New Non-Insulin Therapies for Type 2 Diabetes Mellitus

Transcription

1 New Non-Insulin Therapies for Type 2 Diabetes Mellitus Ally P.H. Prebtani Associate Professor of Medicine Internal Medicine, Endocrinology & Metabolism McMaster University Canada

2 Disclosure Relationships with commercial interests: Advisory Board Member: Novo Nordisk, Eli Lilly Speakers Bureau Member: Novo Nordisk, BMS, Astra Zeneca, Eli Lilly, BI Clinical Trial Participation: Astra Zeneca, BMS Disclosure of Commercial Support This program has received financial support from Bristol Myer Squibb, Unilever, Campbell Company of Canada and Boehringer Ingelheim in the form of an unrestricted educational grant Potential for conflict(s) of interest: Novo Nordisk, Eli Lilly, Astra Zeneca, BI, and BMS developed a product that may be discussed in this program. Mitigating Potential Bias All the recommendations involving clinical medicine are based on evidence that is accepted within the profession All scientific research referred to, reported, or used is in the support or justification of patient care Recommendations conform to the generally accepted standards.

3 Objectives Outline the 2 classes of Incretin agents and their MOA Review efficacy and ADRs Understand differences between DPP-4 inhibitors and GLP-1 analogues

4 Current management often fails to achieve glycemic targets CHINA (CODIC-2) 1 HbA 1c < 7.5% CANADA (DICE) 2 HbA 1c 7% UNITED STATES (NHANES) 3 HbA 1c < 7% EUROPE (CODE-2) 4 HbA 1c < 6.5% 32% 68% 49% 51% 37% 63% 31% 69% 1 Xingbao C. Chinese Health Economics 2003; Ling T. China Diabetic Journal Harris SB et al. Diabetes Res Clin Pract 2005; 70: Saydah SH, et al. JAMA 2004; 291: Liebl A, et al. Diabetologia 2002; 45:S23 S28.

5 Individualizing A1C Targets Consider % if: which must be balanced against the risk of hypoglycemia

6 Pathophysiology of Type 2 Diabetes Liver Glucose Receptor + postreceptor defects Insulin resistance Increased glucose production Pancreas Impaired insulin secretion Peripheral Tissues (Muscle and Adipose) Adapted from Saltiel et al. Diabetes 1996; 45:

7 Promoting GLP-1 Action in T2DM Meal DPP-4 Inhibitor GLP-1 Analogue Incretin, GLP-1 DPP-4 (gut peptide hormone released from L-cells in the jejunum and ileum) X X Inactive GLP-1 insulin secretion (glucose dependent) glucagon secretion gastric emptying food intake satiety β-cell mass (long-term animal studies) Drucker DJ. Diabetes Care 2003;26: ; Drucker DJ. Curr Pharm Des 2001;7:1399; Drucker DJ. Mol Endocrinol 2003;17:161; Degn et al. Diabetes 2004;53: Mari et al. J Clin Endocrinol Metab 2005;90: GLP-1 Analogues result in pharmacologic levels of GLP-1 action, and DPP-4 inhibitors achieve physiological GLP-1 levels in the body.

8 Efficacy of DPP-4 inhibitors in add-on to metformin trials Placebo-corrected, adjusted mean change from baseline Linagliptin 2 Linagliptin 1 * Saxagliptin 3 Sitagliptin 4 Vildagliptin 5 Dosage 5 mg QD 5 mg QD 5 mg QD 100 mg QD 50 mg BID Baseline HbA 1c (%) % -0.7% -0.8% -0.8% -1.1% p-value n = < < < < <0.05 * 12 weeks treatment duration, 24 weeks otherwise 1. Linagliptin data on file 2 4 US PI for linagliptin, saxagliptin, sitagliptin 5. EU SmPC for vildagliptin

9 Liraglutide vs. Exenatide: Reduction in HbA 1c Baseline 8.2% Baseline 8.1% Both Liraglutide and Exenatide was combined with met and/or SU Mean (2SE) Buse et al. Lancet 2009; 374(9683):39 (LEAD-6)

