Diabetes Updates

By

Dr.Karim KammeruddinConsultant Physician & Professor Of

MedicineBaqai University & Hospitals Karachi

Unmet clinical need associated with Abdominal Obesity

Patients with

abdominal obesity

(high waist

circumference)

often present with

one or more

additional

CV risk factors

CV risk factors in a typical patient with abdominal obesity

NHANES 1999–2000. http://www.cdc.gov/nchs/nhanes

Assess “Global Cardiovascular risk” in all hypertensive patients

91%

Rantala A, et al. J Intern Med 1999;245;163-74. Wannamethee S, et al. J Hum Hypertens 1998;12;735-41

Risk factors = Global CV risk

91% of hypertensive patients have at least 1 additional risk factor

Pre-diabetes* is a stage in the transition from normoglycaemia to diabetes

Genuth et al., for the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 2003;26:3160–7

Diabetes

IGT

7.8 mmol/L 11.1 mmol/L

5.6 mmol/L

6.9 mmol/L

2 hr post-load plasma glucose

Fas

ting

plas

ma

gluc

ose

*Defined as patients with IFG and/or IGTIFG: impaired fasting glucoseIGT: impaired glucose tolerance

American Diabetes Association criteria

Normal

IFG

IGT and IFG – differences in progression.Baltimore Longitudinal Study

More than 80% of people with IGT are expected to develop type 2 diabetes over a lifetime

Herman et al. Ann Intern Med 2005;142:323–32

Simulated lifetime cumulative incidence of type 2 diabetes in the Diabetes Prevention Program cohort of 3,234 individuals with impaired glucose tolerance (IGT)

Inci

denc

e of

dia

bete

s (%

)

Time since diagnosis of IGT (years)

90

80

70

60

50

40

30

20

10

0

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 Lifetime

3.4 y

11.1 y

8%20%

PlaceboMetforminLifestyle

Oral Monotherapies

SUs Meglitinides TZDs Metforminα-Glucosidase

Inhibitors

DPP-4 Inhibitors

Improves insulin secretion

Improves insulin resistance

Lowers hepatic glucose production

Inzucchi SE. JAMA 2002;287(3):360–372; Gallwitz B. Minerva Endocrinol. 2006;31(2):133–147.

Efficacy of Monotherapy with OHAs

DeFronzo Annals of Internal Medicine 1999;131:281-303

Nathan N Engl J Med 2002; 347:1342-1349

DrugsFastingPlasma Glucose Reduction

(mg/dl)

A1CReduction

(%)

Thiazolidinedione 35-40 0.5-1.0

Sulfonylurea 60-70 1.0-2.0

Biguanide 60-70 1.0-2.0

Meglitinide 60-70 1.0-2.0

Alpha- glucosidase inhibitor 20-30 0.5-1.0

Clinical Inertia

“Failure to Advance Therapy When Recommended”M

ean

A1C

at

Last

Vis

it* (

%)

8.2 Years

ADA Goal

Diet and Exercise

Years Elapsed Since Initial Diagnosis

Initiation of

insulin therapy

SU or metformin

Combination oral agents

8.6%8.9%

9.6%

7

8

9

10

2.5 Years 2.9 Years 2.8 Years

*Adapted from: Brown JB et al. Diabetes Care. 2004;27:1535-1540.

Early Insulin Use in Type 2 Diabetes Offers No Benefits Over Standard

Approaches

16

ORIGIN Trial Investigators. N Engl J Med. 2012;367:319-328.

Outcome Reduction With an Initial Glargine InterventionCV risk factors + prediabetes or T2DM (N=12,537)

Benefit of Intensifying Glycemic Control Diminishes with Duration of Diabetes

+

–

UKPDS

ACCORD /ADVANCE / VADT

Del Prato S. EASD 2008, Rome, Italy

1%

-18%

-13%

-16%

-17%

-28%

Cardiovascular disease

Peripheral arterialdisease

Stroke

Fatal coronaryheart disease

Coronary heart disease

ReducedRisk*

EVERY 1% reduction in HbA1c

Numberof patients

Numberof studies

7435 10

6684 6

3042 5

5962 3

3748 3

*p<0.0001

Meta-Analysis: Glycosylated Hemoglobin and Cardiovascular Disease in Diabetes mellitus

Selvin et al. Ann. Intern. Med. 2004;141:421

The relative contribution of PPG and FPG varies with HbA1c1

HbA1c Is a Combination of Both FPG and PPG

1. Monnier L, et al. Diabetes Care. 2003;26(3):881-885.

As your patients’ HbA1c level approaches the normal range, PPG takes on greater importance in determining HbA1c.

<7.3 7.3-8.4 8.5-9.2 9.3-10.2 >10.2HbA1c Range (%)

Co

ntr

ibu

tio

n (

%)

100

80

60

40

20

0

PPG

FPG

GUIDELINES ON DIABETES, PRE-DIABETESAND CARDIOVASCULAR DISEASES

New ESC/EASD GuidelinesSuggested policy for the selection of glucose-lowering therapy according to the glucometabolic situation

ESC Pocket Guidelines adapted from European Heart Journal (2007) 28, 88 - 136

Breakfast Lunch Dinner 0.00am 4.00am Breakfast

Monnier L. Eur J Clin Invest 2000;30(Suppl 2):3-11.

