Page 1

Athens, July 4, 2009

New oral antidiabetic drugs: DPP-4 inhibitors and incretin mimetics Prof dr Nebojsa M. Lalic School of Medicine, University of Belgrade, Institute for Endocrinology, Diabetes and Metabolic Diseases, Clinical Center of Serbia Serbian Acadademy of Sciences and Arts, Belgrade, Serbia


New oral antidiabetic drugs: DPP-4 inhibitors and incretin mimetics • The use of oral agents in type 2 diabetes treatment: present state • The incretin effect and the role of GLP-1 • The therapeutic effects of incretin-based treatment: DPP-4 inhibitors and incretin mimetics • Incretin-based therapeutic agents in the recommendations for type 2 diabetes treatment


New oral antidiabetic drugs: DPP-4 inhibitors and incretin mimetics • The use of oral agents in type 2 diabetes treatment: present state • The incretin effect and the role of GLP-1 • The therapeutic effects of incretin-based treatment: DPP-4 inhibitors and incretin mimetics • Incretin-based therapeutic agents in the recommendations for type 2 diabetes treatment


Kahn S et al, Nature, 2006; 444:840


Natural History of Type 2 Diabetes Obesity

Glucose (mg/dL)

Relative Function (%)

350 300 250 200 150 100 50 250 200 150 100 50 0

IFG*

Diabetes Uncontrolled Hyperglycemia

Post-meal Glucose Fasting Glucose

€ Insulin Resistance

Insulin Level -Cell Failure

-10

-5

*IFG=impaired fasting glucose.

0

5

10

15

20

25

30

Years of Diabetes DeFronzo RA. Ann Intern Med. 1999; 131:281-303.


Current Treatment Goals for Glycemic Control

ADA1

ACE2

IDF3

HbA1c

<7.0% (general goal)

≤6.5%

<6.5%

Preprandial capillary plasma glucose

70–130 mg/dL

<110 mg/dL

<110 mg/dL

(3.9–7.2 mmol/L)

(<6.0 mmol/L)

(<6.0 mmol/L)

<180 mg/dL

<140 mg/dL

<145 mg/dL

(<10.0 mmol/L)

(<7.7 mmol/L)

(<8.0 mmol/L)

Peak postprandial capillary plasma glucose

ACE=American College of Endocrinology; ADA=American Diabetes Association; HbA1c=hemoglobin A1c; IDF=International Diabetes Federation Adapted from: 1ADA / EASD consensus statement: Nathan DM, et al. Diabetes Care. 32:193–203; 2American Association of Clinical Endocrinologists, American College of Endocrinology. Endocr Pract. 2002; 8 (Suppl 1): 5–11; 3International Diabetes Federation. Global Guideline for Type 2 Diabetes. Brussels: International Diabetes Federation; 2005.

6


Optimal Glycemic Control Reduces Complications

â&#x20AC;˘ Intensive glucose control in UKPDS 33 results in: 0

12%

Percentage of Risk

Lower

Risk of Diabetesrelated Endpoints *

16% Lower

21%

24%

Lower

Risk of Myocardi al Infarction

Lower

Risk of Retinopath y at 12 Years*

25% Lower

Risk of Cataract Risk of Extraction Microvascular * Endpoints*

-50 *Decreases were statistically significant. From UKPDS 33. Lancet. 1998;352:837-853.


Treatment of diabetes 

Diet

Physical activity

Self control

Oral agents

Insulin


ADA-EASD Hyperglycemia Algorithm 1

2

3

Nathan et al. Diabetologia (2006) 49:1711â&#x20AC;&#x201C;1721


ADA/EASD consensus, October, 2008


Principles in selecting antihyperglycemic interventions 

Choice of specific antihyperglycemic agents is predicated on:  

 

 

their effectiveness in lowering glucose, extraglycemic effects that may reduce long-term complications, safety profiles, tolerability, ease of use, expense Diabetes Care 2009; 32:1–11


Step 1: lifestyle intervention and metformin ď Ž

ď Ž

The authors recognize that for most individuals with type 2 diabetes, lifestyle interventions fail to achieve or maintain the metabolic goals either because of failure to lose weight, weight regain, progressive disease, or a combination of factors. Therefore, the consensus is that metformin therapy should be initiated concurrently with lifestyle intervention at diagnosis. Diabetes Care 2009;32:1â&#x20AC;&#x201C;11


Step 1: lifestyle intervention and metformin 

Metformin is recommended as the initial pharmacological therapy, in the absence of specific contraindications, for its effect on glycemia, absence of weight gain or hypoglycemia, generally low level of side effects, high level of acceptance, and relatively low cost. Metformin treatment should be titrated to its maximally effective dose over 1–2 months, as tolerated. Rapid addition of other glucose-lowering medications should be considered in the setting of persistent symptomatic hyperglycemia. Diabetes Care 2009;32:1–11


