February 23, 2011 — Increasing levels of nonfasting triglycerides are associated with a higher risk for ischemic stroke in men and women.
Increasing cholesterol levels are also associated with an increased risk for ischemic stroke, but in men only, not in women.
The findings come from a 33-year study by Danish investigators and are published online February 21 in the Annals of Neurology.
"So far, the focus has been on cholesterol, but lowering cholesterol levels does not completely reduce the risk of atherosclerotic events, including myocardial infarction and stroke, unless triglyceride levels are also reduced, suggesting that other lipids may also play a role in the pathogenesis of atherosclerosis," lead study author Anette Varbo, MD, University of Copenhagen, Denmark, told Medscape Medical News. "Most previous studies examining this have used fasting triglyceride levels and have perhaps missed this association."
Copenhagen City Heart Study
Dr. Varbo and her colleagues followed up 7579 women and 6372 men who were enrolled in the Copenhagen City Heart Study, a prospective study of the general population that was started in 1976-1978. All patients were white and of Danish decent. The participants had nonfasting triglycerides and cholesterol levels measured at baseline and were followed up for up to 33 years (median, 26 years).
A diagnosis of ischemic stroke was made when focal neurologic symptoms lasted more than 24 hours. During the follow-up period, which was completed by 100% of the participants, 837 women and 837 men developed ischemic stroke.
The researchers found that as the levels of nonfasting triglycerides increased, so did the risk for ischemic stroke.
After adjusting for age, hypertension, smoking, alcohol consumption, atrial fibrillation, lipid-lowering therapy, and — in women — hormone replacement therapy and menopausal status, the researchers found that women with a nonfasting triglyceride level above 445 mg/dL (5 mmol/L) had a 4-fold increased risk for stroke compared with women with a nonfasting triglyceride level below 90 mg/dL (1 mmol/L). The corresponding risk in men was a 2.3-fold increased risk.
Table. Stroke Risk With Triglycerides Level Greater Than 445 mg/dL vs Less Than 90 mg/dL
CI = confidence interval
The study also found that increasing cholesterol levels were not associated with risk for ischemic stroke in women. However, men with cholesterol levels of 348 mg/dL (9.00 mmol/L) or greater had almost a 4.5-fold increased risk for ischemic stroke (hazard ratio, 4.4: 95% confidence interval, 1.9 – 10.6), compared with men with cholesterol levels less than 5.00 mmol/L.
Triglycerides are associated with atherosclerosis but in themselves are not causal in the pathogenesis of atherosclerosis, Dr. Varbo explained. "They are a marker of high levels of atherogenic lipoprotein remnants or very low density lipoproteins and intermediate density lipoproteins."
Desirable levels of triglycerides are below 18 to 200 mg/dL (2 mmol/L), she added.
Guideline Revisions
Senior study author, Marianne Benn, MD, PhD, Copenhagen University Hospital, Herlev Hospital, Herlev, Denmark, said she hopes that nonfasting triglyceride levels will be included in coming revisions of guidelines on stroke prevention as a result of her study findings. "We would like this to encourage clinicians to measure and reduce nonfasting triglyceride levels in patients," she told Medscape Medical News.
Patients should attempt to reach ideal triglyceride goals through lifestyle changes, which include weight loss; reduction of intake of saturated fatty acids, cholesterol, and alcohol; cessation of smoking; and increased physical exercise.
Dr. Benn suggested treatment with lipid-lowering medications, such as statins, fibrates, and niacin, if triglyceride levels remain above 200 mg/dL after 3 months of lifestyle changes. "Fish oil has been suggested to reduce triglyceride levels, but clinical randomized intervention trials are needed to clarify this," she added.
Medscape Medical News invited Adam Kelly, MD, from the University of Rochester Medical Center in New York, to comment on the impact that the results of this study are likely to have.
He said that it is unclear that it will change existing guidelines or practice patterns.
"Currently, national guidelines do not recommend goals for triglyceride levels for primary or secondary prevention of stroke," he said. "Further research may be helpful in determining whether this is an important target for stroke prevention."
Dr. Kelly noted that the study had several strengths, including its prospective design, large sample size, and objective predefined criteria for a diagnosis of stroke, as well as adjustment for other conditions that might have affected stroke risk, including age, hypertension, and smoking status.
"The authors looked for and found a possible stepwise effect, meaning that higher triglyceride levels were associated with higher stroke risks," he said. "The finding of this stepwise response makes one feel more confident that a true association may in fact exist."
The fact that the study was conducted in Denmark and included an all-white population is, however, a limitation, he noted. "As a result, it is unclear whether the findings can be generalized to other populations."
