Oral antidiabetic drugs contains SUs,metformin, glinides ,ddp-4 inhibitors,incretin mimietics liraglutide &exenatide And SGLT-2

1. Control Diabetes: Keep Up-To-Date
Alaa Wafa . MD
Associate Professor of Internal Medicine
Diabetes , Endocrine &Metabolic Disease Unit.
Mansoura University

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

3. Reprinted from Primary Care, 26, Ramlo-Halsted BA, Edelman SV, The natural history of type 2 diabetes. Implications
for clinical practice, 771–789, © 1999, with permission from Elsevier.
Development and Progression of
Type 2 Diabetes and Related Complications*
*Conceptual representation.
Insulin level
Insulin resistance
Hepatic glucose
production
Postprandial
glucose
Fasting plasma glucose
Beta-cell function
Progression of Type 2 Diabetes Mellitus
Impaired Glucose Tolerance
Diabetes Diagnosis
Frank Diabetes
4–7 years
Development of Macrovascular Complications
Development of Microvascular Complications

4. 50 years with NO NEW ADA

5. Pharmacologic Targets of Current Drugs
Used in the Treatment of T2DM
5
-glucosidase
inhibitors
Delay intestinal carbohydrate
absorption
Thiazolidinedione
Decrease lipolysis in adipose
tissue, increase glucose
uptake in skeletal muscle and
decrease glucose production
in liver
Sulfonylureas
Increase insulin secretion
from pancreatic -cells
GLP-1 analogs
Improve pancreatic islet glucose sensing,
slow gastric emptying, improve satiety
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.
Glinides
Increase insulin secretion
from pancreatic -cells
DPP-4 inhibitors
Prolong GLP-1 action leading to improved
pancreatic islet glucose sensing, increase
glucose uptake

7. 7
ß-cell:
SUs work by closing K+ATP channels
 Bind to ATP-dependent potassium (K+) channel (KATP) on the surface of cells, such
as the pancreatic beta cell
 Stimulate the release of insulin from functioning pancreatic beta-cells regardless
of meals and prevailing glucose levels (glucose-independent)
 No effect on hepatic glucose overproduction

8. SULFONYLUREAS
Main Advantages
• Fast significant effect
• Low drug cost
• Long experience
Main Disadvantages
• Hypoglycemia
• Weight gain
• Loss of effectiveness by time (hasten decline of B cell function)

9. 9
UKPDS 34. Lancet 1998:352:854–865. n=at baseline;
Changeinweight(kg)
Years from randomisation
*diet initially then sulphonylureas, insulin and/or metformin if FPG >15 mmol/l
0
1
5
0 3 6 9 12
8
7
6
4
3
2
Insulin (n=409)
Glibenclamide (n=277)
Metformin (n=342)
Conventional treatment (n=411)*
Insulin
SU
Conv.
Met
SU and weight gain (UPKPS 34)

10. Drug Interactions with
sulphonylurea
Increased Hypoglycemia :
• Anticoagulants
• Salicylates
• Sulfonamides
• MAO Inhibitors
• Tricyclic antidepressants
• Azole antifungals
Decreased Action :
• Beta Blockers, Diuretics,
• Ca channel Blockers
• Corticosteroids,
• Estrogens, Thyroid
Hormones
• Sympathomimetics,
• Phenothiazines
• Isoniazid, Phenytoin,
• Nicotinic Acid

12. Metformin
history
• Metformin was discovered in 1922.1 Study in humans began in
1950s by French physician Jean Sterne.1
• It was introduced in France in 1957 and the United States in
1995 2
• It is on the World Health Organization's List of Essential
Medicines, the most important medications needed in a basic
health system.3
• Metformin is believed to be the most widely used medication
for diabetes which is take by mouth1
1. John Wiley & Sons. pp. 47–49. ISBN 9783527632121.
2. St. Louis, Mo.: Mosby/Elsevier. p. 217. ISBN 9780323029643.
3. World Health Organization. October 2013. Retrieved 22 April 2014

13. Metformin
1. Reduction of excessive Hepatic Glucose
Output
2. Stimulation of insulin-mediated muscle
glucose uptake -glycogen synthesis is
increased
3. Inhibition of lipolysis and of FFA
availability
Metabolic actions

14. Metformin
1. Increased insulin binding
2. Stimulation of insulin receptor tyrosine
kinase activity
3. Enhanced glucose transport (GLUT
4. Increased glycogen synthase
5. Doesn't cause hypoglycemia
Cellular actions

15. Metformin
1. Favorable lipid effects
2. Weight loss
3. Increased fibrinolytic activity
4. Decreased platelet aggregability
5. Favorable effect on hypertension
Additional actions
Recently proved that ,
Fasting total GLP-1 was significantly increased by metformin
and After oral glucose, metformin increased significantly
total GLP-1.

