Diabetes cured? - Rosiglitazone trials raise new questions.

What your doctor is reading, or should be.

Today, diabetes in adults is common. Yet, when Banting, Best and others in 1922 showed the effects of a crude extract of pancreatic tissue on the blood sugar of a 14 year old boy the disease was uncommon. <1> Only those who had extremely high blood sugars, usually discovered in childhood with what we would now call Type I diabetes, were diagnosed with diabetes. They were ill, had ketosis (acid in their blood), were extremely ill and usually did not survive long beyond adolescence. Insulin changed that dramatically.

Type II diabetes was obviously around, but was not diagnosed by physicians because it was asymptomatic unless the blood sugar levels were exceedingly high, in which case the patient had loss of sugar in the urine which was accompanied by water and produced symptoms of thirst and frequent urination, day and night. Thus, in the 1960’s and 70’s it was uncommon for physicians to diagnose diabetes unless the patient symptoms, in which case, either insulin or one of the oral agents could be prescribed - in addition to diet and weight loss, neither of which was effective (then and today).

Type II diabetes became a recognized disease when it was observed that individuals with high blood sugars had a higher risk of micro-vascular complications (peripheral small arterial disease in the legs, leading eventually to ulcers and amputations, and microvascular effects on the kidney and retina and associated renal failure and loss of vision) as well as macrovascular complications (atherosclerosis of larger arteries and associated heart attacks and strokes).

Epidemiologic studies revealed a clear association between high blood sugars and these bad outcomes. But it is a jump in logic to assume that the culprit is the blood sugar. Perhaps the blood sugar increases are due to some other cause, which is also causing disease in small and large arteries? In this counter explanation, the blood sugar is but a sign of the disease, not the cause. Reducing blood sugar may not prevent the bad outcomes.

The interest in the new oral agents, for the treatment of asymptomatic increases in blood sugar, and aggressive marketing by manufacturer’s of these agents, along with endorsements by then nascent patient advocacy groups such as national diabetes associations, led to an epidemic of Type II diabetes, later fueled by increasingly sedentary lifestyles and a glut of obesity.

What was needed to unravel this possible paradox - that we were diagnosing and treating a disease that did not exist (treating a blood test not a disease) was a randomized clinical trial tabulating outcomes that really mattered to people - fewer amputations, less renal and visual failure, fewer strokes and heart attacks and perhaps longer life.

Readers will understand the importance of RCTs for this type of question. We understand that such RCTs will be difficult to complete because the outcomes are relatively rare and occur but years later; thus the need for very large numbers of study subjects with Type II diabetes followed for long periods of time. Expensive trials, long durations, prone to missing information and loss to follow-up of many trial subjects makes this type of research unwieldy, unfriendly and open to variable interpretations, all of which has happened. .

There have been but a few such trials. Earliest was the University Group Diabetes Study about 30 years ago. The results were unclear and the trial is still being interpreted. Nonetheless the results form the basis of current therapeutic recommendations.

The other important outcome trial of type II diabetes is the United Kingdom Prospective Diabetes Study (UKPDS), involving over 4,000 patients randomized to receive an oral anti-diabetic agent and followed on average for about 10 years. <2> That study showed improved outcomes, but the trial was messy (patients often took multiple agents over this time frame including insulin, many were lost to follow-up etc.). The results are still discussed.

Since then, as newer oral pharmaceuticals were developed to lower blood sugar or increase insulin sensitivity, regulatory agencies have required RCT evidence only that they work: that they do lower blood sugar. Ignoring patient meaningful outcomes, only small RCTs of short duration are needed.

Recently, however, pharmaceutical companies have conducted larger RCTs to determine if use resulted in fewer serious complications among patients with Type II diabetes. Undoubtedly, the motivation for doing these trials is to develop data that would give their product a competitive edge in an increasingly crowded market of new compounds.

The ADOPT trial (A Diabtes Outcome Prevention Trial), <3>The DREAM trial (Diabetes Reduction Assessment with Rampril and Rosiglitazone Medication), <4> and the RECORD trial (Rosiglitazone Evalutaed for Cardiac Outcomes and Regulation of Glycemia in Diabetes) <5> trials were all sponsored by pharmaceutical companies anxious to show that their particular drugs were better than cheap generic versions of older drugs (sulphonyl ureas and metformin).

All 3 trials showed no benefit. And all 3 trials strongly suggest that the new medications are not only of no benefit, but are harmful to patients with Type II diabetes.

