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Charles DiMaggio, PA-C, MPH
DEPARTMENT EDITOR

Critically appraised topics: Using evidence-based medicine to answer clinical questions

Does a low-carbohydrate diet affect biomarkers for CVD?

Tracy Onega, MA, MPAS, PA-C

Ms. Onega is a doctoral student in evaluative clinical sciences at Dartmouth College in Hanover, NH. Dr. DiMaggio is Director, Program for Healthcare Systems Preparedness, National Center for Disaster Preparedness, Columbia University Mailman School of Public Health, New York, NY, and a member of the editorial board of JAAPA. The author has indicated no relationships to disclose relating to the content of this article.

Earn Category I CME credit by reading this article and the associated article and successfully completing the post-test. Successful completion is defined as a cumulative score of at least 70% correct.

This material has been reviewed and is approved for 1 hour of clinical Category I (Preapproved) CME credit by the AAPA. The term of approval is for 1 year from the publication date of April 2004.

Learning objectives

Review the metabolic rationale for low-carbohydrate diets
Describe the American Dietetic Association and American Heart Association cautions regarding these diets
Discuss the research findings on the effect of these diets on weight loss, serum lipids, glycemic control, and blood pressure
Apply the tenets of evidence-based medicine in evaluating research findings

Disclosure of conflict of interest

The author has indicated no relationships to disclose relating to the content of this article.

Case: Committed to weight loss

A 50-year-old woman explains to her primary care provider that she wants to lose weight and reduce her cardiovascular risk factors by starting a low-carbohydrate diet, such as the Atkins diet. She is moderately obese, with a calculated body mass index (BMI) of 34 kg/m² despite having tried numerous diets. Although she is not currently receiving care for any ongoing problems, she has borderline hypertriglyceridemia and also borderline hypertension. Her family history includes type 2 diabetes. She prefers to avoid using weight-loss medication and is committed to making dietary changes.

Clinical question

In obese but otherwise healthy middle-aged men and women, how does a low-carbohydrate diet affect risk factors for cardiovascular disease compared to conventional diets? This question is increasingly relevant as both the number of obese American adults and the popularity of low-carbohydrate diets increase. Although as many as half of American adults are dieting at any given time,¹ the prevalence of obesity has doubled in the past 20 years.² The Atkins diet, which calls for a daily intake of 20 g of carbohydrate during the first 2 weeks, followed by weekly 5-g increases, is among the most popular, with four times as many dieters having read an Atkins book as any other diet book.³ Despite the popularity of such low-carbohydrate, high-protein, high-fat diets, few randomized, controlled trials have evaluated their efficacy for weight loss and their effects on cardiovascular risk factors such as serum lipids, BP, and insulin sensitivity.

Advocates of low-carbohydrate diets claim that diets high in protein promote the metabolism of adipose tissue, resulting in rapid weight loss without significant long-term adverse effects. Professional organizations such as the American Dietetic Association and the American Heart Association have cautioned against the use of low-carbohydrate diets, citing concerns about serious adverse outcomes, particularly for those with cardiovascular disease, type 2 diabetes, dyslipidemia, and hypertension. Specific concerns include the abnormal metabolism of insulin and impaired liver and kidney function secondary to accumulation of ketones; dehydration and hyponatremia leading to postural hypotension, fatigue, constipation, and nephrolithiasis; excessive consumption of fats resulting in hyperlipidemia; excessive consumption of protein causing impaired renal function; and bone mineral loss.⁴

Search criteria and results

Searches were performed in medline, the Cochrane Database of Systematic Reviews (CDSR), the ACP Journal Club, the Database of Abstracts of Reviews of Effects (DARE), and bibliographic sources for English-language, human studies published between January 1, 1966, and November 2003, using key words such as low carbohydrate, ketogenic, diet, high fat, and high protein. More than 5,000 citations were identified. Limiting this set to randomized, controlled trials of a low-carbohydrate diet yielded 13 titles. A scan of abstracts revealed that the typical study was of short duration and included few subjects. There was a large degree of variability among studies in terms of dietary intervention, participant characteristics, and outcomes measured.

Three studies were randomized, controlled trials that compared a low-carbohydrate diet with a conventional, calorie-restricted diet; lasted for at least 6 months; and measured weight loss and key cardiovascular end points:

(1) Foster GD, Wyatt HR, Hill JO, et al. A randomized trial of a low-carbohydrate diet for obesity. N Engl J Med. 2003;348:2082-2090.

(2) Brehm BJ, Seeley RJ, Daniels SR, D'Alessio DA. A randomized trial comparing a very low carbohydrate diet and a calorie-restricted low fat diet on body weight and cardiovascular risk factors in healthy women. J Clin Endocrinol Metab. 2003;88:1617-1623.