16. UKPDS: Risk reduction with metformin
in overweight patients
N = 4075 with type 2 diabetes
UKPDS Group. Lancet. 1998;352:854-65.
Favors metformin
or intensive
Favors
conventional
All-cause mortality
Metformin
Intensive
Myocardial infarction
Metformin
Intensive
Stroke
Metformin
Intensive
0.021
0.021
0.021
Aggregate endpoints P*
0.1 1 10
*metformin vs intensive therapy
Relative risk reduction
(95% CI)

17. Metformin- side effects
1. Nausea, vomiting, distension
2. Loss of appetite, diarrhoea
3. Skin rashes, urticaria
4. Increase in liver enzymes
5. Rare – Lactic acidosis.

18. • Hypersensitivity to metformin
• Advanced liver disease
• CHF ?
• Metabolic acidosis
• Renal disease (serum creatinine >1.5 mg/dL in males
or >1.4mg/dL in females) ? UK:  dose @GFR <45 &
stop @GFR <30
• Abnormal creatinine clearance resulting from shock,
septicemia, or myocardial infarction
• Radiologic contrast study for 48 hr after
• Lactation ?
Metformin - contraindications

20. Thiazolidinediones (TZD’s) : make cells more sensitive to
insulin (esp. fatty cells)
Pioglitazone
• Binds to and activates the gamma isoform of the peroxisome proliferator-
activated receptor (PPARγ).
• PPARγ is a member of the steroid hormone nuclear receptor superfamily, and is
found in adipose tissue,
• cardiac and skeletal muscle, liver and placenta
PPAR - γ
• Upon activation of this nuclear receptor by a ligand such
as a TZD, PPARγ–ligand complex binds to a specific region
of DNA and thereby regulates the transcription of many
genes involved in glucose and fatty acid metabolism.
S
NH
O
O
ON
5-{4-[2-(5-Ethyl-pyridin-2-yl)-ethoxy]-benzyl}-thiazolidine-2,4-dione
PPAR γ: peroxisome proliferator-activated receptor

21. TZDs
Main Advantages
• Sustained glycemic control
• Low risk of hypoglycemia
• FDC with metformin & SUs
Main Disadvantages
• Weight gain
• Peripheral edema
• Increased risk of CHF
• Increased risk of fractures
• Drug cost

23. Meglitinides : Short acting insulin secretagogues
- REPAGLINIDE
- NATEGLINIDE
O
OHO
NH
N
O
2-Ethoxy-4-{[3-methyl-1-(2-piperidin-1-yl-phenyl)-butylcarbamoyl]-methyl}-benzoic acid
O
OH
NH
O
2-[(4-Isopropyl-cyclohexanecarbonyl)-amino]-3-phenyl-propionic acid

24. Glinides (Prandial Glucose Regulators)
MOA:
•Same as SUs but
• Short acting
• Glucose dependant
• Restore first phase insulin
response
• Reduce post meal glucose
level
Characteristics:
• Reduce postprandial blood glucose
• Weight gain
• Mild hypoglycemia
• Lacking long term efficacy/ safety
data
• Inconvenient dosing
• Drug cost

26. Αlpha – glycosidase inhibitors :
Block enzymes that help digest starches  slowing the rise in
B.G.L.
- Acarbose
- Miglitol
N
OO
O
O
O
H
H H
H H
1-(2-Hydroxy-ethyl)-2-hydroxymethyl-
piperidine-3,4,5-triol

27. Alpha Glucosidase Inhibitors
Advantage
• Weight neutral
• Low risk of hypoglycemia
• Serious side effects are rare
Disadvantages
• Modest glucose lowering efficacy
• GIT side effects (abdominal pain, diarrhea, bloating& flatulence)
• Inconvenient dosing

28. What’s new in Diabetes management in the 21st century

29. Incretins
• Gut-derived hormones, secreted in response to nutrient ingestion, that
potentiate insulin secretion from islet  cells in a glucose-dependent
fashion, and lower glucagon secretion from islet  cells
• Two predominant incretins:
– Glucagon-like peptide–1 (GLP-1)
– Glucose-dependent insulinotropic peptide (GIP)
(also known as gastric inhibitory peptide)
• Incretin effect is impaired in type 2 diabetes
– Known as GLP-1 deficiency

