dr abhay sahoo presented these slides to train doctiors

1. Approach to a newly diagnosed
patients with Type 2 Diabetes
Mellitus
Dr Abhay sahoo
MD,DM (Endocrinology, AIIMS)
Asst. prof. Endocrinology
IMS & SUM Hospital

2. Diabetes Mellitus
• Diabetes Mellitus is derived from two terms:
The Greek word Diabetes means
• to Siphon i.e. pass through....
• ....and the Latin word Mellitus
means as sweet as honey....

3. Prevalence
 In 2010, prevalence has risen to 285 million, representing 6.6%
of the world’s adult population.
 Predicted that by 2030 the number of people with diabetes will
have risen to 438 million globally.
 Currently China has got the largest number of Diabetics.
 Type 2 DM is the commonest form of diabetes globally as well
as in India. Constitutes more than 95% of the diabetic
population in our country.
*IDF Diabetes Atlas, 2010

4. Risk factors
Diabetes Mellitus

5. Indian Diabetes Risk Score (IDRS)
V Mohan , API 2010;20:93-96

6. Major Pathophysiologic Defects
in Type 2 Diabetes
Islet-cell dysfunction
Glucagon
(alpha cell)
Pancreas
Insulin
Insulin resistance
(beta cell)
Hepatic
glucose Glucose uptake in
output muscle and fat
Hyperglycemia Liver
Muscle
Liver Adipose
tissue
Adapted with permission from Kahn CR, Saltiel AR. Joslin’s Diabetes Mellitus. 14th ed.
Lippincott Williams & Wilkins; 2005:145–168.
Del Prato S, Marchetti P. Horm Metab Res. 2004;36:775–781.
Porte D Jr, Kahn SE. Clin Invest Med. 1995;18:247–254.

7. Insulin Resistance:
An Underlying Cause of Type 2 Diabetes
Aging Medications
Obesity and
inactivity Genetic
abnormalities
INSULIN
RESISTANCE
Type 2
PCOS
diabetes
Hypertension Atherosclerosis
Dyslipidemia
Reaven GM. Physiol Rev. 1995;75:473-486
Clauser, et al. Horm Res. 1992;38:5-12.

8. Progression of Type 2 DM
Insulin resistance
Insulin Secretion defect
Hyperglycemia
Type 2 DM
Stimulation of beta cells
More loss of Beta cells
More Insulin release
Progression of Type 2 DM
(Hyperinsulinemia)
Complete loss of Beta cells
Euglycemia
Insulin requiring Type 2 DM
Exhaustion of Beta cells

9. Natural History of Type 2 Diabetes
Postmeal glucose
35
30 IGT Diabetes
25 Fasting glucose
Glucose 20
(mg/dL) 15
10
5
-15 -10 -5 0 5 10 15 20 25
120
100 Insulin resistance
Relative
function (%) 75
50
β cell
25
0
-15 -10 -5 0 5 10 15 20 25
Years of diabetes
Adapted from: International Diabetes Center (Minneapolis, MN).

10. UKPDS: β-Cell Loss Over Time
Almost 50% of the beta cell function is found to be
destructed at the diagnosis of Type II DM
*
Dashed line shows extrapolation forward and backward from years 0 to 6 from diagnosis based on Homeostasis Model Assessment
(HOMA) data from UKPDS.
†
IGT=impaired glucose testing
‡
The data points for the time of diagnosis (0) and the subsequent 6 years are taken from a subset of the UPKDS population and were
determined by the HOMA model.
Lebovitz HE. Diabetes Rev. 1999;7:139-153.

11. Common symptoms

12. Complications at Diagnosis
50% of newly presenting people with type 2 diabetes
already have one or more complications at
diagnosis
Intermittent Retinopathy: 21%
claudication: 3%
Ischaemic skin Hypertension: 35%
changes to feet: 6%
Abnormal ECG: 18%
Stroke or TIA: 1%
Erectile dysfunction: 20%
Plasma creatinine
>120µmol/l: 3% Absent foot pulses: 13%
UKPDS Group. Diabetologia 1991; 34:877–890.

