New Diabetes Drugs: Where do they fit? Kathleen Dungan, MD 3/10/2012

Size: px

Start display at page:

Download "New Diabetes Drugs: Where do they fit? Kathleen Dungan, MD 3/10/2012"

Ferdinand Knight
7 years ago
Views:

1 New Diabetes Drugs: Where do they fit? Kathleen Dungan, MD 3/10/2012

2 Case 1 49 YO male with a 3 year history of T2DM PMH: osteoarthritis unable to exercise PE: weight 120 kg, 5 10, BP 152/90, acanthosis nigricans Metformin 1gm BID, Glimepiride 8 mg. A1C is 7.7%. 2

3 Which of the following will likely get his A1c to goal? a) Begin an exercise program b) Increase Glimepiride to 8 mg BID c) Add Repaglinide 1 mg with meals d) Add long-acting GLP-1 0% 0% 0% 0% a) b) c) d)

4 : Megitinides Thiazolidinediones 2006: DPP IV Inhibitors 2008: Colesevalem 2009: Bromocriptine 1946: Sulfonylureas 1957: Biguanide 1995: α glucosidase Inhibitors 2005: GLP 1 mimetics Amylin analogue Colesevalem 2008 Bromocriptine 2009 Saxagliptin 2009 Liraglutide 2010 Linagliptin 2011 Exenatide QW 2012 Tahrani et al. Lancet. 2011;378(9786):182 97

5 Matching Pharmacology to Physiology Incretins Glucose influx Pramlintide Glucagon secretion Hepatic glucose output Metformin Cycloset (glitazones) α Glucosidase inhibitors Incretins Pramlintide Plasma glucose Insulin SFU Glinides Incretins Insulin secretion Renal glucose excretion SGLT2 Inhibitor Glitazones (metformin) Cycloset (adipose only) Peripheral glucose uptake 5

6 Cycloset (Rapid-Release Bromocriptine) Ventromedial hypothalamus (VMH) Circadian and seasonal changes in metabolism T2DM: Early AM dip in dopaminergic tone in T2DM SNS activity Energy Insulin VMH Activity Dopa Serotonin/NE Summer Expending Sensitive Winter Conserving Resistant Defronzo Diabetes Care 2011;34:789 94

7 Given within 2 hr of awakening Peak plasma conc. 60 min 0.8 mg, titrate QW to max 4.8 mg/day Shift workers excluded from trials Efficacy Defronzo Diabetes Care 2011;34:789 94

8 Safety & Tolerability Contra-indications Orthostasis Syncopal migraines Psychotic disorders Other dopaminergic agonist therapy Tolerability N/V Dizziness, fatigue HA rhinitis

9 Kaplan Meier plot of time to first cardiovascular event T2DM treated with Cycloset or placebo for 52 weeks, N=3070. MACE: MI, stroke, death CVE: MI, stroke, hospitalization for angina or CHF, coronary revascularization, death Copyright 2011 American Diabetes Association, Inc. DeFronzo R A Dia Care 2011;34:

10 Bile Acid Sequestrant Agent in Class: Colesevalam Other BASs less selective for BA May have glucose-lowering properties More likely to bind to other meds Mechanism of action uncertain Efficacy: A1C % added to MTF, SFU or insulin LDL-C reductions of % 10 Bays HE, et al. Arch Intern Med. In press. Handelsman; Diabetes Fonseca Care VA, May et al. 2011;34 Diabetes :S244 S250 Care. 2008; 31: Goldberg RB, et al. Arch Intern Med. 2008; 168:

11 Efficacy of Colesevalem Reference N Background Baseline A1c A1c Reduction* LDL-c Reduction* (%) MTF MTF SFU Insulin MTF TG Increase* (%) *placebo adjusted except for reference 5, in which the comparator was rosiglitazone or sitagliptin and the A1c reduction was relative to baseline 1. Bays HE, et al. Arch Intern Med. 2008;168: Rosenstock et al. Endocrine Practice. 2010;16(4): Fonseca et al. Diabetes Care. 2008;31(8): Goldberg et al. Arch Intern Med. 2008;168(14): Rigby et al. Endocr Pract 2010;16:53 63 Brunetti & Campbell; Journal of Pharmacy Practice 24(4)