30. The Incretin Effect: Insulin Secretion Is Greater in
Response to Oral vs IV Glucose
0
50
100
150
200
-30 0 30 60 90 120 150 180 210
Time (min)
Glucose(mg/dL)
Insulin(pmol/L)
0
100
200
300
400
-30 0 30 60 90 120 150 180 210
Time (min)
Oral
IV
Nauck M et al. J Clin Endocrinol Metab. 1986;63:492-498.
Effect diminished in diabetes

31. DPP4-Is Enhances Active Incretin Levels Through Inhibition of DPP-41–4
By increasing and prolonging active incretin levels, DPP4-Is increases insulin release
and decreases glucagon levels in the circulation in a glucose-dependent manner.
Release of
active incretins
GLP-1 and GIPa
 Blood glucose in
fasting and
postprandial states
Ingestion
of food
 Glucagon
from alpha cells
(GLP-1)
 Hepatic
glucose
production
GI tract
DPP-4
enzyme
Inactive
GLP-1
X(DPP-4
inhibitor)
 Insulin from
beta cells
(GLP-1 and GIP)
Glucose-dependent
Glucose-dependent
Pancreas
Inactive
GIP
Beta cells
Alpha cells
 Peripheral
glucose
uptake
DPP-4=dipeptidyl peptidase 4; GI=gastrointestinal; GIP=glucose-dependent insulinotropic peptide; GLP-1=glucagon-like peptide-1.
aIncretin hormones GLP-1 and GIP are released by the intestine throughout the day, and their levels increase in response to a meal.
1. Kieffer TJ et al. Endocr Rev. 1999;20(6):876–913.
2. Ahrén B. Curr Diab Rep. 2003;3(5):365–372.
3. Drucker DJ. Diabetes Care. 2003;26(10):2929–2940,
4. Holst JJ. Diabetes Metab Res Rev. 2002;18(6):430–441.
Mode of Action of DPP4-Is

32. DPP-4 Inhibitors
MOA Advantage
• Incretin Enhancers
• Inhibits the dipeptidyl-peptidase 4
enzyme and thus prevent rapid
degradation of GLP-1 and GIP and
improves glucose homeostasis
• Glucose dependent
• Physiologic MOA
• Weight neutral
• Low risk of hypoglycemia
• FDCs with Metformin
Members: Sitagliptin, Saxagliptin, Vildagliptin, Alogliptin &
Linagliptin

33. GLP-1 Agonists
MOA Advantage Diadvantage
Incretin mimetic
Mimics the action of GLP-1.
• Raise exogenous GLP-1
plasma concentrations into
the pharmacologic range
• Weight loss
• Low risk of
hypoglycemia
• Serious side
effects are rare
• GIT side effects
(nausea, vomiting &
diarrhoea)
• SC injection
• Drug cost
Members: Exenatide & Liraglutide
Dosing: SC injection once or twice daily

35. Functions of the kidney
35
Filtration and
reabsorption
Acid/base
balance
Electrolyte
Balance
Excretion of
toxic substances
Hormone production:
• Calcitrol (healthy bones)
• Renin (BP regulation)
• Erythropoieitin
(red blood cell production)
Glucose reabsorption
and gluconeogenesis

36. The kidneys’ contribution to glucose homeostasis
• Kidneys contribute to glucose homeostasis in many ways including:
producing, filtering, reabsorbing and excreting glucose
• The kidneys produce approximately 20-25%1,2 of the total endogenous
glucose production
• In a healthy individual* virtually all of the filtered glucose is actively
reabsorbed into the blood by the sodium glucose co-transporters 2 and
1 (SGLT2 and SGLT1); virtually none is excreted in the urine2,3
36
*Normal physiological blood glucose range <6.5mmol/L before meals and <7.8mmol/L after meals
References:
1. Gerich JE. Physiology of glucose homeostasis. Diabetes Obes Metab. 2000;2:345-50.
2. Gerich JE. Role of the kidney in normal glucose homeostasis and in the hyperglycaemia of diabetes mellitus: therapeutic implications. Diabet Med. 2010 Feb;27(2):136-42.
3. Mitrakou A. Kidney: its impact on glucose homeostasis and hormonal regulation. Diabetes Res Clin Pract. 2011 Aug;93 Suppl 1:S66-72

