1. Management of Type 2 Diabetes:
Helmut Brath
First Secretary of Austrian Diabetes Association
Diabetes Outpatient Clinic, Health Centre South
Vienna, Austria
Management of Type 2 Diabetes:
The earlier the better?
Beirut,
Brath: DM

2. Potential Conflicts of Interest
Lectures, Symposia, Seminars: all relevant Diabetes & Lipid Companies
Advisory Boards: all relevant Diabetes Companies
Phase III Studies: GSK, Johnson&Johnson, Takeda, Sanofi, Novartis, MSD, Novo Nordisk, Eli-Lilly, Grünenthal, Lexicon, Astra Zeneca
Reviewer: Ethics Committee Vienna, various Scientific Journals
Employer: Social Insurance Fund of Vienna, Austria
Boardmember: Austrian Diabetes Assocation, Austrian Council on Smoking and Health
For this lecture: Honorary by Novartis
Brath: DM

3. Contents 1. Early vs. late intensification of treatment: Evidence?
2. Do we intensify early enough?
3. Why are we sometimes clinically inert?
4. Time to do more?
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4. Early vs. late intensification of treatment1.
Early vs. late intensification of treatment
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5. UKPDS mother of all diabetes endpoint-studies
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6. UKPDS: reducing HbA1c reduces diabetes complications
21%
death
microvascular complications
37%
HbA1c 1%
14%
heart attacks
amputations, fatal PAVK
43%
12%
strokes
Stratton IM, et al. UKPDS 35. BMJ 2000;321:405–12
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7. Legacy Effect of Early Glucose Control
UKPDS: 10 years follow up
Total Mortality
Legacy Effect of Early Glucose Control
Proportion with event
R. Holman, UKPDS 80 N Engl J Med. 2008;359:
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8. UKPDS
Early lowering of glucose (HbA1c 7,9 → 7,0 %) reduces morbidity & mortality, esp. with metformin
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9. b.
VADT Time is decisive
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10. Diabetes duration & CV-morbidity
Diabetes duration (T2DM, VADT study) & risk for CVD with IGC: hazard ratios increase with diabetes duration1,2
CV events: associated with diabetes duration, not with medication
1.4
mean diabetes duration at start of study: 11.5 yrs
1.2
The ‘Veterans Affairs Diabetes (VADT)’ study, aimed to determine the effects of intensive glucose control on cardiovascular events in patients with long-standing type 2 diabetes mellitus1
1791 military veterans (mean age, 60.4 years) who had a suboptimal response to therapy for type 2 diabetes were assigned to receive either intensive or standard glucose control therapy1
The goal in the intensive-therapy group was an absolute reduction of 1.5 percentage points in the glycated haemoglobin level, as compared with the standard-therapy group
The primary endpoint was the time to first occurrence of a CV event: documented myocardial infarction; stroke; death from cardiovascular causes; new or worsening congestive heart failure; surgical intervention for cardiac, cerebrovascular, or peripheral vascular disease; inoperable coronary artery disease; and amputation for ischaemic gangrene1
In the VADT study, diabetes duration was a significant predictor of the primary endpoint2
The hazard ratios for CVD with intensive vs standard therapy increased with diabetes duration (as shown on slide)2,3
Initially, intensive therapy was found to be protective but the risk of experiencing an event increased with the duration of diabetes
References:
Duckworth W, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009;360:
Duckworth W. VADT: results. ADA Scientific Sessions Available at: Accessed: 5 Oct 2009.
Del Prato S. Megatrials in type 2 diabetes. From excitement to frustration?. Diabetologia. 2009;52: 1
HR for CVD
0.8
P<0.0001
0.6
0.4 3 6 9 12 15 18 21 24
Diabetes duration, y
CVD: Cardiovascular disease; IGC: intensive glukose control
1. Del Prato S. Diabetologia. 2009;52: Duckworth W. ADA Scientific Sessions Available at: Accessed: 5 Oct, 2009. 10
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11. VADT: „bad glycemic legacy“
9.5
Generation of "bad glycemic legacy"
9.0
Drives risk of complications
8.5
HbA1c (%)
8.0
7.5
Taken together, these results suggest that, at least within the timeframe of the intensive treatment period of the most recent trials, there is less opportunity to influence the development and/or progression of complications in individuals with long-standing diabetes. Conversely, in both type 11,2 and type 23 diabetic patients, early strict glycemic control generates a legacy that may confer protection against, or delay, long- term diabetic complications.
This graph tentatively reconstructs the history of the disease of patients included in the VADT:4,5
It is likely that patients had a high HbA1c level at the time of diagnosis and also that they started on dietary therapy and/or some oral hypoglycemics agents that improved, but did not normalize, glycemic control.
Nonetheless, over the time the patients' glycemic control worsened progressively to reach, years later, a HbA1c level of 9.4%, when they were enrolled in the VADT.
Intensive therapy implemented in the trial resulted in a rapid lowering of plasma glucose levels and subsequent maintenance of HbA1c close to the ideal target.
It is, however, readily apparent that this time course is far from the ideal, i.e. the early 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 period that may have had some impact on the effect of subsequent tight glycemic control. First of all, preceding long-standing hyperglycemia may account for the high rate of complications at baseline. Second, it may have generated a "bad glycemic legacy".
Potential mechanisms to explain the molecular basis for this metabolic memory (glucose legacy) include increased formation of cellular reactive species and advanced glycation end products in response to chronic hyperglycemia, resulting in the activation of pathways involved in the pathogenesis of diabetes-related complications.4 Intervention later in the course of the disease provides less opportunity to influence the development and/or progression of complications in patients with long-standing diabetes.
 References:
1. White NH, et al. Prolonged effect of intensive therapy on the risk of retinopathy complications in patients with type 1 diabetes mellitus: 10 years after the Diabetes Control and Complications Trial. Arch Ophthalmol. 2008;126(12):
2. Nathan DM, et al. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med. 2005;353(25):
3. Holman RR, et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359(15):
4. Del Prato S. Megatrials in type 2 diabetes. From excitement to frustration? Diabetologia. 2009;52(7):
5. Del Prato S, et al. Tailoring treatment to the individual in type 2 diabetes practical guidance from the Global Partnership for Effective Diabetes Management. Int J Clin Pract Feb;64(3):
7.0
6.5
6.0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
Yrs since diagnosis
Upper dotted line: time course of HbA1c described by the UKPDS 33 Lower dotted line: ideal time course of glycemic control
Solid line: time course of HbA1c in the VADT.
1. Del Prato S. Diabetologia. 2009;52(7): Del Prato S, et al. Int J Clin Pract Feb;64(3):
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12. Brath: DM

