this is the presentation of DCCT and UKPDS trials in diabetes.

1. LANDMARK TRIALS IN DIABETES
PRESENTOR:
DR. YUGANDHAR
PG-2ND YEAR.

2. LANDMARK TRIALS
• Landmark trials in diabetes were performed according to types and its treatment
in reducing the risk of developing microvascular and macro vascular complications and
prophylaxis.
• TYPE-1:-
– DCCT (The Diabetes Control and Complications Trial )
• TYPE-2:-
– UKPDS (UK Prospective Diabetes Study)
– PRO Active (The Prospective Pioglitazone Clinical Trial in Macro vascular Events)
– ACCORD (Action to Control Cardiovascular Risk in Diabetes)
– ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation)
• PREVENTION TRIALS IN T2DM:-
– FDPS(Finish Diabetes Prevention Study)
– DPP(Diabetes Prevention Project)

3. The Diabetes Control and
Complications Trial
(DCCT):-
AUTHOR
David M. Nathan.

4. AIMS AND OBJECTIVES
• To determine whether the complications of
type 1 diabetes (T1DM) could be prevented
or delayed.
• To determine the effects of standard control
of blood glucose versus intensive control on
the complications of diabetes.

5. • STUDY POPULATION: 1441 Patients with age
between 13-39yrs old
• STUDY GROUPS: 2 GROUPS.
GROUP-1:- Primary prevention.
GROUP-2:- Secondary intervention.
• INTERVENTION: (Unmasked)
– Intensive arm: insulin pump or ≥ 3 daily insulin
injections.
– Conventional arm: 1-2 insulin injections

6. • TYPE OF STUDY: Parallel-arm, randomized
clinical trial.
• PLACE OF STUDY: Twenty-one clinical centres
were selected, and their principal
investigators, study coordinators, dietitians,
and behaviourists, in collaboration with
statisticians from the Coordinating Centre at
The George Washington University.
• DURATION OF STUDY: The median duration of
study was 1983 to 1993.

7. ELIGIBILITY CRITERIA
INTERVENTION

8. METHODOLOGY
• The two treatment arms were called “standard” (conventional) and
“experimental” (intensive), and all diabetes care was provided by the
DCCT clinic teams.
• The clinical goals of conventional therapy (CONV) were absence of
symptoms of hyperglycaemia and avoidance of severe or frequent
episodes of hypoglycaemia.
• CONV included one or two daily injections of single or mixed
insulin, daily urine or SMBG testing, and diabetes education.
• CONV remained unchanged unless the quarterly obtained
haemoglobin A1c (HbA1c) was >13.11%.
• This safety alert represented 2 SD above the mean for patients.

9. • Intensive therapy (INT) had the same clinical goals as CONV but
with superimposed glycaemic targets.
• INT included MDI (multiple daily injection)with at least three
injections of insulin per day or treatment with CSII (continuous
subcutaneous insulin infusion), with dose adjustment guided by four
or more SMBG (self-monitoring of blood glucose) tests per day, meal
size and content, and anticipated exercise.
• The daily goals of INT included pre meal glucose concentrations
between 70 to 120 mg/dl post meal (90–120 min) concentrations, 180
mg/dl, and a weekly 3:00 A.M SMBG concentration that was >65
mg/dl, directed at detecting and preventing nocturnal hypoglycaemia.
• The overall goal of INT was to achieve and maintain HbA1c levels
<6.05%.
• Hospitalization was used to initiate INT with the goal of lowering
HbA1c levels as quickly as safely possible.

10. • The eligibility criteria shown were used in order
to test the primary prevention and secondary
intervention hypotheses.
• Retinopathy was measured every 6 months with
seven-field stereoscopic fundus photography.
• Kidney function (albumin excretion and
creatinine clearance) was tested annually with a 4-h
timed collection.
• Neuropathy was assessed clinically by a board-
certified neurologist, nerve conduction studies, and
cardiac autonomic function tests.

