2. Medical Care In Diabetes
Bijan Iraj,MD Assistant Professor of Internal Medicine and Endocrinology Department of Endocrinology and Metabolism Isfahan Medical School.

3. Management of Type 2 Diabetes MellitusDX
HIS PE
LAB + ECG
REFFERAL
TARGET HBA1C

5. Our First Goal Is to Set Appropriate HbA1c

7. Correlation of A1C with Estimated Average Glucose (eAG)
Mean plasma glucose
A1C (%)
mg/dl
mmol/l 6
126
7.0 7
154
8.6 8
183
10.2 9
212
11.8 10
240
13.4 11
269
14.9 12
298
16.5
Table 9, as shown on this slide, contains the correlation between A1C levels and mean plasma glucose (PG) levels based on data from the international A1C-Derived Average Glucose (ADAG) trial using frequent SMBG and continuous glucose monitoring (CGM) in 507 adults (83% Caucasian) with type 1, type 2, and no diabetes1
The ADA and the American Association of Clinical Chemistry have determined that the correlation (r = 0.92) is strong enough to justify reporting both an A1C result and an estimated average glucose (eAG) when a clinician orders the A1C test2
A calculator for converting A1C results into eAG, in either mg/dl or mmol/l, is available at
These estimates are based on ADAG data of ~2,700 glucose measurements over 3 months per A1C measurement in 507 adults with type 1, type 2, and no diabetes. The correlation between A1C and average glucose was A calculator for converting A1C results into estimated average glucose (eAG), in either mg/dl or mmol/l, is available at
Reference
Nathan DM, Kuenen J, Borg R, et al., for the A1c-Derived Average Glucose Study Group. Translating the A1C assay into estimated average glucose values. Diabetes Care. 2008;31:
American Diabetes Association. Standards of medical care in diabetes—2011. Diabetes Care 2011;34(suppl 1):S18, Table 9.

8. Treat the patient, not the
blood sugar.

9. Lifestyle modification
Lipid treatment
BP control
ASA+/-
Cigarette cessation
Glucose control

15. Lifestyle intervention

16. Lifestyle Therapy medical nutrition therapy regular physical activity
sufficient amounts of sleep
behavioral support
smoking cessation and avoidance of all tobacco products.
Lifestyle therapy begins with nutrition counseling and education.
All patients should strive to attain and maintain an optimal weight through a primarily plant-based diet high in polyunsaturated and monounsaturated fatty acids, with limited intake of saturated fatty acids and avoidance of trans fats.

17. Cardiovascular/CNS outcome CKD NAFLD/NASH Cost
Pharmacotherapy of DM2
Efficacy: HbA1c
Hypoglycemia
Weight
Side effects
Durability
Cardiovascular/CNS outcome
CKD
NAFLD/NASH
Cost

19. ADA Guideline, Diabetes Care 2016
Healthy eating, weight control, increased physical activity
Initial monotherapy
MET
Not at target HbA1c after ~3 months SU
TZD
DPP-4i
SGLT-2i
GLP-1 RA
Insulin
Two-drug combinations
Not at target HbA1c after ~3 months
SU TZD Insulin
SGLT-2i
SU TZD
GLP-1RA Insulin
TZD DPP-4i GLP-1RA Insulin
SGLT-2i
SU TZD Insulin
TZD DPP-4i GLP-1RA
SGLT-2i
ADA/EASD position statement now recommends GLP-1RAs as second line agents
SU DPP-4i GLP-1RA Insulin
SGLT-2i
Three-drug combinations
Not at target HbA1c after 3-6 months combination therapy with insulin
Basal Insulin + GLP-1 RA or Prandial Insulin
More complex strategies
ADA Guideline, Diabetes Care, January 2016

20. ADA/EASD Position Statement: Antihyperglycemic Therapy in T2DM

22. Insulin is the most effective glucose-lowering agent
Clinical challenge: Selecting the appropriate treatment for your patient
1.5
≥2.5
Sulfonylureas
Metformin
Glinides
DPP-IV inhibitors
GLP-1RAs
Insulin
0.0
0.5
1.0
2.0
2.5
3.0
HbA1c reduction (%)
Efficacy as mono therapy
Anti diabetic agents
TZDs
Insulin is the most effective glucose-lowering agent
Nathan DM. N Engl J Med. 2007;356:437-40
Nathan et al. Diabetes Care. 2009;32:

23. Insulin sensitizer with predominant action in the liver:
Metformin:
Dose
Adverse events
Titration

28. Insulin sensitizer with predominant action in Peripheral: TZD
Pioglitazon:
Dose
Advers events

31. Insulin secretagogues: sulfonylureas
Meal plane and Regularity:
Dose
Potency
Age
Drug interaction
Indications

32. Hypoglycemia due to SUR
Glibenclamid  Glimiprid  Glicloasid  Repaglinid/nateglinid  MR Gliclazid SR Glipizid

35. Carbohydrate absorption inhibitors α-glucosidose inhibitors
Acarbose:
Dose
Adverse events

37. GLP-1 Secretion and Inactivation
Mixed meal
Intestinal
GLP-1
release
GLP-1 (9-36)
inactive
(>80% of pool)
DPP-4
T1/2 = 1 to 2 min
GLP-1 (7-36)
active
Quickly after it’s release GLP-1 is converted to it’s inactive form by an enzyme dipeptidyl peptidase 4.
Adapted from Deacon CF, et al. Diabetes. 1995;44:

38. Inhibition of DPP-4 Increases Active GLP-1
Mixed meal
Intestinal
GLP-1
release
GLP-1 (7-36)
active
GLP-1 (7-36)
active
DPP-4
DPP-4 inhibitor
GLP-1 (9-36)
inactive
Adapted from Rothenberg P, et al. Diabetes. 2000;49(suppl 1):A39.

