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Advances in Diabetes Mellitus

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Advances in Diabetes Mellitus
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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%

* *



*p9% 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 *p60% 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




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