Advances in Diabetes Mellitus

Advances in Diabetes Mellitus Dr Noor Al Busaidi, MD Senior consultant physician Division of Endocrinology, Metabolism and Diabetes Royal Hospital President of Oman Diabetes Society Family Physicians 1st CPD 14/5/2009 Objective • Overview of T2DM • Traditional anti-diabetic medication • New anti-diabetic treatment • New approach to treat diabetes 3 Diabetes: the growing global burden 1 International Diabetes Federation (IDF):2 • Diabetes currently affects nearly 250 million people worldwide • It is expected to affect 380 million by 2025 1Adapted from IDF. E-Atlas. Available at: www.eatlas.idf.org (accessed 26.12.08). 2Diabetes Atlas, third edition© International Diabetes Federation, 2006. 4 Type 2 diabetes is a progressive disease: early intervention is critical Macrovascular complications Microvascular complications b-cell function Insulin resistance Blood glucose –10 Prevention IFG/IGT 0 Diagnosis Treatment Type 2 diabetes 10+ Years IFG: impaired fasting glucose IGT: impaired glucose tolerance Adapted from DeFronzo RA. Med Clin N Am 2004;88:787–835. 6 UKPDS: over 10 years every 1% fall in HbA1c is associated with a reduced relative risk of complications Any diabetesrelated endpoint Diabetesrelated death Allcause Myocardial mortality infarction Peripheral vascular Stroke disease‡ Microvascular disease Cataract extraction Reduction in relative risk (%) corresponding to a 1% fall in HbA1c 0 –5 –10 –15 –20 21% * 14% 21% * * 14% * 12% † 19% * –25 –30 –35 –40 –45 –50 37% 43% * * *p<0.0001 vs baseline; †p=0.035 ‡Lower extremity amputation or fatal peripheral vascular disease Adapted from Stratton IM, et al. BMJ 2000;321:405–412. 8 Current management often fails to achieve glycaemic targets CHINA (CODIC-2)1,2 HbA1c <7.5% LATIN AMERICA (DEAL)4 HbA1c <7% EUROPE (CODE-2)6 HbA1c <6.5% 32%  68% 43% 57% CANADA (DRIVE)3 HbA1c 7% 31% 69%   US (NHANES)5 HbA1c <7% 37% 53% 47%  63%  C. Chinese Health Economics 2003; 2Ling T. China Diabetic Journal 2003. 3 Braga M, et al. Presented at ADA 68th Scientific Sessions; 2008: Abstract 1212-P. 4Lopez Stewart G, et al. Rev Panam Salud Publica 2007;22:12–20. 5Saydah SH, et al. JAMA 2004;291:335–342. 6Liebl A, et al. Diabetologia 2002;45:S23–S28. 1Xingbao Education at Diabetes Diagnosis • Nature and natural history of diabetes and its progression • Lifestyle issues including nutrition, physical activity, and smoking cessation • Targets for glucose, A1C, blood pressure, LDL cholesterol, and triglycerides • Sequential therapies, including insulin, likely to be necessary • Self-monitoring of blood glucose (SMBG) • Resources available in the community American Diabetes Association. Diabetes Care. 2004;27(suppl 1):S15-S35; Riddle MC. Endocrinol Metab Clin North Am. 1997;26:659-677 11 Stepwise strategy can delay patients achieving goals and increase complications Diet and exercise OAD monotherapy OAD monotherapy uptitration OAD combination OAD + basal insulin OAD + multiple daily insulin injections 10 HbA1c(%)1 9 Mean 8 7 6 Duration of diabetes Complications2 1Adapted OAD = oral anti-diabetic from Campbell IW. Br J Cardiol 2000;7:625–631. 2Stratton IM, et al. BMJ 2000;321:405–412. 12 The case for early combination therapy: reaching and maintaining glycaemic goals Diet and exercise OAD monotherapy OAD combination Mean OAD uptitration 10 HbA1c(%)1 9 OAD + basal insulin OAD + multiple daily insulin injections 8 7 6 Duration of diabetes Complications2 1Adapted OAD = oral anti-diabetic from Del Prato S, et al. Int J Clin Pract 2005;59:1345–1355. 