Lesson learned form the UKPDS and its reflection on AACE 2016

1. Type 2 DM
Lessons and Guidance
Dr. Mohammad Daoud,MD

2. DM2 … Lessons & Guidance
•The Burden & Barriers
• The lessons : UKPDs Data
• The Guidance : AACE 2016

4. Over time, glycaemic control deteriorates (progression)
*Diet initially then sulphonylureas, insulin and/or metformin if FPG>15 mmol/L
†ADA clinical practice recommendations. UKPDS 34, n=1704
UKPDS 34. Lancet 1998:352:854–65; Kahn et al. (ADOPT). N Engl J Med 2006;355:2427–43
6.2% – upper limit of normal range
Conventional*
Glibenclamide
Metformin
Insulin
UKPDS
MedianHbA1c(%)
6.0
7.0
8.0
9.0
Years from randomisation
2 4 6 8 100
7.5
8.5
6.5
Recommended
treatment
target <7.0%†
ADOPT Glibenclamide
Metformin
Rosiglitazone
8.0
6.0
7.5
7.0
6.5
Time (years)
0 2 3 4 51

5. Beta-cell function progressively declines
Lebovitz. Diabetes Rev 1999;7:139–53 (data are from the UKPDS population: UKPDS 16. Diabetes 1995;44:1249–58); Wright et al. Diabetes Care
2002;25:330–6
FPG, fasting plasma glucose; HOMA, homeostasis model assessment
Beta-cellfunction(%,HOMA)
Extrapolation of
beta-cell function
prior to diagnosis
0
20
40
100
–4 6–10 –8 –6 –2 0 2 4
80
60
–12 8
Diabetes
diagnosis
Time from diagnosis (years)
UKPDS: at 6 years, more than 50% of
patients need insulin to reach target
(FPG ≤108 mg/dL [≤6.0 mmol/L])

6. Type 2 diabetes and the need for insulin
Wright et al. Diabetes Care 2002;25:330–6
20
40
60
0
Patientsrequiringinsulin
(%)
1 2 4 5
Time from randomisation (years)
3 6
UKPDS: at 6 years, more than 50% of
patients need insulin to reach target
(FPG ≤108mg/dL [≤6.0 mmol/L])

7. Except in Diabetes
Almost always too late !!
It is NeverToo Late !!

8. Too Late
Understanding the pathophysiology
Late in Screening & Dx
Risk Reduction: Far From Ideal
LDL ,BP,HbA1c
Residual Risk…Yes
Room to improve

9. Type 2 Diabetes Prevalence
MI, myocardial infarction.
1. IDF Diabetes Atlas 6th Edition 2014 http://www.idf.org/diabetesatlas; 2. The Emerging Risk Factors Collaboration.
JAMA. 2015;314(1):52-60.
9
This will rise to
592 million by 20351
Disease status
at baseline
Hazard ratio
(95% Cl)a
Diabetes, stroke, and
MI
6.9 (5.7, 8.3)
Stroke and MI 3.5 (3.1, 4.0)
Diabetes and stroke 3.8 (3.5, 4.2)
Diabetes and MI 3.7 (3.3, 4.1)
MI 2.0 (1.9, 2.2)
Stroke 2.1 (2.0, 2.2)
Diabetes 1.9 (1.8, 2.0)
None 1.0 (Ref)
Globally, 387 million people are
living with diabetes1
All-cause mortality by disease status of
participants at baseline2
Hazard ratio
(95% CI)
1.0 2.0 4.0 8.0 16.0
Type 2 Diabetes is a CVD

10. DM is Not a Number
DM= A Cardiovascular Disease
Complications : Micro / Macro
Hidden faces of :
Organic : Sexual dysfunction
Diabetic foot
Psychiatric ; Depression

11. DM is Not a Number
Economic Burden
-Complications management : CVD , CKD …
-Admissions for metabolic derangement
(Hypo /Hyper )
-Cost of Rx

12. Barriers
Assessment tools far form ideal
HbA1c
Doesn’t tell the whole story

13. Aa Aa

14. Barriers
Medications
Adverse Reaction
Hypoglycemia ,Weight gain
GI side effects ,CV Concerns
Rx Delivery / frequency
Oral vs Injectable /Pump vs Inhaled …
Daily / Weekly
Insulin
Far from being physiologic

