Te intensieve therapie bij DM niet goed

Iedereen dacht, als we de suiker maar streng regelen, zal dat beter voor de patient zijn. Nu, in een grote studie met ruim 10.000 patienten bleek dat wat we denken, niet altijd juist is. Strenge bloedsuiker regulatie, waarbij de HbA1c net iets boven de 6 was duidelijk veel minder goed voor je dan een suiker regulatie met als resultaat HbA1c iets boven de 7. Er vielen in die strenge groep meer doden! We citeren de onderzoekers, die dit bijzondere resultaat bekend maakten op 6 juni 2008 in het Amerikaanse tijdschrift New England Journal of Medicine:

Our findings indicate that a comprehensive, customized, therapeutic strategy targeting glycated hemoglobin levels below 6.0% increased the rate of death from any cause after a mean of 3.5 years, as compared with a strategy targeting levels of 7.0 to 7.9% in patients with a median glycated hemoglobin level of 8.1% and either previous cardiovascular events or multiple cardiovascular risk factors.

Patients in both groups had lower mortality than reported in epidemiologic studies of similar patients.19,20 However, as compared with the standard-therapy group, the intensive-therapy group had a relative increase in mortality of 22% and an absolute increase of 1.0% during this follow-up period, with similar differences in death from cardiovascular causes. This increase in mortality is equivalent to one extra death for every 95 patients who were treated for 3.5 years.

Een belangrijk resultaat, dat tevens aangeeft dat we soms wat te simpel denken over behandeling van Diabetes Mellitus, goed dat deze studie gedaan is![1]

Wat we denken is soms onwaar! 

Diverse studies die door de farmaceutische industrie opgezet zijn, hebben de laatste tijd laten zien dat het regelen van risico factoren niet altijd leidt tot een verbetering voor de patient. Integendeel. terwijl we denken dat het verlagen van het LDL  cholesterol en het verhogen van het HDL-cholesterol in het bloed goed is, blijkt uit recente grote studies dat dat helemaal niet zo is.[2]

We citeren een bespiegeling uit het NEJM:

The conventional wisdom, which emerged from epidemiologic studies of risk factors and the subsequent successful trials of certain strategies for risk-factor modification, has been that the clinician’s key focus ought to be on reducing risk factors below specific levels. This approach, however, neglects the importance of which specific strategies are used to modify these factors.

A clinical trial is ultimately a test of a strategy, and we should not be surprised that different strategies may have different effects on patients beyond their effect on risk-factor levels.

Awareness of this issue was boosted on December 2, 2006, the day Pfizer stopped the study named ILLUMINATE (Investigation of Lipid Level Management to Understand Its Impact in Atherosclerotic Events) and all other trials involving torcetrapib, which until then had been seen as a promising agent that lowered LDL cholesterol levels and raised high-density lipoprotein (HDL) cholesterol levels. ILLUMINATE was halted because patients receiving torcetrapib plus atorvastatin had a higher mortality rate than those receiving atorvastatin alone — despite 72% increases in HDL levels and 25% decreases in LDL levels.

ILLUMINATE is not alone in raising questions about the wisdom of patient care that prioritizes target levels of some risk factors over attention to the way in which those levels are achieved. The Women’s Health Initiative revealed that hormone-replacement therapy, which reduces LDL cholesterol levels, increased the risk of cardiovascular disease.

Another study, called ENHANCE (Effect of Combination Ezetimibe and High-Dose Simvastatin versus Simvastatin Alone on the Atherosclerotic Process in Patients with Heterozygous Familial Hypercholesterolemia), showed that ezetimibe did not reduce the progression of arteriosclerosis when combined with simvastatin, as compared with simvastatin alone, even though the combination did result in a greater reduction of LDL cholesterol. Rosiglitazone improves glucose control, but it may also be associated with increased cardiovascular risk.

Adding an angiotensin-receptor blocker to an angiotensin-converting–enzyme inhibitor may produce a greater reduction in blood pressure, but it may not reduce cardiovascular risk and it increases the risk of other adverse events.

The importance of understanding clinical trials as tests of strategies has assumed even greater prominence because of two studies being reported on in this issue of the Journal — ACCORD (Action to Control Cardiovascular Risk in Diabetes) and ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation).

These two studies tested the hypothesis that specific strategies involving the use of multiple medications to achieve tight glucose control would improve outcomes in patients with type 2 diabetes mellitus.

The studies, which used different pharmacologic strategies, found that the tight control achieved did not reduce the risk of macrovascular complications. The ACCORD study’s intensive control strategy was associated with a higher risk of death, which led to early discontinuation of this part of the study.

The ADVANCE study’s findings indicate that its strategy may reduce the risk of worsening renal function at the cost of an excess risk of hypoglycemic events.Thus, the risk–benefit ratio of interventions designed to modify risk factors can vary depending on the type and number of medications and other approaches that are concurrently incorporated.

In particular, some medications may have beneficial or harmful effects beyond their effect on a risk factor.

Clearly, the way in which risk factors are modified really does matter. Lifestyle interventions may have few risks, but we cannot assume the same for drugs — and drug-related risks are not always known or appreciated.

In addition, medications may have interactions with other drugs, either directly or through their effect on patient adherence to treatment regimens.