The University Group Diabetes Program
This famous, indeed notorious, study began with the attempt to discover whether asymptomatic hyperglycaemia was worth treating. This coincided with the landmark demonstration that antihypertensive treatment prevented stroke, and was intended to show whether oral hypoglycaemic agents could reduce the risk of vascular disease in diabetes. The study recruited 200 patients to each arm of insulin (variable dose), insulin (fixed dose), tolbutamide or placebo: a phenformin arm was later added. The study found an excess mortality in those treated with tolbutamide, and no benefit for those on insulin as compared with placebo. It generated a storm of controversy. UGDP was the first randomized trial ever performed in diabetes, and had a number of flaws in its execution that many critics considered fatal, for example a failure of effective randomization such that there was an excess of vascular disease in those allocated to tolbutamide. UGDP generated lasting confusion, and the big question - did glucose-lowering therapy reduce cardiovascular risk? - was only partly resolved by the later UK Prospective Diabetes Study (UKPDS). A series of major cardiovascular outcome studies 40 years later were less controversial but almost equally inconclusive. Phenformin was tarnished by the study (and later withdrawn), a move which delayed the use of metformin in the USA until 1995.
The first half of the twentieth century saw the rise of curative or symptomatic treatment of disease; the second half saw the transition to preventive treatment of risk factors predisposing to disease. Two major innovations paved the way for this. One was prospective surveillance of whole populations, as in the Framingham study, and the other was the prospective randomized controlled trial.
In diabetes, this trend was reflected in the quest to determine whether asyptomatic or mildly symptomatic hyperglycaemia was worth treating. Did hyperglycaemia cause vascular disease? If so, did treating hyperglycaemia delay the process? Should you therefore offer insulin to people who could manage without it? Or would newly-introduced oral therapies do just as well?
A group of American academics and statisticians met in 1959 to design a study to answer these questions, and UGDP got under way in the following year.
Eligible patients had been diagnosed with diabetes within the preceding year, and were considered to have a greater than 5 year life expectancy. They were randomized to one of four groups, with 200 patients in each; total recruitment was 1027. All were on diet, with allocation to the following therapies:
- Insulin variable (i.e. adjusted to maintain good glucose control)
- Insulin standard (a once daily fixed dose of insulin, designed to test whether insulin itself influenced the course of vascular disease)
- Tolbutamide (1.5 gm daily in divided doses)
A phenformin arm was later added in 1962 when this new treatment became available.
It should be noted that those designing the study were focused upon detecting possible benefit, not harm, and mortality itself was not considered a relevant outcome - hence the requirement that participants were expected to outlive 5 years.
The tolbutamide arm was stopped prematurely in 1969 because of an increased death rate (12.7% vs 4.9% in the placebo group). Meanwhile, mortality in the two insulin groups did not differ markedly from placebo.
An ADA ad hoc committee reviewed these findings in 1970 and concluded that there was no evidence that intervention with insulin produced any benefit as compared with diet alone. Since insulin did not help, it pointed out, there was no reason to believe that treatments such as tolbutamide that enhanced insulin secretion would be any more effective.
The UGDP controversy
The adverse effect of the tolbutamide arm was entirely unexpected, and generated a storm of controversy. In an eerie preview of later drug controversies, it sparked a highly emotive polarization of views. For the first (but not the last) time, the news leaked via the financial press, followed by the Washington Post, both of whom pre-empted formal statements by the ADA and FDA. Upjohn, the manufacturers of tolbutamide, immediately launched a counterfactual counterstrike, armed with its own statisticians, and the medical and patient public were left adrift on a sea of controversy.
For some, notably Marvin Siperstein, the study merely confirmed that the association between diabetes and vascular disease was genetic and thus unrelated to glucose control.
Contrariwise, the results were profoundly disturbing for those who championed good glucose control, and the resulting fracas was virulent. The study records were obtained in 1971 via the Freedom of Information Act, and offered a happy hunting ground for critics of the study, who found a multitude of problems in execution and design.