10 Incretin Agent Plus Insulin Combination Studies Sita vs PBO Add-on to Basal or Premixed (24 wks) BL ~ 8.7% Sita + Insulin Saxa vs PBO Add-on to Basal or Premixed (52 wks) BL ~ 8.7% Saxa + Insulin Exenatide vs PBO Add-on to Glargine (30 wks) BL ~ 8.4% Exe + Glargine Detemir Add-on to Lira + Met vs Lira +Met (52 wks) BL ~ 7.6% Detemir + Lira Met * *Significant difference NS=Non-Significant difference -0.4* -0.7* -0.5* Diff. in mean Δ Weight (kg): 0 (NS) 0.3 (NS) -2.7* +0.97* (0.1kg vs 0.1 kg) (0.8kg vs 0.5kg) (-1.8kg vs 1.0kg) (-0.05kg vs -1.02kg) Vilsboll T et al. Diab Obes Metab 2010;12: Barnett A et al. EASD Annual Meeting Sept Buse J et al. Ann Intern Med 2011; 154. Bain S et al. EASD Annual Meeting Sept

11 Change in body weight (kg) Weight Reduction Over 52 Weeks With Liraglutide Waist circumference was reduced from baseline by 3.0 cm with liraglutide 1.8 mg * * Waist circumference increased by 0.4 cm with glimepiride (p < ) Time (weeks) Glimepiride 4 mg/day Liraglutide 1.2 mg/day Liraglutide 1.8 mg/day *p < for change from baseline Garber, et al. Diabetes 2008;57(suppl 1):LB3

12 1. Ratner R, et al. Cardiovascular Diabetology. 2011;10:22 2. Johansen O-E., et al. ADA 2011 Late breaker 30-LB; Accessed Sept. 23, Frederich R, et al. Postgrad Med. 2010;122(3): ;3. Williams-Herman D, et al. BMC Endocr Disord. 2010;10:7; CV Meta-analyses of Individual Incretin Agents No increased risk of CV events was observed in patients randomly treated with DPP-4 inhibitors or GLP-1R agonists FDA Upper Bound 95% Criterion for Approvability Total patients in analysis CV composite endpoint Comments Exenatide ,945 MedDRA terms for Stroke, MI, cardiac mortality, ACS, revascularization Post-hoc/ No formal adjudication Linagliptin ,239 CV death, MI, stroke, hospitalisation due to angina pectoris Pre-specified/ independent adjudication Liraglutide ,638 MedDRA terms for MACE Post-hoc/ No formal adjudication Saxagliptin ,607 MI, stroke, CV death Post-hoc/ Independent adjudication Sitagliptin ,246 MedDRA terms for MACE Post-hoc/ No formal adjudication Incretin agent better Comparator better Risk ratio for major CV events 1-5

13 SAVOUR-TIMI 53 Study The SAVOR-TIMI 53 study of saxagliptin versus placebo when added to standard of care in patients with T2DM at high CV risk demonstrated: No increased risk of CV death, or ischemic stroke Significantly improved glycemic control Prevented deterioration in microalbuminuria Increased risk of hypoglycemia Rates of pancreatitis and pancreatic cancer similar to placebo Scirica BM, et al. N Engl J Med /NEJMoa

14 Incretin-Modifying Therapies GLP-1R agonists DPP-4 inhibitors Exenatide (Byetta) Liraglutide (Victoza) Saxagliptin (Onglyza) Sitagliptin (Januvia) Linagliptin (Trajenta) Dosage Reduction in A1C Weight Hypoglycemia 10 µg bid sc 0.6; 1.2; 1.8 mg, od sc 2.5 mg, 5 mg, od, po 100 mg, od, po 5 mg od, po % % % % % Loss of 3 5 kg Loss of 3 5 kg Neutral Neutral Neutral No No No No No Nausea ++ + No No No po = oral, sc = subcutaneous Adapted from product monographs

15 Advantages and Disadvantages of Antihyperglycemic Agents Class Agent A1C Body weight Hypoglycemia Other advantages Other disadvantages Biguanides Metformin (Glucophage) Stable Rare GI side effects Incretin agents (DPP-4 inhibitors and GLP-1R agonists) Sitagliptin (Januvia) Saxagliptin (Onglyza) Linagliptin (Trajenta) Liraglutide (Victoza) Exenatide (Byetta) Stable Rare Improved postprandial control Long-term safety not established* Long-term safety not established*; injections Long-term safety not established*; injections; twice daily dosing; increased adverse events vs. liraglutide Thiazolidinediones Rosiglitazone (Avandia) Pioglitazone (Actos) Rare Durable monotherapy 6-12 weeks for maximal effect; edema, heart failure, fractures, infarcts(?); Health Canada cardiac safety alerts Insulin secretagogues (sulfonylureas and meglitinides) Glyburide (Diabeta) +++ Gliclazide (Diamicron) ++ Glimepiride (Amaryl) ++ Repaglinide (GlucoNorm) +++ Nateglinide (Starlix) ++ Improved postprandial control; newer SUs (gliclazide, glimepiride) associated with less hypoglycemia than glyburide Dosing frequency Alpha-glucosidase inhibitors Acarbose (GlucoBay) Stable Rare Improved postprandial control GI side effects; gas Insulin Human insulin No dose ceiling; many types; flexible Analog insulin ++++ regimens Injections; dosing frequency *see previous slides covering CV safety data. Adapted from: CDA Clinical Practice Guidelines Expert Committee. Can J Diabetes 2008;32(suppl 1):S1-201.

