Modern Therapy in Diabetics with CAD in Adult

DR .OSAMA ELMARAGHIM.B.CH.B , AEX ,EGYPT

MS, Internal Medicine, ALEX,EGYPTDiabetes Diploma Leicester , UK.

NAEEM DIABETIC CLINICJAHRA-KUWAIT

14/11/2015

Diabetes is a global disease!Estimated global prevalence of diabetes

International Diabetes Federation. IDF Diabetes Atlas. sixth Edition. 2014

2000 2014 2035151 million 387 million 592 million

…are frightened to death of cancer and AIDS…or H1N1

…and ultimately die of cardiovascular diseases

The Paradox of DiseasesThe majority of people continuously complain of allergic problems…

Every two seconds,one person dies from cardiovascular

disease

World Health Organisation, Fact Sheet 317: Cardiovascular Diseases February 2007

EAST WEST STUDY

People with Diabetes Have MI Risk Levels Comparable to People with Prior MI

Adapted from Haffner SM et al N Engl J Med 1998;339:229-234.

Ref 8,p 232,T2,R1,2,C2,6

20%19%

0

5

10

15

20

25

Diabetes (no prior MI)(n=890)

Prior MI (no diabetes)(n=69)

Inci

denc

e of

fata

l or

non

fata

l MI (

%)

Patient type

Patients with diabetes without previous MI have as high of a risk of MI as nondiabetic patients with previous MI

These data provide a rationale for treating cardiovascular risk factors in diabetic patients as aggressively as in nondiabetic patients with prior MI

Slide 9Adapted from Alexander CM, Antonello S Pract Diabet 2002;21:21-28.

Two-Thirds of People with Diabetes Die of Cardiovascular Disease

• Among people with diabetes, macrovascular complications, including CHD, stroke, and peripheral vascular disease, are the leading causes of morbidity and mortality.

Guidelines for Glycemic, BP, & Lipid Control American Diabetes Assoc. Goals

HbA1C < 7.0% (individualization)

Preprandial glucose 80-130 mg/dL (4.4-7.2 mmol/l)

Postprandial glucose < 180 mg/dL (7.8 mmol/l)

Blood pressure < 140/90 mmHg

Lipids

LDL: < 100 mg/dL (2.59 mmol/l) < 70 mg/dL (1.81 mmol/l) (with overt CVD)HDL: > 40 mg/dL (1.04 mmol/l) > 50 mg/dL (1.30 mmol/l)TG: < 150 mg/dL (1.69 mmol/l)

. Diabetes Care 2015;38(suppl 1):S37; Table 6.2

THERAPYChoose the treatment…!!!

Critical aspect of managing T2DM in patients with CVD or a high risk for it is the avoidance of : -hypoglycemia as It may exacerbate MI or cause arrhythmias.-Gaining weight as it is independent risk factors for CVD.

.

Fox CS, Golden SH, Anderson C, et al. Update on prevention of cardiovascular disease in adults with type 2 diabetes mellitus in light of recent evidence. A Scientific Statement from the American Heart Association and the American Diabetes Association. Circulation 2015:132 .

Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2015;38(1):140-149.

Insulin resistance and -cell dysfunction are core defects of type 2 diabetes

Insulinresistance

Genetic susceptibility,obesity, Western lifestyle

Type 2 diabetes

IR -celldysfunction

Rhodes CJ & White MF. Eur J Clin Invest 2002; 32 (Suppl. 3):3–13.

Antihyperglycemic Agents: Up to 1999 available oral glucose-lowering agents

Liver

Plasma glucose

GI tract

+

Pancreas

Muscle/Fat

–

Injected Insulin

)–()+(

-GlucosidaseInhibitors

)–(Carbohydrate

Absorption

Metformin )–(

GlucoseProduction

Glitazones1999

)+(GlucoseUptake

InsulinSecretion

SulfonylureasMeglitinides )+( Insulin

Secretion

THE LANCET • Vol 352 • September 12, 1998

The UK Prospective Diabetes Study (UKPDS) demonstrated a reduced risk of all-cause mortality in the subgroup of obese DM2 patients treated with metformin compared with sulphonylureas, insulin or diet alone with less weight gain and fewer hypoglycaemic attacks .

Thus, based on the results from the UKPDS substudy , international treatment guidelines recommend metformin as first-line pharmacological treatment in DM2 patients.

peripheralglucose uptake hepatic

glucose production

pancreatic insulin

secretionpancreatic glucagonsecretion

incretineffect

HYPERGLYCEMIA

Adapted from: Inzucchi SE, Sherwin RS in: Cecil Medicine 2011

Multiple, Complex Pathophysiological Abnormalities in T2DM

_

_

+renal

glucose excretion

Gila monster

Glucagon-Like Peptide–1 (GLP-1) Increases-Cell Response and Decreases -Cell Workload

Larsson H et al. Acta Physiol Scand .1997;160:413-422 | Drucker DJ. Diabetes. 1998;47:159-169.

