (BG <56 mg/dl) All Nocturnal Confirmed (BG <72 mg/dl) Confirmed (BG <56 mg/dl) Rates of Hypoglycemia by type Glargine QHS NPHQHS p value 52.8 % 20.4 % 16.9 % 2.6 % QHS 68 % 43 % 23 % 1.8 % QAM 74 % 56 % 17 % 2.1 % 61.3% 31.3 % 0.04 % (n=1) % 34.8 % 30.0% 4.4 % QHS 75% 58 % 38 % 2.6 % 66.8 % 40.2 % 2.3 % (n=6) <0.001 < > <0.001 > <0.02 <0.005 <0.03 <0.001 <0.001 <0.002 Hsia Yes not BG driven QHS (24 weeks) Symptomatic 6.7 % Nocturnal 0.2 % Fasting 1.8 % Severe 0 M. Mojtahedzadeh et al. / Journal of Diabetes and Its Complications 29 (2015) QAM 9.6 % 0.3 % 3.2 % 0 QHS 8.2 % 0.3 % 4.2 % 0 >0.05 NS >0.05 NS >0.05 NS What About Severe Hypoglycemia? Solomon et al 2013 N=8626 Observational Pts had avg of 4 yrs s/p insulin initiation Prescribed OADs + insulin therapy Authors Conclusions Newer, basal analogues were associated with lower risk of severe hypoglycemia events relative to premixed, isophane (NPH) and rapid-acting insulin Solomon M et al. Diabetes Research and Clinical Practice 2013; Solomon et al 2013 Rate Solomon M et al. Diabetes Research and Clinical Practice 2013;

10 Long-acting insulin analogues versus NPH insulin for T2DM [Cochrane Review] Included 8 studies comparing long-acting insulin analogues to NPH insulin in type 2 DM patients Conclusions: Consistent reduction in symptomatic or overall hypoglycemic effects for therapy with long-acting insulin analogues BUT defining symptoms by hypoglycemia may make results prone to bias Advantage of glargine and detemir could be lowering of nocturnal hypoglycemic events BUT bias cannot be ruled out Horvath K et al. Cochrane Database of Systematic Reviews 2007, Issue 2. Art. No.: CD DOI: / CD pub3. What are your other therapeutic insulin options? NPH, glargine (Lantus, Basaglar), detemir (Levemir), pre-mixed What is your recommendation taking into account and addressing the resident s concerns? Consider # injections, cost, and flexibility desired. Risk of severe hypos ~ SGLT-2 INHIBITORS AND GLP- 1 ANALOGS 10

11 Theory I saw that commercial on TV for <insert name of SGLT2 or GLP-1 agonist> and it says it will help reduce my risk of heart related death. SO is a 58 yo Cambodian speaking male who presents to clinic for DM f/u. At last visit one month ago, you optimized his metformin dose to 1000mg po bid and increased his glipizide to 10mg po bid. Pt refuses to start insulin, saying, My brother was started on insulin and then he went on dialysis and died about 3 months later. I don t mind poking myself, I just don t want insulin. PMH: DM type 2 x 7yrs, HTN, CAD, CHF BP 144/82 HR 87; Wt: lbs, Ht: 65 inches Pertinent Labs: SCr 0.9, A1c 10.3% Meds: Metformin 1000mg po bid Glipizide 10mg po bid Famotidine 20mg po bid prn acid reflux Metoprolol succinate ER 25mg po qday Atorvastatin 80mg po qhs Enalapril 10mg po bid 11

12 ADA 2018 says SGLT2s significantly reduce CV events in patients with type 2 DM Empagliflozin* Canagliflozin* Dapaglizflozin American Diabets Association (ADA). Standards of medical care in diabetes Diabetes Care 2018; 41(Suppl. 1):S86 S104 American Diabets Association (ADA). Standards of medical care in diabetes Diabetes Care 2018; 41(Suppl. 1):S86 S

13 Meds: Metformin 1000mg po bid Glipizide 10mg po bid Famotidine 20mg po bid prn acid reflux Metoprolol succinate ER 25mg po qday Atorvastatin 80mg po qhs Enalapril 10mg po bid START empagliflozin 10mg po qday If pt was open to an injection but not insulin you could consider a GLP-1 agonist Which one would you choose for our patient with PMH: DM type 2 x 7yrs, HTN, CAD, CHF? Theory A GLP-1 agonist is a GLP-1 agonist is a GLP-1 agonist. They all lower CV risk equally. 13

14 American Diabets Association (ADA). Standards of medical care in diabetes Diabetes Care 2018; 41(Suppl. 1):S86 S104 American Diabets Association (ADA). Standards of medical care in diabetes Diabetes Care 2018; 41(Suppl. 1):S86 S104 S009 Conclusions/ Liraglutide only GLP-1 with proven CV benefit so far Consider # and frequency of injections and ADEs Meds: Metformin 1000mg po bid Glipizide 10mg po bid Metoprolol succinate ER 25mg po qday Atorvastatin 80mg po qhs Enalapril 10mg po bid START liraglutide 0.6mg SQ daily x 1 week then increase to 1.2mg SQ daily thereafter 14

15 C-PEPTIDE TESTING Theory If a patient is not producing c- peptide, there is no point in starting a sulfonylurea or incretin mimetic. Background C-peptide Produced in equal amounts to insulin Best measure of endogenous insulin secretion 1. Jones, A. G. & Hattersley, A. T. Diabet Med 30, (2013)

16 Background Clinical Utility of C-Peptide Testing 1. Classification of diabetes 2. Detecting absolute insulin deficiency 3. Assessing treatment response Jones, A. G. & Hattersley, A. T. Diabet Med 30, (2013). Review Article Summary of the role of c-peptide, focusing on postprandial c-peptide to glucose ratio to assess beta cell function Discuss clinical utility for managing glycemic control in T2DM Pathogenesis of Type 1 and 2 Diabetes Saisho, Y. Int. J. Mol. Sci. 17, (2016). 16

17 Progression of Diabetes Saisho, Y. Int. J. Mol. Sci. 17, (2016). NGT= normal glucose tolerance IGT= impaired glucose tolerance Insulin Secretagogues and Incretin Mimetics 1. Sulfonylureas 2. Incretin mimetics Assessing Treatment Response PCPRI: post-prandial c-peptide/glucose FCPRI: fasting c-peptide/glucose Saisho, Y. Int. J. Mol. Sci. 17, (2016). 17

18 Example MS s c-peptide, random 2.3 ng/ml (6 nmol/l) MS s glucose, random 362 mg/dl Calculate c-peptide to glucose ratio (PCPRI) 2.3/362 = x 100 = < 1.53 Plan: Discontinue liraglutide 1.8 mg subcut daily Conclusions 1. C-peptide testing can be used to determine patient s beta-cell function 2. C-peptide testing x1 is more cost-effective than trialing a medication, e.g. Victoza, x3 months Thank You! Speaker Contact Information: Jennifer Toy, PharmD, BCACP Clinical Pharmacist Specialist Highland Hospital Alameda Health System Phone: (510) jentoy@alamedahealthsystem.org 18

19 Thank You! Speaker Contact Information: Crystal Zhou, PharmD, APh, AHSCP-CHC, BCACP Assistant Clinical Professor University of California, San Francisco Phone: (415)