“Our Lives are Spent in the Postprandial State”

Legend:

Postprandial state;

Postabsorptive state;

Fasting state

The damage of postprandial glucose levels is the damage of diabetes

Therapies that Preferentially Lower Postmeal Glucose

Drug Class Postmeal Glucose-lowering Effect

Delays carbohydrate absorptionα-glucosidase inhibitors

Slows gastric emptying, lowers glucagon, increases satietyAmylin analogues

Stimulates glucose-dependent insulin secretion, suppresses glucagon releaseDPP-4 inhibitors

Stimulates rapid but short-lived insulin releaseGlinides

Replaces insulin normally secreted after mealsRapid-acting insulin

analogues

Replaces insulin normally secreted after mealsBiphasic insulins

Stimulates glucose-dependent insulin secretion, suppresses glucagon release, delays gastric emptying,

increases satietyGLP-1 derivatives

DPP-4 = dipeptidyl peptidase-4; GLP-1 = glucagon-like peptide 1.Blevins T. Postgrad Med. 2011;123(4):135-147.

26

Standards of Medical Care in Type 2 Diabetes – 2008 ADA Weight Recommendations

• Weight loss is an important therapeutic objective1

• 85% of patients with T2DM are obese/overweight2 • Physical activity and behavior modification are important1

• Moderate weight loss (5% in short-term studies)1

• Decreased insulin resistance

• Improved measures of glycemia and lipemia

• Reduced blood pressure

• “The importance of controlling body weight in reducing risks related to diabetes is of great importance …” but sustaining weight loss is difficult1

References: 1. Diabetes Care. 2008;31(Suppl1). 2. NHANES 1999-2002

Antidiabetic Agents and Weight

• Risk of additional weight gain must be balanced against the benefits of the agent;

• Sulfonylureas may negate weight loss benefits of GLP-1 receptor agonists or metform in.• Insulin should not be withheld because of the risk of weight gain.

Inzucchi SE, et al. Diabetes Care. 2012;35:1364-1379. Rodbard HW, et al. Endocr Pract. 2009;15:540-559. Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53. Stenlof K, et al. Diabetes Obes Metab 2013;15:372-382.

27

Class Agent(s) Weight EffectAmylin analog Pramlintide ↓Biguanide Metformin ↓GLP-1 receptor agonists Exenatide, exenatide XR, liraglutide ↓SGLT-2 inhibitor Canagliflozin ↓-Glucosidase inhibitors Acarbose, miglitol ↔Bile acid sequestrant Colesevelam ↔DPP-4 inhibitors Alogliptin, linagliptin, saxagliptin, sitagliptin ↔Dopamine-2 agonist Bromocriptine ↔Glinides Nateglinide, repaglinide ↑Sulfonylureas Glimepiride, glipizide, glyburide ↑

Insulin Aspart, detemir, glargine, glulisine, lispro, NPH, regular ↑↑

Thiazolidinediones Pioglitazone, rosiglitazone ↑↑

0

10

20

30

40

50

60

70

80

90

100

Blood Glucose (mg/dL)

Decreased insulin secretion

Increased glucagon, epinephrine, ACTH, cortisol, and growth hormone

Palpitation, sweatingDecreased cognition, hungerAberrant behaviorSeizures, coma

Neuronal cell death

Moghissi E, et al. Endocr Pract. 2013;Feb 20:1-33. [Epub ahead of print].

Symptoms and Signs with Progressive Hypoglycemia

GLP-1 receptor agonists

DPP-4 inhibitors

TZDs

Insulin (basal, basal-plus, premixed)

Sulfonylureas

Metformin

Less Hypoglycemia

MoreHypoglycemia

Initial Treatment Additional Treatment

Moghissi E, et al. Endocr Pract. 2013;Feb 20:1-33. [Epub ahead of print].

Hypoglycemia Risk With Antihyperglycemic Agents Added to Metformin

Incretin Actions

GIP GLP-1

•Stimulates insulin secretion•Expansion of beta cell mass •Min effect on gastric emptying•No effect on glucagon secretion•Normal GIP secretion in T2DM•Defective GIP reponse in T2DM•No effect on Satiety

• Stimulates insulin secretion.• Expansion of B cell mass. • Inhibits gastric emptying• Inhibits glucagon secretion

• ↓ GLP1 secretion in T2DM• GLP1 reponse in T2DM

Normal • Stimulates Satiety - Inhibits

food intake and weight gain

Ahrén. Diabetes Care. 2003;26:2860.Farilla. Endocrinology. 2002;143:4397.

