Type 2 Diabetes - Time to relax: Two clinical trials show no benefit and some risk of tight control of blood sugar

What your doctor is reading or should be

Two clinical trials published earlier this month show that aggressive control of blood sugar not only failed to yield benefits, it made things worse - higher death rates and more myocardial infarctions and strokes in the group with tight control of their blood sugars, compared with the control group managed conventionally.

The ‘ADVANCE’ trial, sponsored by a pharmaceutical company using their drug gliclazide (a sulfonylurea) as the main agent to reduce blood sugar and the ‘ACCORD’, trial, funded almost entirely by the US NIH (National Institutes of Health) using several drugs evaluated the effects of tight control of blood sugar of the risks of developing complications of diabetes. The ACCORD study was terminated before the planned end date because a scheduled interim analysis showed a statistically significant higher death rate among patients in the tight control group. Tight control was a target of maintaining glycalated hemoglobin, Hbg A1C, - a measure of control of blood sugar levels now used by most physicians and patients to evaluate diabetes management - below 6 %.

The objective of both studies was to see if tight control, defined as getting the patient’s glycalated hemoglobin from an average of about 8% before the study to below 6% in patients randomized to tight control and to between 7 and 8% in the usual care group. These targets were fairly well achieved in both studies. Patients in the tight control groups were more likely to be prescribed oral agents and were more likely to be taking insulin (77% in the tight control group vs. 55% - ACCORD study).

The results were spectacular and unexpected - in both studies. The ACCORD study was stopped prematurely because of an excess of deaths in the tight control group (5%) compared to the standard therapy group (4%). This 22% increase in death rates per year (1.41 vs. 1.14 deaths per year) was statistically significant (95% CI 1.01 to 1.46) and forced the premature stop.

The ADVANCE study chose to define its primary outcome for the randomized trial as a combination of microvascular and macro-vascular complications. The rationale for choosing this mixed outcome is not explained. Using the combined outcome, the ADVANCE study showed that patients who were on tight control were more likely to avoid development of macroalbuminuria (an indicator or microvascular disease of the kidneys) 2.9% in the tight control group vs 4.1% in the usual care group, hazard ratio 0.70, 95% CI 0.57 to 0.85). There was no effect on development of clinically important microvascualar renal disease such as a need for dialysis/transplant or death from renal causes. Serum creatinine - a measure of renal deterioration that indicates patients might one day need dialysis or transplant doubled in 1.2% of tightly controlled patients vs 1.1% of usual care patients, a statistically insignificant difference.

In short, after an average of 5 years of tight control in the ADVANCE study, the only difference between the two study groups was in the proportion of patients who developed very early indications (macroalbuminuria) or microvascular disease. The study did not show an excess of deaths from macro-vascular causes (stroke and heart attacks).

While the authors of the industry funded ADVANCE study tout the result as showing “a one-fifth reduction in microvascular complications” the authors of the ACCORD study concluded that there is a previously “unrecognized harm of intensive glucose lowering in high-risk patients with type 2 diabetes mellitus.”

Here is a summary of the key outcomes in both trials:


Both studies, as expected showed that patients on tight control had more insulin reactions although the differences in frequency of severe events (in the ACCORD therapy defined as those that required medical attention) is remarkable. In the ADVANCE study severe hypoglycemia was defined as “transient dysfunction of the central nervous system” to the extent that they “required help from another person”.

Differences in softer (and perhaps harder) clinical outcomes may be due in part to the geographic locations of study participants and differences in the usual patterns of practice of clinical medicine. In the ADVANCE study it appears that patients were drawn from Australia, New Zealand, the UK, several European countries and China (perhaps including members eligible for care in a military hospital) as well as from Montreal and New York. The ACCORD study drew patients from across the US and Canada.

Interpretation

The results of both studies give pause and the results from the ACCORD study demand action on the part of clinicians treating patients with type 2 diabetes mellitus. In the face of an substantial increase in the risk of death from all causes, clinicians must be much less aggressive in encouraging patients to get better control of their blood sugars. This appears to be dangerous in patients with type 2 diabetes mellitus. In the ACCORD study only 50% of patients achieved glycalated hemoglobin Hbg A1C levels of 6.5% or less. Even this modest achievement in blood sugar control resulted in harm.

There is no good explanation for the results (why would more aggressive control of blood sugar in patients with type 2 diabetes lead to heart attacks, stroke and death). But there need not be an explanation in order for clinicians and their patients to change direction on the management of type 2 diabetes mellitus. More is not only not better, it is worse - in terms of life expectancy and the frequency of severe hypoglycemic episodes.

The negligible benefit on microvascular disease noted in the ADVANCE study is perhaps not a surprise as there is some evidence that tight control does result in slower progression of damage to very small blood vessels. Nonetheless it is worth noting that this did not manifest itself in a lesser frequency of development of retinopathy, nor of severe renal failure requiring treatment, nor in the worsening of renal function as measured by serum creatinine. These benefits can be considered minimal and come at a cost of higher death rates overall.

