The United Kingdom Prospective Diabetes Study [UKPDS]
The United Kingdom Prospective Diabetes Study (UKPDS) set out to examine the effect of intensified glucose control upon the subsequent development of complications of diabetes in newly diagnosed patients, and the relative benefits of specific therapies (diet, sulfonylureas, metformin or insulin) in this regard. It recruited 5,102 patients from 23 centres between 1977 and 1991. Patients were followed for an average of 10 years. A blood pressure arm was added in the course of the study and compared rigorous vs less rigorous blood pressure control in hypertensive people with diabetes, and the relative benefits of an ACE inhibitor (captopril) or β-blocker (atenolol) in achieving this. Median HbA1c was 7.9% on conventional therapy and 7.0% on intensified therapy, and this was associated with a 25% reduction in the rates of retinopathy, nephropathy and (possibly) neuropathy. Results were even stronger in the epidemiological arm (which compared achieved HbA1c rather than treatment arm), and no glycaemic threshold for complications was observed. There was a non-significant 16% reduction in myocardial infarction or sudden death with intensified therapy, and a 25% reduction in the risk of death for every 1% drop in HbA1c. Antihypertensive therapy markedly reduced all end-points, microvascular as well as arterial.
The University Group Diabetes Program trial compared intensified control with insulin versus non-intensified control with insulin or treatment with tolbutamide or phenformin as compared with placebo. The study found no benefit of treatment, as compared with placebo, in any treatment arm. Furthermore, it found an increased risk of cardiovascular outcomes with both tolbutamide and phenformin, and generated a storm of protest in so doing.
Thus, while medical opinion increasingly came to the conclusion that improved glucose control was important in type 1 diabetes, later to be confirmed in the Diabetes Control and Complications Trial (DCCT), there was prevailing uncertainty in type 2 diabetes. This was compounded by the fear that sulfonylureas, insulin (or both) might actually accelerate arterial disease.
Robert TurnerHeaded by Robert Turner, a group at Oxford University took up the challenge. Unlike UGDP or DCCT this study was funded on a shoestring and existed in a state of perpetual financial uncertainty. Although UKPDS and the UKPDS- Follow Up study established the basis for our current treatment of diabetes, it has been said that "the study broke many of the rules of trial design, not least by constant addition of further interventions and analyses". Paradoxically this flexibility greatly increased the clinical relevance of the study and proved more of a strength than a weakness.
As initially conceived, the study recruited people with newly diagnosed maturity onset diabetes (the terms type 1 and type 2 diabetes were not yet in general use). To be eligible, patients should not be insulin-dependent, should be aged 25-65 years and have no overt cardiovascular disease or complications of diabetes. They should be asymptomatic and able to control their diabetes on diet alone during the 3-month run-in period, and they should be suitable for randomization either to diet or insulin. The concept of Latent Autoimmune Diabetes in Adults (LADA) did not as yet exist, and islet antibody tests were not available, so a number of people with autoimmune diabetes were also included.
Recruitment began in 1977, and a total of 5102 patients were eventually randomised to treatment at 23 centres. Early experience showed that 95% failed to achieve the desired level of control with diet alone (fasting plasma glucose below 6 mmol/l (108 mg/dl). Those with a blood glucose between 6-15 mmol/l (108-270 mg/dl) were randomised to treatment, either staying on diet alone (diet policy) or starting on treatment with insulin or sulfonylureas with the aim of achieving glucose levels below 6 mmol/l (active policy).
A hypertension in diabetes study was later added in order to ascertain whether antihypertensive therapy provided extra benefit. Patients with BP >160/90 mmHg were allocated to tight control (below 150/85) or less tight control (below 200/105) .
Adapting the study design.
An excellent overview of the study and its implications will be found in the ADA summary: http://care.diabetesjournals.org/content/25/suppl_1/s28.full.