Step 2: addition of a second medication 

If lifestyle intervention and the maximal tolerated dose of metformin fail to achieve or sustain the glycemic goals, another medication should be added within 2–3 months of the initiation of therapy or at any time when the target A1C level is not achieved. The consensus regarding the second medication added to metformin was to choose either insulin or a sulfonylurea. The A1C level will determine in part which agent is selected next, with consideration given to the more effective glycemia-lowering agent, insulin, for patients with an A1C level of 8.5% or with symptoms secondary to hyperglycemia. Diabetes Care 2009;32:1–11


Extrapolation of the time of deterioration of beta-cell dysfunction

Beta-cell function (%)

100 80 60 40 20 0 –12

–10

–8

–6 –4 –2 Years from diagnosis

UKPDS 16. Diabetes 1995;44:1249–1258

0

2

4

6


β-cell Function Continues to Decline Regardless of Intervention in T2DM Progressive Loss of β-cell Function Occurs prior to Diagnosis

100

Sulfonylurea (n=511) Diet (n=110)

Metformin (n=159)

β-cell Function (%)*

80

60

40

20

0 –5

–4

–3

–2

–1

0

1

2

3

4

5

6

Years since Diagnosis T2DM=type 2 diabetes mellitus *β-cell function measured by homeostasis model assessment (HOMA) Adapted from UKPDS Group. Diabetes. 1995; 44: 1249–1258.

19


Traditional Current Oral Therapies Do Not Address Islet Cell Dysfunction

Pancreatic Islet Dysfunction

Insulin Resistance (Impaired insulin action) Inadequate glucagon suppression (-cell dysfunction)

Metformin

TZDs

Insufficient Insulin secretion (β-cell dysfunction)

Progressive decline of β-cell function

Sulfonylureas Glinides

TZD=thiazolidinedione; T2DM=type 2 diabetes mellitus Adapted from DeFronzo RA. Br J Diabetes Vasc Dis. 2003; 3 (Suppl 1): S24–S40.

20


New oral antidiabetic drugs: DPP-4 inhibitors and incretin mimetics • The use of oral agents in type 2 diabetes treatment: present state • The incretin effect and the role of GLP-1 • The therapeutic effects of incretin-based treatment: DPP-4 inhibitors and incretin mimetics • Incretin-based therapeutic agents in the recommendations for type 2 diabetes treatment


The Incretin Effect Ingested glucose results in a more robust insulin response than glucose administered intravenously, indicating the presence of substances within the gastrointestinal tract that stimulate insulin release in a glucose-dependent manner. Creutzfeldt. Diabetologia. 1985;28:565.


Measurement of the Incretin Effect OGTT and Matched IV Infusion

200

Glucose (mg/dL)

Insulin (pmol/L)

400

Oral 150

300

100

200

50

100

0 -30

IV

0 0

30 60 90 120 150 180 210

-30

Time (min)

Nauck MA, et al. J Clin Endocrinol Metab. 1986 Aug;63(2):492-498.

0

30

60 90 120 150 180 210

Time (min)


Definition of Incretins â&#x20AC;&#x153;Gut-derived factors that increase glucose-stimulated insulin secretionâ&#x20AC;?

In cre tin Intestine

Secretion

Insulin

Creutzfeldt. Diabetologia. 1985;28:565.


The Incretins GLP-1: Glucagon-Like Peptide 1 H A E G T F T S D V S S Y L E G Q A A K A K F L R I V E W G G

GIP: Gastric Inhibitory Polypeptide Glucose-Dependent Insulinotropic Polypeptide

A

E G T F I S D Y S I A M D K I H Q K K G K A L L W N V F D Q D N W Q K T Q I N H Y

Amino acids shown in yellow are homologous with the structure of glucagon.

Drucker. Diabetes Care. 2003;26:2929.


GLP-1 and GIP are Synthesized and Secreted from the Gut in Response to Food Intake L-cell (ileum)

ProGIP

Proglucagon

GLP-1 [7–37]

GLP-1 [7–36 NH2]

GIP [1–42]

K-cell (jejunum)

GIP=glucose-dependent insulinotropic peptide; GLP-1=glucagon-like peptide-1 Adapted from Drucker DJ. Diabetes Care. 2003; 26: 2929–2940. 26


GLP-1: An Intestinal Hormone • Secreted from L cells in the intestinal mucosa after meals • Effects – Stimulates insulin secretion – Suppresses glucagon secretion – Delays gastric emptying – Enhances satiety – Enhances -cell mass/replication in animals

• Rapidly degraded by the protease dipeptidyl peptidase IV (DPP-IV) Drucker. Diabetes Care. 2003;26:2929.