37. The role of the kidney in glucose reabsorption
• There are two main sodium-
glucose cotransporters: SGLT2
and SGLT11
• SGLT2 is mainly found in the
proximal tubules of the kidneys1
• SGLT2 is responsible for
reabsorbing approximately 90%
of the glucose reabsorbed by
the kidney2
• The remaining glucose is
reabsorbed by SGLT1 further
along the proximal tubule1
• The reabsorbed glucose is then
returned to the blood2
37
Adapted from Nair S, Wilding JP. J Clin Endocrinol Metab. 2010;95:34-42.
Reference:
1. Nair S, Wilding JP. J Clin Endocrinol Metab. 2010;95:34-42. 2. DeFronzo RA, et al. Diabetes Obes Metab. 2012;14:5-14.

39. Glucose Transport in Tubular Epithelial
Cells
G Glucose
Na+
Sodium
K
Potassium
BloodLumen
S1 Proximal Tubule
G
Na+
K
GLUT2
ATPase
SGLT2
High
Capacity
Low Affinity
BloodLumen
S3 Proximal Tubule
G
2Na+
2K
GLUT1
ATPase
SGLT1
Low
Capacity
High
Affinity
Adapted from Bakris GL et al. Kidney Int 2009;75:1272-7
Marsenic O. Am J Kidney Dis. 2009;53:875-83

40. Glucose Reabsorption in a Nondiabetic Person
(Plasma Glucose <10 mmol/L )
Glomerulus Proximal Convoluted Tubule
Glucose reabsorption into tissue
Early Distal
Glucose SGLT1SGLT2
Urine
Adapted with permission from Rothenberg PL et al.
SGLT = sodium-glucose linked co-transporter.
Rothenberg PL et al. Poster presented at EASD 2010; Stockholm, Sweden

41. The role of the kidney in glucose reabsorption
41
~180L filtered per day by the kidney1
References:
1. DeFronzo RA, Davidson JA, Del Prato S. The role of the kidneys in glucose homeostasis: a new path towards normalizing glycaemia. Diabetes Obes Metab. 2012
Jan;14(1):5-14.
2. Clifford J. Bailey. Medscape Education Diabetes & Endocrinology. The Role of the Kidney in Glucose Control.. CME Released: 02/26/2013 ; Valid for credit through
02/26/2014.
A normal kidney
A kidney in a patient
with type 2 diabetes
Average blood glucose of
~100mg/dL2
Average blood glucose of
~150mg/dL2
~180g of glucose filtered per
day2
No increase in SGLT2
cotransporters2
~250g of glucose filtered per
day2
 glucose reabsorption and
 elimination of glucose in the
urine2
Hyperglycaemia
Increase in SGLT2
cotransporters2

42. Glucose Reabsorption in a Person With T2DM
(Plasma Glucose >10 and <13.3 mmol/L)
Glomerulus Proximal Convoluted Tubule
Increased glucose reabsorption into tissue compared to normal
Early Distal
Urine
Adapted with permission from Rothenberg PL et al.
SGLT = sodium-glucose linked co-transporter.
Rothenberg PL et al. Poster presented at EASD 2010; Stockholm, Sweden
Glucose SGLT1SGLT2

43. Effects of SGLT2 Inhibitors
Inhibition of renal tubular Na+- glucose co-transporter
reversal of hyperglycemia reversal of “glucotoxicity”
Insulin sensitivity in muscle
Insulin sensitivity in liver
Gluconeogenesis
Improved beta cell function
DeFronzo RA, et al. Diabetes Obes Metab. 2012;14(1):5-14.

47. Trends in Treatment of T2DM from
1997 to 2012 in USA
Sulfonylureas
Insulin
GLP-1
agonist

48. We have many
different guidelines

50. What Guidelines Say?

51. Treating patients should be to targets with consideration of
patients individualization
FPG
<110 mg/dl
FPG
<130 mg/dl
HbA1c
<7.0%
HbA1c
<7.0%
ADA1,2/
EASD2
IDF3
PPG
< 160 mg/dl
PPG
<180 mg/dl
1. American Diabetes Association Diabetes Care 2009;32 (Suppl 1):S1-S97
2. ADA/EASD Consensus guideline. Diabetes Care 2009;32(1): 193-203
3. IDF Treatment Algorithm for People with Type 2 Diabetes. 2011