13. First 15 years of diabetes duration:
VADT
First 15 years of diabetes duration:
Timeframe for (later) reduced mortality
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14. c.
Euro Heart Survey
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15. EuroHeart Survey: Early Treatment prevents CV Events
n=3940 pts with known glucometabolic state
Newly detected DM
n= 452 (11%)
After a 1-year follow-up period
On treatment for DM
n= 77 (17%)
No treatment for DM
n= 375 (83%)
mortality p<0.002 MI
stroke
Anselmino et al, Eur Heart J 2008;29:177-84
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16. CV Outcomes stratified by whether treatment initiated
12 month event rate just in newly detected T2DM (n= 452)
Tx for DM
no Tx for DM
Anselmino et al, Eur Heart J 2008;29:177-84
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17. Early vs. Late Treatment Intensification d.
Early vs. Late Treatment Intensification
Simulation Study, Patients
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18. Delay in Treatment Intensification & Outcomes
Delays in treatm. intens. with OAD: risk of microvasc. & macrovasc. events in ptx with poor glyc. control (baseline HbA1c ≥ 8,0%): An individual ptx simulation study.
HbA1c at 1 year: 6,8 % vs. 8,2 %
AIMS:
To use the Archimedes model to estimate the consequences of delays in oral antidiabetic drug (OAD) treatment intensification on glycaemic control and long-term outcomes at 5 and 20 years.
MATERIALS AND METHODS:
Using real-world data, we modelled a cohort of hypothetical patients with glycated haemoglobin (HbA1c) ≥8%, on metformin, with no history of insulin use. The cohort included 3 strata based on the number of OADs taken at baseline. The first add-on in the intensification sequence was a sulphonylurea, next was a dipeptidyl peptidase-4 inhibitor, and last, a thiazolidinedione. The scenarios included either no delay or delay, based on observed and extrapolated times to intensification.
RESULTS:
At 1 year, HbA1c was 6.8% for patients intensifying without delay, and 8.2% for those delaying intensification. For no delay vs delay, risks of major adverse cardiac events, myocardial infarction, heart failure and amputations were reduced by 18.0%, 25.0%, 13.7%, and 20.4%, respectively, at 5 years; severe hypoglycaemia risk, however, increased to 19% for the no delay scenario vs 12.5% for delay. At 20 years, the results showed similar trends to those at 5 years.
CONCLUSIONS:
Timing of intensification of OAD therapy according to guideline recommendations led to greater reductions in HbA1c and lower risks of complications, but higher risks of hypoglycaemia than delaying intensification. These results highlight the potential impact of timely treatment intensification on long-term outcomes.
MACE: MI, stroke, CHD death
MACE: MI, stroke, CHD death
Folse HJ et al, Diabetes Obes Metab Jul;19(7): doi: /dom Epub 2017 Mar 20
Brath: DM

