 |
|
Reduced Coronary Events in Simvastatin-Treated Patients With Coronary Heart Disease and Diabetes or Impaired Fasting Glucose Levels
Subgroup Analyses in the Scandinavian Simvastatin Survival Study
Steven M. Haffner, MD;
Charles M. Alexander, MD;
Thomas J. Cook, MS;
Stephen J. Boccuzzi, PhD;
Thomas A. Musliner, MD;
Terje R. Pedersen, MD;
John Kjekshus, MD;
Kalevi Pyörälä, MD;
for the Scandinavian Simvastatin Survival Study Group
Arch Intern Med. 1999;159:2661-2667.
ABSTRACT
| |
Background Patients with diabetes mellitus (DM) have a marked increase in coronary heart disease (CHD) events relative to those without DM. In a previous report from the Scandinavian Simvastatin Survival Study using a clinical case definition of DM (n = 202), simvastatin-treated patients had significantly fewer CHD events compared with placebo-treated control subjects.
Objective To examine the effect of simvastatin therapy on CHD in patients with DM and impaired fasting glucose levels.
Methods Using the 1997 American Diabetes Association diagnostic criteria, we assessed the effect of simvastatin therapy post hoc for an average of 5.4 years in Scandinavian Simvastatin Survival Study patients with normal fasting glucose (n = 3237), impaired fasting glucose (n = 678), and DM (n = 483).
Results Simvastatin-treated patients with DM had significantly reduced numbers of major coronary events (relative risk [RR] = 0.58; P = .001) and revascularizations (RR = 0.52; P = .005). Total (RR = 0.79; P = .34) and coronary (RR = 0.72; P = .26) mortality were also reduced in DM, but not significantly, due to small sample size. In impaired fasting glucose (IFG) subjects, simvastatin use significantly reduced the number of major coronary events (RR = 0.62; P = .003), revascularizations (RR = 0.57; P = .009), and total (RR = 0.57; P = .02) and coronary (RR = 0.45; P = .007) mortality.
Conclusions Our results extend previous findings in patients with DM to a larger cohort, confirming the benefit of cholesterol lowering with simvastatin treatment on CHD events. In addition, significant decreases in total mortality, major coronary events, and revascularizations were observed in simvastatin-treated patients with impaired fasting glucose levels. These results strongly support the concept that cholesterol lowering with simvastatin therapy improves the prognosis of patients with elevated fasting glucose levels ( 6.0 mmol/L [ 110 mg/dL]) or DM and known CHD.
INTRODUCTION
TYPE 2 diabetes mellitus (DM) is associated with at least a 2-fold increased risk of coronary heart disease (CHD).1-5 In addition, the prognosis of clinical CHD is worse in patients with DM than in nondiabetic patients.6-8 Although the role of glycemia in CHD in nondiabetic patients is controversial,9-10 recent evidence11 suggests that glycemia may be significantly related to mortality, even in the nondiabetic range, in a combined analysis of 3 longitudinal cohorts (the Whitehall, Paris Prospective, and Helsinki Policeman studies). In the Framingham Offspring Study,12 CHD risk that was adjusted for obesity, elevated waist-hip ratio, hypertension, low levels of high-density lipoprotein cholesterol (HDL-C), elevated triglyceride levels, and hyperinsulinemia showed continuous increases across the spectrum of nondiabetic glucose tolerance. Metabolic risk factors for type 2 DM and cardiovascular disease worsened continuously across the spectrum of glucose tolerance categories, beginning in the lowest quintiles of normal fasting glucose (NFG) level.12
Excess risk of CHD in patients with DM is not fully understood, but diabetic dyslipidemia is likely to be a major contributor.13 Patients with type 2 DM have increased levels of triglyceride, decreased levels of HDL-C, and smaller absolute elevations of low-density lipoprotein cholesterol (LDL-C) levels relative to nondiabetic patients.13 However, patients with type 2 DM tend to have total LDL-C values that do not meet the goal by National Cholesterol Education Program Adult Treatment Panel II criteria,14 and have a greater preponderance of smaller, denser LDL-C that seems more atherogenic.13
Several recent studies have focused attention on the benefits of LDL-C lowering in patients with clinical CHD. In the Scandinavian Simvastatin Survival Study (4S),15 simvastatin treatment reduced major coronary events by 55% (P = .002) in 202 patients with DM identified by medical history at baseline. In the Cholesterol and Recurrent Events (CARE) trial,16 pravastatin sodium treatment reduced the incidence of CHD events (CHD death, nonfatal myocardial infarction [MI], coronary artery bypass graft, and revascularization) by 25% (P = .05) in 586 patients with DM. In the Long-term Intervention With Pravastatin in Ischaemic Disease (LIPID) study,17 pravastatin therapy reduced major CHD (fatal CHD and nonfatal MI) by 19% in 782 patients with DM (95% confidence interval [CI] = -10% to 41%; not significant).
In 1997, the American Diabetes Association (ADA) introduced new criteria for the diagnosis of DM (fasting glucose level 7.0 mmol/L [126 mg/dL]).18 At the same time, the ADA introduced a new category of impaired fasting glucose (IFG) (fasting glucose level of 6.0-6.9 mmol/L [110-125 mg/dL]), which may be somewhat analogous to the older classification of impaired glucose tolerance. In this article, we examine the effect of simvastatin on CHD in patients with DM and IFG in the 4S using the 1997 ADA criteria. Use of this criteria would be expected to identify a larger number of patients with DM compared with diagnosis by clinical history of DM alone. The larger number of patients should increase the number of end points, thereby increasing the power of analysis.
PATIENTS AND METHODS
TRIAL DESIGN AND PATIENTS
The 4S was a double-masked, randomized, placebo-controlled multicenter clinical trial of long-term simvastatin therapy in patients with CHD carried out at 94 clinical centers in Denmark, Finland, Iceland, Norway, and Sweden. The design, organization, logistics, and main findings on mortality and morbidity have been described in detail previously.15, 19-20 The study protocol was approved by regional or, if applicable, national ethics committees and by the regulatory agencies in each participating country.