15. Poor
Adherence to
Therapy
Hypoglycemia
(or perceived
risk of
hypoglycemia)
Weight gain (or
fear of weight
gain)
Weight Gain and Hypoglycemia
Influence Patient Adherence
Physicians
Clinical Inertia
Obstacle

16. A retrospective cohort study –UK Clinical Practice Research Data link
81, 573 T2D patients; (2004-2011)
Time to intensify Rx;Years
Groups One OAD Two OAD Three OAD
HbA1c ≥ 7.0%, 2.9 1.9 1.6
HbA1c ≥ 7.5 %, 7.2 7.2 6.9
HbA1c ≥ 8 .0%, 7.2 7.2 7.1
Mean HbA1c
@ Rx Intensification
8.7% 9.1% 9.7%
Khunti K, Wolden ML,Thorsted BL, et al. Diabetes Care. 2013 : 36:3411-3417

17. DM2 … Lessons & Guidance
• The Burden & Barriers
•The lessons : UKPDs Data
• The Guidance : AACE 2016

18. UKPDS 80. N Eng J Med 2008; 359:
UK Prospective Diabetes Study
20-year Interventional Trial from 1977 to 1997
 5,102 patients with newly-diagnosed type 2 diabetes recruited
between 1977 and 1991
 Median follow-up 10.0 years, range 6 to 20 years
 Results presented at the 1998 EASD Barcelona meeting
10-year Post-Trial Monitoring from 1997 to 2007
 Annual follow-up of the survivor cohort
 Clinic-based for first five years
 Questionnaire-based for last five years
Median overall follow-up 17.0 years, range 16 to 30 years

19. UKPDS 80. N Eng J Med 2008; 359:
Glucose Interventional Trial
Intensive
Conventional
Intensive
2,729
Intensive
with sulfonylurea/insulin
1,138 (411 overweight)
Conventional
with diet
342 (all overweight)
Intensive
with metformin
P
Trial end
1997
P
5,102
Newly-diagnosed
type 2 diabetes
744
Diet failure
FPG >15 mmol/l
149
Diet satisfactory
FPG <6 mmol/l
Dietary
Run-in
4209
Randomisation
1977-1991
Mean age 54 years
(IQR 48–60)

20. UKPDS 80. N Eng J Med 2008; 359:
Post-Trial Monitoring: Aims
 To observe HbA1c levels after cessation of the
intervention trial
 To observe glucose therapy regimens after
cessation of the intervention trial
 To determine the longer-term impact of earlier
improved glucose control on microvascular
and on macrovascular outcomes
 To evaluate the health economic implications with a
projected 50% mortality at ten years post trial

21. UKPDS 80. N Eng J Med 2008; 359:
Post-Trial Monitoring: Protocol
 At trial end, patients were returned to usual physician care
for their diabetes management
 No attempt was made to maintain them in randomised
groups, or to influence their therapy
 All endpoints were adjudicated in an identical manner
by the same Adjudication Committee as during the trial
From 1997 to 2002:
 Patients were seen annually in UKPDS clinics for
standardised collection of clinical and biochemical data
From 2002 to 2007:
 Clinical outcomes were ascertained remotely by
questionnaires sent to patients and GPs

22. UKPDS 80. N Eng J Med 2008; 359:
Post-Trial Monitoring: Patients
880
Conventional
2,118
Sulfonylurea/Insulin
279
Metformin
1997
# in survivor cohort
2002
Clinic
Clinic
Clinic
Questionnaire
Questionnaire
Questionnaire
2007
# with final year data
379
Conventional
1,010
Sulfonylurea/Insulin
136
Metformin
P
P
Mortality 44% (1,852)
Lost-to-follow-up 3.5% (146)
Mean age
62±8 years

23. UKPDS 80. N Eng J Med 2008; 359:
Post-Trial Changes in HbA1c
UKPDS results
presented
Mean (95%CI)

24. UKPDS 80. N Eng J Med 2008; 359:
Post-Trial Changes in HbA1c
UKPDS results
presented Mean (95%CI)

25. UKPDS 80. N Eng J Med 2008; 359:
Any Diabetes Related Endpoint Hazard Ratio
Intensive (SU/Ins) vs. Conventional glucose control
HR (95%CI)