19. Delay in Treatment Intensification & Outcomes
AIMS:
To use the Archimedes model to estimate the consequences of delays in oral antidiabetic drug (OAD) treatment intensification on glycaemic control and long-term outcomes at 5 and 20 years.
MATERIALS AND METHODS:
Using real-world data, we modelled a cohort of hypothetical patients with glycated haemoglobin (HbA1c) ≥8%, on metformin, with no history of insulin use. The cohort included 3 strata based on the number of OADs taken at baseline. The first add-on in the intensification sequence was a sulphonylurea, next was a dipeptidyl peptidase-4 inhibitor, and last, a thiazolidinedione. The scenarios included either no delay or delay, based on observed and extrapolated times to intensification.
RESULTS:
At 1 year, HbA1c was 6.8% for patients intensifying without delay, and 8.2% for those delaying intensification. For no delay vs delay, risks of major adverse cardiac events, myocardial infarction, heart failure and amputations were reduced by 18.0%, 25.0%, 13.7%, and 20.4%, respectively, at 5 years; severe hypoglycaemia risk, however, increased to 19% for the no delay scenario vs 12.5% for delay. At 20 years, the results showed similar trends to those at 5 years.
CONCLUSIONS:
Timing of intensification of OAD therapy according to guideline recommendations led to greater reductions in HbA1c and lower risks of complications, but higher risks of hypoglycaemia than delaying intensification. These results highlight the potential impact of timely treatment intensification on long-term outcomes.
Folse HJ et al, Diabetes Obes Metab Jul;19(7): doi: /dom Epub 2017 Mar 20
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20. Do we intensify early enough?3.
Do we intensify early enough?
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21. EDGE: Effectiveness of Diabetes control with vildaGliptin and vildagliptin/mEtformin LAF237A2403 Observational Study
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22. Worldwide Cohortstudy (n = 45
Worldwide Cohortstudy (n = ) under “real world” conditions: Comparison between Vildagliptin based dual therapie with DPP-4 free dual therapie on effectivity without side effects
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23. Jordan, Palestine, Lebanon, Bahrain, Kuwait, Oman
27 participating countries, 5 regions East Asia, Europe, LatAm, Middle East, India
Europe
Austria, Belgium, Czech Republic, Germany, Greece, Netherlands, Portugal, Slovakia, Sweden, Bulgaria, Luxembourg, Russia
East Asia
South Korea
The Philippines
India
Latin America
Mexico, Venezuela,
Argentina, Colombia,
Ecuador
Middle East
Jordan, Palestine, Lebanon, Bahrain, Kuwait, Oman
United Arab Emirates
LatAm, Latin America
Criteria for grouping: based on the assumption of homogeneous genetic background
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24. Baseline HbA1c by Region
LatAm, Latin America; SD, standard deviation
H Brath, PM Paldánius,…., PM Nilsson, Nutr Diabetes Jul 4;6(7):e217
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25. VERIFY: early intense treatment?
Newly diagnosed (≤ 24 months) people with T2DM
Treatment naïve
HbA1c ≥6.5% and ≤7.5%
18 – 70 a
Metformin
Monotherapy
Durability of glycemic control
Time to initial treatment failure
Rate of loss of beta cell function
The purpose of this study is to determine whether the initiation of a vildagliptin plus metformin combination regimen would result in more durable glycemic control than metformin monotherapy in treatment-naïve patients with T2DM.
Primary Outcome Measures: Rate of loss in glycemic control over time [ Time Frame: Week 26 ] [ Designated as safety issue: No ] Time to initial treatment failure [ Time Frame: 5 years ] [ Designated as safety issue: No ] Secondary Outcome Measures: Rate of loss in glycemic control in fasting plasma glucose [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ] Rate of loss in glycemic control in fasting plasma glucose (FPG) during period 2 [ Time Frame: up to 5 years ] [ Designated as safety issue: No ] Rate of loss of beta cell function from baseline to end of study ( 5 years) [ Time Frame: From baseline to end of study (5 years) ] [ Designated as safety issue: No ] Number patients with adverse events, death and serious adverse events [ Time Frame: 5 years ] [ Designated as safety issue: Yes ] Rate of loss in glycemic control in over time [ Time Frame: up to 5 years ] [ Designated as safety issue: No ] Rate of change in insulin sensitivity from baseline to end of study (5 years) [ Time Frame: From baseline to end of study (5 years) ] [ Designated as safety issue: No ]
Inclusion Criteria:
Type 2 Diabetes Mellitus (T2DM) diagnosed ≤ 24 months ago
glycosylated hemoglobin (HbA1c) ≥6.5% and ≤7.5% at Visit 1
Treatment-naïve.
Body mass index (BMI) ≥22 and ≤40 kg/m2 at Visit 1
Exclusion Criteria:
Pregnant or nursing (lactating) women
Fasting plasma glucose (FPG) ≥ 270 mg/dL (≥ 15.0 mmol/L)
Previous or current participation in any vildagliptin clinical study.
History of hypersensitivity to dipeptidyl peptidase-4 (DPP-4) inhibitors.
Concurrent medical condition that may interfere with the interpretation of efficacy and safety data during the study.
Donation of blood or significant blood loss equaling to at least one unit of blood within the past 2 weeks of start of study or a blood transfusion within the past 12 weeks or planned regular transfusions during the study period
Other protocol-defined inclusion/exclusion criteria may apply
Metformin +
Vildagliptin
last accessed
Brath: DM