Implications

For patients and families

Patients with type 2 diabetes can’t escape being told daily on television and in magazine and Web advertisements that controlling blood sugar is essential to their health and longevity. Devices to measure blood glucose (after every meal and before and after every physical activity) abound, along with advertisements from multiple drug companies anxious about their market and share values.

Blood sugar, however, does not appear to be a central or perhaps even a peripheral cause of the complications of diabetes. Blood sugar more and more looks like an innocent bystander or itself the product (not the cause) of some other disorder of blood vessels. This is a bit like the old saw that a carpenter with only one tool - a hammer - sees the solution to every building problem as requiring a nail. We can measure blood sugar. So we develop ways to smash it down to the ‘normal’ range, with glucose meters, oral hypoglycemic agents and insulin.

Certainly blood sugar can be problematic, especially when it is very high and other metabolic changes occur - but these are rare in type 2 diabetes. When first diagnosed with diabetes, most patients have no symptoms. The diagnosis is an unwelcome surprise. Patients then learn they are at risk of developing ‘complications’ of diabetes such as renal failure, leg ulcers, blindness, heart attacks, congestive heart failure and stroke.

Commentators on these 2 studies agree that patients (and their physicians) should back away from the target of achieving ‘normal’ levels of glycalated hemoglobin (6%). They agree that it is more important to emphasize efforts to achieve normal body weight, to follow a Mediterranean diet, to take medication for hypercholesterolemia, and treated for hypertension if present. All interventions reduce the chances of heart attack, stroke and death.

But these 2 studies force a larger consideration - the wisdom of screening asymptomatic individuals for abnormal blood sugars. By doing so we label individuals as being at risk of later serious and life threatening complications for which there is no effective therapy. The ‘do no harm’ principle of medicine is violated. Sure, we can make weak arguments that perhaps their long term risks of microvascualar complications could be reduced by close attention to blood sugar, but even this is modest at best and comes with additional risks that are much more serious.

A diagnosis of type 2 diabetes mellitus is not a gift, it is a burden that patients will have to carry for the rest of their lives. A burden of increased frequency of visits to physicians, of glucose measuring devices, or pharmaceuticals with side effects of hypoglycemia and perhaps other risks and an instantaneous trip from the land of the healthy to the land of the sick, with no return ticket.

For society

The FDA and similar agencies in other countries must revise approvals for the advertisement to physicians and directly to patients of information about diabetes and its treatment. In future advertisements need to include a warning that tight control of blood sugar increases the likelihood of death.

Current guidelines (US American Diabetes Association) suggest “the A1C goal for the individual patient is an A1C as close to normal (<6%) as possible without significant hypoglycemia.” This recommendation requires revision as do the screening and case-finding recommendations for the detection of asymptomatic type 2 diabetes mellitus.


References
Advance Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008;358:2560-72

Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2009;358:2545-59

Type 1 Diabetes - Ongoing clinical trials of immune suppressant therapy

What your doctor is reading or should be.
April 16, 2008

(photo courtesy of nicointhebus (Nicolas Monnot)

The recent onset of diabetes in the child of friends of ours led me to the registry of clinical trials. There are 68 studies in the registry recruiting children for studies on type 1 diabetes in children. Our friends, whose son is 8, had already contacted an investigator for one of the trials who encouraged their participation.

This trial and several others take advantage of new understandings of the proximate causes of Type 1 diabetes now believed to be related to autoimmunity, or said another way, due to the body somehow reacting against itself, or parts of itself, in this case the beta cells in the pancreas that make insulin. The result is a gradual decrease in beta cells and usually the gradual onset of diabetes, high blood sugars and later the vascular and other complications that may arise.

The idea behind many of the trials of aggressive intervention in new onset Type 1 diabetes is to try to slow the gradual destruction of beta cells by interfering with the autoimmune system that is producing antibodies that stimulate T-Lymphocytes that are causing the damage. One way to do this is to block the antibody receptor site on the T-Lymphocyte.

One of the trials (registry number NCT00129259) involves the molecule hOKT3gammal (Ala-Ala), which is administered intravenously over a 14 day period. This regimen is repeated a year later. The aim is to determine if patients receiving the molecular antibody (drug) will retain more of their ability to produce insulin. In a previous study of a very small number of patients, this seemed to be the case with about 70% of patients with new onset Type 1 diabetes receiving the drug maintaining or increasing their insulin production compared to about only 20% of control patients, who received usual care for their diabetes.<1> For information on this trial see www.clinicaltrials.gov


Interpretation

While this is an exciting area of new research, the results so far are but preliminary. All the trials do not rule out the possibility of the results being due to chance (as the number of patients in the trials is small) or bias (most studies are open label - meaning that the investigators and the patient’s physicians know whether their patient is in the treatment or control group).