Investigators and clinicians were relatively inexperienced in the performance and interpretation of trial data at this period, and the trial did indeed have some major defects in execution, not least because of variable quality of recruitment and patient handling at the different centres. All the aberrant results for tolbutamide, for example, came from 4/12 participating centres, in which there was an excess of cardiovascular disease or abnormal ECGs in the tolbutamide arm. Furthermore (and a source of many future problems in clinical trials) the number of cardiovascular deaths was so small that reallocation of 3 deaths in the tolbutamide arm would have cancelled the positive finding. Over and beyond this, underprivileged patients were over-represented, and compliance was poor.
UGDP in retrospect
UGDP and the controversy it generated have influenced medical practice to this day, although it is probable that few practicing physicians are aware of this pervasive legacy. Here are some of the issues raised:
1. Who owns drug safety?
This was the first major post-war controversy concerning drug safety and the public, and it raised a number of still unresolved issues. First of all, it raised the question of the right (or duty, or otherwise) of academic researchers to throw doubt on drug safety. The manufacturers vigorously contested what they depicted as irresponsible interference on the part of investigators.
2. Role of the FDA?
The FDA for the first time in its history staked a claim to legislate for drug safety in a proactive way, mandating drug labelling, issuing "Dear Doctor" alerts and so forth. This role was bitterly contested by physicians who considered that their own clinical experience outweighed the views of distant administrators and statisticians.
3. The role of physicians?
The medical public proved very hostile to hastily publicised safety concerns which appeared to throw doubt on its own judgment in advocating and prescribing the new agents. This pattern was to be repeated with troglitazone and rosiglitazone.
4. Do patients have a right to know"?
At an even more basic level, the controversy raised the issue of right-to-know. Hitherto physicians, manufacturers and regulators had adopted the paternalistic attitude that patients were to be shielded from worrying information. Some patients agreed with this, others felt that they were entitled to know if a concern existed. The debate continues.
5. How do manufacturers defend themselves?
The manufacturers became actively involved in a campaign of denial and counter-attack, typically recruiting key opinion leaders in the medical profession to lead the charge, and thus prefiguring many subsequent controversies. Upjohn, in particular, were fighting a battle on two fronts: in addition to marketing Orinase (tolbutamide), they also marketed a combination antibiotic marketed as Panalba. The decision by the Board of Upjohn to continue marketing Panalba in the face of undeniable evidence of lack of added benefit and increased harm went on to become a classic teaching exercise in business schools.
Although Upjohn lost the labelling battle (not until 1984) with tolbutamide, they cleverly sidestepped the safety issue by badging subsequent sulfonylureas "second generation", thus implying that they were new entities which were exempt from cardiovascular risk. These concerns still persist.
6. Financial implications of safety concerns
The financial press, for the first time, became major players in drug safety issues which could affect stock values, and has ever since actively shadowed the results of clinical trials and announced possible safety concerns, in some cases before prescribing physicians were aware of any potential problem.
7. Legal implications of safety concerns
The legal profession quickly latched on to the possibilities afforded by drug labelling to sue doctors for off-label use of drugs, and soon became another major player in drug safety, and in raising the cost of prescriptions (since manufacturers now had to figure litigation costs into their financial projections).
8. Role of the media
Last but not least, the media became a major vehicle for broadcasting safety concerns. Effective media control became a major objective for manufacturers seeking damage limitation.
Aftermath of UGDP
It will be noted that a series of major cardiovascular outcome trials were to be launched 40 years later, with almost equally disappointing results. Possible reasons are (1) hyperglycaemia is a relatively weak cardiovascular risk factor as compared with antihypertensive or lipid-lowering therapy, and/or (2) insulin itself promotes vascular disease, thus offsetting any potential benefit of improved glucose control.
Last of all, the condemnation of phenformin extended to metformin - a clear example of guilt by association - thus blocking entry of this useful drug to the US market until 1995. Metformin is to date the only agent for the treatment of type 2 diabetes with unequivocal cardiovascular benefit.