Landmark Trial, LANCET

1. UKPDS
OVMC LANDMARK TRIALS SERIES
UK Prospective Diabetes Study (UKPDS). “Intensive
blood-glucose control with sulfonylureas or insulin
compared with conventional treatment and risk of
complications in patients with type 2 diabetes.”
Lancet. 1998; 352:837

2. UK Prospective Diabetes Study (UKPDS) Group
Summarized by: Maria Morkos, MD; Laxmi Suthar, MD

3. BACKGROUND
 In patients with T1DM, good blood
glucose control can slow
microvascular complications
 However, the effect of intense blood
glucose control on
micro/macrovascular complications
in T2DM is unknown

4. CLINICAL QUESTION
What are the effects on microvascular and
macrovascular complications in Type 2
diabetics when comparing intervention
with a sulfonylurea or insulin vs.
conventional treatment?

5. DESIGN
 Randomized, multicenter: 23 hospitals in United Kingdom
 Unblinded; computer-generated randomization
 N= 3,867
 Group 1: intensive treatment group
 Group 2: conventional treatment group
 Median follow-up: 10 years
 Outcomes:
 any diabetes-related endpoint (sudden death, death from hyperglycemia or hypoglycemia,
fatal/nonfatal MI, CHF, CVA, renal failure, amputation, retinopathy requiring photocoagulation,
cataract extraction, vitreous hemorrhage, or blindness)
 diabetes-related death (death from MI, stroke, PVD, renal disease, hypo/hyperglycemia)
 all cause mortality

6. POPULATION
Inclusion Criteria
 Newly diagnosed T2DM
 25-65 years old
 Fasting glucose of >108
Exclusion Criteria
 Patients with significant ketonuria
 MI within previous year
 Cr > 1.98 mg/dL
 Current angina or HF
 >1 major vascular event
 Significant retinopathy
 Malignant HTN
 Other severe illness

7. INTERVENTIONS
 Intensive therapy
 Sulfonylurea or insulin with goal fasting glucose <110 mg/dL
 Conventional therapy
 Goal “asymptomatic DM” <270 mg/dL with diet modification
 If further hyperglycemia occurred, would be secondarily
randomized to SU or insulin

8. RESULTS
 No difference between intensive (SU or insulin) and conventional treatment groups in
any of the endpoints
 Diabetes-related mortality and all-cause mortality did not differ between the two arms
 Median A1c was lower in the intensive vs conventional group (7% vs 7.9%)
 Higher rates of hypoglycemic episodes were found in the intensive therapy arm
(especially in insulin subgroup)

9. CRITICISMS
 Multiple crossovers
 Done in newly diagnosed diabetics
 Excluded participants that had significant medical history
 Looked at only three sulfonylureas (chlorpropamide, glibenclamide, and
glipizide)
 Insulin regimen unclear
 Did not look at exercise as a lifestyle modification

10. BOTTOM LINE
In T2DM, intensive blood glucose
control (with SU or insulin) decreases
the risk of microvascular
complications but not macrovascular
complications.

11. DISCUSSION QUESTIONS
 What were the two arms of the UKPDS trial?
 What were the inclusion criteria?
 Did the two arms differ in any endpoints?
 What was a major difference between the two arms?

12. DISCUSSION ANSWERS
 What were the two arms of the UKPDS trial?
 ANSWER: Intensive tx (SU or insulin) vs conventional tx (diet modification)
 What were the inclusion criteria?
 ANSWER: Newly diagnosed DM, age 25-65, fasting glucose of >108
 Did the two arms differ in any endpoints/outlined outcomes?
 ANSWER: No, there were no differences in macrovascular complications
 What was a major difference between the two arms?
 ANSWER: Hypoglycemia was increased in the intensive tx arm (also less
microvascular complications in the intensive tx arm)

13. BOARD-LIKE QUESTION
64 yo M with T2DM, stage 4 CKD is
evaluated for continued glycemic
management. He is followed closely by Renal
who is preparing him for HD, with initiation
of erythropoietin therapy within the last 3
months. His average fasting and preprandial
blood glucose values are 145-190. He does
not have hypoglycemia. His insulin regimen
consists of insulin detemir at bedtime and
insulin glulisine before meals. His most
recent A1c value decreased from 7.5% to
6.2%.
(Adapted from MKSAP)
QUESTION
Which of the following is the most
appropriate management for this patient’s
diabetes?
A. Continue current therapy
B. Decrease insulin detemir dose
C. Discontinue preprandial insulin glulisine
D. Measure postprandial glucose level

14. BOARD-LIKE QUESTION
Educational Objective:
Manage the limitations of hemoglobin A1c
measurements in a patient with diabetes
mellitus and CKD.
Key Point:
- A1c is not always reliable in certain states
- A1c an be falsely elevated in CKD b/c of
carbamylated Hb 2/2 uremia interfering
with some of the assays
- A1c an be falsely decreased in setting of
reduced erythrocyte span, iron deficiency,
blood transfusions, and increased
erythropoiesis with erythropoietin (like this
patient)
QUESTION
Which of the following is the most
appropriate management for this patient’s
diabetes?
A. Continue current therapy
B. Decrease insulin detemir dose
C. Discontinue preprandial insulin glulisine
D. Measure postprandial glucose level

15. REFERENCES
 Intensive blood-glucose control with sulfonylureas or insulin compared
with conventional treatment and risk of complications in patients with
type 2 diabetes (1998). Lancet, 352:837.