Suffice to look at Rosiglitazone.

In an extraordinary piece of research, Nisan and Wolski <6> found 26 reports of small clinical trials with rosiglitazone. Summarizing these in a meta-analysis they showed that patients randomized to receive this drug, often along with metformin or a sulfonyl urea were at a statistically significant higher risk (43%) of heart attacks and/or death than the control groups receiving just sulfonyl urea or metformin. [Relative risk 1.43, 95% CI 1.03 to 1.98]

In an effort to refute the Nisan Wolski paper, GalaxoSmithKlein hurriedly released an unplanned interim analysis of their ongoing trial (RECORD) that, unfortunately for the pharmaceutical company, not only failed to refute the previous results but rather confirmed them; although the company interpretation disparaged the seriousness of the harms (heart attacks, strokes and death).<4>

Pharmaceutical company sponsors generally attribute the unexpected bad-for-sales results (for their products) to unforeseen difficulties in carrying out the trials (for example lower than expected frequencies of outcome events) and, curiously, tend to attribute the unfavourable results - even if statistically significant, to chance.

But even a casual observer would interpret these studies as showing no benefit form these newer compounds. And with the potential for harm, cautious physicians and patients would conclude that is best to avoid prescribing and taking them.

Interpretation

These results are striking and deserve our attention. The evidence is clear that even within the company sponsored RCT, patients taking rosglitazone along with another agent suffered more heart attacks, strokes and/or death than those taking a single older agent such as metformin or a sulphonylurea.

These results are applicable to all drugs of this class - thiazolidinediones

Implications

For patients

Patients with type II diabetes should not be taking thiazolidinediones. Those receiving these compounds should be switched to sulphonylureas and or metformin or insulin.

Patients with type II diabetes, who are asymptomatic and have blood sugars lower than their renal threshold (no sugar in the urine), should be encouraged to lose weight and exercise. Often this will bring their blood sugars into more normal ranges.

Current guidelines <7> are less cautious than I am and continue to recommend aggressive lowering of blood sugar even in asymptomatic patients. There is some evidence from randomized trials of insulin and from animal experiments that maintaining blood sugars in near normal ranges is associated with reductions in micro-vascular disease and thus ought to reduce the risk of peripheral vascular disease, renal failure and loss of vision. Thus theoretically, a lower blood sugar is better. But there is little clinical evidence to support the guideline recommendations which are all financed by pharmaceutical companies with deeply vested interests.

For society

The epidemic of type II diabetes is the result of the hard work and clever execution of projects hatched by marketing divisions of pharmaceutical companies eager to expand markets for their products. The fact that all trials of treatments of type II diabetes have shown that treatment can cause harm (or might in the UKPDS trial), makes it imperative that we once again consider a large scale simple trial of these oral agents, and measure the simple but devastating outcomes that count for patients; amputations, renal failure, blindness, myocardial infarctions and stokes and deaths.

In the interim, patients with abnormal blood sugars as their only ‘abnormality’ might be best to avoid drugs.

References used - links to those that are free

1. Banting FG, Best CH, Collip JB, Campbell WR, Fletcher AA. Pancreatic extracts in the treatment of diabetes mellitus. Preliminary report. CMAJ 1922;12:141-6

2, UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications
in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UDPKS) Group

3, Kahn SE, Haffner SM, Heise MA, et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med 2006;355:2427-43. [Erratum, N Engl J Med 2007;356:1387-8.]

4. Gerstein HC, Yusuf S, Bosch J, et al. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose toleranceor impaired fasting glucose: a randomised controlled trial. Lancet 2006;368:1096-105. [Erratum, Lancet 2006;368:1770.]

5. Home PD, Pocock SJ, Beck-Nielsen H, et al. Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes (RECORD) Study: interim findings on cardiovascular hospitalizations and deaths. N Engl J Med 2007;357.
DOI: 10.1056/NEJMoa073394.

6. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular disease. N Engl J Med 2007;356:2457-2471. [Erratum, N Engl J Med 2007;357:100.]
online free

7. Nathan, D. M., Buse, J. B., Davidson, M. B., Ferrannini, E., Holman, R. R., Sherwin, R., Zinman, B. (2008). Management of Hyperglycemia in Type 2 Diabetes: A Consensus 8. Algorithm for the Initiation and Adjustment of Therapy: Update regarding thiazolidinediones: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes . Diabetes Care 31: 173-175
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