Also, the immune system is complex, important for a very large number of body functions and protections and incompletely understood. Alterations in T-cells, a key component of our immune systems, may generate adverse events during the trials (so far no serious events have been detected) or later. Early trials involving small numbers of patients are unlikely to detect infrequent yet serious adverse events.

Implications

For the patient and family

Type 1 diabetes always comes as an unexpected and unpleasant surprise. The possibility of a treatment that could reverse or slow the onset of insulin-dependent diabetes, or reduce the need for insulin and perhaps even delay or deny the onset of known adult complications of diabetes, generates hope. It is unlikely, however,  that the drugs being studied will be released for clinical use for at least several years.

Participation in a trial may provide parents with a way to express their non-competing feelings of hope and anxiety by ‘doing something’. Unfortunately, outside the US there are few trials to available.

To find a trial in your area, use the search function at the registry (www.clinicltrials.gov) and enter the search terms: type 1 diabetes, open studies, interventional studies, child and country. The trials are described and contact information is provided (usually a telephone number and address).

For Society

While type 1 diabetes is not common, it is a serious illness and deserves our attention, research and treatment resources. Finding a way to prevent the illness or severely limit its effects would provide relief to many families, especially those who harbour the genetic signatures that in some way enable the disease to take hold.

Reference

Herold KC, Gitelman SE, Masharani U. et al. A single course of anti-CD3 monocoloanal antibody hOKT3 1(Ala-Ala) results in improvement in C-peptide responses and clinical parameters for at least 2 years after onset of type 1 diabetes. Diabetes 2005;54:1763-9

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
online free

Ovarian Cancer

What your doctor is reading - or should be
January 28, 2008
Ovarian Cancer
Cancer of the ovaries occurs in about 1 in 50 women over the age of 50 or so. While not that common, the disease is troublesome because it is difficult to diagnosis early and most forms of ovarian cancer are highly malignant, spreading quickly. Thus there has been an interest in detecting the causes of ovarian cancer and perhaps preventing it.

January 28, 2008

Most of these studies are case-control designs. Here women with diagnosed ovarian cancer are interviewed about possible risk factors. Their answers are compared with answers to the same questions by women without ovarian cancer. These types of studies provide the most of the evidence we have, but are fraught with difficulties: For example, people with a particular condition may remember past events they think might have caused their illness more frequently than people without the condition or illness. A bias (recall bias) results, distorting the true picture and creating a false association and a misleading risk factor.

In this week’s issue of The Lancet evidence is summarized from 48 different case-control and prospective studies that included questions about past or present use of oral contraceptives. The evidence is coherent and consistent across all studies and in the two research designs (case control and prospective): Women who reported using oral contraceptives had a lower risk of developing ovarian cancer. The risk ratio was 0.42 (about a 60% reduction in risk) for women who had reported using oral contraceptives for 15 years or more. Of great interest, the protective effect of taking oral contraceptives early in life, persists for years after a woman has stopped taking them. A podcast by one of the authors and a Lancet editor is available free.

Implications

For an individual woman:

As ovarian cancer is relatively rare, the chances of benefit for any one woman are small. For example if 250 women took oral contraceptives for 10 years, 1 case of ovarian cancer would be prevented.

There are hazards of oral contraceptives - mainly deep vein thrombosis (clots in the veins in the legs and abdomen) which may lead to pulmonary emboli and death, but these events are extremely rare especially with the newer low estrogen dose contraceptive pills. Oral contraceptive use has also been linked, but not strongly, with other cancers, particularly breast and cervical cancer - although the latter is most likely confounded (misleading) because we now know that it is caused by several papilloma viruses, themselves associated with more frequent sex (and now potentially preventable with the new vaccines).

And there are benefits. Oral contraceptives are the most effective form of birth control and prevention of unwanted pregnancy and even more unwanted abortions, (both of which carry substantially higher health risks than oral contraceptives).


For society:

The widespread use of oral contraceptives in high and middle-income countries means that millions of women are taking them. Thus even if the benefits of risk reduction for a single woman are small, for all women, as many as 300,000 cases of ovarian cancer will be prevented by use of oral contraceptives. This is an argument for making oral contraceptives more easily available throughout the world. Indeed, The Lancet editors have called for making the pill available over the counter, without a physicians prescription.

Cautions

This research was carefully done by experienced epidemiologists. Nonetheless, the fundamental problem with cancer prevention research on humans, is that we have to rely on non-experimental information. Thus, it remains possible that some other factor, unknown to the women or to the researchers, may have led women who were unlikely to ever get ovarian cancer to be more likely to use oral contraceptives, and women, more likely to get ovarian cancer, less likely to use them. We have no way of knowing if this bias exists.

Warnings

Women with previous deep vein thrombi, migraines, heart disease or liver disease should probably not take oral contraceptives, or at least should discuss this with their physicians.

http://en.wikipedia.org/wiki/Ovarian_cancer
http://www.nlm.nih.gov/medlineplus/ovariancancer.html
http://podcast.thelancet.com/audio/lancet/2008/9609_26january.mp3