16 Treatment Options Available to Our Patient (Public System): Ontario Classes Agents A1C $/day* Biguanides Metformin (Glucophage) 0.23 Exceptional medications Regular listed medication Not listed Thiazolidinediones Rosiglitazone (Avandia) 2.87 Pioglitazone (Actos) 2.30*** Secretagogues Glyburide (Diabeta) 0.93 Glimepiride (Amaryl) 0.39 Gliclazide (Diamicron) 0.37 Repaglinide (GlucoNorm) Alpha-glucosidase inhibitors Acarbose (GlucoBay) 1.10 Insulins Human insulin 0.82 Basal insulin analogues 2.00 DPP-4 inhibitors Sitagliptin (Januvia) 2.80 Saxagliptin (Onglyza) 2.76 Linagliptin (Trajenta) 2.55 GLP-1R agonists Liraglutide (Victoza) 7.30 Exenatide (Byetta) 4.88 The patient can take a drug other than those reimbursed by the public system if he agrees to pay for it. DPP-4 = dipeptidyl peptidase-4; GLP-1R = glucagon-like peptide 1 receptor *Price of the maximum daily dose = < 1.0% reduction in A1C; = % reduction in A1C; = > 2,0% reduction in A1C Adapted from: CDA Clinical Practice Guidelines Expert Committee. Can J Diabetes 2008;32(Suppl 1):S79.

17 Antihyperglycemic agents and Renal Function CKD Stage: GFR (ml/min): < Acarbose 25 Metformin Linagliptin Saxagliptin mg Sitagliptin mg mg Exenatide Liraglutide 50 Gliclazide/Glimepiride Glyburide Repaglinide Thiazolidinediones Not recommended / contraindicated Caution and/or dose reduction Safe Adapted from: Product Monographs as of March 1, 2013; CDA Guidelines 2008; and Yale JF. J Am Soc Nephrol 2005; 16:S7-S10.

18 AT DIAGNOSIS OF TYPE 2 DIABETES L I F E S T Y L E 2013 Start lifestyle intervention (nutrition therapy and physical activity) +/- Metformin A1C <8.5% If not at glycemic target (2-3 mos) Start / Increase metformin A1C 8.5% Start metformin immediately Consider initial combination with another antihyperglycemic agent If not at glycemic targets Add an agent best suited to the individual: Patient Characteristics Degree of hyperglycemia Risk of hypoglycemia Overweight or obesity Comorbidities (renal, cardiac, hepatic) Preferences & access to treatment Other See next page Symptomatic hyperglycemia with metabolic decompensation Agent Characteristics BG lowering efficacy and durability Risk of inducing hypoglycemia Effect on weight Contraindications & side-effects Cost and coverage Other Initiate insulin +/- metformin

19 From prior page L I F E S T Y L E If not at glycemic target Add another agent from a different class Add/Intensify insulin regimen 2013 Make timely adjustments to attain target A1C within 3-6 months

20 Patient targets for incretin-based therapy GLP-1 agonists Obese type 2 diabetes patients Patients failing to maintain goals on oral agents Add-on to other agents, including insulin* Advantages weight loss easy dosing new mechanism with possible beta cell sparing DPP-4 inhibitors Dysfunctional needlephobia Add-on to other oral agents, including insulin* Advantages oral availability excellent tolerance weight neutral new mechanism with possible beta cell sparing

21 Vascular Protection Checklist 2013 A A1C optimal glycemic control (usually 7%) B BP optimal blood pressure control (<130/80) C Cholesterol LDL 2.0 mmol/l if decided to treat D Drugs to protect the heart A ACEi or ARB S Statin A ASA if indicated E Exercise regular physical activity, healthy diet, achieve and maintain healthy body weight S Smoking cessation

22 Future SGLT-2 Inhibitors New Insulins

23 CDA Clinical Practice Guidelines for professionals BANTING ( ) for patients