1. Contents Physiology and pathophysiology of type 2 diabetes
5/15/2018 3:51 PM
Contents
Physiology and pathophysiology of type 2 diabetes
Role of Incretins, DPPIV inhibitors, SGLT 2, inhibitors,
How intensely should we treat and are there problems
Contents
Now we will discuss the role of incretins.

2. Treatment of Type 2 Diabetes
Go For Goal!!
The Earlier the Better

3. So What is the Window of Opportunity

4. Published Conceptual Approach
Earlier and More Aggressive Intervention May Improve Patients’ Chances of Reaching Goal
Published Conceptual Approach
OAD +
multiple daily
insulin injections
Diet and exercise
OAD
monotherapy
OAD up-titration
OAD
combination
OAD +
basal insulin 10 9
A1C Goal 8
Earlier and More Aggressive Intervention May Improve Patients’ Chances of Reaching Goal
The yellow line depicts a conceptual view of a conventional stepwise treatment approach. Hypothetically, patients treated with this approach would have a considerable glycemic burden (time spent above A1C goals).1
The orange line depicts a conceptual view of an aggressive A1C goal-oriented approach that would initiate changes in therapy earlier (within several months of goals not met).1
Hypothetically, patients treated with this approach might be able to attain such A1C results as those depicted by the straight orange line. This approach also calls for earlier use of combination therapy in appropriate patients.1 7
Purpose
To show conceptually that early, aggressive intervention may reduce the glycemic burden of type 2 diabetes.
Takeaway
A treat-to-goal therapeutic approach should include aggressive treatment whenever A1C is above goal. The overall glycemic burden can be reduced with this approach. 6
Mean A1C of patients
Duration of Diabetes
Conventional stepwise treatment approach
Earlier and more aggressive intervention approach
OAD=oral antidiabetic agent.
Adapted from Del Prato S et al. Int J Clin Pract. 2005;59(11):1345–1355. Permission pending. 4
Reference
1. Del Prato S, Felton A-M, Munro N, Nesto R, Zimmet P, Zinman B; on behalf of the Global Partnership for Effective Diabetes Management. Improving glucose management: ten steps to get more patients with type 2 diabetes to glycaemic goal. Int J Clin Pract. 2005;59(11):1345–1355.

5. The Paradigm Shift in the Management of Type 2 Diabetes
Patient Age
Disease Duration 40 45 50 55 60 65 70 75 5 10 15 20
Other Comorbidities
None
Few/Mild
Multiple/Severe
Hypoglycemia Risk
Low
High
Moderate
Least Intensive
8.0%
Most Intensive
6.0%
Less Intensive
7.0%
Established Vascular Complications
Early Microvascular
Advanced Microvascular
Psychosocioeconomic Considerations
Highly Motivated, Adherent, Knowledgeable, Excellent Self-Care Capacities, Comprehensive Support Systems
Less Motivated, Nonadherent, Limited Insight, Poor Self-Care Capacities, Weak Support Systems CV
6/14
Ismail-Beigi F et al: Ann Intern Med 154: ; 2011 and Inzucchi SE et al: Diabetes Care 35: ; 2012

6. Mr. and Mrs. Smith What is your target A1C?
79 year old male with CAD s/p CABG in 2002, DM II (dx over 20 years), BPH, HTN, and OA
He is independent in his ADLs but his daughter helps with groceries and cleaning.
“Doting husband” who helps to take care of his wife with Alzheimer’s.
He is seeing you in clinic for medical management.
What is your target A1C?

7. What is your Target A1c for Mr Smith?
Please select one of the following:
A. 6.5
B. 7.0
C. 7.5
D. 8.0
E. 8.5

8. Kendall DM, Bergenstal RM. © International Diabetes Center 2009
Impact of Intensive Therapy for Diabetes: Summary of Major Clinical Trials
Study
Microvasc
CVD
Mortality
UKPDS  
DCCT / EDIC*
ACCORD 
ADVANCE
VADT
Overview of the microvascular, macrovascular and mortality outcomes from large T2DM and T1DM randomized clinical trials that focused on the relationship between glycemic control and complications.
Initial Trial
Kendall DM, Bergenstal RM. © International Diabetes Center 2009
UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:854.
Holman RR et al. N Engl J Med. 2008;359: DCCT Research Group. N Engl J Med 1993;329;977.
Nathan DM et al. N Engl J Med. 2005;353: Gerstein HC et al. N Engl J Med. 2008;358:2545.
Patel A et al. N Engl J Med 2008;358: Duckworth W et al. N Engl J Med 2009;360:129. (erratum:
Moritz T. N Engl J Med 2009;361:1024)
Long Term Follow-up
* in T1DM