2Stratton IM, et al. BMJ 2000;321:405–412. The Past • Diet • Insulin • Sulfonylureas The Present • Metformin • Thiazolidinediones • Sulfonlyureas/glinides • GLP-1 agonists • DPP IV inhibitors • Alpha glucosidase inhibitors • Insulin 15 Primary sites of action of anti-diabetic agents Muscle Thiazolidinediones4 Metformin1 DPP-4 inhibitors2 Adipose tissue Liver Sodium glucose transporter-2 inhibitors5 Pancreas DPP-4 GLP-1 Insulin Glucose Kidney Intestines GLP-1 agonists3 Sulphonylureas and meglitinides1 a-glucosidase inhibitors1 1Adapted from Krentz A and Bailey C. Drugs 2005;65:358–411. 2Ahren B. Expert Opin Emerg Drugs 2008;3:593–607. 3Todd JF, et al. Diabet Med 2007;24:223–232. 4Nattrass M, et al. Baillieres Best Pract Res Clin Endocrinol Metab 1999;13:309–329. 5Jabbour S and Goldstein B. Int J Clin Pract 2008;62:1279–1284. Oral Antihyperglycemic Monotherapy Maximum Therapeutic Effect on A1C Nateglinide Acarbose Repaglinide Rosiglitazone Pioglitazone Glimepiride/ Glicazide Glipizide GITS Metformin 0 -0.5 -1.0 -1.5 -2.0 Reduction in A1C (%) Diabetes Care. 2000;23:202-207; Precose (acarbose) package insert; Drugs. 1995;50:263-288; J Clin Endocrinol Metab. 2001;86:280-288; Diabetes Care. 2000;23:1605-1611; Diabetes Care. 1996;19:849-856; Diabetes Care. 1997;20:597-606; Am J Med. 1997;102:491-497 Compliance is a major barrier to achieving glycemic control* in type 2 diabetes mellitus management therapy Compliance is likely to be influenced by safety and tolerability issues • Patients are less likely to be compliant with treatments that cause**: • weight gain • increased risk of heart attack • persistent nausea and vomiting • hypoglycemic events • A 10% increase in adherence has been associated with a 0.1% decrease in HbA1c*** *American Diabetes Association. Diabetes Care 2006;29(suppl 1):S68-9. **Hauber AB, et al. Preferences for oral antidiabetic agents among people with type 2 diabetes. Submitted to ISPOR 13th Annual Meeting, 3–7 May 2008, Toronto, Canada ***Rozenfeld Y, et al. Am J Manag Care 2008;14:71-5. Incretin-based therapies for Type 2 Diabetes • GLP-1 Receptors Agonists: Exenatide – Byetta liraglutide • DPP-4 inhibitors Sitagliptine Viladagliptin Vildagliptin offers powerful HbA1c reductions as add-on therapy to metformin, the most widely used type 2 diabetes mellitus drug Vildagliptin added to metformin lowers HbA1c by an additional 1.1% (on average) in patients not controlled with metformin* Add-on treatment to metformin (2.1 g mean daily) 8.6 8.4 Mean HbA1c (%) 8.2 8.0 7.8 7.6 Vildagliptin 50 mg twice-daily + met (n=143) PBO + met (n=130) 7.4 7.2 −4 0 4 12 16 Time (weeks of treatment) 24 −1.1% vs. PBO HbA1c: hemoglobin A1c; met: metformin; PBO: placebo p<0.001. Primary intention-to-treat population *Bosi E, et al. Diabetes Care 2007;30:890-895. Vildagliptin in combination with metformin is as effective as pioglitazone in combination with metformin Add-on treatment to metformin (2.0 g mean daily) in patients not adequately controlled on metformin alone Overall Mean BL ~8.4% 0.0 -0.2 HbA1c >9% Mean BL ~9.7% 63 58 n= 264 246 Adjusted mean change in HbA1c (%) -0.4 -0.6 -0.8 -1.0 -1.2 -1.4 -1.6 -1.8 -0.9 -1.0 Noninferior* Vilda 50 mg twice-daily + met Pio 30 mg once-daily + met -1.5 -1.5 BL: baseline; HbA1c: hemoglobin A1c; met: metformin; pio: pioglitazone; vilda: vildagliptin Per protocol population. Noninferiority of vildagliptin to pioglitazone established at both 0.4% and 0.3% margins, 95% confidence interval (0.1, 0.3). Adjusted mean change derived from analysis of covariance model. Bolli G, et al. Diabetes Obes Metab 2008;10:82-90. Vildagliptin add-on to metformin: Modest