Subclinical diabetes mellitus: is it really“sub-clinical”?
Article Outline
Diabetes mellitus has emerged as 1 of the most dire global public health issues. In 2000, data from the Centers for Disease Control Behavioral Risk Factor Surveillance System estimated a prevalence of diagnosed diabetes mellitus among US adults of 7.3%, which represents a 49% increase from 1990.1 This equates to approximately 15 million US adults aged ≥18 years with diagnosed diabetes mellitus, the vast majority of which is type 2 diabetes mellitus. This epidemic is not limited to the United States; there are an estimated 150 million affected persons worldwide, and a doubling of the global population is expected in the next 25 years.2 Even more startling are recent reports estimating that in as many as 50% of patients with the disease, diabetes mellitus remains undiagnosed,3, 4, 5 suggesting that studies relying on a prior diagnosis of diabetes mellitus dramatically under-estimate the breadth of the problem.
Historically, the focus of diabetes mellitus has centered on microvascular complications, including retinal, renal, and neuropathic disease, and these risks have been the basis for the present diagnostic criteria for diabetes mellitus.6, 7 However, it is becoming increasingly clear that the primary risk of diabetes mellitus is macrovascular atherosclerotic disease, which affects as many as 80% of patients with diabetes mellitus. This prevalence represents a 3- to 5-fold higher risk for macrovascular versus microvascular disease among patients with diabetes mellitus.8 As suggested by data from the population-based National Health and Nutrition Examination Survey II,3 the incremental cardiovascular risk associated with abnormal glucose metabolism extends well below the present diagnostic criteria for diabetes mellitus, significantly increasing risk among patients with impaired glucose tolerance and impaired fasting glucose levels. Therefore, increased surveillance for diabetes mellitus, increased appreciation about the cardiovascular risk associated with impaired glucose metabolism, and ongoing review of the adequacy of the diabetes mellitus diagnostic criteria are all important clinical objectives. In this issue of the Journal, Muhlestein et al report findings from a prospectively collected database of patients with obstructive coronary artery disease undergoing percutaneous coronary intervention (PCI) that support these objectives.9
There were 4 key findings in this study of 1612 consecutive patients undergoing PCI. The first is the remarkably high prevalence of abnormal glucose metabolism detected with a simple analysis of fasting plasma glucose values, affecting 61% of this unselected population.9 The second key finding is the high prevalence of undiagnosed diabetes mellitus in a cohort with recent clinical evaluation by virtue of the referral for cardiac catheterization, which suggests a failure of identification in the primary care setting. In addition to the 24% of patients with diagnosed diabetes mellitus, Muhlestein et al identified an additional 18% of the cohort with previously undiagnosed diabetes mellitus and 19% with impaired fasting glucose. The third important finding was the observed graded relationship with long-term mortality risk across the spectrum of abnormal glucose metabolism, from impaired fasting glucose to newly diagnosed diabetes mellitus to previously diagnosed diabetes mellitus. Using the cohort with normal fasting glucose as the referent group, the adjusted hazard for mortality in nearly 3 years of follow-up was significantly increased in patients with diabetes mellitus, whether it was previously diagnosed (HR = 5.0; 2.6–9.6) or newly diagnosed (HR = 4.1; 2.1–8.2). More importantly, the increment of cardiovascular risk associated with impaired glucose metabolism extended below the diagnostic cutoff for diabetes mellitus, with patients who met the criteria for impaired fasting glucose level (110–125mg/dL) exhibiting >3-fold increased adjusted mortality risk (HR = 3.2; 1.5–6.5). Finally, the most provocative result from this study is the demonstration of an optimized diagnostic threshold for fasting glucose level ≥109mg/dL in the context of defining mortality risk, which supports the importance of the impaired fasting glucose/impaired glucose tolerance classifications to guide prognosis and risk modification.