9. Can we apply data to Mr. Smith?
RCT – tight glycemic control
Mean age
Initial HgbA1C
Intensive vs. conventional
Duration of DM
UKPDS 33
UK Prospective Diabetes Study (1998) 53
7.09 vs. 7.05
“Newly” dx
UKPDS 34
7.1 vs. 7.2/7.3
ADVANCE
Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (NEJM 2008) 66
7.5 vs. 7.5
8 years
Mean
ACCORD
Action to Control Cardiovascular Risk in Diabetes (NEJM 2008)
62.2
8.3 vs. 8.3
10 years
Median
STENO-2
(NEJM 2008) 55
8.4 vs. 8.8
Not reported
VADT
Veterans Affairs Diabetes Trial (NEJM 2009) 60
9.4 vs. 9.4
11.5 years

10. Can we apply data to Mr. Smith?
RCT – tight glycemic control
Achieved HgbA1c
(Intensive vs. conventional)
Benefit/Risk
Time to
derive benefit
UKPDS 33 vs
↓ microvascular endpoint
*retinal photocoagulation
10 years
UKPDS 34 vs
Median
↓ all cause mortality, MI, and “any DM related endpoint”
*metformin
10.7 years
ADVANCE vs
Mean
↓ in new onset microalbuminuria
↓ in nephropathy
5 years
ACCORD vs
↓ in non-fatal MI
↑ All cause and CV mortality
3.5 years, stop
STENO-2
vs. 9
vs. 8
↓ in all cause mortality
↓ in CV mortality*
8 years,
5.5 years
VADT vs
↓ progression of albuminuria
5.6 years

11. Benefit vs. Risk for Mr. Smith?
UKPDS
ACCORD
Ann Intern Med. 2009;150(11): doi: /

12. Risk for Mr. Smith? UKPDS VADT ADVANCE ACCORD
Ann Intern Med. 2009;150(11): doi: /

13. *Hypoglycemia rates were 2-fold higher for older patients (≥75 years)
Rates of Estimated Hospital Admissions for Hyperglycemia and Hypoglycemia Among Medicare Beneficiaries With DM, 1999 to 2011
hypoglycemia
hyperglycemia
*More likely to be admitted with hypoglycemia than hyperglycemia in DMII
*Hypoglycemia rates were 2-fold higher for older patients (≥75 years)
JAMA Intern Med Jul;174(7): doi: /jamainternmed

14. Survival as a Function of HgbA1c
in People with Type 2 DM
Hazard Ratio (95% CI)
HbA1c
The Lancet, Volume 375, Issue 9713, 2010,

15. Metabolic Memory and Glycemic Legacy
UKPDS and VADT
Start of intensive therapy in VADT
Start of intensive therapy in UKPDS 98
Drives risk of Complications
Risk of complications continues
despite glycemic control
A1C (%)
Bad Glycemic Legacy 76
SPEAKER NOTES:
This figure is a hypothetical representation of the natural history of patients with T2DM in the VADT study.
The upper dashed line represents the time course of HbA1c estimated by the average glucose profile in the UKPDS, based on the premise that duration of diabetes in VADT would be similar to that in UKPDS.
The lower dashed line represents the ideal time course of glycemic control (early and sustained at time of diagnosis).
The solid line to the right represents the time course of HbA1c in the VADT (mean time between diagnosis and start of intensive treatment in VADT = 11.4 years).
Intensive therapy implemented in VADT resulted in a rapid lowering of plasma glucose levels close to the ideal target.
However, this time course is far from the ideal (ie, the achievement and maintenance of near-normal glycemia from the time of diagnosis).
The difference between the ideal and the actual time course of glycemic control represents a time period that may have had some impact on the effect of subsequent tight glycemic control (ie, the glycemic legacy).
REFERENCE:
1. Del Prato S. Diabetalogia. 2009;52:
Ideal course = early and sustained glycemic control 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
Time Since Diagnosis (years)
Del Prato S. Diabetalogia. 2009;52:

16. Diabetes in Older Adults:
A Consensus Report
Pt characteristics
Rationale
A1C goal*
Healthy
Longer remaining life expectancy
< 7.5
Multiple co-existing chronic illnesses or 2+ iADL impairments
Intermediate remaining life expectancy, high tx burden, hypoglycemia vulnerability, fall risk
<8
LTC, end stage of chronic illnesses, or 2+ ADL impairments
Limited remaining life expectancy makes benefit uncertain
<8.5
*Reasonable goal
JAGS 2012: Kirkman et al.
Diabetes in older adults: a consensus report.

17. Conclusions TREAT for SUCCESS not for FAILURE
Choose your targets and go for goal with the window of opportunity
Titration does not work in clinical practice ( Titration is a tardy task)
Overcome Clinical Inertia
Combine drugs initially depending on goal and use half maximal dosages in combinations
We now have the tools to target the risk factors for CVD in Diabetes and the Metabolic Syndrome
There is still a large proportion of morbidity and mortality and choose therapy and goal based upon risk stratification
TREAT for SUCCESS not for FAILURE