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