Inhibition of DPP-4 Increases Active GLP-1 Meal Intestinal GLP-1 release

GLP-1 t½=1–2 min Active GLP-1 DPP-4

GLP-1 inactive (>80% of pool) DPP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1 Adapted from Rothenberg P, et al. Diabetes. 2000; 49 (Suppl 1): A39. Abstract 160-OR. Adapted from Deacon CF, et al. Diabetes. 1995; 44: 1126–1131. 28


Dimeric Structure of DPP-4 / CD26 Cytosol

Intracellular

Cell membrane

N Extracellular

Rasmussen, H.B., et al, (2003) Nat.Struct.Biol., 10, 19-25

C

C

N


Drucker D. Cell Metabolism 3, 153â&#x20AC;&#x201C;165, 2006


Contrasting roles of GLP-1 and GIP on glucose homeostasis

Drucker D. Cell Metabolism 3, 153â&#x20AC;&#x201C;165, 2006


Incretin Actions on Different Target Tissues Neuroprotection Appetite Brain Stomach Heart

Gastric emptying

Cardioprotection Cardiac output

GLP-1

Liver GI tract

Insulin biosynthesis ď ˘ cell proliferation ď ˘ cell apoptosis

Insulin sensitivity Muscle

Glucose production Drucker D. J. Cell Metabolism 2006

Insulin secretion Glucagon secretion


ď ˘-Cell Secretory Response 40

38.9 34.7

(mmol/L/min)

Insulin

35 30

23.5

25 20 15

11.3

10 5 0

NGT

Glucose:

T2DM

Contributions of Incretin Factors (%)

The Incretin Effect Is Reduced in T2DM Compared With NGT Incretin Effect 80

72.8

70 60 50 40

30.0

30 20 10 0

NGT

T2DM

Oral (50 g) IV (isoglycemic infusion) NGT=normal glucose tolerance

Nauck. Diabetologia. 1986;29:46.


Release of GLP-1 Is Impaired in Patients With T2DM 20

GLP-1 (pmol/L)

Breakfast

*

*

*

*

NGT IGT T2DM

*

15

*

*

10 * 5

0 0

60

120

180

240

Time (min) *P<0.05 vs T2DM NGT = normal glucose tolerance IGT = impaired glucose tolerance Toft-Nielsen. J Clin Endocrinol Metab. 2001;86:3717


6-Week Subcutaneous GLP-1 Infusion Treatment Effects in 20 Patients With T2DM

Saline

GLP-1

(n=9*)

(n=10)

Baseline A1C (%)

Rx Effect

8.9

9.2

A1C (%)

+0.2

-1.3

-1.5%

Weight (kg)

-0.7

-1.9

-1.2 kg

*One patient was excluded because no veins were accessible. Zander. Lancet. 2002;359:824.


GLP-1 Actions are Glucose Dependent in Patients with Type 2 Diabetes mmol/L 15.0 12.5 10.0 Fasting 7.5 Glucose 5.0

*

*

*

*

*

*

250 mg/dL 200 150 100 50

*

*P <0.05

Infusion pmol/L

Insulin

mU/L

250 200 150 100 50

*

*

Placebo GLP-1

*

*

*

*

*

*

*

*

n = 10

40 30 20 10 0

pmol/L 20

Glucagon

15 *

10

*

5

0

60

120 180 Minutes

240 Nauck NA, et al. Diabetologia. 1993;36:741-744.


Effect of GLP-1 on β-cell mass in Zucker diabetic fatty rats β-Cell mass

β-Cell proliferation 30

12

8

4

Proliferating β-cells (%)

P<0.01

P<0.05

2.0 1.5 1.0 0.5

Control

GLP-1 treated

Farilla et al. Endocrinology. 2002;143:4397.

20 P<0.001

10

0

0

0

Apoptotic β-cells (%)

2.5

16

β-Cell mass (mg)

β-Cell apoptosis

Control

GLP-1 treated

Control

GLP-1 treated


Effect of GLP-1 on ď ˘-Cell Apoptosis in Isolated Human Islets

Apoptotic Nuclei (%)

Control

18.9

20

15.5 15

Day 1

P<0.01 for days 3 and 5 8.9

10

+ GLP-1

Day 3

6.1

Day 5

5

0

Control

GLP-1

Farilla, L. et al. Endocrinology 144: 5149-5158, 2003


1. Endocrinology 2003; 2. J Hypertens 2003; 3. Circulation 2004; 4. Diabetes 2005; 5. Am j Physiol Endo Metab 2004


JPET 317:1106–1113, 2006


Changes in LVEF after 72 hours of rGLP-1 infusion versus control subjects

Circulation. 2004;109:962-965.


New oral antidiabetic drugs: DPP-4 inhibitors and incretin mimetics • The use of oral agents in type 2 diabetes treatment: present state • The incretin effect and the role of GLP-1 • The therapeutic effects of incretin-based treatment: DPP-4 inhibitors and incretin mimetics • Incretin-based therapeutic agents in the recommendations for type 2 diabetes treatment


Pharmacologic Approaches to Enhancing GLP-1 Action in Diabetes

â&#x20AC;˘ GLP-1 receptor agonists â&#x20AC;˘ DPP-IV inhibitors

Drucker. Diabetes Care. 2003;26:2929. Dungan. Clin Diabetes. 2005;23:56.


Pharmacologic Approaches to Enhancing GLP-1 Action in Diabetes

• GLP-1 receptor agonists – Mimetics • Possess physiologic characteristics and biologic activity of native GLP-1 but resist degradation by DPP-IV • Exenatide (exendin-4)

– Analogues • Half-lives increased by modification of rHu GLP-1 to resist DPP-IV degradation • Liraglutide Drucker. Diabetes Care. 2003;26:2929. Dungan. Clin Diabetes. 2005;23:56.


