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.
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