GLP-1 Effects in HumansUnderstanding the Natural Role of Incretins

Adapted from Flint A, et al. J Clin Invest. 1998;101:515-520Adapted from Larsson H, et al. Acta Physiol Scand. 1997;160:413-422Adapted from Nauck MA, et al. Diabetologia. 1996;39:1546-1553Adapted from Drucker DJ. Diabetes. 1998;47:159-169

Stomach: Helps regulate gastric emptying

Promotes satiety and reduces appetite

Liver: Glucagon reduces hepatic glucose outputBeta cells:

Enhances glucose-dependent insulin secretionDecreased apoptosisBeta cell regeneration

Alpha cells: Postprandialglucagon secretion

GLP-1 secreted upon the ingestion of food

Beta-cellworkload

Beta-cellworkload

Beta-cellresponse

Beta-cellresponse

GLP-1 levels are decreased in DM 2

Degradation of GLP-1

1 2 3 30

GLP-1

Des-HA-GLP-1 (inactive)

Enzymatic cleavage of GLP-1 by DPP-4 inactivates GLP-1

1 2 3 30

DPP-4

Two possible solutions to utilize GLP-1 action therapeutically:1) Long-acting DPP-4-resistant GLP-1 analogues/incretin mimetics.2) DPP-4 inhibitors / incretin enhancers.

Mentlein et al. Eur J Biochem. 1993; Gallwitz et al. Eur J Biochem. 1994

*

GLP-1 Levels Are Decreased in Type 2 Diabetes

** *

*

**

Control (n=33)Type 2 diabetes (n=54)

0

5

10

15

20

0 60 120 180 240

GL

P-1

(p

mo

l/L

)

*p<0.05, type 2 diabetes vs control

Adapted from Toft-Nielsen M-B et al. J Clin Endocrinol Metab. 2001;86:3717–3723.

Meal Started

Meal Finish

ed

(10–15)

Time after start of meal, minutes

BUT, the levels are never ZERO

DPP4 activity increases in

Hyperglycemia

0

5

10

15

20

25

30

T2DM T2DM-ND IGT NGT

T2DM

T2DM-ND

IGT

NGT

Mannucci et al, Diabetologia April 2005

Incretin-based Therapy for DMT2

GLP-1- based therapies exert unique glucose-lowering effects; Improve islet beta and alpha cell function. Unique effects on body weight (vs. other glucose lowering therapies).

GLP-1 Analogs DPP-4 Inhibitors

• HbA1c reduction -0.8%-1.9%• Significant and sustained weight loss• Injected therapy• GI side effects• Low rates of hypoglycemia• Multiple mechanism of action;

↑Insulin secretion, ↓ glucagon release, ↓Food intake, slows gastric emptying

• HbA1c reduction 0.5%-1.1%• Weight neutral• Oral administration• No significant GI side effects• Low rates of hypoglycemia• Improves islet function;

• ↑Insulin secretion, ↓ glucagon release, β cell regeneration and hypertrophy with reduced apoptosis

HbA1c Reduction with Sitagliptin

Pooled Results from all Phase III studies of Sitagliptin

100mg monotherapyGlycemic endpoints analyzed by duration of type 2 diabetes

Influence of Measures of Beta Cell Function on Efficacy of Sitagliptin in Patients with Type 2 Diabetes – pooled analysis of data from 4 phase III placebo controlled studies of Sitagliptin 100 mg monotherapy, involving 1691 patients. Poster by Harvey L. Katzeff et al. at ADA 2008.

Pla

ce

bo

ad

just

ed

LS

mea

n c

ha

ng

e

fro

m b

ase

lin

e H

bA

1c,%

, (9

5%

CI)

Pla

ceb

o a

dju

sted

LS

mea

n c

han

ge

fro

m

bas

elin

e F

PG

mg

/dl,

(95

% C

I)

Pla

ceb

o a

dju

sted

LS

mea

n c

han

ge

fro

m

bas

elin

e 2-

h P

PG

mg

/d)

(95%

CI)

*Significant reduction of A1c across all duration

Long-Term Efficacy with Sitagliptin as Monotherapy or Add-On Therapy to Metformin

ADA 2009 Abstract 540-P

Sitagliptin Is the Most Widely Dispensed DPP-4 Inhibitor With the Most Approved Uses of Any DPP-4

Inhibitor

Sitagliptin: Powerful efficacy and proven experience as an adjunct to diet and exercise

As initial therapy for appropriate patients (Monotherapy)

As initial therapy in combination with metformin

As initial therapy in combination with thiazolidinedione

In combination with metformin

In combination with sulfonylurea

In combination with thiazolidinedione

In combination with insulin

In combination with sulfonylurea + metformin

In combination with thiazolidinedione + metformin

In combination with insulin + metformin

Earlier and Appropriate Intervention May Improve Patients’ Chances of Reaching Goal

OAD=oral antidiabetic agent.Adapted from Del Prato S et al. Int J Clin Pract. 2005;59(11):1345–1355. Copyright © 2005. Adapted with permission of Blackwell Publishing Ltd.

Published Conceptual Approach

HbA

1c G

oal

Mean HbA1c

of patients Duration of Diabetes

OAD monotherapy

Diet andexercise

OAD combination

OAD up-titration

OAD + multiple dailyinsulininjections

OAD + basal insulin

Conventional stepwisetreatment approach

Earlier and more aggressive intervention approach

6

7

8

9

10