12 Colesevelam 3.75 gm/day Take with meals: 6 tablets QDAY or 3 tablets BID Not systemically absorbed: no dose adjustments with hepatic or renal disease Take 4 hours after Glyburide, levothyroxine, and oral contraceptives containing ethinyl estradiol and norethindrone, phenytoin, warfarin,?vitamins Welchol (colesevelam HCl) prescribing information. Daiichi Sankyo, Inc., Parsippany, NJ. January

13 Colesevalem Adverse effects: constipation Contraindications: History of bowel obstruction Serum triglycerides >500 mg/dl (those with TG >300 were excluded from trials)?fat soluble vitamins Welchol (colesevelam HCl) prescribing information. Daiichi Sankyo, Inc., Parsippany, NJ. January 2008.

14 GLP-1 Analog/mimetic and DPP-4 inhibitors: major differences Properties/effect Stimulation of insulin secretion exclusively through GLP-1 GLP-1 Analog/mimetic Hypoglycaemia No No Yes DPP-4 inhibitors Unknown Inhibition of gastric emptying Yes Marginal Effect on body weight Weight loss Weight neutral Side effects Nausea None observed Administration Subcutaneous Oral Gallwitz. Eur Endocr Dis

15 GLP-1 Based Therapies Generic Name Brand Name Dose forms Weight Contra-indications Renal dosing Interactions DPP-IV inhibitors Sitagliptin Januvia 25, 50, 100 mg Neutral Pancreatitis CrCl <30: 25 mg CrCl 30-50: 50 mg NA Linagliptin Tradjenta 5 mg Neutral Pancreatitis NA Avoid use with CYP3A4 or P-gp inducers Saxagliptin Onglyza 2.5, 5 mg Neutral Pancreatitis 2.5 mg for CrCl< mg with strong CYP3A4/5 inhibitor GLP-1 Analogues/Agonists Exenatide Byetta 5, 10 mcg twice daily Loss Pancreatitis, gastroparesis contra-indicated if CCl<30 NA Liraglutide Victoza 1.6, 1.2, 1.8 mg once daily Loss Pancreatitis, gastroparesis, MEN2, medulary thyroid CA NA NA Exenatide QW (pending FDA) Bydureon 2 mg Once weekly Loss Pancreatitis, gastroparesis, MEN2A, medullary thyroid CA? NA

16 DPP-4 Inhibitors: Pharmacologic Comparisons DPP 4 selectivity Sitagliptin Saxagliptin Linagliptin Vs. DPP 8 or 9 >2600 <100 >10,000 Effect on active GLP 1 levels Vs. DPP 2 >5550 >50,000 >100,000 2x 1.5 3x 4x Renal excretion Predominant Predominant Minor Plasma DPP 4 Inhibition >80% >80% >80% Baetta & Corsini; Drugs 2011; 71 (11):

17 Linagliptin N Duration Background Compar ator Baseline A1c A1c Reduction Taskinen wk MTF PBO Gomis wk PIO PBO Owens wk MTF + SFU PBO Del Prato wk None PBO Taskinen et al. Diabetes Obes Metab. 2011;13: Gomis et al. Diabetes Obes Metab. 2011;13: Owens et al. Diabet Med ;28(11): Del Prato et al. Diabetes Obes Metab. 2011;13:

18 Saxagliptin N Duration Background Compara tor Baseline A1c A1c Reduction Rosenstock* wk None PBO DeFronzo* wk MTF PBO Chacra* wk Glyburide Glyburide uptitration Hollander* wk TZD PBO Jadzinsky wk MTF PBO *Sustained A1c reduction over 76 weeks 1.Rosenstock et al. Curr Med Res Opin. 2009;25: DeFronzo et al. Diabetes Care. 2009;32: Chacra et al. Int J Clin Pract. 2009;6 4.. Hollander P, et al. J Clin Endocrinol Metab. 2009;94: Jadzinsky et al. Diabetes Obes Metab. 2009;11:

19 Safety of DPP-4 Meta-analysis of 53 trials at least 24 wk duration 20,312 DPP-4, 13,569 comparators 176 malignancies: MH-OR 1.02 [ ]; p= MACE: MH-OR 0.69 [ ], p = pancreatitis: 0.79 [ ], p = 0.55 Monami et al. Curr Med Res Opin 2011;27:57-64

20 Liraglutide: A1c reduction Blonde & Russell Jones. Diab Obes & Metab 2009;11:

21 Liraglutide: weight loss Garber et al. Lancet. 2009;373(9662):

22 Liraglutide vs. Exenatide Victoza associated with larger A1c reduction (0.33%, p<0.0001) Larger FBG reduction (18 mg/dl, p=0.0001) Less PPG reduction (24 mg/dl, p=0.0005) Similar weight loss 3.2 vs. 2.9 kg (p=0.22) Shorter duration of nausea (Treatment rate ratio 0.45, p<0.001), similar initial incidence Better treatment satisfaction (DTSQ, p=0.0004) Buse et al. Lancet Jul 4;374(9683):39-47.