13. Diagnosis criteria of Diabetes
Mellitus
NORMAL PREDIABETES DIABETES
FPG 80-100 mg/dl 101-126 mg/dl >126 mg/dl
(IFG)
PPG <140 mg/dl 141-199mg/dl ≥ 200mg/dl
(IGT)
HbA1C <6 % >6.5%
FPG: Fasting Plasma glucose
PPG: Post prandial glucose
HbA1C: Glycated/ glycosylated Hemoglobin
IFG : Impaired Fasting Glucose
IGT : Impaired Glucose Tolerance

14. Early diagnostic criteria of DM
• “Pre-diabetes” is a new term applied to
hyperglycemia that does not meet the
diagnostic criteria.
• Impaired fasting glucose (IFG) = fasting plasma
glucose of 100–125 mg/dl or
• Impaired glucose tolerance (IGT) = OGTT 2-hr
plasma glucose of 140–199 mg/dl
• IFG and IGT are associated with a high risk
for diabetes and cardiovascular disease.

15. Previously identified IGT and IFG
• Previously Identified IFG or IGT Inmates with
impaired glucose homeostasis are at increased
risk of developing diabetes.
• Approximately one third of patients with IFG
or IGT will develop diabetes within five years.
• Annual screening by fasting plasma glucose is
recommended for these patients.

16. Goals in Management
of Type 2 Diabetes
• Fasting BG < 110 mg/dL
• Post-meal < 140 mg/dL
• HbA1c < 6.5%
• Blood Pressure < 130/80
• LDL < 100 mg/dl
• HDL > 45 mg/dl

17. Need for an early and intensive
approach to new onset of T2DM
• At diagnosis of type 2 DM
• 50% of patients already have complications
• Upto 50% of β cell function has already been lost
• Current management:
• ⅔rd of patients do not achieve HbA1C
• Majority require poly pharmacy to meet glycemic
goals over time
UKPDS Group. Diabetologia 1991:34:877-890.
Saydah SH et al JAMA 2004; 291:335-342
Turner RC et al JAMA 1999; 281:2005-2012

18. ADA/EASD Revised Consensus Statement
Tier 1 : Well-validated core therapies
Lifestyle + Metformin Lifestyle + Metformin
+ +
At diagnosis: Basal Insulin Intensive Insulin
Lifestyle
+
Metformin Lifestyle + Metformin
+
Sulphonlyureasa
Step 1 Step 2 Step 3
Tier 2 : Less well-validated core therapies
Lifestyle + Metformin
+ Lifestyle + Metformin
Pioglitazone +
No hypglycemia Pioglitazone
Oedema/CHF +
Bone loss Sulphonylureas
Lifestyle + Metformin
+
GLP-1 agonistb Lifestyle + Metformin
David Nathan et al. No hypglycemia +
Diabetes Care 2009; 32:193-203 Weight loss Basal insulin
Nausea/Vomitting
a
A Sulphonylurea other than Glibenclamide or Chlorpropamide b
Insufficient clinical use to be confident regarding safe