Recruitment and randomization of patients took place from May 19, 1988, to August 16, 1989. Patients were men and women aged 35 to 70 years with previous MI or active, stable angina pectoris who were identified by systematic screening of the medical records of potentially eligible patients.
To qualify for randomization, serum total cholesterol level had to be 5.5 to 8.0 mmol/L (212-309 mg/dL) and serum triglyceride level had to be 2.5 mmol/L or less ( 220 mg/dL) measured after 2 months of following a lipid-lowering diet. At randomization, patients who had given informed consent were randomly assigned to take simvastatin, 20 mg/d, or placebo.
Follow-up clinic visits and the methods used in laboratory measurements have been described previously.15, 19-20 Data on fasting blood glucose levels at baseline and the final study visit are based on whole blood, serum, or plasma glucose determinations carried out in local laboratories as part of routine safety data collection. Fasting glucose information was not available for 46 patients, leaving 4398 patients whose fasting glucose levels were available for analysis. Whole blood values were converted to plasma glucose values by multiplying the whole blood value by 1.15, and serum glucose values were considered equivalent to plasma values.21 A total of 678 patients had plasma glucose levels of 6.0 mmol/L or greater (110 mg/dL) but less than 7.0 mmol/L (<126 mg/dL), which is diagnostic for IFG by the 1997 ADA criteria.18 A total of 281 patients had plasma glucose levels of 7.0 mmol/L or greater (126 mg/dL) (diagnostic for DM by ADA criteria) but did not have a clinical history of DM. Regardless of fasting glucose level, the 202 previously described15 patients with a clinical history of DM were classified as having DM. The remaining patients (n = 3237) were classified as having NFG. Analysis of National Health and Nutrition Examination Study III data showed that about 4% of the US population have DM by clinical history (DM-Hx), 3% have DM only by elevated glucose values (DM-FG), 7% have IFG, and 86% have NFG using these criteria.14
Simvastatin dose was titrated to 40 mg/d in patients who did not reach the target serum total cholesterol level of 3.0 to 5.2 mmol/L (116-201 mg/dL) after 6 or 18 weeks using methods that preserved the masked nature of the study, as previously described.15, 19-20
Total mortality was the primary end point of 4S. Major coronary events (CHD death, nonfatal MI, and resuscitated ischemic cardiac arrest) constituted the secondary end point. Tertiary end points included (1) any CHD event, which consisted of any secondary end-point event plus any hospital admission for an acute CHD event without a diagnosis of MI (eg, prolonged chest pain or revascularization); (2) any atherosclerotic event, which consisted of any CHD event and fatal or nonfatal cerebrovascular events or other events directly attributed to atherosclerosis; and (3) myocardial revascularization procedures (coronary artery bypass grafting or coronary angioplasty). The procedures for event reporting and diagnostic classification of all study end-point events have been described previously.15, 19-20
STATISTICAL METHODS
Analysis of variance or the  2 test was used, as appropriate, in statistical testing of differences in the baseline characteristics of normal, impaired fasting glucose, and diabetic subjects who were randomized to receive simvastatin or placebo.
The effect of simvastatin treatment was assessed by calculating relative risk (RR) and 95% confidence intervals for the simvastatin group vs the placebo group with the Cox regression model.22 The assumption of proportionality of hazards in the Cox model was met. Kaplan-Meier survival curves and 6-year survival probability estimates were also calculated for both groups, and the differences between groups were tested using the log-rank test. Two-sided P<.05 was regarded as significant.
RESULTS
Table 1 shows the baseline characteristics of patients in the 4S (placebo and simvastatin groups combined) by glucose status (NFG, IFG, or DM). Patients with DM are shown separately as DM-FG (n = 281) and DM-Hx (n = 202). Glucose status was significantly related to age, male sex, baseline diagnosis, body mass index (calculated as weight in kilograms divided by the square of the height in meters: weight [kg]/[height (m)]2), systolic blood pressure, triglyceride and HDL-C levels, fasting glucose level, apolipoprotein B level, and smoking status (borderline, P = .05). Low-density lipoprotein and total cholesterol levels did not differ by glucose status.
|
|
|
|
Table 1. Baseline Characteristics of 4398 Patients by Glucose Status*
|
|
|
We also compared the baseline characteristics of patients randomized to receive placebo or simvastatin within each category of glucose status (Table 2). As expected, within each category of glucose status (NFG, IFG, or DM), patients randomized to the placebo and simvastatin groups did not differ in cardiovascular risk factors or in characteristics related to CHD, according to demographic variables.
|
|
|
|
Table 2. Baseline Chararcteristics of 4398 Patients by Glucose Status and Treatment Assignment*
|
|
|
Figure 1 shows the incidence of major coronary events in the placebo group by glucose status at baseline. Rate of major CHD events relative to patients with NFG increased by glucose status, with a progressive rise in events from IFG (RR = 1.15, 95% CI = 0.92-1.42) to DM-FG (RR = 1.19, 95% CI = 0.87-1.63) to DM-Hx (RR = 1.83, 95% CI = 1.34-2.50). When both DM categories (DM-FG and DM-Hx) were combined, patients with DM had a significantly increased risk of CHD events relative to those with NFG (RR = 1.44, 95% CI = 1.14-1.82). To increase statistical power, all patients with DM (DM-FG and DM-Hx) are combined in the remainder of this article, except as noted.
|
|
|
|
Figure 1. Incidence of major coronary heart disease events by glucose status in the placebo group in the Scandinavian Simvastatin Survival Study. NFG indicates normal fasting glucose; IFG, impaired fasting glucose; DM-FG, diabetes by elevated fasting glucose; and DM-Hx, diabetes by clinical history.
|
|
|
Figure 2 shows the effect of simvastatin therapy on lipoprotein values by glucose status. Simvastatin therapy significantly decreased LDL-C, total cholesterol, and triglyceride levels, and increased HDL-C levels. These effects were similar in each simvastatin-treated group (NFG, IFG, and DM).
|
|
|
|
Figure 2. Mean percentage change in lipid and lipoprotein levels by glucose status and treatment assignment (placebo vs simvastatin). NFG indicates normal fasting glucose; IFG, impaired fasting glucose; DM, diabetes mellitus; TC, total cholesterol; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; and TG, triglycerides. Error bars indicate SEM.