but favorable effect on blood pressure in hypertensive patients (SBP ≥140 mmHg and DBP ≥90 mmHg) Add-on treatment to metformin (2.1 g mean daily) in patients not controlled with metformin DBP 0.0 SBP 59 57 59 n= 57 Change from BL (mmHg) -2.0 -4.0 -4.0 -6.0 -8.0 -10.0 -0.9 * -6.3 * Vilda 50 mg twice-daily + met PBO + met -9.8 * BL: baseline; DBP: diastolic blood pressure; met: metformin; PBO: placebo; SBP: systolic blood pressure; vilda: vildagliptin *p<0.05 vs. BL. Bosi E, et al. Presented at ADA Annual Meeting; June 22–26, 2007; Chicago, IL. 2165-PO. Vildagliptin add-on to metformin: Neutral effect on fasting lipids Add-on treatment to metformin (2.1 g mean daily) in patients not controlled with metformin 25.0 20.0 TG 19.4 TC LDL-C HDL-C Change from BL (%) 15.0 10.0 5.0 1.0 4.8 Vilda 50 mg once-daily + met (n=142) Vilda 50 mg twice-daily + met (n=141) PBO (n=128) * 1.7 0.4 1.9 0.7 -0.5 0.2 2.0 0.0 -1.5 -1.6 -5.0 BL: baseline; HDL-C: high-density lipoprotein cholesterol; LDL-C: low-density lipoprotein cholesterol; met: metformin; PBO: placebo; TC: total cholesterol; TG: triglycerides; vilda: vildagliptin Primary intention-to-treat population; n refers to the patient number in the TG test. *p=0.014 vs. PBO; all other values did not reach statistical significance. Bosi E, et al. Diabetes Care 2007;30;890-895. Vildagliptin: Significant reductions in HbA1c when added to the sulfonylurea glimepiride (4 mg once-daily) Vildagliptin added to glimepiride lowers HbA1c by an additional 0.7% (vs. placebo)* 9.0 Vilda 50 mg once-daily + glim (n=132) Vilda 50 mg twice-daily + glim (n=132) PBO + glim (n=144) Mean HbA1c (%) Mean HbA1c (%) 8.8 8.6 8.4 8.2 8.0 7.8 7.6 −4 0 4 8 12 16 20 * −0.6% vs. PBO −0.7% vs. PBO * 24 Glim: glimepiride; HbA1c: hemoglobin A1c; PBO: placebo; vilda: vildagliptin *p<0.001 vs. PBO. Primary intention-to-treat population. Garber A, et al. Diabetes Obes Metab 2008 [Epub]. Time (weeks) Combination of vildagliptin with pioglitazone or glimepiride also caused infrequent and mild hypoglycemic events Study 2304 Study 2305 Patients Vilda 50 mg Vilda Vilda once-daily 50 mg 50 mg + pio 45 twice-daily PBO once-daily mg + pio 45 mg + pio 45 mg + glim N=146 N=158 N=158 N=170 n (%) n (%) n (%) n (%) 0 1 (0.6) 3 (1.9) 2 (1.2) PBO + glim N=176 n (%) 1 (0.6) With ≥1 hypoglycemic events Discontinued due to hypoglycemic events With grade 2 hypoglycemic events 0 0 0 0 0 0 0 0 0 0 Hypoglycemic events are defined as: (a) symptoms patient is able to self-treat, and plasma glucose is <3.1 mmol/L (grade 1); (b) symptoms patient is unable to self-treat, and plasma glucose is <3.1 mmol/L (grade 2); and (c) symptoms patient is unable to self-treat, and no plasma glucose value available (suspected grade 2). Glim: glimepiride; PBO: placebo; Pio: pioglitazone; Vilda: vildagliptin Data on file, Novartis Pharmaceuticals, CLAF237A2304, 2305. The typical vildagliptine pateint • Has received metformin as first line treatment • No longer adequately controlled , HbA1c <8.5 % • Maybe previous use of sulfonylureas with weight gain and/or hypoglycemia • Obesity , but willing to eat a healthy diet in order to attempt weight maintenance or loss • Potentially dangerous professional or recreational activities LEAD covers the continuum of T2D care, compared with standard treatments Liraglutide monotherapy vs. SU LEAD 3 Liraglutide+MET vs. SU+MET LEAD 2 Add a third oral or start insulin Add another oral agent Liraglutide+SU vs. TZD+SU LEAD 1 Liraglutide+MET+TZD vs. MET+TZD+Placebo LEAD 4 Liraglutide+MET+SU vs. glargine+MET+SU Start an oral agent LEAD 5 Liraglutide +MET, SU or both vs. exenatide +MET, SU or both Diet/exercise LEAD 6 LEAD: Liraglutide Effect and Action in Diabetes. All studies 26 weeks’ duration (LEAD 3=52 weeks); all RCT; all with double dummy except LEAD 5 vs. glargine. Studies NN2211-1436, -1572, -1573 and -1697 presented as Marre et al. Diabetes 2008;57(Suppl. 