The study is also observational, so confounding is always a possibility, and causation can't be proven from observational data, he added. "Therefore, based on these results, you cannot assume that lowering triglyceride levels will prevent strokes," Dr. Kelly said.
Finally, he pointed out that the study was started in the 1970s and patients were followed up for a median of 26 years. "It's unclear if the care these patients received at the start of the study is reflective of practice patterns today."
Inconsistent Results
John W. Cole, MD, from the University of Maryland in College Park, commented that the results of epidemiologic studies evaluating the relationships between triglycerides and ischemic stroke have been inconsistent, in part because some studies evaluated fasting levels, whereas others used nonfasting levels.
He added that the ischemic stroke risk relationships between various combinations of lipid measures remain uncertain, specifically with regard to how stroke risk relates to levels of nonfasting triglycerides and cholesterol within the same individual.
"The study data includes nonfasting triglycerides and cholesterol levels as measured in the same individuals. This enabled a direct comparison of the 2 lipids as risk markers of ischemic stroke in the population — a clinically important comparison, particularly among those with very high levels of both markers," Dr. Cole said.
"Overall the results are interesting and provide further evidence that optimizing triglyceride levels might act to reduce stroke risk. The results warrant additional study."
He added that, in addition to the white-only population, another limitation is the relatively small sample sizes and wide confidence intervals in groups with the highest levels.
Weighing in with his opinion, Jeffrey L. Saver, MD, professor of neurology at the Geffen School of Medicine at UCLA and director of the UCLA Stroke Center in Los Angeles, California, commented, "This large, longitudinal study provides further evidence that triglyceride levels are an additional salient indicator of stroke risk, in addition to standard risk factors."
Dr. Saver added that clinical trials of treatments that target triglyceride lowering using stroke endpoints are warranted "to determine if this epidemiologic association can be translated into an effective prevention intervention."
This study was supported by grants from the Danish Medical Research Council, the Danish Heart Foundation, and Chief Physician Johan Boserup and Lise Boserup’s Fund. Dr. Varbo reports that she has received grants from the Danish Medical Research Council, the Danish Heart Foundation, and Chief Physician Johan Boserup and Lise Boserup’s Fund. Dr. Benn, Dr. Kelly, Dr. Cole, and Dr. Saver have disclosed no relevant financial relationships.
Ann Neurol. Published online February 21, 2011.
Increasing cholesterol levels are also associated with an increased risk for ischemic stroke, but in men only, not in women.
The findings come from a 33-year study by Danish investigators and are published online February 21 in the Annals of Neurology.
"So far, the focus has been on cholesterol, but lowering cholesterol levels does not completely reduce the risk of atherosclerotic events, including myocardial infarction and stroke, unless triglyceride levels are also reduced, suggesting that other lipids may also play a role in the pathogenesis of atherosclerosis," lead study author Anette Varbo, MD, University of Copenhagen, Denmark, told Medscape Medical News. "Most previous studies examining this have used fasting triglyceride levels and have perhaps missed this association."
Copenhagen City Heart Study
Dr. Varbo and her colleagues followed up 7579 women and 6372 men who were enrolled in the Copenhagen City Heart Study, a prospective study of the general population that was started in 1976-1978. All patients were white and of Danish decent. The participants had nonfasting triglycerides and cholesterol levels measured at baseline and were followed up for up to 33 years (median, 26 years).
A diagnosis of ischemic stroke was made when focal neurologic symptoms lasted more than 24 hours. During the follow-up period, which was completed by 100% of the participants, 837 women and 837 men developed ischemic stroke.
The researchers found that as the levels of nonfasting triglycerides increased, so did the risk for ischemic stroke.
After adjusting for age, hypertension, smoking, alcohol consumption, atrial fibrillation, lipid-lowering therapy, and — in women — hormone replacement therapy and menopausal status, the researchers found that women with a nonfasting triglyceride level above 445 mg/dL (5 mmol/L) had a 4-fold increased risk for stroke compared with women with a nonfasting triglyceride level below 90 mg/dL (1 mmol/L). The corresponding risk in men was a 2.3-fold increased risk.
Table. Stroke Risk With Triglycerides Level Greater Than 445 mg/dL vs Less Than 90 mg/dL
| Group | Hazard Ratio (95% CI) | P for trend |
| Women | 3.9 (1.3 – 11.1) | <.001 |
| Men | 2.3 (1.2 – 4.3) | .001 |
The study also found that increasing cholesterol levels were not associated with risk for ischemic stroke in women. However, men with cholesterol levels of 348 mg/dL (9.00 mmol/L) or greater had almost a 4.5-fold increased risk for ischemic stroke (hazard ratio, 4.4: 95% confidence interval, 1.9 – 10.6), compared with men with cholesterol levels less than 5.00 mmol/L.