19. A1C 6.5 – 7.5%** A1C 7.6 – 9.0% A1C > 9.0%
Drug Naive Under Treatment
Symptoms No Symptoms
Monotherapy Dual Therapy 8
MET † DPP4 1 GLP-1 TZD 2 AGI 3 GLP-1
GLP-1 or DPP4 1
INSULIN or DPP4 1 ± SU 7 INSULIN
*** MET + or TZD 2
2 - 3 Mos. ± Other ± Other
Agent(s)
MET + TZD 2 Agent(s)
4,5
SU or Glinide
Dual Therapy 6 GLP-1 6
± TZD 2
or DPP4 1
GLP-1 or DPP4 1 2 - 3 Mos.*** * May not be appropriate for all patients
MET + TZD 2 ** For patients with diabetes and A1C <
9
5
Triple Therapy 6.5%, pharmacologic Rx may be
Glinide or SU considered
GLP-1 *** If A1C goal not achieved safely
TZD + GLP-1 or DPP4 1
1 + TZD 2 † Preferred initial agent
or DPP4
Colesevelam 1 DPP4 if ↑ PPG and ↑ FPG or GLP-1 if ↑↑
MET + MET + GLP-1 AACE/ACE Algorithm for Glycemic
PPG
AGI 3 Control Committee 2 TZD if metabolic syndrome and/or
or DPP4 1 + SU 7
Cochairpersons: nonalcoholic fatty liver disease (NAFLD)
2 - 3 Mos.*** TZD 2 Helena W. Rodbard, MD, FACP, 3 AGI if ↑ PPG
MACE 4 Glinide if ↑ PPG or SU if ↑ FPG
Triple Therapy Paul S. Jellinger, MD, MACE
*** 5 Low-dose secretagogue recommended
MET + 2 - 3 Mos. Zachary T. Bloomgarden, MD, FACE
TZD 2 6 a) Discontinue insulin secretagogue
Jaime A. Davidson, MD, FACP, MACE
GLP-1 or + Daniel Einhorn, MD, FACP, FACE
with multidose insulin
b) Can use pramlintide with prandial
DPP4 1 Glinide or SU 4,7 INSULIN Alan J. Garber, MD, PhD, FACE
insulin
James R. Gavin III, MD, PhD
± Other George Grunberger, MD, FACP, FACE 7 Decrease secretagogue by 50% when
2 - 3 Mos.*** Agent(s) Yehuda Handelsman, MD, FACP, added to GLP-1 or DPP-4
6 FACE 8 If A1C < 8.5%, combination Rx with
Edward S. Horton, MD, FACE agents that cause hypoglycemia should
INSULIN Harold Lebovitz, MD, FACE be used with caution
± Other Philip Levy, MD, MACE
Etie S. Moghissi, MD, FACP, FACE 9 If A1C > 8.5%, in patients on Dual
Agent(s) Therapy,
6 Stanley S. Schwartz, MD, FACE
insulin should be considered
Available at www.aace.com/pub
© AACE December 2009 Update. May not be reproduced in any form without express written permission from AACE

20. LIFESTYLE
MODIFICATION A1C 6.5 – 7.5%**
AACE/ACE DIABETES
ALGORITHM FOR
Monotherapy GLYCEMIC CONTROL
MET † DPP4 1 GLP-1 TZD 2 AGI 3
2 - 3 Mos.***
Dual Therapy
GLP-1 or DPP4 1
MET + TZD 2
Glinide or SU 5
TZD + GLP-1 or DPP4 1
Colesevelam
***
If A1C goal not achieved safely
MET + † Preferred initial agent
AGI 3 1 DPP4 if ↑ PPG and ↑ FPG or
GLP-1
2 - 3 Mos.*** if ↑↑ PPG
2 TZD if metabolic syndrome
Triple Therapy and/or nonalcoholic fatty liver
disease (NAFLD)
MET + TZD 2 3 AGI if ↑ PPG
GLP-1 or + 4 Glinide if ↑ PPG or SU if ↑ FPG
DPP4 1 Glinide or SU 4,7 5 Low-dose secretagogue
recommended
6 a) Discontinue insulin
2 - 3 Mos.*** secretagogue with multidose
insulin
b) Can use pramlintide with
INSULIN prandial insulin
± Other 7 Decrease secretagogue by 50%
Agent(s) 6 when added to GLP-1 or DPP-4
Available at www.aace.com/pub
© AACE December 2009 Update. May not be reproduced in any form without express written permission from AACE