Exenatide Lowered HbA1c at 30 Weeks Placebo BID Exenatide 5 µg BID Exenatide 10 µg BID

0.5

SFU

MET

0.2

0.1

0.1 Change in HbA1c (%)

MET + SFU

0

-0.5 -0.4

-0.5

*

*

-0.6

* -1

-0.8

*

-0.9

*

ITT population; Mean (SE); MET (N = 336), SFU (N = 377), MET + SFU (N = 733); *P <.005 vs placebo. Mean baseline HbA1c ranged from 8.2% to 8.7% across all trial arms. Exenatide DeFronzo RA, et al. Diabetes Care. 2005;28:1092-1100.; Buse JB, et al. Diabetes Care. 2004;27:2628-2635.; GEX060209 Kendall DM, et al. Diabetes Care. 2005;28:1083-1091.

-0.8

*


Exenatide Reduced Body Weight Over 30 Weeks Placebo BID Exenatide 5 µg BID Exenatide 10 µg BID

MET 0

10

SFU 20

30

0

10

20

30

MET + SFU 10 20

0

30

Change in Weight (kg)

0 -0.5

* -1.0

-1.5

*

*

* **

-2.0 -2.5 -3.0 -3.5

*

* *

**

*

*

** ** Time (week)

** Time (week)

Time (week)

ITT population; Mean (SE); MET (N = 336), SFU (N = 377), MET + SFU (N = 733); *P <.05 vs placebo; **P <.001 vs placebo. Mean baseline weight ranged from 95 kg to 101 kg across all trial arms. Exenatide DeFronzo RA, et al. Diabetes Care. 2005;28:1092-1100.; Buse JB, et al. Diabetes Care. 2004;27:2628-2635.; GEX060209 Kendall DM, et al. Diabetes Care. 2005;28:1083-1091.

*


Exenatide once weekly versus twice daily for the treatment of type 2 diabetes - DURATION-1 Study Effect on HbA1c

Drucker D et al. Lancet 2008; 372: 1240â&#x20AC;&#x201C;50

Exenatide GEX060209


Exenatide once weekly versus twice daily for the treatment of type 2 diabetes - DURATION-1 Study Effect on body weight

Drucker D et al. Lancet 2008; 372: 1240â&#x20AC;&#x201C;50

Exenatide GEX060209


Exenatide once weekly versus twice daily for the treatment of type 2 diabetes - DURATION-1 Study Effect on cardiovascular parameters

Drucker D et al. Lancet 2008; 372: 1240â&#x20AC;&#x201C;50

Exenatide GEX060209


HbA1c (%)

0

12

1.9 mg OD

0.5

2.0 mg OD

Up to 10 µg twice daily

0.75 mg OD

1.0

Up to 2 mg weekly

Glycaemic effects of GLP-1 agonists: HbA1c

5

14 wks

Exenatide BID Exenatide LAR 1/week Liraglutide OD Placebo Insulin glargine

-0.5 -1.0

Glimepiride

*

*

*

*

-1.5 -2.0

Drucker and Nauck, Lancet 2006;368:1696-705

* *

* Significant differences vs. placebo or respective comparator; if no comparator shown, results placebo-subtracted. †AMIGO I; ††AMIGO II; †††AMIGO III


Change in body weight (kg)

15

26

15

2

12

5

1.9 mg OD

30

3

2.0 mg OD

Duration (weeks)

0.75 mg OD

Weight effects of GLP-1 agonists

14 wks

Exenatide BID Exenatide LAR 1/week

1

Liraglutide OD

0

Placebo Insulin glargine

-1

Glimepiride

-2

*

-3

-4 -5

*

*

*

*

*

*

Drucker and Nauck, Lancet 2006;368:1696-705; Kim et al, Diabetes Care 2007; In press

*

* Significant differences vs. placebo or respective comparator; if no comparator shown, results placebo-subtracted. †AMIGO I; ††AMIGO II; †††AMIGO III


Side effects of GLP-1 agonists: nausea 100 Exenatide BID

* 40

*

* * *

12

14 wks

Liraglutide OD Placebo Insulin glargine Glimepiride

*

* 20

5

1.9 mg OD

60

2.0 mg OD

Exenatide LAR 1/week 0.75 mg OD

Nausea (%)

80

* *

0

Drucker and Nauck, Lancet 2006;368:1696-705; Kim et al, Diabetes Care 2007; In press

* Significant differences vs. placebo or respective comparator; if no comparator shown, results placebo-subtracted. †AMIGO I; ††AMIGO II; †††AMIGO III


Pharmacologic Approaches to Enhancing GLP-1 Action in Diabetes

• DPP-IV inhibitors – Advantage of oral administration – Improve glucose tolerance and increase insulin release

• Vildagliptin, sitagliptin

Drucker. Diabetes Care. 2003;26:2929. Dungan. Clin Diabetes. 2005;23:56.