11. • The power calculations required 700 subjects (350 in
each treatment arm) for each of the primary prevention
and secondary intervention.
• Recruitment began in 1983.
• A 1-year feasibility phase with 278 subjects, including
87 adolescents, was conducted to determine whether
recruitment could be successfully initiated, and random
assignment and protocol implementation were
performed with adequate separation of glycaemia.
• During the feasibility phase, emphasis was placed on
the recruitment of adolescents, who were considered
more challenging than adults with regard to recruitment and
management.

12. • Patients already using CSII were excluded, and
those expressing a strong preference for one or
the other treatment assignment were
considered inappropriate candidates.
• With the successful completion of the
feasibility phase (12), recruitment for the full-scale
trial began in 1986 and 8 centers were added,
bringing the total to 29 centers (Supplementary
Data).
• Recruitment ended in 1989 with a total of 1,441
participants.

13. • Participants had either no or relatively early
diabetes complications and was generally healthy.
• Study included a total of 196 adolescents, aged
13–17 years (13).
• The mean age of the entire cohort was 27 years.
• The mean T1D duration was 2.6 and 8.7 years in
the primary and secondary cohorts, respectively.

14. RESULTS

15. • 99% competed the study.
• 11 died out of 1441 participants.
• Only 8 of 1,430 survivors failed to participate in the
final closeout.
• 95 women, originally on conventional treatment
transferred to intensive treatment during pregnancy.
• The aggressive initiation of INT achieved a large fall in
HbA1c levels by 3–6 months, with a mean nadir of 6.9%
at 1 year and stable maintenance of this level with a 2%
separation in HbA1c between INT and CONV over the
course of the DCCT.

17. How did intensive treatment affect
diabetic eye disease?
• All DCCT participants were monitored for diabetic
retinopathy
• Study results showed that intensive therapy
reduced the risk for developing retinopathy by 76
percent.
• In participants who had some eye damage at the
beginning of the study, intensive management slowed the
progression of the disease by 54 percent.

18. •

19. How did intensive treatment affect
diabetic kidney disease?
• Participants in the DCCT were tested to assess
the development of diabetic kidney disease, or
nephropathy.
• Findings showed that intensive treatment
prevented the development and slowed the
progression of diabetic kidney disease by 56
percent.

22. How did intensive treatment affect
diabetic nerve disease?
• Participants in the DCCT were examined to
detect the development of nerve damage, or
diabetic neuropathy.
• Study results showed the risk of nerve damage
was reduced by 60 percent in people on
intensive treatment.

24. How did intensive treatment affect
diabetes-related cardiovascular
disease?
• Detection macrovascular events were unlikely
due to short time frame.
• Reduced development of
hypercholesterolemia (LDL >160mg/dl) by
34%.

25. What are the risks of intensive
treatment?
• HYPOGLYCEMIA:-
– 3x increase both in the intensive and conventional treatment
groups.
– 62 px in intensive vs 19 px in conventional treatment.
– Seizure due to hypoglycemia - 16 px in intensive vs 5 px in
conventional treatment.
– 2 – vehicular accident
– Hospitalization due to hypoglycemia - 54 px in intensive vs 36 px
in conventional treatment.
• WEIGHT GAIN:-
– Body weight > 120% of IBW
– Increased by 33% in intensive treatment

26. DISCUSSION
• Intensive therapy delays the progression of clinically
important retinopathy.
• There is transient worsening of retinopathy with intensive
therapy which occurred mainly on the first year of therapy.
• Intensive therapy reduced the risk of albuminuria and
microalbuminuria.
• Whether the decrease in albuminuria and
microalbuminuria result in the decrease of renal
insufficiency, follow-up of the entire cohort must be done.

27. • The ability of intensive therapy to reduce
development of neuropathy suggests that
neuropathy may be preventable.
• Whether intensive therapy may reduce
macrovascular complications requires further
investigation.
• Benefits of reducing hyperglycemia are
extended to NIDDM patients.