|
|
|
Figure 3 shows the 6-year Kaplan-Meier curves for major coronary events by glucose status and treatment group. For all 3 glucose status categories, patients randomized to receive simvastatin had significantly fewer CHD events (59 [23.5%] of 251 patients) than those randomized to receive placebo (428 [26.2%] of 1631 patients). The Kaplan-Meier curve for patients with DM randomized to receive simvastatin was higher than the curve for those with NFG randomized to receive placebo, although these differences were not statistically significant (RR = 0.83; P = .18).
|
|
|
|
Figure 3. Kaplan-Meier survival curves from the probability of remaining free of a major coronary heart disease event during follow-up in placebo- and simvastatin-treated patients with normal fasting glucose (NFG) levels, impaired fasting glucose (IFG) levels, and diabetes mellitus (DM).
|
|
|
Figure 4 shows the incidence of several end points by glucose status and treatment group. Among patients with NFG, the risk reduction in the simvastatin group was statistically significant for (1) major coronary events, odds ratio (OR), -32% (95% CI, -41% to -21%; P<.001); (2) total mortality, OR, -28% (95% CI, -43% to -10%; P = .005); (3) coronary mortality, OR, -42% (95% CI, -57% to -22%; P = .001); and (4) revascularizations, OR, -33% (95% CI, -45% to -19%; P<.001). Among patients with IFG, the risk reductions in the simvastatin group were, again, statistically significant for (1) major coronary events, OR, -38% (95% CI, -54% to -15%, P = .003); (2) total mortality, OR, -43% (95% CI, -65% to -7%, P = .02); (3) coronary mortality, OR, -55% (95% CI, -75% to -19%; P = .007); and (4) revascularizations, OR, -43% (95% CI, -63% to -13%; P = .009). Among patients with DM overall, the risk reductions were statistically significant for (1) major coronary events, OR, -42% (95% CI, -59% to -20%; P = .001), and (2) revascularizations, OR, -48% (95% CI, -58% to -18%; P = .005). Simvastatin-treated patients with DM had lower rates of overall mortality (OR, -21%; P = .34) and coronary mortality (OR, -28%; P = .26), which did not reach statistical significance. Due to small sample size, the risk reduction in patients with DM-FG was statistically significant only for revascularizations, OR, -57% (95% CI, -78% to -19%; P = .009). Risk reduction in patients with DM-Hx was statistically significant only for major coronary events, OR, -57% (95% CI, -74% to -29%; P = .001).
|
|
|
|
Figure 4. Incidence of end-point events during the Scandinavian Simvastatin Survival Study and relative risk (RR) by glucose status. A, Major coronary heart disease events. B, Revascularizations. C, Total mortality. NFG indicates normal fasting glucose; IFG, impaired fasting glucose; DM, diabetes mellitus; and CI, confidence interval.
|
|
|
Figure 5 shows the relation of baseline serum lipid levels to the effect of simvastatin treatment on the risk of major coronary events in patients with DM. This issue was examined by dividing the placebo- and simvastatin-treated groups into 2 strata using the median concentrations for each baseline-level lipid variable in the overall study. Risk reduction by simvastatin treatment did not depend on the baseline levels of LDL-C, HDL-C, or triglycerides (P = .89, .80, and .16, respectively, test of heterogeneity), although for triglyceride levels, there was a trend toward a more marked treatment effect among patients with DM in the upper half of the triglyceride distribution.
|
|
|
|
Figure 5. Effects of simvastatin therapy on major coronary events by glucose status, stratified by level of lipid variables. NFG indicates normal fasting glucose; IFG, impaired fasting glucose; DM, diabetes mellitus; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; and TG, triglycerides. Error bars indicate SEM. To convert HDL-C and LDL-C from millimoles per liter to milligrams per deciliter, divide millimoles per liter by 0.02586. To convert TG from millimoles per liter to milligrams per deciliter, divide millimoles per liter by 0.01129.
|
|
|
Table 3 shows the absolute risk and RR of simvastatin therapy for major coronary events by glucose status.
|
|
|
|
Table 3. Absolute and Relative Benefit of Simvastatin Therapy by Glucose Status for Major Coronary Events*
|
|
|
COMMENT
Results of the present study from the 4S confirm earlier findings15 based on data from patients in the 4S identified by DM-Hx (n = 202). It is based on a larger number of patients (n = 483) by also including those without a clinical history of DM but with fasting glucose levels (DM-FG) above the threshold of fasting plasma glucose defined as diagnostic for DM by the 1997 ADA diagnostic criteria (7.0 mmol/L [126 mg/dL]). In addition, analysis included patients without DM but with IFG (n = 678).18 Using the ADA criteria, simvastatin treatment reduced the risk of major coronary events by 42% in patients with DM, and by 38% in those with IFG. Because the present study includes additional patients diagnosed solely by fasting plasma glucose values, the severity of DM in patients identified in this way may have been less than in those identified by DM-Hx, as indicated by the lower mean fasting glucose value in the former group (7.6 [137] vs 9.7 mmol/L [175 mg/dL], respectively). Thus, the current expanded group of patients with DM might be more representative of DM in the general population.