26. Why are we sometimes clinically inert?4.
Why are we sometimes clinically inert?
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27. What does „Clinical Inertia“ mean?
“a failure to initiate or intensify treatment in a timely manner in people with diabetes whose health is likely to improve with this intensification”
“a failure to establish appropriate targets and escalate treatment to achieve treatment goals”
Claiming individualising treatment targets retrospectively, i.e. allowing ‘the goal’ to retrospectively move to meet achieved value
Unterlassen, Versagen
Strain WD et al, DRCP 2014,
Strain WD et al. Clinical Inertia in Individualising Care for Diabetes: Is There Time to do More in T2DM? Diabetes Ther
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28. Physicians 29
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29. Perceived patient incompetence Time constraints
Insufficient Infrastructure
Reliance on (only) lifestyle changes
Concerns about outcomes and hypoglycemia
Desire to avoid Unpleasant Confrontation
Potential for
weight gain
Impact on patient QoL and employment
Lack of confidence in clinical data (studies)
Fear of seeming incompetent to colleagues
Unsure when and how to intensify therapy
Unsure, when
to initiate insulin
Believe barriers reside mainly with patients
Kunt and Snoek. Int J Clin Pract 2009;63(Suppl. 164):6–10
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30. Patients 31
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31. It´s not important, what we prescribe…
Pre-scrip-tion
Some studies suggest that long-term adherence of chronically prescribed CV medications such as anti-hypertensives or statins may be as low as 50%.
All we know about the value of these chronic medications in reducing untoward outcomes are usually based on rigorous RCT that involve frequent visits, free medications, and pill counts to verify adherence.
The actual benefit of CV medications when they are taken only intermittently or for a short period of time and then stopped is not known for sure, but is thought to be worse based on observational studies in routine practice.
Filled in Pharmacy
Medica-tion
taken
Long-term
Adherence
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32. 1 Sick Late Complications No tasty food any more
Renouncing……. Myocardial Infarction
Education (.....School .... Teachers...)
Medication Life Restrictions
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33. Just great!
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34. Why didn´t you come sooner?2
How much do you eat?
Why didn´t you come sooner?
…….. GUILT………!
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35. You should watch your weight more, Gisela.
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36. 3
Motherboard, Remote Data Transmission, Virtual Memory, Bit Rate, Remote Data Transmission, Browser, Wireless LAN, Hard Disk, Ethernet, Remote Data Transmission, WLAN, Hardware, Data Transmission, Tool, Benchmark, Upload, Processor, Hard Disk, Remote Data Transmission, Videocard, Keyboard, Software, Motherboard, Computing Crash, Hacker, HTML, Internet, Antivirus
Brath: DM