28. CONCLUSION
• IDDM patient are better treated with closely
monitored intensive therapy.
• Keeping blood glucose levels as close to normal
as possible slows the onset and progression of the
eye, kidney, and nerve damage caused by diabetes.
• The study demonstrated that any sustained
lowering of blood glucose helps, even if the person
has a history of poor control.

29. EDIC STUDY
• The major goal of EDIC was to follow the DCCT cohort
for the time required to determine whether the original
DCCT therapies would have a longer-term effect on more
advanced stages of diabetes microvascular complications
and their clinical sequelae and on CVD.
• At the end of the DCCT, as a consequence of the
salutary effects of INT versus CONV, all of the CONV group
participants were trained in INT by DCCT staff, although
hospitalization to implement such therapy was not
performed.

30. • In addition, since EDIC was envisioned as observational
in nature, the diabetes care of all participants was
subsequently transferred to their own care providers,
with 50% initially maintaining clinical care at the
institution that housed their DCCT clinic.
• EDIC evaluations were performed annually with
methodologies that were identical as in DCCT, and
extensive efforts were made to ensure consistency of
these methods over time. Ninety-six percent (N = 1,394)
of the surviving DCCT cohort elected to continue their
participation in the observational follow-up.

31. • By year 5 of EDIC, the HbA1c levels were
no longer statistically different, and the
mean levels over the past 20 years of EDIC
have been similar.
• Compared with former CONV-treated
subjects, former INT treatment subjects
showed a dramatic 70% reduction in the risk
of further progression of retinopathy from
the level present at the close of the DCCT.

32. •

33. EDIC/Metabolic Memory
• Term used to describe beneficial effects of immediate
intensive treatment of hyperglycaemia and the
observation that they are maintained for many years,
regardless of glycaemia in the later course of diabetes.
• The first 4 years of the EDIC follow-up demonstrated a
further widening of the differences in outcomes, after
adjusting for EDIC baseline outcomes. A phenomenon of
a durable effect on complications of prior metabolic
control was named “metabolic memory. It affects all of
the macrovascular complications.

34. • Regardless of the mechanism, metabolic memory has
lasted for at least 10 years.
• Finally, measurements of atherosclerosis in several
macro vascular beds, including carotid intima media
thickness and computed tomography–measured coronary
artery calcification, have revealed less atherosclerosis in the
INT group.
• The clinical expression of these changes, fatal and nonfatal
myocardial infarctions and stroke, were also reduced by INT,
with a 58% reduction in CVD events after a mean of 18 years
of follow up from the beginning of the DCCT.

35. •

36. UK Prospective Diabetes
Study
(UKPDS)
AUTHOR:-
Dr Robert Turner and colleagues

37. AIMS AND OBJECTIVES
• The primary aim was to determine the effect
of intensive glycaemic control on the
incidence of complications.
• The secondary aim was to see different
treatments have specific advantages or
disadvantages?

38. • TYPE OF STUDY: Randomised Control Trial
• PLACE OF STUDY: 23 centres across the UK
• DURATION OF STUDY:
– Median follow-up was 10 years.
– Range from 6-20 years.
– 1977 to 1997.

39. • STUDY POPULATION: 5102
• STUDY GROUPS:
– Intensive arm.
– Conventional arm.

40. ELIGIBILITY CRITERIA
• INCLUSION:-
– Age between 25 to 65 years.
– Type 2 diabetes mellitus based on a fasting plasma
glucose concentration > 100 mmol/l on two
occasions were recruited to the study.

41. • EXCLUSION:-
– Myocardial infarction in the previous year,
– Current angina or Heart failure,
– Accelerated hypertension,
– Proliferative or pre proliferative retinopathy,
– Renal failure
– Other life threatening disease such as cancer,
– An illness requiring systemic steroids
– An occupation which precluded insulin treatment.
– Language difficulties.

42. METHODOLOGY
• Subjects were randomized to receive ‘conventional’ or
‘intensive’ therapy.
• Laboratory and clinical tests were performed and all end
points were satisfactorily documented.
• Designed as a straight forward randomized clinical trial
comparing the effects of an “intensive treatment policy” with
four pharmacological monotherapies, versus a diet control
group, on the cardiovascular and microvascular complications.