21. LIFESTYLE
MODIFICATION A1C 7.6 – 9.0%
AACE/ACE DIABETES
ALGORITHM FOR
Dual Therapy 8 GLYCEMIC CONTROL
GLP-1 or DPP4 1
MET + or TZD 2
SU or Glinide 4,5
2 - 3 Mos.***
***
If A1C goal not achieved safely
† Preferred initial agent
Triple Therapy 9 1 DPP4 if ↑ PPG and ↑ FPG or
GLP-1
GLP-1 if ↑↑ PPG
+ TZD 2 2 TZD if metabolic syndrome
or DPP4 1
and/or nonalcoholic fatty liver
MET + GLP-1 disease (NAFLD)
4 Glinide if ↑ PPG or SU if ↑ FPG
or DPP4 1 + SU 7
5 Low-dose secretagogue
TZD 2 recommended
6 a) Discontinue insulin
*** secretagogue with multidose
2 - 3 Mos. insulin
b) Can use pramlintide with
prandial insulin
7 Decrease secretagogue by 50%
INSULIN when added to GLP-1 or DPP-4
8 If A1C < 8.5%, combination Rx
± Other with agents that cause
Agent(s) 6 hypoglycemia should be used
with caution
9 If A1C > 8.5%, in patients on Dual
Therapy, insulin should be
considered
Available at www.aace.com/pub
© AACE December 2009 Update. May not be reproduced in any form without express written permission from AACE

22. LIFESTYLE
MODIFICATION A1C > 9.0%
AACE/ACE
DIABETES
Drug Naive Under Treatment
ALGORITHM FOR
GLYCEMIC
Symptoms No Symptoms CONTROL
GLP-1 or DPP4 1
INSULIN ± SU 7 INSULIN
± Other MET + TZD 2 ± Other
Agent(s) 6 Agent(s) 6
GLP-1 or DPP4 1 ± TZD 2
1 DPP4 if ↑ PPG and ↑ FPG or
GLP-1
if ↑↑ PPG
2 TZD if metabolic syndrome
and/or nonalcoholic fatty liver
disease (NAFLD)
6 a) Discontinue insulin
secretagogue with multidose
insulin
b) Can use pramlintide with
prandial insulin
7 Decrease secretagogue by 50%
when added to GLP-1 or DPP-4
Available at www.aace.com/pub
© AACE December 2009 Update. May not be reproduced in any form without express written permission from AACE

23. Most Patients With Type 2 Diabetes May Fail to Attain A1C
Goal With Conventional Treatment Paradigm
Published Conceptual Approach
OAD +
multiple daily
Diet and OAD OAD OAD OAD + insulin
Mean A1C exercise monotherapy up-titration combination basal insulin injections
of patients
10
A1C, 9
%
8
7
6
Duration of Diabetes
OAD=oral antihyperglycemic drug.
Adapted from Del Prato S et al. Int J Clin Pract. 2005;59:1345–1355.

24. Earlier and More Aggressive Intervention May Improve
Treating to Target Compared With Conventional Therapy
Published Conceptual Approach
OAD +
multiple daily
Diet and OAD OAD OAD OAD + insulin
exercise monotherapy up-titration combination basal insulin injections
10
A1C, 9
%
8
Mean A1C
of patients
7
6
Duration of Diabetes
Adapted from Del Prato S et al. Int J Clin Pract. 2005;59:1345–1355.

25. Initial treatment plan for new onset of DM
• Many studies have demonstrated that diabetes can be delayed,
and sometimes prevented in individuals at high risk for
developing diabetes (those with IFG, IGT, or both)
• Self-monitoring: HbA1C, FPG, PPG
• Recognizing and treating severe hypoglycemic and
hyperglycemic episodes
• Identifying the diabetic complications
• Lifestyle modifications: Improving food selection, increasing
physical exercise, and smoking cessation.

26. Initial treatment plan for new onset
of DM
• Daily self-examination of the feet.
• Regular screenings: fasting blood glucose, A1C,
lipid levels, and kidney monitoring (BUN, creatinine,
GFR)
• Annual eye exams (funduscopic) done by an
optometrist or ophthalmologist.

27. Ideal diabetic diet
• Total Calorie content and their derivation
from proximate principles of diet
• Glycemic index
• Fibre content
• Consistency or physical form of food.