Previously, data were also published from the CARE trial16 showing a significant 25% reduction in fatal and nonfatal MI and revascularization in patients with DM and previous MI. The reasons for the somewhat smaller decrease in coronary events in the CARE trial than in the 4S is not well understood, but could be due to chance, the lower level of baseline LDL-C in the CARE trial, or the lower degree of LDL lowering with pravastatin than with simvastatin therapy. The larger number of patients in the present study makes chance a less likely explanation for those differences. We compared the efficacy of simvastatin treatment in patients above and below the median value for LDL-C (4.9 mmol/L [187 mg/dL]) (Figure 5). In these strata, the effectiveness of simvastatin treatment in reducing major coronary events was 40% in the higher LDL-C group and 45% in the lower LDL-C group. Median LDL-C level in the lower group was 4.4 mmol/L (170 mg/dL). Although the overlap of LDL-C levels in the CARE trial and the 4S was limited, at least in the 4S data, the effectiveness of simvastatin treatment in reducing CHD was similar at different LDL-C levels. In the LIPID study,17 pravastatin treatment reduced CHD by 19% in patients with DM compared with 25% in those without DM. Although the effect of pravastatin therapy on CHD in the diabetic subgroup was not statistically significant, the test of heterogeneity (ie, whether the effect of pravastatin use on CHD was different in patients with and without DM) was not statistically significant. The LIPID study contained more patients with DM (n = 782) than either the 4S (n = 483) or the CARE trial (n = 586). Median LDL-C level in the LIPID study was 3.9 mmol/L (150 mg/dL), which is intermediate between the baseline LDL-C levels in the 4S and CARE trial data. The test for heterogeneity for the effect of pravastatin use on CHD by LDL levels in the LIPID study was also rejected, a result that contrasts with that reported by the CARE trial investigators.16 All patients in the 4S, CARE trial, and LIPID study had clinical CHD at baseline. In the Air Force Coronary Atherosclerosis Prevention Study/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS)23 (a primary prevention trial), in which mean LDL-C was 4.0 mmol/L (150 mg/dL), the percentage reduction in major CHD events with another 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, lovastatin, was -43% (although the number of patients with DM was small [n = 264] and the results for the subgroup were not statistically significant). Thus, the results in patients with DM from AFCAPS/TexCAPS seem to be similar to the 4S in terms of percentage reduction in major coronary events.
In patients with IFG, the RRs of main end points in simvastatin-treated groups were (1) -38% for major coronary events (P = .003), (2) -43% for total mortality (P = .02), (3) -55% for coronary mortality (P = .007), and (4) -43% for revascularizations (P = .009). In data from the CARE trial,16 pravastatin therapy was associated with a decrease in CHD events in the IFG group similar to that seen in those with NFG, although the results were not statistically significant in the IFG group alone. We also showed a modest increase in major coronary events in the IFG group relative to the NFG group (Figure 1), although these results are not statistically significant (P = .22). In a recent analysis of 3 prospective studies (n = 17,285) (the Whitehall, Paris Prospective, and Helsinki Policeman studies), Balkau et al11 showed that the RR (relative to patients without DM in the lowest 80% of the 2-hour glucose distribution) for CHD varied from 1.1 for patients in the 80% to 90% range, 1.2 for those in the 90% to 95% range, 1.0 for those in the 95% to 97.5% range, and 1.3 for those with glucose levels above 97.5% in the maximum. Although the results in the present article are not statistically significant (P = .22), they are comparable in magnitude for the effect of glycemia to the study by Balkau et al. Our study was done in patients with a history of previous CHD vs the study by Balkau et al, in which patients were free of CHD at baseline. Also supporting this increased risk for CHD across the spectrum of glucose status are the results of a cross-sectional study14 using the National Health and Nutrition Examination Study III dataset, which show that IFG had twice and DM had 3 times the prevalence of CHD compared with NFG.
We also analyzed the data in the present study using a number-needed-to-treat (NNT) approach.24-25 The NNT was 12 for NFG, 8 for IFG, and 7 for DM, which compare favorably with the NNT for hypertension derived from the Systolic Hypertension in the Elderly (SHEP) study.26 In that study overall, the NNT was 48, and in patients with a history or electrocardiographic evidence of previous MI, the NNT was 15. Thus, considering that statin therapy was at least as effective in patients with as without DM in the CARE trial and the 4S, a strong case can be made for more aggressive lowering of LDL-C levels in patients with DM without a previous MI than is provided by currently accepted national guidelines for cholesterol.27 In their 1999 position paper28 on management of diabetic dyslipidemia, the ADA recommended more aggressive management, for instance, that the LDL-C goal should be 2.59 mmol/L (100 mg/dL) for all adults with type 2 DM. This evidence supports the ADA position that all patients with DM should have the same LDL-C goal as those with CHD, and is supported by the high rate of CHD events in patients with DM1-5 and the poor prognosis of CHD in patients with DM after MI.6-8
It has recently been shown8 that the 1-year case fatality rate for first MI (from the onset of symptoms, thus including prehospitalization mortality) in the Finnish Monitoring International Cardiovascular Disease (FINMONICA) population was 45% in men with DM and 39% in women with DM. These rates were significantly higher than those in nondiabetic men and women (38% and 25%, respectively). Of patients with DM who died, 50% of men and 25% of women died before hospitalization. These individuals, by definition, could not benefit from secondary prevention strategies, indicating that aggressive management of cardiovascular risk factors in patients with DM (especially men) should precede the onset of clinical coronary artery disease. Recently, the 7-year incidence of MI in nondiabetic patients (aged 45-64 years) with a previous MI at baseline was shown to be similar to that for nondiabetic patients without previous MI (18.8% vs 20.2%, respectively).5 If this result can be confirmed in other studies, it might suggest that patients with DM without a previous MI might have an NNT similar to (or even lower than) that for patients with NFG with CHD in the 4S (ie, 12.5). This would support the need for aggressive lipid-lowering therapy, even for patients with DM who do not have clinical evidence of CHD. There is little clinical trial data (except for the AFCAPS/TexCAPS study) currently available to calculate the NNT for lipid lowering in patients with DM without preexisting CHD. Further studies of patients with DM without CHD to evaluate this issue are needed.
One limitation of the present study in patients with DM, and in articles from the CARE trial16 and the recently published LIPID study,17 is that these analyses represent results of post hoc subgroup analyses and thus, should be interpreted cautiously. Nevertheless, in each study, the percentage reduction of LDL-C levels in patients with DM was similar to that seen in nondiabetic patients in the same studies, which supports the inference that reduction of LDL cholesterol levels by using 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors is likely to benefit patients with DM.
In conclusion, the findings from this study confirm and extend results of a previous analysis showing the benefit of cholesterol lowering with simvastatin therapy in an expanded cohort of patients with DM and overt CHD. They also suggest that patients with CHD and IFG (6.0-6.9 mmol/L [110-125 mg/dL]) benefit from treatment by significant reductions in total and coronary mortality, major coronary events, and revascularizations.
