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10-Year Follow-up of Intensive Glucose Control in Type 2 Diabetes. N Eng J Med 2008; 359

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

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 end1997

P

5,102Newly-diagnosedtype 2 diabetes

744Diet failure

FPG >15 mmol/l

149Diet satisfactory FPG <6 mmol/l

DietaryRun-in

4209

Randomisation1977-1991

Mean age 54 years(IQR 48–60)

UKPDS 80. N Eng J Med 2008; 359:

Post-Trial Monitoring: Aims

To observe HbA1c levels after cessation of theintervention trial

To observe glucose therapy regimens aftercessation of the intervention trial

To determine the longer-term impact of earlier improved glucose control on microvascularand on macrovascular outcomes

To evaluate the health economic implications with a projected 50% mortality at ten years post trial

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 mannerby 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

UKPDS 80. N Eng J Med 2008; 359:

Post-Trial Monitoring: Patients

880 Conventional

2,118Sulfonylurea/Insulin

279 Metformin

1997# in survivor cohort

2002

Clinic

Clinic

Clinic

Questionnaire

Questionnaire

Questionnaire

2007# with final year data

379 Conventional

1,010Sulfonylurea/Insulin

136 Metformin

P

P

Mortality 44% (1,852)Lost-to-follow-up 3.5% (146)

Mean age62±8 years

UKPDS 80. N Eng J Med 2008; 359:

Therapy for Glycaemia at 5 Years

0%

20%

40%

60%

80%

100%Conventional Intensive

Original randomisation

Pro

port

ion

of p

atie

nts

Diet aloneOral monotherapy

Combined oral

Oral + insulin

Basal insulin

Basal + soluble

77%

UKPDS 80. N Eng J Med 2008; 359:

Post-Trial Changes in HbA1c

UKPDS resultspresented

Mean (95%CI)

UKPDS 80. N Eng J Med 2008; 359:

Any Diabetes-related Endpoint

Intervention TrialMedian follow-up 10.0 years

Intervention Trial + Post-trial monitoringMedian follow-up 16.8 years

RR=0.88 (0.79-0.99)P=0.029

Conventional

Sulfonylurea/Insulin

Conventional

Sulfonylurea/Insulin

UKPDS 80. N Eng J Med 2008; 359:

Any Diabetes Related Endpoint Hazard Ratio

Intensive (SU/Ins) vs. Conventional glucose control

HR (95%CI)

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)

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)

UKPDS 80. N Eng J Med 2008; 359:

All-cause Mortality Hazard Ratio

Intensive (SU/Ins) vs. Conventional glucose control

HR (95%CI)

UKPDS 80. N Eng J Med 2008; 359:

Post-Trial Changes in HbA1c

UKPDS resultspresented Mean (95%CI)

UKPDS 80. N Eng J Med 2008; 359:

Any Diabetes Related Endpoint Hazard Ratio

Intensive (metformin) vs. Conventional glucose control

HR (95%CI)

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)

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)

UKPDS 80. N Eng J Med 2008; 359:

All-cause Mortality Hazard Ratio

Intensive (metformin) vs. Conventional glucose control

HR (95%CI)

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

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

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 myocardial infarction 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.

Conclusions