44. •

45. • The treatment goal in all the intensive pharmacotherapy
groups was a fasting plasma glucose (FPG) level <100mg/dl
and in the conventional diet control group was an FPG level
<270 mg/dl.
• However, it became apparent that none of the oral
pharmacological monotherapies were capable of maintaining
the intensive treatment goal, and therefore adequate
glycaemic separation from the control group has been
jeopardized. Thus, combination therapy was used, mixing insulin or
metformin with sulfonylureas.
• When patients in diet group exceeded an FPG level of <270 mg/dl,
they were also treated with the same pharmacological agents.
• Ultimately, 80% of the patients in the diet group required one or
more of the same pharmacological agents.

46. • Thus, all effects of each of the pharmacological
treatment groups has made it difficult to discern
specific drug effects.
• Patients were seen every three months in the
clinics, and any events that were clinically
important were noted.
• Height, waist, and hip circumferences were measured,
and the smoking status and amount of exercise taken
were ascertained by questionnaire.
• Retinopathy was assessed by modified Wisconsin
grading of four colour photographs of each eye taken at
30° to the horizontal.

47. • Blood pressure was recorded as the mean of
measurements taken 2 and 9 months after
diagnosis with sphygmomanometers.
• After the initial treatment diet, patients were
fasted overnight and the following concentrations
measured:
– Fasting plasma glucose
– Haemoglobin A1c
– Low density lipoprotein cholesterol
– High density lipoprotein cholesterol
– Insulin

48. RESULTS

50. • Major hypoglycemic episode:-
– Conventional 0.7%
– Intensive Chlorpropramide 1%, glibenclamide
1.4%, insulin 1.8%
• Weight Gain:-
– Insulin 4 kg,
– Glibenclamide 1.7kg
– Chlorpropramide 2.6 kg

51. • The intensive glucose control policy
maintained a lower HbA1c by mean 9 % over a
median follow up of 10 years from diagnosis
of type 2 diabetes with reduction in risk of:
– 21% for retinopathy at twelve years
– 33% for albuminuria at twelve years

52. MICROVASCULAR

53. DIABETES RELATED DEATHS

54. MYOCARDIAL INFARCTION

55. Blood Pressure Control Study
• Aims:-
– to determine whether tight blood pressure control
policy can reduce morbidity and mortality in Type
2 diabetic patients.
– To determine ACE inhibitor (captopril) or Beta
blocker (atenolol) is advantageous in reducing the
risk of development of clinical complications

56. • Inclusion criteria:-
– If patients NOT on anti-hypertensive therapy:-
• systolic >160 and/or diastolic > 90 mmHg.
– If patients already ON anti-hypertensive therapy:-
• systolic >150 and/or diastolic > 85 mmHg
• Exclusion criteria:-
– If required strict blood pressure control;
– Severe illness;
– Contraindication to study medication or declined
informed consent

58. BLOOD PRESSURE

60. • CONCLUSION:-
– ACE inhibitors and Beta blockers were equally
effective in lowering mean blood pressure in
hypertensive patients with type 2 diabetes and in
reducing the risks.

61. Choice of Therapies
• Diabetes :
– Each of the available therapies studied can be
used
– In overweight, diet-treated patients, metformin
may be advantageous.
• Hypertension:-
– Beta blockers and ACE inhibitors each provide
protection.

62. • LIMITATIONS:-
– Limited separation between conventional and
intensive glucose groups (patient compliance?)
– Insufficient statistical power for subgroup analyses

63. • Which goals of therapy are suggested?
– HbA1c <7%.
– Blood pressure <140/80mmhg.
• BENEFICIAL EFFECTS:-
– The UKPDS has shown that more intensive monitoring
and more intensive use of existing therapies which
improves:-
• Blood glucose control
• Blood pressure control
– This will reduce the complications.

64. THANK YOU