AUTHOR INFORMATION
Accepted for publication March 1, 1999.
This study was supported by Merck & Co Inc, West Point, Pa.
Reprints: Steven M. Haffner, MD, Department of Medicine, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr, San Antonio, TX 78284-7873 (e-mail: haffner{at}UTHSCSA.edu).
From the Department of Medicine, University of Texas Health Science Center at San Antonio (Dr Haffner); US Medical & Scientific Affairs, Merck & Co Inc, West Point, Pa (Drs Alexander and Boccuzzi); Merck Research Laboratories, Rahway, NJ (Mr Cook and Dr Musliner); Cardiology Section, Medical Department, Aker Hospital (Dr Pedersen), and Section of Cardiology, Rikshospitalet (Dr Kjekshus), Oslo, Norway; and Department of Medicine, University of Kuopio, Kuopio, Finland (Dr Pyörälä). A list of members of the Scandinavian Simvastatin Survival Study Group appears in the Lancet, 1994;344:1388-1389.
REFERENCES
| |
1. Kannel WB, McGee DL. Diabetes and glucose tolerance as risk factors for cardiovascular disease: the Framingham Study. Diabetes Care. 1979;2:120-126.
ABSTRACT
2. Wingard DL, Barrett-Connor E. Heart disease and diabetes. In: National Diabetes Data Group, ed. Diabetes in America. 2nd ed. Washington, DC: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 1995:429-448. NIH publication 95-1468.
3. Pyörälä K, Laakso M, Uusitupa M. Diabetes and atherosclerosis: an epidemiologic view. Diabetes Metab Rev. 1987;3:463-524.
PUBMED
4. Stamler J, Vaccaro O, Neaton JD, Wentworth D. Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care. 1993;16:434-444.
ABSTRACT
5. Haffner SM, Lehto S, Rönnemaa T, Pyörälä K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med. 1998;339:229-234.
FREE FULL TEXT
6. Abbott RD, Donahue RP, Kannel WB, Wilson PW. The impact of diabetes on survival following myocardial infarction in men vs. women: the Framingham Study. JAMA. 1988;260:3456-3460. [published correction appears in JAMA. 1989;261:1884]
FREE FULL TEXT
7. Herliz J, Karlson BW, Edvardsson N, Emanuelsson H, Hjalmarson Å. Prognosis in diabetics with chest pain or other symptoms suggestive of acute myocardial infarction. Cardiology. 1992;80:237-245.
WEB OF SCIENCE
| PUBMED
8. Miettinen H, Lehto S, Salomaa VV, et al. Impact of diabetes on mortality after the first myocardial infarction. Diabetes Care. 1998;21:69-75.
ABSTRACT
9. Haffner SM. Impaired glucose tolerance: is it relevant for cardiovascular disease? Diabetologia. 1997;40(suppl 2):S138-S140.
10. Morris ML, Eastman RC. Is there a glycemic threshold for mortality risk? Diabetes Care. 1998;21:334-335.
WEB OF SCIENCE
| PUBMED
11. Balkau B, Shipley M, Jarrett RJ, et al. High blood glucose concentration is a risk factor for mortality in middle-aged nondiabetic men: 20-year follow-up in the Whitehall Study, the Paris Prospective Study, and the Helsinki Policeman Study. Diabetes Care. 1998;21:360-367.
ABSTRACT
12. Meigs JB, Nathan DM, Wilson PW, Cupples LA, Singer DE. Metabolic risk factors worsen continuously across the spectrum of nondiabetic glucose tolerance: the Framingham Offspring Study. Ann Intern Med. 1998;128:524-533.
FREE FULL TEXT
13. Haffner SM. Technical review: management of dyslipidemia in adults with diabetes. Diabetes Care. 1998;21:160-178.
ABSTRACT
14. Alexander CM, Landsman PB, Boccuzzi SJ, Berger ML. Impaired fasting glucose, lipid levels and prevalence of coronary heart disease: a U.S. population perspective. Diabetes. 1998;47(suppl l):A75.
15. Pyörälä K, Pedersen TR, Kjekshus J, Faergeman O, Olsson AG, Thorgeirsson G. Cholesterol lowering with simvastatin improves prognosis of diabetic patients with coronary heart disease: a subgroup analysis of the Scandinavian Simvastatin Survival Study (4S) [published correction appears in Diabetes Care.1997;20:1048]. Diabetes Care. 1997;20:614-620.
ABSTRACT
16. Goldberg RB, Mellies MJ, Sacks FM, et al. Cardiovascular events and their reduction with pravastatin in diabetic and glucose-intolerant myocardial infarction survivors with average cholesterol levels: subgroup analyses in the Cholesterol and Recurrent Events (CARE) trial. Circulation. 1998;98:2513-2519.
FREE FULL TEXT
17. The Long-term Intervention With Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med. 1998;339:1349-1357.
FREE FULL TEXT
18. American Diabetes Association. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 1997;20:1183-1197.
WEB OF SCIENCE
| PUBMED
19. Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344:1383-1389.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
20. The Scandinavian Simvastatin Survival Study Group. Design and baseline results of the Scandinavian Simvastatin Survival Study of patients with stable angina and/or previous myocardial infarction. Am J Cardiol. 1993;71:393-400.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
21. Kost GJ, Bowen TP. New whole blood methods and instruments: glucose measurements and test menus for critical care. J Int Fed Clin Chem. 1991;3:160-172.
PUBMED
22. Cox DR. Regression methods of life tables (with discussion). J R Stat Soc Ser B Method. 1972;34:187-200.
23. Downs JR, Clearfield M, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels. JAMA. 1998;279:1615-1622.
FREE FULL TEXT
24. Cook RJ, Sackett DL. The number needed to treat: a clinically useful measure of treatment effect. BMJ. 1995;310:452-454.
FREE FULL TEXT
25. Sackett DL, Haynes RB. Summarizing the effects of therapy: a new table and some terms. ACP J Club. 1997;127:A15-A16.
26. Kostis JB, Davis BR, Cutler J, et al. Prevention of heart failure by antihypertensive drug treatment in older persons with isolated systolic hypertension: SHEP Cooperative Research Group. JAMA. 1997;278:212-216.