23 Least squares mean CT concentration over 104 wk for liraglutide 0.6 mg (n = 242), 1.2 mg (n = 492), and 1.8 mg (n = 489); active comparator (n = 492); and placebo (n = 122). Hegedüs L et al. JCEM 2011;96: by Endocrine Society 23

24 24 2 mg once weekly, no dose titration

25 25

26 Adverse Event (AE) Related Withdrawals, and Selected AEs ExQW 1,2 (n = 1379) ExBID 1 (n = 147) Sita 1 (n = 329) DURATION Studies Pio 1 (n = 328) IG 1 (n = 223) MET 1 (n = 246) Lira 2 (n = 450) AE-Related Withdrawals (%) Selected AE Incidences (%)* Nausea Vomiting Diarrhea Injection-Site Nodules The relative incidence of mild-to-moderate intensity nausea was reported to decrease over time with both exenatide formulations In DURATION-2 injection-site reactions with ExQW (10%) were comparable to injection-site reactions with placebo microsphere injections (7%) *The only AEs not included in this table that occurred at an incidence of 10% in the DURATION program were nasopharyngitis in 18.4% of IG patients, upper respiratory infection in 11.2% of ExBID patients and headache in 12.2% of MET patients; AE indicates adverse event; 1. Data on file, Amylin Pharmaceuticals; 2. Buse JB, et al. EASD 2011; 75-Oral 26

27 Long-Acting GLP-1s 17 RCT, 6899 pts included Liraglutide and Exenatide QW Typically 26 weeks duration A1c reduction about 1%. 0.2% greater reduction than glargine Greater reduction than exenatide BID, sitagliptin and TZD Similar reduction to SFU (Liraglutide) Greater weight loss than most active comparators, including patients without nausea. Shyangdan et al. Cochrane Database Syst Rev Oct 5;(10):CD006423

28 AACE Guidelines Endocrine Practice 2010

29 Approach to Therapy Best Next best No Weight loss GLP 1 SFU, Insulin, TZD Weight sparing DPP 4, MTF Bromocriptine, Colesevalem SFU, Insulin, TZD Cheap MTF, SFU Insulin, AGI All others Renal disease DPP 4 (may require dose adjust) Liraglutide, Meglitinide, AGI A1c lowering Insulin LA GLP 1, MTF, TZD, SFU No hypoglycemia Postprandial control Hyperlipidemia MTF, GLP 1, DPP 4, TZD, AGI SA GLP 1 Colesevalem (except for high TG) Bromocriptine, Colesevalem DPP 4, Meglitinide, LA GLP 1, Prandial Insulin Durability GLP 1, TZD MTF? SFU MTF, TZD Insulin, SFU Rosiglitazone

30 Case 2 58 YOF with a 5-year h/o T2DM PMH: HTN, dyslipidemia, CKD Glipizide 10 mg BID monotherapy PE: BP 110/70, BMI 29, 2+ pitting edema Labwork: HbA1c 7.5% Creatinine 1.6 mg/dl Lipids: TC 198, LDLc 110 mg/dl, TG 401, HDLc 32 MCR: 1200 mg/gm

31 Which of the following is appropriate next therapy? 1. Pioglitazone 2. Colesevalem 3. RA Bromocriptine 4. Metformin 0% 0% 0% 0%

Noninsulin Diabetes Medications Summary Chart Medications marked with an asterisk (*) can cause hypoglycemia MED GROUP DESCRIPTOR

Noninsulin Diabetes Medications Summary Chart Medications marked with an asterisk (*) can cause MED GROUP DESCRIPTOR INSULIN SECRETAGOGUES Sulfonylureas* GLYBURIDE* (Diabeta) (Micronase) MICRONIZED GLYBURIDE*