26. UKPDS 80. N Eng J Med 2008; 359:
Microvascular Disease Hazard Ratio
Intensive (SU/Ins) vs. Conventional glucose control
(photocoagulation, vitreous haemorrhage, renal failure)
HR (95%CI)

27. UKPDS 80. N Eng J Med 2008; 359:
Myocardial Infarction Hazard Ratio
(fatal or non-fatal myocardial infarction or sudden death)
Intensive (SU/Ins) vs. Conventional glucose control
HR (95%CI)

28. UKPDS 80. N Eng J Med 2008; 359:
All-cause Mortality Hazard Ratio
Intensive (SU/Ins) vs. Conventional glucose control
HR (95%CI)

29. UKPDS 80. N Eng J Med 2008; 359:
Any Diabetes Related Endpoint Hazard Ratio
Intensive (Metformin) vs. Conventional glucose control
HR (95%CI)

30. UKPDS 80. N Eng J Med 2008; 359:
Microvascular Disease Hazard Ratio
(photocoagulation, vitreous haemorrhage, renal failure)
Intensive (Metformin) vs. Conventional glucose control
HR (95%CI)

31. UKPDS 80. N Eng J Med 2008; 359:
Myocardial Infarction Hazard Ratio
(fatal or non-fatal myocardial infarction or sudden death)
Intensive (Metformin) vs. Conventional glucose control
HR (95%CI)

32. UKPDS 80. N Eng J Med 2008; 359:
All-cause Mortality Hazard Ratio
Intensive (Metformin) vs. Conventional glucose control
HR (95%CI)

35. Reductions in MI (15% Su/ InsulinVs 33% MFN)
All-cause mortality (13% and 27%, respectively)
N Engl J Med 2008;359:1577–1589

36. UKPDS 80. N Eng J Med 2008; 359:
After median 8.5 years post-trial follow-up
Aggregate Endpoint 1997 2007
Any diabetes related endpoint RRR: 12% 9%
P: 0.029 0.040
Microvascular disease RRR: 25% 24%
P: 0.0099 0.001
Myocardial infarction RRR: 16% 15%
P: 0.052 0.014
All-cause mortality RRR: 6% 13%
P: 0.44 0.007
RRR = Relative Risk Reduction, P = Log Rank
Legacy Effect of Earlier Glucose Control

37. UKPDS 80. N Eng J Med 2008; 359:
After median 8.8 years post-trial follow-up
Aggregate Endpoint 1997 2007
Any diabetes related endpoint RRR: 32% 21%
P: 0.0023 0.013
Microvascular disease RRR: 29% 16%
P: 0.19 0.31
Myocardial infarction RRR: 39% 33%
P: 0.010 0.005
All-cause mortality RRR: 36% 27%
P: 0.011 0.002
RRR = Relative Risk Reduction, P = Log Rank
Legacy Effect of Earlier Metformin Therapy

38. Does a intensive therapy targeting HbA1c
< 6.0% versus 7.0–7.9% reduce CVD risk in
middle-aged/older patients with high CV risk?
Complex relationship between hyperglycaemia and CV risk
Current evidence does not support intensive glycaemic control for reducing CV risk
YES – early intensive glycaemic control in newly
diagnosed patients reduces long-term CV risk
(myocardial infarction, RR = 0.85, p = 0.014)
NO – intensive glycaemic control had non-
significant reduction in CV events (HR = 0.9,
p = 0.16); may increase mortality (HR = 1.22,
p = 0.04); increased risk of hypoglycaemia
NO – intensive control has no impact on CV
events (HR = 0.88, p = 0.14). Increased risk
of hypoglycaemia
Study Conclusion
UKPDS
ACCORD
ADVANCE
VADT
NO – intensive glycaemic control had no effect
on CV events (HR = 0.94, p = 0.32), but did
reduce microvascular events (HR = 0.86,
p < 0.01); increased risk of hypoglycaemia
Question
Does intensive glucose control with SU
or insulin in newly diagnosed patients with
T2D provide any benefit?
Are micro- and macrovascular events
reduced by intensive glucose control (HbA1c
 6.5%) compared with standard therapy?
Does intensive glycaemic control affect CVD
risk compared with standard therapy in older
male patients with T2D?
ACCORD Study Group. N Engl J Med. 2008;358:2545–2559; ADVANCE Collaborative Group.
N Engl J Med. 2008;358:2560–2572; Duckworth W, et al. N Engl J Med. 2009;360:129–139;
Holman RR, et al. N Engl J Med. 2008;359:1577–1589.

