leture to diabetologist

1. Modern Therapy in Diabetics with
CAD in Adult
DR .OSAMA ELMARAGHI
M.B.CH.B , AEX ,EGYPT
MS, Internal Medicine, ALEX,EGYPT
Diabetes Diploma Leicester , UK.
NAEEM DIABETIC CLINIC
JAHRA-KUWAIT
14/11/2015

3. Diabetes is a global disease!
Estimated global prevalence of diabetes
International Diabetes Federation. IDF Diabetes Atlas. sixth Edition. 2014
2000 2014 2035
151 million 387 million 592 million

4. …are
frightened to
death of cancer
and AIDS…or
H1N1
…and ultimately die of
cardiovascular diseases
The Paradox of Diseases
The majority of people continuously
complain of allergic problems…

5. Every two seconds,
one person dies from cardiovascular
disease
World Health Organisation, Fact Sheet 317: Cardiovascular Diseases February 2007

6. 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)
Incidenceoffatal
ornonfatalMI(%)
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

9. 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.

10. 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

11. THERAPY
Choose the treatment…!!!

12. 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 positio
statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2015;38(1):140-149.

13. Insulin resistance and -cell
dysfunction are core defects of type 2
diabetes
Insulin
resistance
Genetic susceptibility,
obesity, Western lifestyle
Type 2 diabetes
IR
-cell
dysfunction
Rhodes CJ & White MF. Eur J Clin Invest 2002; 32 (Suppl. 3):3–13.

14. Antihyperglycemic Agents:
Up to 1999 available oral glucose-lowering agents
Liver
Plasma glucose
GI tract
+
Pancreas
Muscle/Fat
–
Injected
Insulin
(–)
(+)
-Glucosidase
Inhibitors
(–)
Carbohydrate
Absorption
Metformin (–)
Glucose
Production
Glitazones
1999
(+)
Glucose
Uptake
Insulin
Secretion
Sulfonylureas
Meglitinides
(+)
Insulin
Secretion

15. 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.

18. peripheral
glucose
uptake
hepatic
glucose
production
pancreatic
insulin
secretion
pancreatic
glucagon
secretion
incretin
effect
HYPERGLYCEMIA
Adapted from: Inzucchi SE, Sherwin RS in: Cecil Medicine 2011
Multiple, Complex Pathophysiological
Abnormalities in T2DM
_
_
+
renal
glucose
excretion

19. Gila monster

20. 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-4
Enzymes

22. 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

23. 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

24. Blood
glucose
Inactive
GIP
Inactive
GLP-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 dependent
DPP-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 cells
Alpha cells
Glucose
production
by liver
Glucose
uptake by
peripheral tissue
X
dr.osama elmaraghi ,
diabetologist,naeem,jahra,kuwait

25. 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 .

26. DPP4i
- Available as oral
- Reduce Hba1c
- No hypoglycemia
- Neutral effect on weight

27. Role of the Kidney in Glucose Metabolism
27
Wright EM, et al. J Intern Med. 2007;261(1):32-43.
Production Utilization
Reabsorption

28. Contribution of Tissues to
Fasting Plasma Glucose Liver
80%
Kidney
20%
Gluconeogenesis
Gluconeogenesis
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.

33. 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

34. 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

35. 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

38. Ongoing CV Outcomes Trials for New Antihyperglycemic Agents

39. Healthy eating, weight control, increased physical activity & diabetes education
Metformin
high
low risk
neutral/loss
GI / lactic acidosis
low
If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (order not meant to denote
any specific preference - choice dependent on a variety of patient- & disease-specific factors):
Metformin
+
Metformin
+
Metformin
+
Metformin
+
Metformin
+
high
low risk
gain
edema, HF, fxs
low
Thiazolidine-
dione
intermediate
low risk
neutral
rare
high
DPP-4
inhibitor
highest
high risk
gain
hypoglycemia
variable
Insulin (basal)
Metformin
+
Metformin
+
Metformin
+
Metformin
+
Metformin
+
Basal Insulin +
Sulfonylurea
+
TZD
DPP-4-i
GLP-1-RA
Insulin§
or
or
or
or
Thiazolidine-
dione
+
SU
DPP-4-i
GLP-1-RA
Insulin§
TZD
DPP-4-ior
or
or GLP-1-RA
high
low risk
loss
GI
high
GLP-1 receptor
agonist
Sulfonylurea
high
moderate risk
gain
hypoglycemia
low
SGLT2
inhibitor
intermediate
low risk
loss
GU, dehydration
high
SU
TZD
Insulin§
GLP-1 receptor
agonist
+
SGLT-2
Inhibitor
+
SU
TZD
Insulin§
Metformin
+
Metformin
+
or
or
or
or
SGLT2-i
or
or
or
SGLT2-i
Mono-
therapy
Efficacy*
Hypo risk
Weight
Side effects
Costs
Dual
therapy†
Efficacy*
Hypo risk
Weight
Side effects
Costs
Triple
therapy
or
or
DPP-4
Inhibitor
+
SU
TZD
Insulin§
SGLT2-i
or
or
or
SGLT2-i
or
DPP-4-i
If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (order not meant to denote
any specific preference - choice dependent on a variety of patient- & disease-specific factors):
If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on oral combination, move to injectables, (2) on GLP-1 RA, add
basal insulin, or (3) on optimally titrated basal insulin, add GLP-1-RA or mealtime insulin. In refractory patients consider adding TZD or SGL T2-i:
Metformin
+
Combination
injectable
therapy‡
GLP-1-RAMealtime Insulin
Insulin (basal)
+
Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442

