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Division of Metabolism, Endocrinology, and Nutrition (S.E.K.), Department of Medicine, Veterans Affairs Puget Sound Health Care System and University of Washington, Seattle, Washington 98108; and Division of Nutrition and Chronic Diseases (W.T.C.), Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana 70808
Address all correspondence and requests for reprints to: Steven E. Kahn, M.B., Ch.B., Veterans Affairs Puget Sound Health Care System (151), 1660 South Columbian Way, Seattle, Washington 98108. Email: skahn{at}u.washington.edu.
The increase in prevalence of diabetes worldwide continues unabated with recent estimates in the United States alone being 24 million, amounting to 8% of the population. The major concern with the growing number of diabetes cases is the resulting micro- and macrovascular complications resulting in significant morbidity and mortality for more individuals and their families. Thus, development of new approaches that incorporate both pharmacology and lifestyle factors that will lead to prolonged and better life is desperately needed.
It is noteworthy that the last few years have seen the release of a wealth of new information regarding glycemia and diabetes complications, with much attention focused on glucose control and macrovascular disease. Although epidemiological analyses suggest that each 1% increase in hemoglobin A1c increases the risk for cardiovascular disease (CVD) by approximately 18%, the unanswered question for diabetes management was whether treating patients to near normal levels for hemoglobin A1c reduced CVD events (1). As such, both primary analyses on macrovascular outcomes from long-term clinical trials examining the effect of improved glucose control on CVD per se and secondary analyses of data obtained during studies of glucose-lowering medications have been attempted. In the process of considering these observations, there has also been debate about the veracity of the approaches used to reach some of the conclusions. The net result has been a great deal of consternation in the clinic, and significant confusion for the provider, as to what constitutes the best therapeutic regimen for the diabetic patient who has significant cardiovascular risk factors. So where are we currently in our understanding of the role of glucose control in reducing macrovascular disease events?
Findings in the United Kingdom Prospective Diabetes Study (UKPDS) suggested that improved glucose control may benefit those with type 2 diabetes (2). This was supported by the epidemiological follow-up of the cohort of type 1 diabetic patients in the Diabetes Control and Complications Trial in whom a 42% reduction in the risk of any CVD event was still present 10 yr after the end of the aggressive control period (3). These data provided reasonable assurance that it was just a matter of time before definitive clinical data could be obtained demonstrating conclusively that intensive glucose control, in addition to effective lipid and blood pressure management, reduced CVD events in individuals with type 2 diabetes. However, with the release over the last few months of the findings of three large clinical trials in patients with type 2 diabetes, the results have not clarified the situation but, if anything, appeared to have muddied the waters!
In early 2008, the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study was terminated prematurely due to a 22% increase in all-cause mortality (4). A closer look demonstrates there were inconsistencies in the direction of components of the composite outcome. Although the intensively treated group had significantly greater overall mortality and cardiovascular death, nonfatal myocardial infarction was significantly less for intensive treatment, as compared with standard therapy, suggesting a benefit for improved glycemia. Nonfatal stroke and fatal/nonfatal congestive heart failure were not different between groups. Interestingly, this observation of increased overall mortality was not confirmed in the ADVANCE study (5) or Veterans Affairs Diabetes Trial. All three studies recruited subjects at increased risk of macrovascular disease, and subgroup analyses suggest that at the time of study entry, those who were known to have a longer duration of diabetes, higher hemoglobin A1c, and more underlying macrovascular disease were less likely to experience a cardiovascular benefit of glucose control. The underlying mechanism for the increased mortality remains unclear, but episodes of recognized or unrecognized hypoglycemia, rate of reduction in hemoglobin A1c, weight gain, and interaction of multiple classes of drugs have been advanced as a possible explanations.
Over the recent past, we have also seen a great deal of attention devoted to the effects of glucose-lowering medications on cardiovascular outcomes. Much of this scrutiny arose after a metaanalysis that suggested that the thiazolidinedione rosiglitazone was associated with an increased risk of myocardial infarction (6). The statistical approach used for this analysis has come under fire (7), so one is left pondering whether the effect is clinically significant or not. Of further interest and less publicly debated is the possible interaction of glucose-lowering agents. In the UKPDS, an increase in myocardial infarction was observed in individuals assigned to a sulfonylurea who subsequently also received metformin (8). Although this observation was felt to be the result of a statistical quirk, a recent metaanalysis suggests this may not have been the case in that this long-trusted combination was associated with an increase of 43% for a composite endpoint of CVD hospitalizations or mortality (9). And of course, nothing should be simple. In ACCORD, where increased mortality was clearly documented in a large clinical trial, no single medication or combination of medications, be they oral or injectable, could be shown to be responsible; however, the potential existed for undetected adverse effects due to a greater use of multiple drug classes and higher doses and number of drug changes (4). Thus it would appear that the issue of the responsibility of glucose-lowering medications in all-cause and cardiovascular mortality is not finite or easily resolved.