Recent studies have suggested that in as many as 50% of patients with diabetes mellitus it remains undiagnosed in a variety of clinical settings.3, 4, 5 In the popu-lation-based Second National Health and Nutrition Examination Survey (NHANES) II, the proportion of patients with diabetes mellitus in whom it was previously undiagnosed was 40%.3 More recently, the proportion of undiagnosed diabetes mellitus among patients referred for cardiac catheterization and among patients surviving an acute coronary ischemic event was reported to be similarly high, approaching 50% in both studies.4, 5 These observations are supported by the findings of Muhlestein et al, who found that in 43% of patients with diabetes mellitus who were undergoing PCI, it was undiagnosed, and unlike the previous studies that used oral-glucose tolerance testing to increase the sensitivity of diagnoses, Muhlstein et al’s study based the diagnoses on the much more readily available fasting plasma glucose level results.9
Extending beyond the diagnosis of diabetes mellitus, impaired glucose metabolism less than the diabetes mellitus diagnostic threshold was associated with notably increased mortality risk in the study by Muhlestein et al. Similar observations have been made using the NHANES II data, which revealed a stepwise increment in cardiovascular disease risk from normal glucose to impaired glucose tolerance to overt diabetes mellitus in a population-based sample.3 The present study demonstrated an even steeper graded relationship between the severity of impaired glucose metabolism and all-cause mortality in the high-risk population of patients undergoing PCI. The qualitative relationships depicted in Muhlestein et al’s study are supported by the objective demonstration of an optimized diagnostic threshold for prediction of 3-year mortality, using receiver-operator characteristic analysis, of ≥110 mg/dL. These results serve to validate the relevance of the American Diabetes Association’s diagnostic category of impaired fasting glucose in the context of clinical risk.
Historically, the diagnosis and treatment of diabetes mellitus has been based on microvascular disease risk (retinopathy, nephropathy, neuropathy), and despite the accumulated data on the cardiovascular risk associated with diabetes mellitus, the focus remains on microvascular disease. This is evidenced by a recent survey demonstrating that the overwhelming concern of patients with diabetes mellitus is blindness, with only 1 in 3 patients aware of the cardiovascular consequences of their disease (http://www.diabetes.org/main/uedocuments/executivesummary.pdf). These survey results demonstrate the importance of continued education of patients with diabetes mellitus, which can only be accomplished by continued education of their physicians. In the wake of these survey results, the American Diabetes Association has launched a dedicated campaign toward that end, “Make the Link” (http://www.diabetes.org/main/info/link.jsp?WTLPromo=SEARCH_heart_makethelink).
Taking Muhlestein et al’s receiver operating characteristic results 1 step further, if confirmed in other datasets, it would imply that the diagnostic criteria for diabetes mellitus may need to be re-defined on the basis of the more prevalent cardiovascular risk. This will be especially true if the promise of the insulin-sensitizing drugs, such as the thiazolidinediones and metformin, as modifiers of cardiovascular risk pans out, a concept that is being prospectively tested in several ongoing trials. However, for now, it would be most prudent to apply aggressive cardiovascular risk modification for all patients with diabetes mellitus and consider a similar approach for patients meeting the criteria for impaired fasting glucose levels.
In conclusion, the study by Muhlestein et al once again demonstrates the complex relationship between diabetes mellitus and cardiovascular disease. These observations mandate a continued evolution of our clinical focus to encompass aggressive macrovascular disease risk modification among the high-risk population of patients with diabetes mellitus. Cardiologists should complement the role of the primary care physician in actively screening for diabetes mellitus, and once it is diagnosed, patients with diabetes mellitus should be treated aggressively with an evidence-based approach focused on cardiovascular risk modification with a similar fervor given to glycemic control, as recommended by present professional guidelines.10, 11 Such therapy should include daily aspirin (or clopidogrel for patients with aspirin intolerance); aggressive blood pressure management (goal ≤130/80) using therapies shown to favorably influence outcomes (eg, angiotensin-converting enzyme inhibitors, β-blockers, thiazide diuretics, and angiotensin receptor blockers); aggressive lipid management, preferably with the statin drugs, to an low-density lipoprotein cholesterol target level of at least <100mg/dL; and independent of blood pressure, daily use of 10 mg of ramipril of the pharmacodynamically equivalent dose of an alternative angiotensin-converting enzyme inhibitor. In patients with impaired fasting glucose levels and impaired glucose tolerance, there is less rigorous evidence to guide therapeutic decision-making, but the incremental clinical risk associated with these conditions likely warrants an aggressive treatment strategy similar to that recommended for patients with diabetes mellitus, especially once cardiovascular disease has been documented. Continued education of physicians and patients will be required to continually improve the treatment of patients along the continuum of impaired glucose metabolism, especially for cardiovascular risk modification, and will require the collaboration of cardiologists, diabetologists, and primary care physicians both in the research arena and in the clinics.
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PII: S0002-8703(03)00236-9
doi:10.1016/S0002-8703(03)00236-9
© 2003 Mosby, Inc. All rights reserved.