Initial Combination Therapy With Sitagliptin Plus Metformin Study: HbA1c Results at 104 Weeks (Extension Study) APT Population (Extension Study) Sitagliptin 100 mg qd (n=50)

Sitagliptin 50 mg bid + metformin 500 mg bid (n=96)

Metformin 500 mg bid (n=64)

Sitagliptin 50 mg bid + metformin 1000 mg bid (n=105)

LSM HbA1c Change From Baseline, %

Metformin 1000 mg bid (n=87)

24-week phase

9.0

Continuation phase

Extension Study Mean baseline A1C = 8.5%–8.7%

8.5 8.0

–1.1 a 7.5

–1.1 a

7.0

–1.3 –1.4

6.5

–1.7

6.0 0

6

12

18

24

30

38

46

54

62

70

78

91

104

APT=all-patients-treated; bid=twice a day; LSM=least-squares mean; qd=daily.Weeks aValues represented are rounded. Actual values are 1.15 for sitagliptin 100 mg qd and 1.06 for metformin 500 mg bid. D. Willams-Herman et al. Substantial Improvement in β-cell Function with Initial Combination Therapy of Sitagliptin and Metformin in Patients with Type 2 Diabetes after 1 Year of Treatment, Poster presented at ADA 2008


HbA1c With Sitagliptin or Glipizide as Add-on Combination With Metformin: Comparable Efficacy Per-protocol Population LSM change from baseline at 52 weeks (for both groups): –0.7%

8.2 8.0

Sulfonylureaa + metformin (n=411) Sitagliptinb + metformin (n=382)

7.8

HbA1c, % ±SE

7.6

Achieved primary hypothesis of noninferiority to sulfonylurea

7.4 7.2 7.0 6.8 6.6 6.4

6.2 0

6

12

18

24

Weeks

30

38

46

52

aSpecifically

glipizide ≤20 mg/day; 100 mg/day with metformin (≥1500 mg/day). LSM=least squares mean. SE=standard error. bSitagliptin

Adapted from Nauck MA, Meininger G, Sheng D, et al, for the Sitagliptin Study 024 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trial. Diabetes Obes Metab. 2007;9:194–205 with permission from Blackwell Publishing Ltd., Boston, MA.


Sitagliptin With Metformin Provided Weight Reduction (vs Weight Gain) and a Much Lower Incidence of Hypoglycemia All-patients-as-treated Population Least squares mean change from baseline 3

Hypoglycemia

Sulfonylureaa + metformin (n=416)

Sulfonylureaa + metformin (n=584)

Sitagliptinb + metformin (n=389)

Sitagliptinb + metformin (n=588)

Body Weight, kg ± SE

2

1  between groups at Week 52 = –2.5 kg

0

P<0.001

−1

−2

−3

Patients With ≥1 Episode Over 52 Weeks, %

50

40

32% P<0.001

30

20

10

5%

0 0

12

24

38

52

Week 52

Weeks aSpecifically

glipizide ≤20 mg/day; bSitagliptin (100 mg/day) with metformin (≥1500 mg/day); Least squares mean between-group difference at week 52 (95% CI): change in body weight at Week 52 = –2.5 kg [– 3.1, –2.0] (P<.001); Least squares mean change from baseline at week 52: glipizide: +1.1 kg; sitagliptin: –1.5 kg (P<.001). Add-on sitagliptin with metformin vs sulfonylurea with metformin study. Adapted from Nauck MA, Meininger G, Sheng D, et al, for the Sitagliptin Study 024 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trial. Diabetes Obes Metab. 2007;9:194–205 with permission from Blackwell Publishing Ltd., Boston, MA.


Vildagliptin Enhances GLP-1 Levels in Patients with T2DM Meal 16.0

Vildagliptin 100 mg (n=16)

*

Placebo (n=16)

Active GLP-1 (pmol/L)

* *

12.0

*

*

*

*

*

**

8.0

* * * 4.0

0.0 17:00

20:00

23:00

02:00

GLP-1=glucagon-like peptide-1; T2DM=type 2 diabetes mellitus Time *P <0.05. Balas B, et al. J Clin Endocrinol Metab. 2007; 92: 1249â&#x20AC;&#x201C;1255. Vildagliptin 100 mg once daily was used in this study. Galvus (vildagliptin) is approved for 50 mg once or twice daily in combination with metformin or a TZD, and Galvus (vildagliptin) 50 mg once daily in combination with a sulfonylurea.

05:00

08:00

63 63


Vildagliptin Add-on to Metformin: Significantly Lowers HbA1c over 52 Weeks Duration: 52 weeks Vilda add-on to met

Vilda 50 mg daily + met (extension, ITT n=42) PBO + met (extension, ITT n=29) Vilda 50 mg daily + met (core, ITT n=56)

8.4

PBO + met (core, ITT n=51)

HbA1c (%)

8.0

P <0.0001  –1.1 0.2%

7.6

P <0.0001 7.2

6.8 −4

0

4

8

12

16

20

24

28

32

36

40

44

48

52

Week n refers to ITT population. HbA1c=hemoglobin A1c; ITT=intention-to-treat; met=metformin; PBO=placebo; vilda=vildagliptin Adapted from Ahrén B, et al. Diabetes Care. 2004; 27: 2874–2880.