37. Motherboard, Remote Data Transmission, Virtual Memory, Bit Rate, Remote Data Transmission, Browser, Wireless LAN, Hard Disk, Ethernet, Remote Data Transmission, WLAN, Hardware, Data Transmission, Tool, Benchmark, Upload, Processor, Hard Disk, Remote Data Transmission, Videocard, Keyboard, Software, Motherboard, Computing Crash, Hacker, HTML, Internet, Antivirus
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38. Medication…. 4
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39. 5 Already too late? Brath: DM
Clinical outcomes for metformin in the UKPDS
Clinical outcomes for heart attacks and strokes are worthy of special consideration, as these are the two key cardiovascular complications which influence long-term survival in patients with type 2 diabetes.
UK Prospective Diabetes Study Group. Effect of intensive blood glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998;352:
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40. How compliant are you? 41
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41. Knowledge does not (always) lead to action
How compliant are you?
Knowledge does not (always) lead to action
Last 7 days: at least 5x minimum of min exercise?
Last 7 days: daily vegetables & salad?
Do you (still) smoke?
Last 7 days: each night > 7 hours sleep?
Brath: DM

42. Discussing too private matters Unknown (medical) jargon
Why Noncompliance?
Renouncing too much….
Discussing too private matters
Unknown (medical) jargon
Too much information
Too much medication
Already too late…
Aren´t we familiar with “Noncompliance” from ourselves?
Brath: DM

43. 4. Time to do more?
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44. HOW to treat Hyperglycemia?
WITHOUT side effects
hypoglycemia
weight gain
nontheless efficient
early enough
easy (no frequent changes or adaptations, fixed dose comb.)
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45. EDGE: primary endpoint
Responding to 12-month therapy (HbA1c drop > 0,3%)
WITHOUT
peripheral edema OR
hypoglycemic events OR
discontinuation due to GI event OR
significant weight gain (>5 %)
under “real world” conditions
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46. EDGE: Secondary Endpoints
Secondary effectiveness endpoints:
Treatment response without any: peripheral edema, hypos, discontinuation due to GI-events, or weight ↑ ≥ 3 %
Treatment response without: ≥ 3 % weight ↑, hypos
HbA1c < 7,0 %, without ≥ 3 % weight↑, hypos
Secondary safety endpoints:
Mortality, SAEs, AEs
Discontinuation due to SAEs
Discontinuation due to AEs
Discontinuation due to any other reason than AE/SAE
Effect of Vildagliptin add-on dual therapy on individual tolerability factors (body weight, peripheral edema, proven hypoglycemic events, and gastrointestinal events), relative to comparator OADs used as add-on dual therapy
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47. Matthiew C, Barnet A, Brath H et al, Int J Clin Pract, Int J Clin Pract. 2013 Oct;67(10):947-56
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48. Second. Effectiveness endpoint 3: HbA1c < 7,0 at EOT without weight gain ≥ 3 %, hypos
0.6
0.8 1
1.2
1.4
1.6
1.8 2
2.2
2.4
2.6
2.8 3
3.2
3.4
3.6
3.8 4
SEP Adjusted
SEP Unadjusted
East
Asia
Europe
Latin America
Middle East
India
HbA1c ≤8.0
HbA1c >
HbA1c >9.0
BMI <25
BMI 25-<30
BMI 30-<35
BMI ≥35
Alpha-Gl
Sulfonylureas
Thiazolidinediones
Metformin
Glinides
Adjusted odds ratio, 95% CI and p-value are from logistic regression analysis with baseline HbA1c, baseline BMI, race, region, age, gender, duration of diabetes, background OAD at entry to study and patient type as covariates
Unadjusted
Comparator better
Vildagliptin better
Odds Ratio
PP Population und baseline HbA11c > 7,0 %
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49. HbA1c: Overall time course
Vildagliptin
Comparator N
Mean (CI 95%)
Baseline
27181
(8.15 – 8.18
14832
(8.13 – 8.18) Δ
24480
-1.19 (-1.21 – -1.18)
13813
-0.99 (-1.01 – -0.97)
Time (weeks)
Vildagliptin, N Comparator, N
CI, confidence intervals; SE, standard error
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50. Regions: change in HbA1c
H Brath, PM Paldánius,…., PM Nilsson, Nutr Diabetes Jul 4;6(7):e217
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51. Regions: % at Goal (< 7.0%)
H Brath, PM Paldánius,…., PM Nilsson, Nutr Diabetes Jul 4;6(7):e217
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52. Vildagliptin or SUs: Durability
Cohort from the EDGE-Study; n = (SH), n = (Vildagliptin)
Brath H et al, Diabetes Ther
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53. 5. Summary
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54. Management of Type 2 Diabetes:
The earlier the better?
Brath: DM