52. Smoking
Lifestyle
Control blood
pressure
Education
Statin
Metformin
Aspirin
Control blood
glucose
Individualised
care of patients:
based on
evidence for each
intervention
Type 2 diabetes management is multifactorial

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

54. peripheral
glucose
uptake
hepatic
glucose
production
pancreatic
insulin
secretion
pancreatic
glucagon
secretion
gut
carbohydrate
delivery &
absorption
incretin
effect
HYPERGLYCEMIA
?
Adapted from: Inzucchi SE, Sherwin RS in: Cecil Medicine 2011
Multiple, Complex Pathophysiological
Abnormalities in T2DM
_
_
+
renal
glucose
excretion
DA
agonists
T Z D sMetformin
S U sGlinides
DPP-4
inhibitors
GLP-1R
agonists
A G I s
Amylin
mimetics
Insulin
Bile acid
sequestrants

55. What’s missing
5 principles in selecting
Antihyperglycemic interventions
1. Efficacy
2. Hypoglycemia
3. Weight
4. Side effects
5. Cost

56. Standards of
Medical Care in
Diabetes — 2016

57. 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)
+
Figure 2. Anti-hyperglycemic therapy
in T2DM: General recommendations Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442

58. 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)
+
Figure 2. Anti-hyperglycemic therapy
in T2DM: General recommendations Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442

59. 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)
+
Figure 2. Anti-hyperglycemic therapy
in T2DM: General recommendations Diabetes Care 2016;38:140-149; Diabetologia 2015;58:429-442

60. 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

61. 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
HbA1c
≥9%
Metformin
intolerance or
contraindication
Uncontrolled
hyperglycemia
(catabolic features,
BG ≥300-350 mg/dl,
HbA1c ≥10-12%)

62. 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)
+
Figure 2A. Anti-hyperglycemic
therapy in T2DM:
Avoidance of hypoglycemia Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442

63. 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
Figure 2B. Anti-hyperglycemic
therapy in T2DM:
Avoidance of weight gain

64. 1-Aspirin therapy for women aged 50 and older(changed from women
›60 previously)
2-antiplatlet use in patients younger than 50 with multiple risk factor
3- addition of Ezetimibe to moderate-intensity statin therapy
in patient with diabetes based on Recent IMPROVED-IT trial.
4-- some linguistic shift as ASCVD is more specific than CVD,
And Diabetic Kidney Disease DKD instead of nephropathy.
5-tailoring treatment for vulnerable populations with diabetes ,such as
HIV infection, Mental illness Food insecurity.
What is new in ADA 2016?

65. ● Diabetes treatment must be
individualized, patient-centered, and
culturally appropriate.
● In Asian Americans, consider DM
testing in adults of any age with 1
risk factor and a BMI ≥23.
● To decrease disparities, all providers and
groups are encouraged to use the National
Quality Forum’s National Voluntary
Consensus Standards for Ambulatory Care—
Measuring Healthcare Disparities
Tailoring Treatment
American Diabetes Association Standards of Medical Care in Diabetes.
Strategies for improving diabetes care. Diabetes Care 2016; 39 (Suppl. 1): S6-S12

66. ● Lack of health insurance
● Food insecurity (FI)
o Carefully evaluate hyperglycemia and
hypoglycemia and propose solutions A
o Recognize that homelessness and poor
literacy often occur with food insecurity;
appropriate resources should be made
available for patients with diabetes. A
Health Disparities
American Diabetes Association Standards of Medical Care in Diabetes.
Strategies for improving diabetes care. Diabetes Care 2016; 39 (Suppl. 1): S6-S12

67. 1. Intensive glucose control is not
advised for the improvement of poor
cognitive function in hyperglycemic
individuals with T2DM. B
2. In individuals with poor cognitive
function or severe hypoglycemia,
glycemic therapy should be tailored
to avoid significant hypoglycemia. C
Cognitive Dysfunction
American Diabetes Association Standards of Medical Care in Diabetes.
Strategies for improving diabetes care. Diabetes Care 2016; 39 (Suppl. 1): S6-S12

68. 3. In individuals with diabetes at high
CVD risk, the cardiovascular benefits
of statin therapy outweigh the risk of
cognitive dysfunction. A
4. If a second-generation antipsychotic
medication is prescribed, changes in
weight, glycemic control, and
cholesterol levels, should be
carefully monitored and the
treatment regimen reassessed. C
Cognitive Dysfunction (2)
American Diabetes Association Standards of Medical Care in Diabetes.
Strategies for improving diabetes care. Diabetes Care 2016; 39 (Suppl. 1): S6-S12