64


Vildagliptin: as Effective as Glimepiride when Added to Metformin at 52 Weeks Duration: 52 weeks Add-on to met: vilda vs glim

Add-on Treatment to Metformin (~1.9 g Mean Daily) Vildagliptin 50 mg twice daily + metformin

Mean HbA1c (%)

Glimepiride up to 6 mg once daily + metformin

â&#x2C6;&#x2019;0.4% NI: 97.5% CI (0.02, 0.16)

â&#x2C6;&#x2019;0.5%

Time (Weeks) CI=confidence interval; glim=glimepiride; HbA1c=hemoglobin A1c; met=metformin; NI=not inferior; vilda=vildagliptin Per protocol population. Vildagliptin (n=1396); glimepiride (n=1393). Ferrannini E, et al. Diabetes Obes Metab. 2008; Epub ahead of print.

65


Vildagliptin: No Weight Gain Add-on Treatment to Metformin (~1.9 g Mean Daily)

Body Weight (kg)

Duration: 52 weeks Add-on to met: vilda vs glim

â&#x2C6;&#x2019;1.8 kg difference

Time (Weeks) Vildagliptin 50 mg twice daily + metformin Glim=glimepiride; met=metformin; vilda=vildagliptin Per protocol population. Vildagliptin (n=1396); glimepiride (n=1393). Ferrannini E, et al. Diabetes Obes Metab. 2008; Epub ahead of print. Data on file, Novartis Pharmaceuticals, LAF237A2308.

Glimepiride up to 6 mg once daily + metformin 66


Vildagliptin Improves Postprandial Lipid and Lipoprotein Metabolism Plasma TG

Chylomicron TG

0.8

4.0

0.6

3.0

mmol/L

mmol/L

3.5 2.5 2.0

0.4 0.2

1.5

1.0 −1 0 1 2 3 4 5 6 7 8

0.0 −1 0 1 2 3 4 5 6 7 8

Chylomicron apo B-48

Chylomicron cholesterol

0.08

0.50

0.30 0.20 0.10 0.00 −1 0 1 2 3 4 5 6 7 8 Time (h)

0.06 mmol/L

0.40 mg/L

Before vilda, Week 0 (n=13) Vilda 50 mg twice daily, Week 4 (n=15)

0.04 0.02 0.00 −1 0 1 2 3 4 5 6 7 8 Time (h)

Vilda=vildagliptin Matikainen N, et al. Diabetologia. 2006; 49: 2049–2057. 67


Vildagliptin: Mean Change in Blood Pressure in T2DM Patients with SBP >140 mmHg and DBP >90 mmHg Duration: 52 weeks Vildagliptin vs metformin

DBP n= BL=

89 94

SBP 53 94

150 149

84 150

Change from BL (mmHg)

0.0

-4.2

-5.0

-5.3

-7.5

* -10.0

-9.1

*

BL=baseline; DBP=diastolic blood pressure; SBP=systolic blood pressure; T2DM=type 2 diabetes mellitus *P <0.05 vs metformin. Bosi E, et al. Presented at ADA Annual Meeting, June 22-26, 2007; Chicago, IL. Abstract 521-P.

Vildagliptin 50 mg twice daily Metformin 1000 mg twice daily 68


Overall Incidence of Serious Cardiovascular Events by Treatment Safety population up to 24 weeks

Odds Ratio Serious CV events

n/N (%)

Vilda 50 mg qd*

08/1469 (0.54)

0.79

Vilda 50 mg bid*

25/4594 (0.54)

0.79

Placebo

09/1304 (0.69)

Vilda 50 mg qd**

08/1469 (0.54)

0.70

Vilda 50 mg bid** 25/4594 (0.54)

0.70

All comparators

Vildagliptin 50 mg once daily Vildagliptin 50 mg twice daily

34/4357 (0.78) 0.01

0.1 Vildagliptin better

1

10

100

Vildagliptin worse

*Comparison vs placebo; **Comparison vs all comparators. bid=twice daily; comparators=all non-vildagliptin treatment groups; CV=cardiovascular; qd=once daily; vilda=vildagliptin Kothny W, et al. Poster 915. Presented at: 44th Annual Meeting of the European Association for the Study of Diabetes; September 7-11, 2008; Rome, Italy.