28. Medical Nutritional therapy
Dietary composition should be :
 Carbohydrate : 50- 60 %
 Protein : 15-20%
 Fats : 15-25%
 Saturated fats : <10 %
 PUFA : up to 10%

29. Exercise
• Exercise improves the metabolism of a
diabetic patient by several mechanism.
• Increase the number of Insulin receptor as well
as the Sensitivity
• Increase in uptake of glucose

30. Currently Available agents for the
treatment of Type 2 Diabetes

34. Incretins (GLP-1 and GIP)
• GLP-1(Glucogen like peptide 1) are secreted from
L cells
• GIP ( Glucose dependant insulinotrpic
polypeptide ) are secreted from K cells
• Rapidly metabolized by Dipeptidyl peptidase 4
(DPP4)
• Half life of GLP-1 is 2 mins
• GIP- 5 mins

35. Incretins (GLP-1 and GIP)

36. Dipeptidyl-Peptidase 4 Inhibitors
• Agent in Class: Vildagliptin Sitagliptin,
Saxagliptin
• Mechanism of action:
• slows the inactivation of incretin hormones (glucagon-
like peptide 1 and glucose-dependent insulinotropic
polypeptide)
• Increases glucose-stimulated insulin secretion
• Causes glucose-stimulated glucagon suppression
• primarily lowers postprandial glucose levels but has
also been shown to reduce fasting plasma glucose
AACE Diabetes Mellitus Guidelines, Endocr Pract. 2007; 13 (suppl 1) 2007
Medical Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and
Adjustment of Therapy: Diabetes Care, Vol 31(12):1-11, 2008

37. No Single Class of Oral Antihyperglycemic Monotherapy
Targets All Key Pathophysiologies
Alpha- Meglitinides3 SUs4,5 TZDs6,7 Metformin8 DPP-4
Glucosidase Inhibitors
Inhibitors1,2
Insulin
Major Pathophysiologies
deficiency
  
Insulin
resistance
 
Excess hepatic
glucose output
  
Intestinal
glucose
absorption  
1. Glyset [package insert]. New York, NY: Pfizer Inc; 2004. 2. Precose [package insert]. West Haven, Conn: Bayer; 2004.
3. Prandin [package insert]. Princeton, NJ: Novo Nordisk; 2006. 4. Diabeta [package insert]. Bridgewater, NJ: Sanofi-Aventis; 2007.
5. Glucotrol [package insert]. New York, NY: Pfizer Inc; 2006. 6. Actos [package insert]. Lincolnshire, Ill: Takeda Pharmaceuticals; 2004.
7. Avandia [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2005.
8. Glucophage [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2004.

38. Potential advantages of early
combination therapy
• Earlier achievement of therapeutic goals
• Potential reduction in risk of side effects if you
combine drugs at lower doses versus up-titration
of single dose
• Opportunity to combine oral anti diabetic
drugs with complementary modes of action
• Potential to delay disease progression

39. Guidelines for Starting Insulin
Insulin therapy is indicated if the following
measures fail to achieve glycaemic targets:
• Maximum tolerated dose of Oral
Hypoglycaemic Agents (OHA)
• Failure to reach glycemic targets
• Remediable factors considered (e.g. food
and exercise plan, inter current problems)

41. Guidelines for Starting Insulin
•If more than 30-36 IU of insulin necessary to
obtain good metabolic control, consider stopping
insulin secretagogues and continue on same total
dose of insulin + metformin or actos
•Divide the dose into 2 daily injections:
2/3 before breakfast
1/3 at bedtime

42. Targets of control
in Diabetes Mellitus

43. Stages of
Diabetic Nephropathy
• Stage I – Hyperfiltration - increased blood flow through the kidney,
early renal hypertrophy
• Stage II – Glomerular lesions without clinically evident disease
• Stage III – Incipient nephropathy with microalbuminuria - alb/cr
ratio .03 - .3 or albumin 20-200 mcg/min on timed specimen
• Stage IV – Overt diabetic nephropathy with proteinuria >500 mg/24
hr & creatinine clearance <70 ml/min
• Stage V – End stage renal disease (ESRD)
– creatinine clearance <15 ml/min
– creatinine = 6mg/dl
•

44. Stages of
Diabetic Nephropathy
180
160
140 II III
120 I
100
GFR
IV
80
60
40
20
0 V
0 5 10 15 20 25 30
Duration of Diabetes