Triglycerides are associated with atherosclerosis but in themselves are not causal in the pathogenesis of atherosclerosis, Dr. Varbo explained. "They are a marker of high levels of atherogenic lipoprotein remnants or very low density lipoproteins and intermediate density lipoproteins."
Desirable levels of triglycerides are below 18 to 200 mg/dL (2 mmol/L), she added.
Guideline Revisions
Senior study author, Marianne Benn, MD, PhD, Copenhagen University Hospital, Herlev Hospital, Herlev, Denmark, said she hopes that nonfasting triglyceride levels will be included in coming revisions of guidelines on stroke prevention as a result of her study findings. "We would like this to encourage clinicians to measure and reduce nonfasting triglyceride levels in patients," she told Medscape Medical News.
Patients should attempt to reach ideal triglyceride goals through lifestyle changes, which include weight loss; reduction of intake of saturated fatty acids, cholesterol, and alcohol; cessation of smoking; and increased physical exercise.
Dr. Benn suggested treatment with lipid-lowering medications, such as statins, fibrates, and niacin, if triglyceride levels remain above 200 mg/dL after 3 months of lifestyle changes. "Fish oil has been suggested to reduce triglyceride levels, but clinical randomized intervention trials are needed to clarify this," she added.
Medscape Medical News invited Adam Kelly, MD, from the University of Rochester Medical Center in New York, to comment on the impact that the results of this study are likely to have.
He said that it is unclear that it will change existing guidelines or practice patterns.
"Currently, national guidelines do not recommend goals for triglyceride levels for primary or secondary prevention of stroke," he said. "Further research may be helpful in determining whether this is an important target for stroke prevention."
Dr. Kelly noted that the study had several strengths, including its prospective design, large sample size, and objective predefined criteria for a diagnosis of stroke, as well as adjustment for other conditions that might have affected stroke risk, including age, hypertension, and smoking status.
"The authors looked for and found a possible stepwise effect, meaning that higher triglyceride levels were associated with higher stroke risks," he said. "The finding of this stepwise response makes one feel more confident that a true association may in fact exist."
The fact that the study was conducted in Denmark and included an all-white population is, however, a limitation, he noted. "As a result, it is unclear whether the findings can be generalized to other populations."
The study is also observational, so confounding is always a possibility, and causation can't be proven from observational data, he added. "Therefore, based on these results, you cannot assume that lowering triglyceride levels will prevent strokes," Dr. Kelly said.
Finally, he pointed out that the study was started in the 1970s and patients were followed up for a median of 26 years. "It's unclear if the care these patients received at the start of the study is reflective of practice patterns today."
Inconsistent Results
John W. Cole, MD, from the University of Maryland in College Park, commented that the results of epidemiologic studies evaluating the relationships between triglycerides and ischemic stroke have been inconsistent, in part because some studies evaluated fasting levels, whereas others used nonfasting levels.
He added that the ischemic stroke risk relationships between various combinations of lipid measures remain uncertain, specifically with regard to how stroke risk relates to levels of nonfasting triglycerides and cholesterol within the same individual.
"The study data includes nonfasting triglycerides and cholesterol levels as measured in the same individuals. This enabled a direct comparison of the 2 lipids as risk markers of ischemic stroke in the population — a clinically important comparison, particularly among those with very high levels of both markers," Dr. Cole said.
"Overall the results are interesting and provide further evidence that optimizing triglyceride levels might act to reduce stroke risk. The results warrant additional study."
He added that, in addition to the white-only population, another limitation is the relatively small sample sizes and wide confidence intervals in groups with the highest levels.
Weighing in with his opinion, Jeffrey L. Saver, MD, professor of neurology at the Geffen School of Medicine at UCLA and director of the UCLA Stroke Center in Los Angeles, California, commented, "This large, longitudinal study provides further evidence that triglyceride levels are an additional salient indicator of stroke risk, in addition to standard risk factors."
Dr. Saver added that clinical trials of treatments that target triglyceride lowering using stroke endpoints are warranted "to determine if this epidemiologic association can be translated into an effective prevention intervention."
This study was supported by grants from the Danish Medical Research Council, the Danish Heart Foundation, and Chief Physician Johan Boserup and Lise Boserup’s Fund. Dr. Varbo reports that she has received grants from the Danish Medical Research Council, the Danish Heart Foundation, and Chief Physician Johan Boserup and Lise Boserup’s Fund. Dr. Benn, Dr. Kelly, Dr. Cole, and Dr. Saver have disclosed no relevant financial relationships.
Ann Neurol. Published online February 21, 2011.
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