69


Glycaemic effects of DPP-4 inhibitors: HbA1c 50 mg 25 100 mg mg

1.0

Up to 100 mg

Up to 200 mg

100 mg Placebo

0.5

Vildagliptin

HbA1c (%)

0

Sitagliptin Metformin

-0.5

Rosiglitazone

* -1.0

*

*

*

*

-1.5 -2.0

Drucker and Nauck, Lancet 2006;368:1696-705

* *

* * Significant differences vs. placebo or respective comparator; if no comparator shown, results placebo-subtracted


Weight effects of DPP-4 inhibitors Duration (weeks) 3

12

52

12

52

24

Change in body weight (kg)

Insulin glargine Vildagliptin

*

Sitagliptin

0 -1

24 Placebo

2 1

18

*

Metformin Rosiglitazone

-2 -3 -4 -5

Drucker and Nauck, Lancet 2006;368:1696-705

* Significant differences vs. placebo or respective comparator; if no comparator shown, results placebo-subtracted


Side effects of DPP-4 inhibitors: nausea 100

Nausea (%)

80 60

Placebo Insulin glargine Vildagliptin Sitagliptin Metformin

40 20 0

Drucker and Nauck, Lancet 2006;368:1696-705

* Significant differences vs. placebo or respective comparator; if no comparator shown, results placebo-subtracted


New oral antidiabetic drugs: DPP-4 inhibitors and incretin mimetics • The use of oral agents in type 2 diabetes treatment: present state • The incretin effect and the role of GLP-1 • The therapeutic effects of incretin-based treatment: DPP-4 inhibitors and incretin mimetics • Incretin-based therapeutic agents in the recommendations for type 2 diabetes treatment


Incretin mimetics and DPP-4 inhibitors: major differences Properties/effect

Incretin mimetics

DPP-4 inhibitors

Mechanism of stimulation of insulin secretion exclusively through GLP-1 effect

Yes

Unknown

Restitution of insulin secretion (2 phases)

Yes (exenatide)

Yes

Hypoglycaemia

No

No

Maintained counter-regulation by glucagon in hypoglycaemia

Yes

Not tested

Inhibition of gastric emptying

Yes

Marginal

Effect on body weight

Weight loss

Weight neutral

Side effects

Nausea

None observed

Administration

Subcutaneous

Oral

Gallwitz. Eur Endocr Dis. 2006


Road Maps to Achieve Glycemic Control In Type 2 Diabetes Mellitus ACE/AACE Diabetes Road Map Task Force Chairpersons Paul S. Jellinger, MD, MACE, Co-Chair Jaime A. Davidson, MD, FACE, Co-Chair

Task Force Members Lawrence Blonde, MD, FACP, FACE Daniel Einhorn, MD, FACP, FACE George Grunberger, MD, FACP, FACE Yehuda Handelsman, MD, FACP, FACE Richard Hellman, MD, FACP, FACE Harold Lebovitz, MD, FACE Philip Levy, MD, FACE Victor L. Roberts, MD, MBA, FACP, FACE

Š 2007 AACE. All rights reserved. No portion of the Roadmap may be altered, reproduced or distributed in any form without the express permission of AACE. Revision March 2008


Road Map to Achieve Glycemic Goals: Naïve to Therapy (Type 2) Achieve ACE Glycemic Goals† ( FPG, PPG, and A1C )

Initial A1C%

If ≤ 6.5% A1C Goal Not Achieved

Initial Therapy

Lifestyle

Modification

6-7

Intervention

Continuous Titration of Rx ( 2 - 3 months )

Assess FPG and PPG

Preferred: • Metformin4 • TZD10,11,12 • AGI • DPP-4 Inhibitor

Alternatives • Glinides • SU (low dose) • Prandial insulin5,8

Monitor / adjust Rx to maximal effective dose to meet ACE Glycemic Goals

Intensify Lifestyle Modification Intensify or combine Rx including incretin mimetic*1

If ≤ 6.5% A1C Goal Not Achieved

Lifestyle

Modification

7-8

Combine Therapies

Target: PPG and FPG

• Metformin • Glinides • AGI • TZD12 • SU • DPP-4 Inhibitor + met • Colesevelam + met, SU or insulin

6,7

Alternatives • Prandial insulin5,8 • Premixed insulin preparations8 • Basal insulin analog9

* Available as exenatide †ACE Glycemic Goals 1 Indicated for patients not at goal despite SU and/or metformin or TZD therapy; incretin mimetic is not indicated for ≤ 6.5% A1C insulin-using patients < 110 mg/dL FPG 4 Preferred first agent in most patients < 110 mg/dL Preprandial 5 Rapid-acting insulin analog (available as lispro, aspart and glulisine), inhaled insulin, or regular insulin < 140 mg/dL 2-hr PPG 6 Appropriate for most patients 7 2 or more agents may be required 8 Analog preparations preferred 9 Available as glargine and detemir 10 A recent meta-analysis suggests a possible link of rosiglitazone to cardiovascular events; other studies do not confirm or exclude this risk. The FDA has stated “In their entirety, the available data on the risk of myocardial infarction are inconclusive.” 11 Cannot be used in NYHA CHF Class 3 or 4 12 According to the FDA, rosiglitazone not recommended with insulin Access Roadmap Endocr Pract. 2007;13:260-268

at: www.aace.com/pub

Monitor / adjust Rx to maximal effective dose to meet ACE Glycemic Goals

Intensify Lifestyle Modification Intensify or combine Rx, including incretin mimetic with SU, TZD, and/or metformin

ACE/AACE Diabetes Road Map Task Force Paul S. Jellinger, MD, MACE, Co-Chair Jaime A. Davidson, MD, FACE, Co-Chair Lawrence Blonde, MD, FACP, FACE Daniel Einhorn, MD, FACP, FACE George Grunberger, MD, FACP, FACE Yehuda Handelsman, MD, FACP, FACE Richard Hellman, MD, FACP, FACE Harold Lebovitz, MD, FACE Philip Levy, MD, FACE Victor L. Roberts, MD, MBA, FACP, FACE

Revision March 2008

© 2007 AACE. All rights reserved. No portion of the Roadmap may be altered, reproduced or distributed in any form without the express permission of AACE.