45. Prevention of Diabetic
Nephropathy
• Optimal Glycemic Control
• Intensive Blood Pressure control (>130/80 mm Hg)
• Use of ACE –I
• Reduce Salt Intake
• Reduce Alcohol Intake

46. Diabetic Retinopathy

47. Prevention for Diabetic
Retinopathy
• Optimal Blood Preesure Control
• Optimal Glycemic Control
• Control Lipid Profile
• Use of Aspirin
• Regular Screening Must

48. Neuropathy
• Develops within 10 years after onset of diabetes in
40-50% of patients with diabetes
• Some type 2 patients already have neuropathy at
diagnosis
• Increased risk of foot ulcers and amputation
• 45% of lower extremity amputations occur in patients
with diabetes

49. Prevention for Diabetic Neuropathy
• Intensive Glycemic control
• Lifestyle Modification
– Quit Smoking
– Reduce Alchol Intake
• Foot Care:
– Wear Non Weight bearing Comfortable Shoes
– Keep feet Clean & Dry
– Wash feet daily with Warm Water
– Do not go barefeet
– Trim your toenails straight across
– Wear fresh socks every day

50. UKPDS 33
Risk Reduction of Various Endpoints
Microvascular P=0.0099
25%
Retinopathy 21% P=0.015
Albuminuria 33%P=0.000054
Myocardial
infarction 16% P=0.052
Diabetes-related
12% P=0.029
end points
0 5 10 15 20 25 30 35
Risk Reduction (%)
UK Prospective Diabetes Study (UKPDS) Group. Lancet.
1998;352:837-853.

51. Indians are Different
• Earlier onset of diabetes as compared to Caucasians
• Considerably thinner (particularly in the limbs) but
more centrally obese than the Caucasian
• Despite being lean, Indians are more insulin resistant
and hyperinsulinaemic.
• Obese and physical inactivity
• High procoagulant tendency
• Genetic predisposition
Indian J Med Res 129, May 2009, pp 485-499

52. What should be the target HbA1c?

53. Primary Prevention of CVD
in People with Diabetes Mellitus
A Scientific Statement from ADA & AACE
• A1c goal for patients in general is <6.5%
• A1c goal for the individual patients is an A1c
as close to normal (<6%) as possible without
causing hypoglycemia

54. Intensive Glycemic Control and the Prevention of
Cardiovascular Events: Implications of the
ACCORD, ADVANCE and VA Diabetes Trials
A Position Statement of the ADA and a
Scientific Statement of the ACC & AHA
• Lower A1c goal if can be achieved without
significant hypoglycemia:
– Short duration of diabetes
– Long life expectancy
– No significant CVD
Skyler et al, J Am Coll Cardiol 2009;53:298-304

55. Intensive Glycemic Control and the Prevention of
Cardiovascular Events: Implications of the ACCORD,
ADVANCE and VA Diabetes Trials
A Position Statement of the ADA and a
Scientific Statement of the ACC & AHA
• Less stringent A1c goal:
– History of severe hypoglycemia
– Limited life expectancy
– Advanced micro- or macrovascular complications
or extensive comorbid conditions
– Long-standing diabetes which is difficult to
control
Skyler et al, J Am Coll Cardiol 2009;53:298-304

56. Glycemic Recommendations for type-2 DM
Goals should be individualized based on
• Duration of diabetes
• Age/life expectancy
• Comorbid conditions
• Known CVD or advanced microvascular complications
• Hypoglycemia unawareness
• Individual patient considerations
• Hypoglycemia unawareness
• Individual patient considerations
ADA. V. Diabetes Care. Diabetes Care 2011;34(suppl 1):S21. Table 10.

57. Current Practice
• Emphasize achieving current standards of care in the diabetic
patient
– A1c Goal of ~ 7%
– BP Goal of 130/80
– LDL Goal of 100 mg/dl (70 mg/dl in patients with
established CVD)
– Assist in behavior controls of diet, exercise, tobacco
cessation
– Emphasis should be on translation research and
implementing programs to assist patients in reaching
current goals.

58. Thank you