Stomach: Helps regulate

gastric emptying

-Cell workload

-Cell response

-Cells: Enhance glucose-dependent insulin

secretion

GLP-1 secreted upon the ingestion of food

-Cells: Postprandial

glucose secretion

Promotes satiety and reduces appetite

Liver: Glucagon reduces

hepatic glucose output

DPP-4Enzymes

Incretin based therapies

Exogenous GLP-1 analogue that resist DPP4 :(Incretin mimetic)• Exenatide and Exenatide LAR (Byetta) lilly• Liraglutide (victoza) novonordisk• Albiglutide (syncria) GSK• Lixisenatide Sanofiaventis

GLP1

-Available as injection twice, or once daily ,or given once weekly- Reduce Hba1c- No hypoglycemia- Reduce wight- Reduce systolic BP- Can cause nausia and vomiting

dr.osama elmaraghi , diabetologist,naeem,jahra,kuwait

Blood glucose

InactiveGIP

InactiveGLP-1

DPP-4 Actions With a Single Oral Agent

Insulin(GLP-1 and GIP)

Glucagon(GLP-1)

Release of active incretins GLP-1 and GIP

Pancreas

Glucose dependentDPP-4

enzyme

Glucose dependent

GI tract

X(DPP-4 inhibitor)

•Incretin hormones GLP-1 and GIP are released by the intestine throughout the day; their levels increase in response to a meal.

Beta cellsAlpha cells

Glucose production

by liver

Glucose uptake by

peripheral tissue

X

Therapeutic approaches to enhancing GLP-1 action in type 2 diabetes1,2

1. Mentlein R, et al. Eur J Biochem. 1993;214:829-35. 2. Eng J, et al. J Biol Chem. 1992;267:7402-5. 3. Byetta. Summary of Product Characteristics, EMEA, 23 October 2009. 4. Victoza. Summary of Product Characteristics, EMEA, 23 October 2009. 5. Ahrèn B. Expert Opin Emerg Drugs. 2008;13:593-607. 6. Januvia. Summary of Product Characteristics, EMEA, 23 October 2009. 7. Onglyza. Summary of Product Characteristics, EMEA, 23 October 2009. 8. Galvus/Jalra. Summary of Product Characteristics, EMEA, 23 October 2009. 9. Pratley RE, Gilbert M. Rev Diabet Stud. 2008;5:73-94. 10. Tiwari A. Curr Opin Investig Drugs. 2009;10:1091-104.

DPP-4 inhibitors›Sitagliptin. ›Saxagliptin.›Vildagliptin (EMEA approved)8 ›Alogliptin .

› Linagliptin .

DPP4i

- Available as oral- Reduce Hba1c- No hypoglycemia- Neutral effect on weight

Role of the Kidney in Glucose Metabolism

27Wright EM, et al. J Intern Med. 2007;261(1):32-43.

Production Utilization

Reabsorption

Contribution of Tissues to Fasting Plasma Glucose Liver

80%Kidney20%

GluconeogenesisGluconeogenesis

Glycogenolysis

Gerich JE. Diabet Med. 2010;27(2):136-142 .

The kidneys synthesize glucose from amino acids and other precursors during prolonged fasting, a process referred to as gluconeogenesis. The kidneys' capacity to add glucose to the blood during prolonged periods of fasting rivals that of the liver.

New T2 diabetes drugs should demonstrate no unacceptable increase in CV events

• All new diabetes medications have to demonstrate that they will not result in an unacceptable increase in cardiovascular risk

Saxagliptin had a neutral effect on ischemic events, including MI, stroke, and CV death, but the rate of hospitalization for heart failure increased compared to patients receiving placebo (3.5% vs 2.8%; HR 1.27).

Alogliptin had a neutral effect on the primary endpoint of major adverse coronary events (MACE) and there was no increase in heart failure rates

Sitagliptin had a neutral effect on the primary endpoint of major adverse coronary events (MACE) and there was no increase in heart failure rates

The ELIXA study It found that lixisenatide had a neutral effect on the primary outcome of CV death, nonfatal MI, nonfatal stroke, or hospitalization for unstable angina. Furthermore, there was no increase in hospitalization for heart failure.[34

Ongoing CV Outcomes Trials for New Antihyperglycemic Agents

Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442

Avoidance of hypoglycemia

Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442

Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442Avoidance of weight gain

HOME MASSAGE• Glycemic control reduces macro- and microvascular

complications of diabetic patients• Sulfonylureas and TZDs are associated with increased CV

risk• In choosing antihyperglycemic agents, select drugs that do

not cause hypoglycemia , and that not causing gain weight as it is risk factor of CAD.

• Metformin and incretins (DPP-4 inhibitors and GLP-1 receptor agonists) are associated with lower CV risk

• SGLT2i reduce CV deaths and heart failure hospital admission

• Definitive CV effects of antihyperglycemic agents in DM2 will await the results of ongoing CV trials