FREE FULL TEXT
27. National Cholesterol Education Program. Second Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Washington, DC: National Heart Lung and Blood Institute; 1993. NIH publication 93-3095.
28. American Diabetes Association. Management of dyslipidemia in adults with diabetes. Diabetes Care. 1999;22(suppl 1):S56-S59.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati  Twitter
What's this?
RELATED ARTICLES
The Benefits of Lowering Cholesterol in Subjects With Mild Hyperglycemia
Ronald B. Goldberg
Arch Intern Med. 1999;159(22):2627-2628.
EXTRACT
| FULL TEXT
Archives of Internal Medicine Reader's Choice: Continuing Medical Education
Arch Intern Med. 1999;159(22):2751.
FULL TEXT
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES
|
Should All Diabetic Patients Be Treated With a Statin?
Kamari et al.
Diabetes Care 2009;32:S378-S383.
FULL TEXT
Oral hypoglycaemic agents, insulin resistance and cardiovascular disease in patients with type 2 diabetes
Hemmingsen et al.
Eur J Endocrinol 2009;161:1-9.
ABSTRACT
| FULL TEXT
CHAPTER 14 Diabetes Mellitus and Metabolic Syndrome
Cosentino et al.
ESC Textbook of Cardiovascular Medicine 2009;2:med-9780199566990-chapter-med-9780199566990-chapter.
ABSTRACT
| FULL TEXT
Improved Survival of Diabetic Foot Ulcer Patients 1995-2008: Possible impact of aggressive cardiovascular risk management
Young et al.
Diabetes Care 2008;31:2143-2147.
ABSTRACT
| FULL TEXT
Screening for Type 2 Diabetes Mellitus in Adults: U.S. Preventive Services Task Force Recommendation Statement
U.S. Preventive Services Task Force
ANN INTERN MED 2008;148:846-854.
ABSTRACT
| FULL TEXT
Screening Adults for Type 2 Diabetes: A Review of the Evidence for the U.S. Preventive Services Task Force
Norris et al.
ANN INTERN MED 2008;148:855-868.
ABSTRACT
| FULL TEXT
PROactive: time for a critical appraisal
Betteridge et al.
Eur Heart J 2008;29:969-983.
ABSTRACT
| FULL TEXT
Screening for Coronary Artery Disease in Patients With Diabetes
Bax et al.
Diabetes Care 2007;30:2729-2736.
ABSTRACT
| FULL TEXT
Guidelines on diabetes, pre-diabetes, and cardiovascular diseases: full text: The Task Force on Diabetes and Cardiovascular Diseases of the European Society of Cardiology (ESC) and of the European Association for the Study of Diabetes (EASD)
Authors/Task Force Members et al.
Eur Heart J Suppl 2007;9:C3-C74.
FULL TEXT
Serum Lipids and Glucose Control: The SEARCH for Diabetes in Youth Study
Petitti et al.
Arch Pediatr Adolesc Med 2007;161:159-165.
ABSTRACT
| FULL TEXT
Guidelines on diabetes, pre-diabetes, and cardiovascular diseases: executive summary: The Task Force on Diabetes and Cardiovascular Diseases of the European Society of Cardiology (ESC) and of the European Association for the Study of Diabetes (EASD)
Authors/Task Force Members et al.
Eur Heart J 2007;28:88-136.
FULL TEXT
Rational therapy of mixed dyslipidaemia in a patient with diabetes
Reasner
British Journal of Diabetes & Vascular Disease 2007;7:25-30.
ABSTRACT
The Cardiovascular Disease Continuum Validated: Clinical Evidence of Improved Patient Outcomes: Part I: Pathophysiology and Clinical Trial Evidence (Risk Factors Through Stable Coronary Artery Disease)
Dzau et al.
Circulation 2006;114:2850-2870.
FULL TEXT
Acute coronary syndromes and diabetes: is intensive lipid lowering beneficial? Results of the PROVE IT-TIMI 22 trial
Ahmed et al.
Eur Heart J 2006;27:2323-2329.
ABSTRACT
| FULL TEXT
Lipid-lowering therapy in type 2 diabetes: a review of the evidence
Steinmetz
Diabetes and Vascular Disease Research 2006;3:S10-S15.
ABSTRACT
Efficacy of lipid lowering drug treatment for diabetic and non-diabetic patients: meta-analysis of randomised controlled trials
Costa et al.
BMJ 2006;332:1115-1124.
ABSTRACT
| FULL TEXT
Metabolic Syndrome: Connecting and Reconciling Cardiovascular and Diabetes Worlds
Grundy
J Am Coll Cardiol 2006;47:1093-1100.
ABSTRACT
| FULL TEXT
Rosuvastatin improves cerebrovascular function in Zucker obese rats by inhibiting NAD(P)H oxidase-dependent superoxide production
Erdos et al.
Am. J. Physiol. Heart Circ. Physiol. 2006;290:H1264-H1270.
ABSTRACT
| FULL TEXT
Diabetes and Coronary Risk Equivalency: What does it mean?
Grundy
Diabetes Care 2006;29:457-460.
FULL TEXT
REVIEW: Efficacy and Mechanisms of Action of Statins in the Treatment of Diabetic Dyslipidemia
Ginsberg
J. Clin. Endocrinol. Metab. 2006;91:383-392.
ABSTRACT
| FULL TEXT
Evolving treatment paradigms for vascular risk reduction in type 2 diabetes: Report of an international symposium held in Barcelona, Spain, January 27-29, 2006
British Journal of Diabetes & Vascular Disease 2006;6:S1-S12.
Efficacy of intensive multitherapy for patients with type 2 diabetes mellitus: a randomized controlled trial
Menard et al.
CMAJ 2005;173:1457-1466.
ABSTRACT
| FULL TEXT
Reducing cardiovascular risk in patients with type 2 diabetes: the potential contribution of nicotinic acid
Van Gaal et al.
British Journal of Diabetes & Vascular Disease 2005;5:344-350.