Road Map to Achieve Glycemic Goals: Naïve to Therapy (Type 2) Achieve ACE Glycemic Goals† ( FPG, PPG, and A1C )

Initial A1C%

Combine Therapies to Address FPG and PPG7

Lifestyle

Modification

8-9

Intervention

Target: FPG and PPG

• Metformin • TZD10,11,12 • SU • Glinides • DPP-4 Inhibitor • Basal insulin analog9

• Prandial • Premixed insulin preparations8 • NPH • Other approved combinations

insulin5,8

Continuous Titration of Rx ( 2 - 3 months )

If ≤ 6.5% A1C Goal Not Achieved

Monitor / adjust Rx to maximal effective dose to meet ACE Glycemic Goals

Intensify Lifestyle Modification Intensify or combine Rx including prandial insulin5,8, incretin mimetic1, or amylin analog** (with prandial insulin5,8)

If ≤ 6.5% A1C Goal Not Achieved

Lifestyle

Modification

9 - 10

Target: FPG and PPG

Combine Therapies to Address FPG and PPG7 • Prandial insulin5,8 • Metformin • TZD12 • Premixed insulin preparations8 • SU • NPH • Glinides • Basal insulin analog9 • Other approved combinations

Monitor / adjust Rx to maximal effective dose to meet ACE Glycemic Goals

Intensify Lifestyle Modification Initiate or intensify insulin therapy or add incretin mimetic1

** Available as pramlintide 1 Indicated for patients not at goal despite SU and/or metformin or TZD therapy; incretin mimetic is not indicated for †ACE Glycemic Goals insulin-using patients ≤ 6.5% A1C 5 Rapid-acting insulin analog (available as lispro, aspart and < 110 mg/dL FPG glulisine), inhaled insulin, or regular insulin < 110 mg/dL Preprandial 7 2 or more agents may be required < 140 mg/dL 2-hr PPG 8 Analog preparations preferred 9 Available as glargine and detemir 10 A recent meta-analysis suggests a possible link of rosiglitazone to cardiovascular events; other studies do not confirm or exclude this risk. The FDA has stated “In their entirety, the available data on the risk of myocardial infarction are inconclusive.” 11 Cannot be used in NYHA CHF Class 3 or 4 Access Roadmap 12 According to the FDA, rosiglitazone not recommended with insulin Endocr Pract. 2007;13:260-268

at: www.aace.com/pub

ACE/AACE Diabetes Road Map Task Force Paul S. Jellinger, MD, MACE, Co-Chair Jaime A. Davidson, MD, FACE, Co-Chair Lawrence Blonde, MD, FACP, FACE Daniel Einhorn, MD, FACP, FACE George Grunberger, MD, FACP, FACE Yehuda Handelsman, MD, FACP, FACE Richard Hellman, MD, FACP, FACE Harold Lebovitz, MD, FACE Philip Levy, MD, FACE Victor L. Roberts, MD, MBA, FACP, FACE Revision March 2008

© 2007 AACE. All rights reserved. No portion of the Roadmap may be altered, reproduced or distributed in any form without the express permission of AACE.


How to treat hyperglycemia, Finland + metformin

Diabetes: K채yp채 hoito -suositus, Duodecim 2007


NICE clinical guideline 87, May 2009


Pharmacologic Targets of Current Drugs Used in the Treatment of T2DM GLP-1 analogues Improve pancreatic islet glucose sensing, slow gastric emptying, improve satiety

DPP-4 inhibitors Prolong GLP-1 action leading to improved pancreatic islet glucose sensing, increase glucose uptake

Sulfonylureas Increase insulin secretion from pancreatic -cells Glinides Increase insulin secretion from pancreatic -cells DDP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1; T2DM=type 2 diabetes mellitus Adapted from Cheng AY, Fantus IG. CMAJ. 2005; 172: 213–226. Ahrén B, Foley JE. Int J Clin Pract 2008; 62: 8-14.

Thiazolidinediones Decrease lipolysis in adipose tissue, increase glucose uptake in skeletal muscle and decrease glucose production in liver

-glucosidase inhibitors Delay intestinal carbohydrate absorption

82

010_LALIC  

Prof dr Nebojsa M. Lalic School of Medicine, University of Belgrade, Institute for Endocrinology, Diabetes and Metabolic Diseases, Clinical...

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