55. Treat early and stay focused
9.5
Generation of "bad glycemic legacy"
9.0
Drives risk of complications
8.5
HbA1c (%)
8.0
7.5
Taken together, these results suggest that, at least within the timeframe of the intensive treatment period of the most recent trials, there is less opportunity to influence the development and/or progression of complications in individuals with long-standing diabetes. Conversely, in both type 11,2 and type 23 diabetic patients, early strict glycemic control generates a legacy that may confer protection against, or delay, long- term diabetic complications.
This graph tentatively reconstructs the history of the disease of patients included in the VADT:4,5
It is likely that patients had a high HbA1c level at the time of diagnosis and also that they started on dietary therapy and/or some oral hypoglycemics agents that improved, but did not normalize, glycemic control.
Nonetheless, over the time the patients' glycemic control worsened progressively to reach, years later, a HbA1c level of 9.4%, when they were enrolled in the VADT.
Intensive therapy implemented in the trial resulted in a rapid lowering of plasma glucose levels and subsequent maintenance of HbA1c close to the ideal target.
It is, however, readily apparent that this time course is far from the ideal, i.e. the early 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 period that may have had some impact on the effect of subsequent tight glycemic control. First of all, preceding long-standing hyperglycemia may account for the high rate of complications at baseline. Second, it may have generated a "bad glycemic legacy".
Potential mechanisms to explain the molecular basis for this metabolic memory (glucose legacy) include increased formation of cellular reactive species and advanced glycation end products in response to chronic hyperglycemia, resulting in the activation of pathways involved in the pathogenesis of diabetes-related complications.4 Intervention later in the course of the disease provides less opportunity to influence the development and/or progression of complications in patients with long-standing diabetes.
 References:
1. White NH, et al. Prolonged effect of intensive therapy on the risk of retinopathy complications in patients with type 1 diabetes mellitus: 10 years after the Diabetes Control and Complications Trial. Arch Ophthalmol. 2008;126(12):
2. Nathan DM, et al. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med. 2005;353(25):
3. Holman RR, et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359(15):
4. Del Prato S. Megatrials in type 2 diabetes. From excitement to frustration? Diabetologia. 2009;52(7):
5. Del Prato S, et al. Tailoring treatment to the individual in type 2 diabetes practical guidance from the Global Partnership for Effective Diabetes Management. Int J Clin Pract Feb;64(3):
7.0
6.5
6.0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
yrs. since diagnosis
Upper dotted line: time course of HbA1c described by the UKPDS 33 Lower dotted line: ideal time course of glycemic control
Solid line: time course of HbA1c in the VADT.
1. Del Prato S. Diabetologia. 2009;52(7): Del Prato S, et al. Int J Clin Pract Feb;64(3):
Brath: DM

56. 1 % ↑ HbA1c → 26 % ↑ Cancer Risk Mikrodiab-Study – Chromosomal Damage
Grindel A, Brath H….. Wagner KH. Sci Rep Feb 2;7: doi: /srep41985

57. Is late too late?
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58. Brath: DM