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lowcarbUgh posted:
What do you mean by marketing studies? You realize, of course, that many diabetics would look on this study as containing the truth on how they are supposed to control their diabetes, that looser control is better control
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Yeah I know diabetics reading this might think it was important. But how many diabetics read this? They may have heard some news report about it. If they did they'd probably ask their doctors what they thought of it. I forgot this was a NHLBI study, which means I think it is only in a small way a study meant to actually answer a question and not just help market a drug, like most studies are. But look at the disclosures of the authors at the very end of the quote. These guys may be members of the NHLBI but I'd bet their vacation homes have been paid for by their "other" jobs as spokesmen for the multitudes of drug companies they represent.
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GypsyByrd posted:
I don't believe the authors used time to target as an excuse to explain the higher mortality
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Actually I think they used it quite a bit--
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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.
This study was not designed to test the components of the intervention strategy. Analyses that we have performed to date have not identified any clear explanation for this higher mortality. In the intensive-therapy group, a median glycated hemoglobin level of 6.4% was rapidly achieved and maintained by a combination of behavioral and pharmacologic approaches. The standard-therapy group had fewer study visits and used fewer drugs and drug combinations. Thus, the higher rate of death in the intensive-therapy group may be related to factors associated with the various strategies. These factors include but are not limited to differences in the achieved glycated hemoglobin level of 6.4% in the intensive-therapy group, as compared with 7.5% in the standard-therapy group; in the magnitude of the reduction in glycated hemoglobin levels in the two study groups; in the speed of the reduction in glycated hemoglobin levels, with reductions of approximately 1.4% in the intensive-therapy group and 0.6% in the standard-therapy group within the first 4 months after randomization; in changes in drug regimens and in the rate of hypoglycemia; in adverse effects due to an undetected interaction of the various drug classes used at high doses; or in some combination of these or many other possibilities, perhaps in combination with the clinical characteristics of the patients in the study.
Differences in mortality emerged 1 year to 2 years after randomization. It is notable that after about 3 years, a nonsignificant decrease in the rate of the primary outcome emerged in the intensive-therapy group (Figure 2A), due to significantly fewer nonfatal myocardial infarctions, despite more deaths from cardiovascular causes and a similar number of strokes (Table 4). These patterns with respect to mortality and the primary outcome suggest that if there is any benefit associated with intensive glucose lowering, it may take several years to emerge, during which time there is an increased risk of death. This intriguing possibility can be answered only by further research.
The strengths of our study include the random assignment of patients to study groups and follow-up of a large number of high-risk patients according to a common protocol, a high rate of follow-up, achievement and maintenance of an absolute difference in glycated hemoglobin levels of 1.1% for 3.5 years, implementation within clinics that routinely treat patients in the community, adjudication of outcomes by a committee unaware of study-group assignment, a factorial design in which blood-pressure and lipid interventions continue to be tested, and safety auditing by an independent committee. However, our study did not address the risks and benefits of various approaches to lowering glycated hemoglobin levels (including what rate of glucose lowering is optimal), the prevention of increased glycated hemoglobin levels in patients with type 2 diabetes mellitus who have glycated hemoglobin levels below 7.5%, the prevention of diabetes altogether, and the lowering of glycated hemoglobin levels in people who do not have cardiovascular disease or additional cardiovascular risk factors. Indeed, the suggestion of a greater benefit in the primary outcome for patients with a lower glycated hemoglobin level or those without cardiovascular disease raises the possibility that certain subgroups of patients may benefit from intensive glucose lowering. However, our study was not designed to test these possibilities. Finally, glucose-lowering strategies were adjusted for each patient in an open fashion on the basis of their study-group assignment, their subsequent glycemic response to a drug or drug combination, and the development of clinical symptoms, such as hypoglycemia. This linkage of the study-group assignment to post-randomization exposures means that analyses to discern which aspects of the therapeutic strategy contributed to the observed outcomes were unlikely to clearly identify or exclude a cause. Thus, nonprespecified analyses of possible causes of the higher mortality in the intensive-therapy group can be only exploratory and require prospective testing.
Follow-up of the patients after they were switched from intensive therapy to standard therapy may provide crucial information regarding the long-term rates of death and cardiovascular events after a 3.5-year period of intensive therapy. Other trials investigating the long-term outcome of intensive glucose lowering21,22,23,24,25 will report the effect of a variety of therapeutic approaches on mortality and cardiovascular events in patients with type 2 diabetes mellitus and a range of clinical characteristics. Regardless of the results of these other trials, our study has identified a previously unrecognized harm of intensive glucose lowering in high-risk patients with type 2 diabetes mellitus and high glycated hemoglobin levels. This harm may be due either to the approach used for rapidly lowering glycated hemoglobin levels or to the levels that were achieved. Our findings highlight the importance of conducting trials with sufficient statistical power to assess commonly used approaches on clinically relevant outcomes.
Supported by grants (N01-HC-95178, N01-HC-95179, N01-HC-95180, N01-HC-95181, N01-HC-95182, N01-HC-95183, N01-HC-95184, IAA-Y1-HC-9035, and IAA-Y1-HC-1010) from the National Heart, Lung, and Blood Institute; by other components of the National Institutes of Health, including the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute on Aging, and the National Eye Institute; by the Centers for Disease Control and Prevention; and by General Clinical Research Centers. The following companies provided study medications, equipment, or supplies: Abbott Laboratories, Amylin Pharmaceutical, AstraZeneca, Bayer HealthCare, Closer Healthcare, GlaxoSmithKline, King Pharmaceuticals, Merck, Novartis, Novo Nordisk, Omron Healthcare, Sanofi-Aventis, and Schering-Plough.
Dr. Gerstein reports receiving consulting fees from Sanofi-Aventis, GlaxoSmithKline, Merck, Abbott, Novo Nordisk, Novartis, and Lilly, lecture fees from Sanofi-Aventis, GlaxoSmithKline, Merck, and Lilly, and grant support from Sanofi-Aventis, GlaxoSmithKline, King, and Merck and holding a patent that is completely assigned to Sanofi-Aventis, for which he receives no royalties or benefit; Dr. Goff, receiving grant support from Merck; Dr. Bigger, receiving grant support from McMaster University; Dr. Buse, having an equity interest in Insulet, MicroIslet, and dLife and receiving grant support from Bristol-Myers Squibb, Novartis, Pfizer, Novo Nordisk, Amylin, Eli Lilly, and Medtronic; Dr. Cushman, receiving consulting fees from Novartis, King, Takeda, and Sanofi-Aventis, lecture fees from Novartis, and grant support from Novartis, Hamilton Health, and Abbott; Dr. Genuth, receiving consulting fees from Merck, Mannkind, Sanofi-Aventis, and Novartis and lecture fees from Lilly and having an equity interest in Bristol-Myers Squibb; Dr. Grimm, receiving lecture fees from Merck, Pfizer, and Novartis; and Dr. Probstfield, receiving consulting fees from King and grant support from King and Sanofi-Aventis. No other potential conflict of interest relevant to this article was reported.
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