1): A4 (LEAD 1); Nauck et al. Diabetes Care 2008; published online 10.2337/dc08-1355 (LEAD 2); Garber et al. Lancet 2008; online early publication 25 Sept 2008 (LEAD 3); Russell-Jones et al. Diabetes 2008;57(Suppl. 1):A159 (LEAD 5); Blonde et al. Can J Diabetes 2008;32 (Suppl): A107 (LEAD 6). Subjects achieving HbA1c targets previously on diet/exercise Garber et al. Lancet 2008; online early publication 25 Sept 2008 Body weight change from baseline Mean±2SE Garber et al. Lancet 2008; online early publication 25 Sept 2008 SBP change from baseline Mean±2SE Garber et al. Lancet 2008; online early publication 25 Sept 2008 Efficacy summary - LEAD 3 • HbA1c reduction of 1.13% (1.8 mg), significantly greater than glimepiride • 1.6% reduction in diet-treated subjects • 51% of subjects achieved HbA1c ≤7.0% with 1.8 mg/day liraglutide • >60% diet/exercise-treated patients achieved HbA1c ≤7.0% • Rapid, sustained FPG reduction • Effect evident after only 2 weeks • Clinically-relevant weight reduction • More than 3 kg difference in weight change versus glimepiride with either dose of liraglutide • Up to 4 kg weight reduction in highest BMI subjects • Significant reduction of trunk fat mass versus glimepiride • Significant reduction in systolic blood pressure • Sustained reduction 3.6 mmHg from baseline with 1.8 mg/day liraglutide • SBP effect precedes changes in body weight Garber et al. Lancet 2008; online early publication 25 Sept 2008 Slide No 46 Liraglutide provides higher levels of GLP-1 than a DPP-4 inhibitors GLP-1 levels after 7 days’ liraglutide 6 µg/kg OD* (n=13) 120 GLP-1 (pmol/L) 90 60 30 0 8 12 16 20 Time (h) 24 Liraglutide dose GLP-1 levels after 28 days’ vildagliptin 100 mg BD (n=9) 120 GLP-1 (pmol/L) 90 60 30 0 8 12 16 20 Time (h) 24 Vildagliptin dose *GLP-1 levels for liraglutide calculated as 1.5% free liraglutide Degn et al. Diabetes 2004;53:1187–94. Mari et al. J Clin Endocrinol Metab 2005;90:4888–94 Slide No 47 Once-daily liraglutide provides high pharmacological levels of GLP-1 analog Plasma liraglutide (pmol/L) 8000 Single individual profile: steady-state reached after three doses 6000 4000 2000 1 2 3 4 5 6 7 8 Time (days) 9 10 11 12 13 Model curve fitted to 30 data points Agersø et al. Diabetologia 2002;45:195–202 Slide No 48 Steady state levels of GLP-1with liraglutide and exenatide Normalised concentration (%) exenatide BD T½ 2.4 h liraglutide OD T½ 13 h 100 50 40 30 80 60 40 20 16 12 8 20 10 0 20 0 4.0 4.5 5.0 5.5 6.0 Time after first dose (days) 6.5 0 7.0 • Modelling of plasma concentration of active drug vs maximal concentration at steady state achieved following clinically relevant doses OD or BD. Based on published exenatide data and modelled liraglutide data. Jonker et al. Diabetes 56(Suppl. 1):A160 (Abstract 0605-P) Absolute concentration 24 28 pM nM Gastrointestinal Adverse Events are Common during Treatment with Exenatide* 50 45 44% Proportion of Patients (%) 40 35 30 25 20 15 10 5 0 Nausea Vomiting Diarrhea 4% 18% 13% 6% 13% Exenatide (n=963) Placebo (n=483) *In three 30-week placebo-controlled trials. Adapted from Byetta [prescribing information]. San Diego, CA: Amylin Pharmaceuticals Inc, 2005. 