40. Healthy eating, weight control, increased physical activity & diabetes education
Metformin
high
low risk
neutral/loss
GI / lactic acidosis
low
If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (order not meant to denote
any specific preference - choice dependent on a variety of patient- & disease-specific factors):
Metformin
+
Metformin
+
Metformin
+
Metformin
+
Metformin
+
high
low risk
gain
edema, HF, fxs
low
Thiazolidine-
dione
intermediate
low risk
neutral
rare
high
DPP-4
inhibitor
highest
high risk
gain
hypoglycemia
variable
Insulin (basal)
Metformin
+
Metformin
+
Metformin
+
Metformin
+
Metformin
+
Basal Insulin +
Sulfonylurea
+
TZD
DPP-4-i
GLP-1-RA
Insulin§
or
or
or
or
Thiazolidine-
dione
+
SU
DPP-4-i
GLP-1-RA
Insulin§
TZD
DPP-4-i
GLP-1-RA
high
low risk
loss
GI
high
GLP-1 receptor
agonist
Sulfonylurea
high
moderate risk
gain
hypoglycemia
low
SGLT2
inhibitor
intermediate
low risk
loss
GU, dehydration
high
SU
TZD
Insulin§
GLP-1 receptor
agonist
+
SGLT-2
Inhibitor
+
SU
TZD
Insulin§
Metformin
+
Metformin
+
or
or
or
or
SGLT2-i
or
or
or
SGLT2-i
Mono-
therapy
Efficacy*
Hypo risk
Weight
Side effects
Costs
Dual
therapy†
Efficacy*
Hypo risk
Weight
Side effects
Costs
Triple
therapy
or
or
DPP-4
Inhibitor
+
SU
TZD
Insulin§
SGLT2-i
or
or
or
SGLT2-i
or
DPP-4-i
If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (order not meant to denote
any specific preference - choice dependent on a variety of patient- & disease-specific factors):
If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on oral combination, move to injectables, (2) on GLP-1 RA, add
basal insulin, or (3) on optimally titrated basal insulin, add GLP-1-RA or mealtime insulin. In refractory patients consider adding TZD or SGL T2-i:
Metformin
+
Combination
injectable
therapy‡
GLP-1-RAMealtime Insulin
or
or
or
Insulin (basal)
+
Avoidance of hypoglycemia
Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442

41. Healthy eating, weight control, increased physical activity & diabetes education
Metformin
high
low risk
neutral/loss
GI / lactic acidosis
low
If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (order not meant to denote
any specific preference - choice dependent on a variety of patient- & disease-specific factors):
Metformin
+
Metformin
+
Metformin
+
Metformin
+
Metformin
+
high
low risk
gain
edema, HF, fxs
low
Thiazolidine-
dione
intermediate
low risk
neutral
rare
high
DPP-4
inhibitor
highest
high risk
gain
hypoglycemia
variable
Insulin (basal)
Metformin
+
Metformin
+
Metformin
+
Metformin
+
Metformin
+
Basal Insulin +
Sulfonylurea
+
TZD
DPP-4-i
GLP-1-RA
Insulin§
or
or
or
or
Thiazolidine-
dione
+
SU
DPP-4-i
GLP-1-RA
Insulin§
TZD
DPP-4-i
GLP-1-RA
high
low risk
loss
GI
high
GLP-1 receptor
agonist
Sulfonylurea
high
moderate risk
gain
hypoglycemia
low
SGLT2
inhibitor
intermediate
low risk
loss
GU, dehydration
high
SU
TZD
Insulin§
GLP-1 receptor
agonist
+
SGLT-2
Inhibitor
+
SU
TZD
Insulin§
Metformin
+
Metformin
+
or
or
or
or
SGLT2-i
or
or
or
SGLT2-i
Mono-
therapy
Efficacy*
Hypo risk
Weight
Side effects
Costs
Dual
therapy†
Efficacy*
Hypo risk
Weight
Side effects
Costs
Triple
therapy
or
or
DPP-4
Inhibitor
+
SU
TZD
Insulin§
SGLT2-i
or
or
or
SGLT2-i
or
DPP-4-i
If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (order not meant to denote
any specific preference - choice dependent on a variety of patient- & disease-specific factors):
If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on oral combination, move to injectables, (2) on GLP-1 RA, add
basal insulin, or (3) on optimally titrated basal insulin, add GLP-1-RA or mealtime insulin. In refractory patients consider adding TZD or SGL T2-i:
Metformin
+
Combination
injectable
therapy‡
GLP-1-RAMealtime Insulin
Insulin (basal)
+
or
or
or
Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442
Avoidance of weight gain

42. 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

43. 