ABSTRACT
Diagnosis and Management of the Metabolic Syndrome: An American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement
Grundy et al.
Circulation 2005;112:2735-2752.
FULL TEXT
Management of patients with type 2 diabetes after acute coronary syndromes
Bartnik et al.
Diabetes and Vascular Disease Research 2005;2:144-154.
ABSTRACT
The statin studies: from targeting hypercholesterolaemia to targeting the high-risk patient
Ong
QJM 2005;98:599-614.
ABSTRACT
| FULL TEXT
Impact of statins in microalbuminuric subjects with the metabolic syndrome: a substudy of the PREVEND Intervention Trial
Geluk et al.
Eur Heart J 2005;26:1314-1320.
ABSTRACT
| FULL TEXT
Pathophysiology of dyslipidaemia in the metabolic syndrome
Kolovou et al.
Postgrad. Med. J. 2005;81:358-366.
ABSTRACT
| FULL TEXT
Barriers to Diabetes Education in Urban Patients: Perceptions, Patterns, and Associated Factors
Rhee et al.
The Diabetes Educator 2005;31:410-417.
ABSTRACT
| FULL TEXT
Impact of Intensive Lifestyle and Metformin Therapy on Cardiovascular Disease Risk Factors in the Diabetes Prevention Program
The Diabetes Prevention Program Research Group
Diabetes Care 2005;28:888-894.
ABSTRACT
| FULL TEXT
Adherence to Statin Therapy and LDL Cholesterol Goal Attainment by Patients With Diabetes and Dyslipidemia
Parris et al.
Diabetes Care 2005;28:595-599.
ABSTRACT
| FULL TEXT
Screening for type 2 diabetes mellitus to prevent vascular complications: updated recommendations from the Canadian Task Force on Preventive Health Care
Feig et al.
CMAJ 2005;172:177-180.
FULL TEXT
Cardiovascular disease incidence and mortality in older men with diabetes and in men with coronary heart disease
Wannamethee et al.
Heart 2004;90:1398-1403.
ABSTRACT
| FULL TEXT
Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines
Grundy et al.
J Am Coll Cardiol 2004;44:720-732.
ABSTRACT
| FULL TEXT
Implications of Recent Clinical Trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines
Grundy et al.
Arterioscler. Thromb. Vasc. Bio. 2004;24:e149-e161.
ABSTRACT
| FULL TEXT
Implications of Recent Clinical Trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines
Grundy et al.
Circulation 2004;110:227-239.
ABSTRACT
| FULL TEXT
Reduction of Cardiovascular Events by Simvastatin in Nondiabetic Coronary Heart Disease Patients With and Without the Metabolic Syndrome: Subgroup analyses of the Scandinavian Simvastatin Survival Study (4S)
Pyorala et al.
Diabetes Care 2004;27:1735-1740.
ABSTRACT
| FULL TEXT
Treating dyslipidaemia in the patient with type 2 diabetes
Betteridge
Eur Heart J Suppl 2004;6:C28-C33.
ABSTRACT
| FULL TEXT
Rosuvastatin treatment reverses impaired coronary artery vasodilation in fructose-fed, insulin-resistant rats
Miller et al.
Am. J. Physiol. Regul. Integr. Comp. Physiol. 2004;287:R157-R160.
ABSTRACT
| FULL TEXT
Diabetes: preventing coronary heart disease in a high risk group
Feher
Heart 2004;90:iv18-iv21.
ABSTRACT
| FULL TEXT
The Burden of Diabetes-Associated Cardiovascular Hospitalizations in Veterans Administration (VA) and Non-VA Medical Facilities
Smith and Maynard
Diabetes Care 2004;27:B27-B32.
ABSTRACT
| FULL TEXT
Clinical Trials and Lipid Guidelines for Type II Diabetes
Prisant
J Clin Pharmacol 2004;44:423-430.
ABSTRACT
| FULL TEXT
Multi-vessel coronary disease and percutaneous coronary intervention
Casey and Faxon
Heart 2004;90:341-346.
FULL TEXT
Inpatient to Outpatient Transfer of Care in Urban Patients With Diabetes: Patterns and Determinants of Immediate Postdischarge Follow-up
Wheeler et al.
Arch Intern Med 2004;164:447-453.
ABSTRACT
| FULL TEXT
Early Benefit from Structured Care with Atorvastatin in Patients with Coronary Heart Disease and Diabetes Mellitus: A Subgroup Analysis of the GREek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) Study
Athyros et al.
ANGIOLOGY 2003;54:679-690.
ABSTRACT
Secondary Prevention of Cardiovascular Events With Long-Term Pravastatin in Patients With Diabetes or Impaired Fasting Glucose: Results from the LIPID trial
Keech et al.
Diabetes Care 2003;26:2713-2721.
ABSTRACT
| FULL TEXT
Epidemic Obesity and the Metabolic Syndrome
Haffner and Taegtmeyer
Circulation 2003;108:1541-1545.
FULL TEXT
Associations of Diabetes Mellitus and Ethnicity with Mortality in a Multiethnic Asian Population: Data from the 1992 Singapore National Health Survey
Ma et al.
Am J Epidemiol 2003;158:543-552.
ABSTRACT
| FULL TEXT
Diabetes mellitus and cardiovascular risk: just another risk factor?
Torp-Pedersen et al.
Eur Heart J Suppl 2003;5:F26-F32.
ABSTRACT
Sex Differences in Risk for Coronary Heart Disease Mortality Associated With Diabetes and Established Coronary Heart Disease
Natarajan et al.
Arch Intern Med 2003;163:1735-1740.
ABSTRACT
| FULL TEXT
Type 2 Diabetes and Coronary Heart Disease: We Keep Learning How Little We Know
Reaven
Arterioscler. Thromb. Vasc. Bio. 2003;23:917-918.
FULL TEXT
Clinical trials of lipid-lowering medication in diabetes
Durrington
British Journal of Diabetes & Vascular Disease 2003;3:217-220.
ABSTRACT
Prevention of Cardiovascular Ischemic Events: High-Risk and Secondary Prevention
Genest and Pedersen
Circulation 2003;107:2059-2065.