40. Incretin – Based therapies
DPP-4 Inhibitors:
Sitagliptin
Linagliptin
Saxagliptin
Alogliptin

41. Incretin – Based Therapies
GLP1 agonists:
Exenetide
Liraglutide
Exenetide QW

42. Sodium Glucose Co-Transports 2 inhibitors
SGLT2IS

43. Targeting the Kidney
Chao EC, et al. Nat Rev Drug Discovery. 2010;9:

45. The Kidneys Play an Important Role in Glucose Control
Normal Renal Glucose Physiology
180 g of glucose is filtered each day
Virtually all glucose reabsorbed in the proximal tubules & reenters the circulation
SGLT2 reabsorbs about 90% of the glucose
SGLT1 reabsorbs about 10% of the glucose
Virtually no glucose excreted in urine
Mather, A & Pollock, C. Kidney International. 2011;79:S1-S6.

46. SGLT2 Inhibitors in Phase 3 Development
Empagliflozin
Canagliflozin
Dapagliflozin
Ipragliflozin

47. ADA-EASD Position Statement: Management of Hyperglycemia in T2DM
4. OTHER CONSIDERATIONS
Age
Weight
Sex / racial / ethnic / genetic differences
Comorbidities
Coronary artery disease
Heart Failure
Chronic kidney disease
Liver dysfunction
Hypoglycemia
Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

48. ADA-EASD Position Statement: Management of Hyperglycemia in T2DM
4. OTHER CONSIDERATIONS
Age: Older adults
Reduced life expectancy
Higher CVD burden
Reduced GFR
At risk for adverse events from polypharmacy
More likely to be compromised from hypoglycemia
Less ambitious targets
HbA1c <7.5–8.0% if tighter targets not easily achieved
Focus on drug safety
Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

49. ADA-EASD Position Statement: Management of Hyperglycemia in T2DM
4. OTHER CONSIDERATIONS
Weight
Majority of T2DM patients overweight / obese
Intensive lifestyle program
Metformin
GLP-1 receptor agonists
? Bariatric surgery
Consider LADA in lean patients
Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

50. ADA-EASD Position Statement: Management of Hyperglycemia in T2DM
4. OTHER CONSIDERATIONS
Comorbidities
Coronary Disease
Heart Failure
Renal disease
Liver dysfunction
Hypoglycemia
Metformin: CVD benefit (UKPDS)
Avoid hypoglycemia
? SUs & ischemic preconditioning
? Pioglitazone &  CVD events
? Effects of incretin-based therapies
Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

51. ADA-EASD Position Statement: Management of Hyperglycemia in T2DM
4. OTHER CONSIDERATIONS
Comorbidities
Coronary Disease
Heart Failure
Renal disease
Liver dysfunction
Hypoglycemia
Metformin: May use unless condition is unstable or severe
Avoid TZDs
? Effects of incretin-based therapies
Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

52. ADA-EASD Position Statement: Management of Hyperglycemia in T2DM
4. OTHER CONSIDERATIONS
Comorbidities
Coronary Disease
Heart Failure
Renal disease
Liver dysfunction
Hypoglycemia
Increased risk of hypoglycemia
Metformin & lactic acidosis
US: ≥ 1.5 (1.4 women)
UK:  <45 & <30
Caution with SUs (esp. glyburide)
DPP-4-i’s – dose adjust for most
Avoid exenatide if GFR <30
Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

53. ADA-EASD Position Statement: Management of Hyperglycemia in T2DM
4. OTHER CONSIDERATIONS
Comorbidities
Coronary Disease
Heart Failure
Renal disease
Liver dysfunction
Hypoglycemia
Most drugs not tested in advanced liver disease
Pioglitazone may help steatosis
Insulin best option if disease severe
Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

54. ADA-EASD Position Statement: Management of Hyperglycemia in T2DM
4. OTHER CONSIDERATIONS
Comorbidities
Coronary Disease
Heart Failure
Renal disease
Liver dysfunction
Hypoglycemia
Emerging concerns regarding association with increased mortality
Proper drug selection in the hypoglycemia prone
Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

55. IDF treatment algorithm (2013 update)
Sulfonylurea
Consider fourth line
Basal + mealtime insulin
Basal or pre-mix (later basal+mealtime)
Lifestyle measures
Consider first line
Consider second line
Consider third line
Metformin
Basal insulin or pre-mix insulin
α-gluc or DPP-4 or TZD or
Then, at each step, if not to target (generally HbA1C<7.0%)
Metformin (if not first line)
GLP-1 agonist
Sulfonylurea or α-glucosidase
Usual approach
Alternative approach
IDF 2013 Global Guidelines for Type 2 diabetes

56. Blood glucose monitoring individualized HbA1C at 3-mo intervals
Recommended standards of care for patients with type 2 Diabetes Mellitus
Weight at each visit
Bp at each visit
Blood glucose monitoring individualized
HbA1C at 3-mo intervals
at diagnosis and then yearly
Dilated eye exam
Lipid profile
Urine micro albumin