This points out that "The UKPDS was originally designed as a straightforward 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 of type 2 diabetes. The three main original monotherapies to which all patients were randomized were chlorpropamide, glyburide [glibenclamide], and insulin. In the subgroup of overweight subjects, metformin as monotherapy was compared with the control group and to the other three pharmacological agents.
"The primary and major question of the study was whether lowering blood glucose was beneficial. Therefore, the treatment goal in all the intensive pharmacotherapy groups was a fasting plasma glucose (FPG) level <6.0 mmol/l (108 mg/dl), and the treatment goal in the conventional diet control group was an FPG level <15 mmol/l (270 mg/dl). These widely different treatment targets were meant to insure attainment of adequate glycemic separation to test the main hypothesis. However, it became apparent that none of the oral pharmacological monotherapies were capable of maintaining the intensive treatment goal, and therefore adequate glycemic separation from the control group might be jeopardized. Thus, combination therapy was used, mixing insulin or metformin with sulfonylureas, as well as crossing over patients into the alternate pharmacological treatment groups. The final main “intention to treat” comparison was between intensive therapy, which now included all patients originally assigned to insulin and sulfonylurea drugs, and conventional therapy, which included all patients originally randomized to diet treatment".
A further problem was that many people in the diet alone group showed deteriorating glucose control and required rescue therapy. This had the effect of narrowing the glucose gap between the intensive and conventional arms, but the difference in outcome was nonetheless impressive. A further disadvantage was that treatment crossover limited the ability of the investigators to make clean comparisons between different treatment strategies at the end of the study.
Possibly for this reason, the most impressive correlations for the study were based upon the "epidemiological" analyses, which related the various endpoints to achieved HbA1c regardless of treatment arm. These results were presented as UKPDS 35 , and the accompanying slide set can be accessed at http://www.dtu.ox.ac.uk/generic/slides.php.
Major Findings of UKPDS
Glucose Control and Microvascular Complications The study confirmed beyond doubt that better glucose control reduced the risk of microvascular and non-vascular (e.g. cataracts) complications of type 2 diabetes, thus confirming the findings of DCCT and other studies in this respect.
Glucose Control and Macrovascular Complications Notoriously, UKPDS showed a reduction in cardiovascular end-points or sudden death, but just failed to reach conventional levels of statistical significance. The UKPDS- Follow Up study did however confirm a reduction in cardiovascular events in the intensified treatment group.
Effect of Blood Pressure Control Antihypertensive treatment proved highly effective in delaying progression of diabetic retinopathy and nephropathy.
Effect of sulfonylureas. Sulfonylureas proved as effective as insulin in the prevention of late complications and cardiovascular events, and there was no evidence of excess cardiovascular mortality as suggested by UGDP.
Effect of metformin The metformin are was relatively small yet showed a significant reduction in cardiovascular mortality which became even more marked in the course of the follow-up study.
Quality of Life Allocation to intensified treatment neither improved nor reduced quality of life measures.
Translation into Clinical practice
The study was enormously influential, and set the scene for the management of type 2 diabetes over more than a decade. The use of metformin increased dramatically, and it soon became established as the treatment of choice in the initial management of type 2 diabetes.
Although the study did not show any advantage of insulin as compared with sulfonylureas in the treatment of type 2 diabetes, publication of the study results did lead to greatly increased use of insulin in the treatment of type 2 diabetes in primary care, and at an earlier stage of the disease process. Ironically, use of the sulfonylureas began to decline at around the same time, despite trial-based evidence of their safety and efficacy.
Overall, therefore, the study produced a much more positive and aggressive approach to the management of type 2 diabetes, and this was reflected in treatment guidelines world-wide.
^ Gale EAM. Glucose control in the UKPDS: what did we learn? Diabetic Medicine 2008;25 Suppl 2:9-12
^ UK Prospective Diabetes Study (UKPDS) VIII. Study design, progress and performance. Diabetologia 1991;34(12):877-90
^ Stratton IM et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 2000;321(7258):405-412