47 Incidence of Hypoglycemia during Treatment with Exenatide* 40 35.7% 35 Exenatide 5 mcg bid Exenatide 10 mcg bid Placebo 27.8% Proportion of Patients (%) 30 25 20 15 10 5 0 Combination with metformin Combination with SU 5.3% 4.5% 5.3% 3.3% 14.4% 19.2% 12.6% Combination with metformin + SU bid=twice daily; GLP-1=glucagon-like peptide-1; SU=sulfonylurea *In three 30-week placebo-controlled trials; exenatide and placebo were administered before the morning and evening meals. Adapted from Byetta [prescribing information]. San Diego, CA: Amylin Pharmaceuticals Inc, 2005. 49 Gastrointestinal Adverse Events are Common during Treatment with Metformin 60 53.2% 50 40 30 20 11.7% 10 0 8.3% 12.1% 5.5% Metformin Placebo 25.5% Proportion of Patients (%) Diarrhea Nausea / Vomiting Flatulence Adapted from Glucophage, Glucophage XR [package insert]. Princeton, NJ: Bristol-Myers Squibb Company, 2004. 46 Hypoglycemia is Common with Sulfonylureas 25 Incidence of Hypoglycemia (%) 21.3% 20 15.3% 15 14% 11% 10 5% 5 2.9%* 0 Glyburide1 Chlorpropamide2 Glibenclamide3 Glimepiride3 Sulfonylureas *Hypoglycemia: fingerstick blood glucose measurement 50 mg/dL (2.75 mmol/L) 1Glucovance 3Draeger Gliclazide4 Glipizide5 [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2004. 2UKPDS Group. Lancet. 1998; 352: 837–853. KE, et al. Horm Metab Res. 1996; 28: 419–425. 4McGavin JK, et al. Drugs. 2002; 62; 1357–1364. 5Metaglip [package insert]. Princeton, NJ: Bristol-Myers Squibb Company, 2002. 48 Edema is Common with TZDs (Pioglitazone) 18 Pioglitazone1 Placebo or combination 15.3 Proportion of Patients (%) 16 14 12 10 8 6 4 2 0 Monotherapy Combination with SU Combination with metformin 1.2 4.8 2.1 2.5 7.2 6.0 7.0 Combination with insulin SU=sulfonylurea; TZD=thiazolidinedione 1Actos [prescribing information]. Indianapolis, IN: Eli Lilly and Company, 2004. 50 Use of TZDs is Associated with Increased Incidence of Congestive Heart Failure 20 DREAM Study PROactive Study 15 14 P=0.01 15 11 10 P <0.0001 Number of CHF Events 10 % Patients with HF 8 5 2 5 0 Rosiglitazone Placebo CHF=congestive heart failure; HF=heart failure; TZD=thiazolidinedione Adapted from DREAM Trial Investigators, et al. Lancet. 2006; 368: 1096–1105. 0 Pioglitazone =45 mg daily Placebo Adapted from Dormandy JA, et al. Lancet. 2005; 366: 1279–1289. 52 However most of the currently available oral treatments used to reduce HbA1C in type 2 diabetes mellitus do not address islet dysfunction Class Sulfonylureas Examples Chlorpropamide (first generation); glimepiride, glipizide (second generation) Metformin Acarbose; miglitol Rosiglitazone; pioglitazone Repaglinide; nateglinide Primary mechanism Enhance insulin secretion1 by binding to the sulfonylurea receptor Decrease hepatic glucose output; lower fasting glycemia1 Reduce the rate of polysaccharide digestion in the small intestine1 Increase insulin sensitivity of muscle, fat, and liver by modulating PPARγ1 Stimulate insulin secretion; bind to the sulfonylurea receptor at different site to sulfonylureas1 Prevent GLP-1 degradation, thereby increasing activity of incretin hormones2 Binds to GLP-1 receptors; stimulates insulin secretion; suppresses glucagon secretion; slows gastric emptying; reduces food intake3 Biguanides α-glucosidase inhibitors Thiazolidinediones Non-sulfonylurea secretagogues DPP-4 inhibitors Incretin mimetics Vildagliptin; sitagliptin Exenatide DPP-4: dipeptidyl peptidase-4; GLP-1: glucagon-like peptide-1 (7-36) amide; PPARγ: peroxisome-proliferator-activated receptor γ; 1. Nathan DM, et al. Diabetes Care 2006;29:1963-1972; 2. Richter B, et al. Cochrane Database Syst Rev 2008;CD006739; 3. Guerci B, et al. Ann Endocrinol 2008;69(3):201-209. Thank You