In much of the writing frenzy that has followed release of new information on glucose lowering and adverse macrovascular outcomes, the role of glucose control in diabetic microvascular disease has essentially gone unnoticed. In the course of discussions in recent months, the fact that ADVANCE demonstrated a significant reduction in nephropathy and extends our understanding of the beneficial effect of intensive glucose control on microvascular events in type 2 diabetes has gone virtually unnoticed. One cannot help observe how quickly we forget the days when it was promulgated that improved glycemia had no bearing on the progression of diabetic small vessel disease (10), a thesis that was subsequently and in convincing manner shown to be completely incorrect (2, 5). The failure in this debate regarding macrovascular disease to appropriately recognize the critical role of improved glucose control in reducing the morbidity from blindness, renal failure, and neuropathy leaves the uninformed with a rather distorted view.
One also has to believe that this pronounced focus on glucose-lowering medications and macrovascular disease with a near total disregard of the role of glucose lowering in microvascular disease has not been good for the patient and, as stated above, confused the clinician. Many physicians have and continue to find themselves needing to convince patients that it is essential to keep the focus on the benefits of glucose lowering and to continue the drive to improve glycemia. One has to also wonder how some of this rather unbalanced discussion shaped the drive by many to criticize the Food and Drug Administration (FDA) and demand reform to the drug approval process. The result has been a recommendation by a special FDA advisory panel that approval of new glucose-lowering medications include adequate testing to exclude any possible adverse cardiovascular effect.
We fully agree with the panel’s recommendation to the FDA; what we ask is that the FDA weigh these suggestions and determine that testing for cardiovascular safety be done after approval with a firm commitment and absolute requirement that this be carried out in a manner that provides the true answer. The rationale for our suggestion comes from the fact that although it is clear that patients with type 2 diabetes mellitus die of CVD at rates two to four times higher than patients without diabetes who have similar demographic characteristics, over the last several decades, efforts to prevent or treat CVD risk factors have resulted in significantly lower rates of CVD-related mortality (11). Thus, it will become progressively more difficult to power clinical trials to test the effect of glucose control on CVD rates. One has to also question the ethics of maintaining a control group to test the impact of glucose control on CVD events. Finally, what level of glycemia will be required to test the effect on CVD events, given the difficulty and inability to achieve the set goals in the large trials presented to date. Thus, requiring large clinical trials to address cardiovascular safety before approval we believe could seriously stifle future development of glucose-lowering agents. Although some advocate that we don’t need any additional therapeutic choices (12), we strongly disagree. There are still many barriers to effective glucose control for the majority of subjects, and only in the past few years have agents been released that address some of these barriers such as weight gain and hypoglycemia. Failure to discover agents that have the potential to safely and decisively improve glucose control or, even better, halt the progression of the disease will be a disservice to the millions afflicted with type 2 diabetes and destined to suffer some form of morbidity as a result of microvascular disease.
As we reflect on and debate the events of the last decade or so that have produced great advances in our understanding of the role of glycemia in diabetic vascular complications and approaches to lowering glucose, we must not lose sight of the fact that these tremendous advances have been good for our patients. And, as we weigh the pros and cons of glucose control on micro- and macrovascular disease, we also believe it is the duty of all of us to ensure that the FDA continue to provide us the opportunity to offer our patients new, innovative, and safe tools that ensure that glucose control can be achieved and protect those with diabetes from the ravages of the microvascular disease for which they are uniquely at risk.
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Disclaimer: The views expressed in this article are those of the authors and do not necessarily reflect those of the Department of Veterans Affairs.
Disclosure Statement: The authors have nothing to disclose.
First Published Online September 2, 2008
Abbreviation: CVD, Cardiovascular disease.
Received August 14, 2008.
Accepted August 21, 2008.
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