PubMed · 11393039
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I K Smith. 2001-05-28. Cholesterol alert.. https://pubmed.ncbi.nlm.nih.gov/11393039/
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A statistical definition of surrogate endpoints as well as validation criteria was first presented by Prentice. Freedman et al. supplemented these criteria with the so-called proportion explained. Buyse and Molenberghs pointed to inadequacies of these criteria and suggested a new definition of surrogacy based on (i) the relative effect linking the overall effect of treatment on both endpoints and (ii) an individual-level measure of agreement between both endpoints. Using data from a randomized trial, they showed how a potential surrogate endpoint can be studied using a joint model for the surrogate and the true endpoint. Whereas Buyse and Molenberghs restricted themselves to the fairly simple cases of jointly normal and jointly binary outcomes, we treat the situation where the surrogate is binary and the true endpoint is continuous, or vice versa. In addition, we consider the case of ordinal endpoints. Further, Buyse et al. extended the approach of Buyse and Molenberghs to a meta-analytic context. We will adopt a similar approach for responses of a mixed data type.
Cerebrovascular disease is the leading cause of disability in Western societies. In the United States, it has been estimated that a stroke occurs every 53 seconds. Consequently, the societal costs attributable to cerebrovascular disease are immense and encourage the medical community to seek new therapies that can reduce stroke's frequency and impact. Although serum lipid levels have not been shown to act as a surrogate marker for stroke, in landmark lipid-lowering trials, statin therapy has been associated with reductions in the incidence of ischemic stroke in patient populations with manifest ischemic heart disease. This observation is supported by a recently published meta-analysis of statin trials that reported an average reduction of about 30% in the incidence of cerebrovascular disease. However, to date, statin studies have only been conducted in patients with, or at high risk for coronary artery disease, who are not truly representative of the overall stroke population. The ongoing Stroke Prevention by Aggressive Reduction of Cholesterol Levels (SPARCL) trial has been designed to prospectively evaluate the benefits of aggressive lipid-lowering therapy on cerebrovascular events in patients who have had a previous stroke or transient ischemic attack, but who have no prior history of coronary artery disease.
Patients with type 2 diabetes mellitus have an elevated risk of morbidity and mortality from cardiovascular disease. This risk is partly attributable to an increased prevalence of classic coronary artery disease risk factors and partly because of hyperglycemia itself and a highly atherogenic lipid profile. The altered composition of lipoproteins and lipids in type 2 diabetic patients, termed diabetic dyslipidemia, is characterized by: (1) elevated levels of triglyceride; (2) normal levels of total and low-density lipoprotein cholesterol (LDL-C); (3) reduced levels of high-density lipoprotein cholesterol (HDL-C); (4) elevated levels of apolipoprotein B; (5) a preponderance of small, dense LDL particles; and (6) increased levels of cholesterol-rich very-low-density lipoprotein. In most cases, diabetic dyslipidemia is preceded by hyperinsulinemia resulting from insulin resistance. Because patients with type 2 diabetes and insulin resistance are at a markedly increased risk of atherosclerosis, and because strict control of glycemia has proved beneficial in reducing microangiopathy but not macroangiopathy, treatment of diabetic dyslipidemia should be aggressive. Target levels have, therefore, been set at <2.6 mmol/L (100 mg/dL) for LDL-C, <2.3 mmol/L [200 mg/dL] for triglycerides, and >1.15 mmol/L (45 mg/dL) for HDL-C. Trial data suggest that these target levels are likely to be achieved with statins, if necessary, in combination with fibrates or nicotinic acid derivatives. Furthermore, in large-scale clinical trials (eg, Scandinavian Simvastatin Survival Study [4S] and the Cholesterol and Recurrent Events [CARE] study), it has been demonstrated that lipid lowering can appreciably reduce cardiovascular events in diabetic patients.