Landmark Clinical Trials
The introduction of the Randomized Controlled Trial (RCT) revolutionized the evaluation of therapeutic interventions for diabetes and its prevention. The RCT is considered the highest level of clinical evidence, but it is not without its pitfalls, as some of the studies described in this section will illustrate. This section presents the landmark clinical trials that have most influenced the clinical practice of diabetes.
Although the first attempts at randomization of therapy (allocating sequential patients to alternate therapies) date back to the study of antitoxins in the 1890s, the first formal RCT, inspired by the work of Austin Bradford-Hill, was performed by the British Medical Research Council in the 1940s to test newly available therapies for tuberculosis.
The principle of the RCT is to create an experiment in which the comparison groups are identical in every respect other than the therapeutic intervention. This means that a group of people is recruited according to certain pre-defined criteria and then randomly allocated to two or more treatments. In principle, and provided the study design is adequate and the samples are of adequate size, randomization should ensure that the samples are adequately matched in terms of demographic characteristics, pre-existing risk factors and so forth. See Interpreting Clinical Trials for further discussion of these issues.
Types of Clinical Trial
Clinical trials may be undertaken to prevent or to cure, and their design may vary accordingly. In general it is easier to identify reversal of a problem (for example TB, as in the first RCT) than prevention. Prevention studies require larger numbers, more time, and may be influenced by unmeasured variables not allowed for in the study design, otherwise known as confounders.
The most influential studies have in general been designed to address a general principle, have had independent investigators and a non-commercial source of funding. Drug trials undertaken by a manufacturer have been required by the FDA since the 1960s. There are many examples of good practice in studies of this type, but they require more cautious interpretation, since there is an obvious conflict of interest and greater scope for conscious or unconscious bias. Those who believe that a clinical trial cannot be designed in order to produce the desired outcome have probably never consulted for the pharmaceutical industry.
Landmark Trials in Diabetes
The biggest practical questions in the management of diabetes are first, how to avoid it? And second, how to assure the best possible future for those who develop the condition? This section of Diapedia will consider clinical trials that set out to address the second question. Information on prevention trials in type 1 diabetes can be found in Clinical trials in humans, and prevention trials in type 2 diabetes in Prevention of T2DM: Interventions.
The first big question in clinical management was whether good glucose control would delay or prevent the vascular complications of diabetes. The first trial to tackle this question - UGDP - was essentially negative. DCCT and UKPDS returned a definitive answer on the benefits of treating microvascular complications such as retinopathy or nephropathy together with other complications such as cataracts and neuropathy. Neither study demonstrated a significant effect upon arterial disease within the study period, yet both showed delayed benefits in intensively treated individuals following conclusion of the trial.
Microvascular complications are specific to diabetes, and glucose levels are the major avoidable influence upon their development; DCCT, UKPDS and other studies, while confirming this, did however show that blood pressure control exerts an important influence upon the progression of retinopathy and nephropathy once these have become established.
Arterial disease, unlike small vessel complications of diabetes, is prevalent in the background population and strongly influenced by non-glycaemic factors such as smoking, blood pressure and lipids. Not surprising, therefore, that it has proved difficult to demonstrate a unique contribution of glucose control to this multifactorial disease process, especially when these other risk factors have been addressed.
Second generation intervention trials such as ACCORD have pursued more detailed questions, including optimal treatment targets for glucose, blood pressure and lipids in type 2 diabetes, quality of life and costs and benefits. These studies, consistent with observational studies, suggest that there is a point of therapeutic balance beyond which there are diminishing benefits in terms of disease prevention, and accumulating dysbenefits in terms of side effects such as hypoglycaemia and weight gain. Achieving this balance remains a challenge for all who deal with diabetes.
The University Group Diabetes Program (UGDP) was the first major RCT to be undertaken in diabetes. It set out to test the utility of two recently introduced oral therapies for diabetes (tolbutamide and phenformin) against insulin and diet in the prevention of the vascular complications of diabetes. Study participants had recently diagnosed stable diabetes (and also prediabetes by modern criteria). The study began in 1961, and the tolbutamide arm was discontinued in 1969 because of increased cardiovascular mortality; phenformin was later discontinued for the same reason. Worse still, none of the treatment arms outperformed placebo in the prevention of vascular complications. UGDP became the most controversial trial in the history of diabetes. Subsequent analysis suggests that there was a genuine increase in cardiovascular mortality in the tolbutamide arm, but this now appears to have been the nightmare of every triallist - a fluke outcome. Tolbutamide remains on the market to this day, and its dangers have never been convincingly replicated.
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 Diabetes Control and Complications Trial (DCCT) ran from 1983-1993 and tested the value of intensified versus conventional control in 1441 patient volunteers with type 1 diabetes aged 13-39 years. They had a diabetes duration >1 year but <15 years, and had either no retinopathy (primary prevention group) or early retinopathy (secondary prevention group). The patients in the intensified treatment group aimed to achieve an HbA1c ~6.0% by any treatment strategy (usually multiple injections or CSII). The study demonstrated a dramatic benefit of intensified glucose control in primary prevention of retinopathy, kidney disease or neuropathy; secondary prevention was associated with additional factors such as control of blood pressure and lipids. No cardiovascular benefit had emerged by the end of the trial in 1993, but long term follow-up showed that the risk of heart disease was 42% lower in participants in the intensified arm by 2005.
The Action to Control Cardiovascular Risk (ACCORD) study set out to define the role ensified glucose, lipid and and blood pressure control in the prevention of coronary heart disease in type 2 diabetes. The aims were to compare outcomes in patients who strove for normoglycaemia (HbA1c <6.0%) as against more standard control (HbA1c 7.0-7.9%). A total of 10,251 patients were randomized to one or other glucose strategy, and 50% of these were then randomized either to intensified vs standard lipid-lowering or to intensified vs standard BP-lowering therapy. The major outcome measure was a coronary event or stroke; secondary outcomes included other CV outcomes, total mortality, microvascular outcomes, quality of life and cost-effectiveness. The unexpected outcome of the trial was increased mortality in the intensified glucose control arm, and this was terminated prematurely in 2009; the main study ended in 2010. Further, although intensive therapy delayed the onset of microalbuminuria, there was no overall difference in microvascular outcomes. The BP study provided no conclusive evidence that targeting a systolic BP of 120 vs 140 mmHg reduced major CVD events, and the lipid substudy showed no additive benefit of combining fenofibrate with a statin in the prevention of major cardiovascular outcomes.