39. UKPDS 80. N Eng J Med 2008; 359:
• Despite an early loss of glycemic differences, a continued reduction in
microvascular risk and emergent risk reductions for MI and death from
any cause were observed during 10 years of post-trial follow-up
• A continued benefit after metformin therapy was evident among
overweight patients.
UKPDs … Conclusions

40. DM2 … Lessons & Guidance
• The Burden & Barriers
• The lessons : UKPDs Data
•The Guidance : AACE 2016

45. 17%
In the 6-year Da Qing study, intervention led to
lower incidence of type 2 DM
0
20
40
60
80
100
2 4 6 8 10 12 14 16 18 20
Follow-up (years)
6-year intervention hazard ratio: 0.49 (95% CI: 0.33;0.73)
20-year follow-up hazard ratio: 0.57 (95% CI: 0.41;0.81)
Cumulativeincidenceof
type2diabetes(%)
0
Lifestyle intervention (diet + exercise)Control
Intervention Follow-up
n=530 overweight Chinese men and women with IGT;
mean BMI=26
Li et al. Lancet 2008;371:1783–9
BMI, body mass index; CI, confidence interval

46. Reduction in the incidence of type 2 DM
with lifestyle intervention or metformin
20
25
30
35
15
10
5
1 42 3
Time (years)
Placebo
Lifestyle intervention
Metformin
0
Cumulativeincidenceof
type2diabetes(%)
3234 participants
2.8 years’ duration
Risk reduction:
58% lifestyle intervention
31% metformin
Knowler et al. N Engl J Med 2002;346:393–403

47. Established DM Patients : Glycemic Goals

48. SU TZD DPP-4i GLP-1RA
Insulin
(Basal)
Physiological
action(s)
↑ Insulin
secretion
↑ Insulin
sensitivity
↑ Insulin
secretion†
↓ Glucagon
secretion†
↑ Insulin
secretion†
↓ Glucagon
secretion†
Slows gastric
emptying
↑ satiety
↑ Glucose
disposal
↓ Hepatic
glucose
production
Efficacy
(↓HbA1c) High High Intermediate High Highest
Hypoglycaemia
risk
Moderate Low Low Low High
Weight effect ↑ ↑ ↔ ↓ ↑
Major side
effects
Hypoglycaemia
Oedema
Heart failure
Bone fractures
Rare GI Hypoglycaemia
Beyond Metformin: Pros/Cons
*Limited comparative data are available; †Glucose dependent.
DPP-4i, dipeptidyl peptidase-4 inhibitor; GI, gastrointestinal; GLP-1RA, glucagon-like peptide-1 receptor agonist; HbA1c, glycosylated haemoglobin; SU, sulphonylurea; TZD, thiazolidinedione; ↑,
increase; ↓, decrease; ↔, neutral.
Adapted from Inzucchi SE et al. Diabetologia 2012;55:1577–1596.

50. 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-
ADA 2015

56. Lixi- Lan :
1 mcg Lixi /
2 or 4 u Glargine
Lira- Deg
3.6 mg Lira /
100 u Degludec

58. Conclusions

59. Conclusions
HbA1c doesn’t tell the whole story
Rx other CVD risk factors simultaneously
We are too late on many fronts of management
Barriers : Therapeutics (ex: adverse reactions)
Physicians (Inertia) and
Patients (ex: Adherence /Compliance)

60. Conclusions
• TLC modifications and DM Rx can delay DM-2
• Individualize … Individualize
• Achieve Targets ; Safely
As early as possible ;Legacy effect
• Insulin is inevitable for many DM patients

62. Glycemic Control
The “ Deadly “ Triad

63. Glycemic Control
The “ Deadly “ Triad
The
Patient
All Sides of the Story
The
Doctor
The
Disease(s)

64. Thank You