69. ● Screen patients with HIV for diabetes
and prediabetes before starting
antiretroviral (ARV) therapy, and 3
months after starting or changing it. E
● If initial screening results are normal,
check fasting glucose annually. E
● If prediabetes is detected, continue to
measure levels every 3-6 months to
monitor for progression to diabetes. E
Human Immunodeficiency Virus (HIV)
American Diabetes Association Standards of Medical Care in Diabetes.
Strategies for improving diabetes care. Diabetes Care 2016; 39 (Suppl. 1): S6-S12

70. New section of Obesity ,covering life
style modofication,pharmacological
management & bariatric surgery has
been added.
Cont. What is new in ADA 2016?

71. ● Guidelines support gastric banding,
gastrectomy, and bypass as effective
treatments for overweight T2DM
patients.
● In 72% of patients, bariatric surgery
helped achieve near- or complete
normalization of glycemia 2 yrs post-
surgery.
● In one meta-analysis, gastric banding
resulted in less weight loss than
gastrectomy or Roux-en-Y.
Bariatric Surgery
American Diabetes Association Standards of Medical Care in Diabetes. Obesity management
for the treatment of type 2 diabetes. Diabetes Care 2016; 39 (Suppl. 1): S47-S51

72. ● Bariatric surgery may be considered
for adults with BMI >35 and T2DM,
especially if diabetes or associated
comorbidities are difficult to control
with lifestyle & medications. B
● Patients with T2DM who have
undergone bariatric surgery need
lifelong lifestyle support and annual
medical monitoring, at a minimum. B
Recommendations:
Bariatric Surgery
American Diabetes Association Standards of Medical Care in Diabetes. Obesity management
for the treatment of type 2 diabetes. Diabetes Care 2016; 39 (Suppl. 1): S47-S51

73. ● Although small trials have shown
glycemic benefit of bariatric surgery
in patients with T2DM and BMI 30–35,
there is currently insufficient
evidence to generally recommend
surgery in patients with BMI ≤35. E
Recommendations:
Bariatric Surgery
American Diabetes Association Standards of Medical Care in Diabetes. Obesity management
for the treatment of type 2 diabetes. Diabetes Care 2016; 39 (Suppl. 1): S47-S51

74. ● Costly
● Some associated risks
● Outcomes vary
● Patients undergoing bariatric surgery
may be at higher risk for substance
abuse including drug and alcohol use
and cigarette smoking.
Disadvantages of bariatric surgery
American Diabetes Association Standards of Medical Care in Diabetes. Obesity management
for the treatment of type 2 diabetes. Diabetes Care 2016; 39 (Suppl. 1): S47-S51

77. Despite treatment advances, mean HbA1C
in type 2 diabetes is elevated in most
countries
Canada 7.36–8.7%11
Latin America 7.6%1
US 7.2%7
China 9.5%11
India 8.7–9.6%9,11
Japan 7.05–9.6%11
Korea 7.9–8.7%4
Russia 9.6%11
Spain 9.2%8
Sweden 8.7%3
Turkey 10.6%3
UK 8.510–9.8%2
Germany 8.42–9.2%8
Greece 8.911–9.7%3,8
Italy 8.4%11
Poland 9.0%11
Portugal 9.7%3
Romania 9.9%3
1. Lopez Stewart et al. Rev Panam Salud Publica 2007;22:12–20; 2. Kostev & Rathmann Primary Care Diabetes 2013;7:229–33; 3. Oguz et al. Curr Med Res Opin
2013;29:911–20; 4. Ko et al. Diab Med 2007;24:55–62; 5. Arai et al. Diab Res Clin Prac 2009;83:397–401; 6. Harris et al. Diabetes Res Clin Pract 2005;70:90–7; 7.
Hoerger et.al. Diabetes Care 2008;31:81–6; 8. Liebl et al. Diab Ther 2012;3:e1–10; 9. Shah et al. Adv Ther 2009;26:325–35; 10. Blak et al. Diab Med 2012;29:e13–20;
11. Valensi et al. Int J Clin Pract 2008;62:1809–19

78. Every day exercise
Choosing the …….. Drug for the ………..….. patientbest Appropriate

79. dralaawafa@hotmail.com
dralaa@mans.edu.eg
Thank
you