FULL TEXT
Lipid Management in Patients With Diabetes: Translating guidelines into action
Inzucchi and Amatruda
Diabetes Care 2003;26:1309-1311.
FULL TEXT
Dietary Fat Predicts Coronary Heart Disease Events in Subjects With Type 2 Diabetes
Soinio et al.
Diabetes Care 2003;26:619-624.
ABSTRACT
| FULL TEXT
Screening Adults for Type 2 Diabetes: A Review of the Evidence for the U.S. Preventive Services Task Force
Harris et al.
ANN INTERN MED 2003;138:215-229.
ABSTRACT
| FULL TEXT
Aldosterone Function in Diabetes Mellitus: Effects on Cardiovascular and Renal Disease
McFarlane and Sowers
J. Clin. Endocrinol. Metab. 2003;88:516-523.
FULL TEXT
References
Circulation 2002;106:3373-3421.
FULL TEXT
Diabetes, Plasma Insulin, and Cardiovascular Disease: Subgroup Analysis From the Department of Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT)
Rubins et al.
Arch Intern Med 2002;162:2597-2604.
ABSTRACT
| FULL TEXT
Variation in Diabetes Care Among States: Do patient characteristics matter?
Arday et al.
Diabetes Care 2002;25:2230-2237.
ABSTRACT
| FULL TEXT
Treatment of Cardiovascular and Renal Risk Factors in the Diabetic Hypertensive
Sowers and Haffner
Hypertension 2002;40:781-788.
FULL TEXT
Response to Lamotte et al.
Edelsberg et al.
Diabetes Care 2002;25:1899-1900.
FULL TEXT
Atorvastatin and Micronized Fenofibrate Alone and in Combination in Type 2 Diabetes With Combined Hyperlipidemia
Athyros et al.
Diabetes Care 2002;25:1198-1202.
ABSTRACT
| FULL TEXT
New Strategies for the Treatment of Diabetic Dyslipidemia
Haffner and Goldberg
Diabetes Care 2002;25:1237-1239.
FULL TEXT
A review of the carotid and femoral intima-media thickness as an indicator of the presence of peripheral vascular disease and cardiovascular risk factors
Cheng et al.
Cardiovasc Res 2002;54:528-538.
ABSTRACT
| FULL TEXT
Prevention Conference VI: Diabetes and Cardiovascular Disease: Writing Group IV: Lifestyle and Medical Management of Risk Factors
Grundy et al.
Circulation 2002;105
:e153-e158.
FULL TEXT
Control of Cardiovascular Risk Factors in Patients With Diabetes and Hypertension at Urban Academic Medical Centers
McFarlane et al.
Diabetes Care 2002;25:718-723.
ABSTRACT
| FULL TEXT
Modifiable Cardiovascular Risk Factors in Adults With Diabetes: Prevalence and Missed Opportunities for Physician Counseling
Egede and Zheng
Arch Intern Med 2002;162:427-433.
ABSTRACT
| FULL TEXT
Lipids and Atherosclerosis: Lessons Learned from Randomized Controlled Trials of Lipid Lowering and Other Relevant Studies
Kreisberg and Oberman
J. Clin. Endocrinol. Metab. 2002;87:423-437.
FULL TEXT
The Impact of Outpatient Diabetes Management on Serum Lipids in Urban African-Americans With Type 2 Diabetes
Erdman et al.
Diabetes Care 2002;25:9-15.
ABSTRACT
| FULL TEXT
Influence of Low High-Density Lipoprotein Cholesterol and Elevated Triglyceride on Coronary Heart Disease Events and Response to Simvastatin Therapy in 4S
Ballantyne et al.
Circulation 2001;104:3046-3051.
ABSTRACT
| FULL TEXT
Are high density lipoprotein (HDL) and triglyceride levels relevant in stroke prevention?
Rizos and Mikhailidis
Cardiovasc Res 2001;52:199-207.
ABSTRACT
| FULL TEXT
Prevention and Treatment of Coronary Heart Disease: Who Benefits?
LaRosa
Circulation 2001;104:1688-1692.
ABSTRACT
| FULL TEXT
Hypertriglyceridemic HyperapoB: The Unappreciated Atherogenic Dyslipoproteinemia in Type 2 Diabetes Mellitus
Sniderman et al.
ANN INTERN MED 2001;135:447-459.
ABSTRACT
| FULL TEXT
Lipid Disorders : Justification of Methods and Goals of Treatment
Braunstein et al.
Chest 2001;120:979-988.
ABSTRACT
| FULL TEXT
Risk factors for a major coronary event after myocardial infarction in the Scandinavian Simvastatin Survival Study (4S). Impact of predicted risk on the benefit of cholesterol-lowering treatment
Wilhelmsen et al.
Eur Heart J 2001;22:1119-1127.
ABSTRACT
Preventing Cardiovascular Complications of Type 2 Diabetes: Focus on Lipid Management
Henry
Clin. Diabetes 2001;19:113-120.
ABSTRACT
| FULL TEXT
Response to Egede
Grover et al.
Diabetes Care 2001;24:1306-1307.
FULL TEXT
Vascular effects of HMG CoA-reductase inhibitors (statins) unrelated to cholesterol lowering: new concepts for cardiovascular disease
Lefer et al.
Cardiovasc Res 2001;49:281-287.
FULL TEXT
How Cost-Effective Is the Treatment of Dyslipidemia in Patients With Diabetes but Without Cardiovascular Disease?
Grover et al.
Diabetes Care 2001;24:45-50.
ABSTRACT
| FULL TEXT
Identifying patients at risk for coronary heart disease: implications from trials of lipid-lowering drug therapy
Isles and Paterson
QJM 2000;93:567-574.
ABSTRACT
| FULL TEXT
Diabetes care needs evidence based interventions to reduce risk of vascular disease
Byrne and Wild
BMJ 2000;320:1554-1555.
FULL TEXT
The Benefits of Lowering Cholesterol in Subjects With Mild Hyperglycemia
Goldberg
Arch Intern Med 1999;159:2627-2628.
FULL TEXT
|