(3) Samaha FF, Iqbal N, Seshadri P, et al. A low-carbohydrate as compared with a low-fat diet in severe obesity. N Engl J Med. 2003;348:2074-2081.

Foster and colleagues reported the longest study—12 months—and included 63 moderately obese (BMI, 30-34 kg/m²) men and women with no concurrent medical problems.⁵ Brehm and coworkers followed 53 women who were moderately obese, but otherwise healthy, for 6 months.⁶ Samaha and colleagues enrolled the most participants (n = 132) for their 6-month trial but included severely obese (mean BMI, 43 kg/m²) adults with a high prevalence of diabetes (39%) or the metabolic syndrome (43%).⁷

Evaluating the evidence

Statistical analyses between intervention groups and across time points for each participant were performed in all three studies. Statistical power may have been weak in these studies because the numbers of subjects were relatively low. Only Samaha and colleagues addressed this issue, admitting that their study was underpowered to detect a weight-loss difference less than 5 ± 12 kg because of a greater than anticipated dropout rate. Importantly, therefore, each study analyzed the results for completion, as well as intention to treat, with no differences noted. Outcomes analyzed included weight loss, serum lipids, BP, and glycemic control.

Weight loss

Weight loss among the low-carbohydrate group was significantly different from that among the conventional calorie-restricted group in the Brehm and colleagues study at both 3 months (-7.6 ± 0.7 kg vs -4.2 ± 0.8 kg) and 6 months (-8.5 ± 1.0 kg vs -3.9 ± 1.0 kg; P = .001). Foster's group found a similar result, with significantly more weight loss for the low-carbohydrate diet at 3 months (-6.8% ± 5.0% vs -2.7% ± 3.7% of body weight; P = .001) and 6 months (-7.0% ± 6.5% vs -3.2% ± 5.6% of body weight; P = .02), but there was no difference at 12 months (-4.4% ± 6.7% vs -2.5% ± 6.3% of body weight; P = .26). In the 6-month-long Samaha trial, a significant difference in weight loss between groups was noted between the low-carbohydrate group and the conventional diet group (-5.8 ± 8.6 kg vs -1.9 ± 4.2 kg, respectively; 95% confidence interval for the difference in weight loss between groups, -1.6 to -6.3; P = .002). Taken together, these results suggest that a short-term benefit of increased weight loss with a low-carbohydrate diet may not be sustained beyond 6 months.

Serum lipid levels

Total cholesterol, LDL cholesterol, and HDL cholesterol levels were not significantly different between the two diets in either the Brehm or Samaha studies, although Brehm reported significant improvements in each of these lipids for subjects when comparing baseline values with those at the end of the study. Foster and colleagues found a transient, significant decrease in LDL levels at 3 months for the conventional diet group but otherwise noted no differences between the groups for LDL or total cholesterol. They did report a relative increase in HDL concentrations (11.0% ± 19.4% vs 1.6% ± 11.1% change at 12 months; P = .04) and a relative decrease in triglycerides (-17.0% ± 23.0% vs 0.7% ± 37.7% change at 12 months; P = .04) in the low-carbohydrate diet versus the conventional diet throughout most of the study. This significant reduction in triglycerides for participants on a low-carbohydrate diet compared with a conventional diet was also seen in the other two studies. The Brehm researchers suggest that the decrease they found was due to baseline differences between the groups. Samaha, however, adjusted for baseline variables and still found a significant reduction in plasma triglycerides (-38 ± 80 mg/dL in the low-carbohydrate diet vs -7 ± 54 mg/dL in the conventional diet; P = .001), particularly for subjects who lost more than 5% of their baseline weight. Thus, a low-carbohydrate diet may improve triglyceride levels more than a conventional diet but is unlikely to have a significant effect on other plasma lipids. This assertion does not support the concern that low-carbohydrate diets have a negative impact on lipids due to excess consumption of high-fat foods.

Glycemic control

Fasting glucose levels were comparable between the two interventions throughout these three studies. The Samaha trial, which included patients with diabetes, separately analyzed the data for those without diabetes. Samaha found a greater increase in insulin sensitivity for subjects on the low-carbohydrate diet, even after adjustment (-0.01 ± 0.03 vs 0.02 ± 0.03; P = .01). Foster and colleagues reported increased insulin sensitivity for both groups at 6 months, but values at 1 year were not significantly different from baseline. Significant time effects for improvement in both glucose and insulin levels for the two groups were seen in the Brehm trial. These findings suggest that while weight loss may improve glucose utilization, neither diet strategy is likely superior.

Blood pressure

None of the three studies found a significant difference between groups in systolic or diastolic BP. Foster's group reported a decrease in diastolic BP in both groups. Any reduction in BP, then, is likely to be attributed to weight loss rather than to a particular diet.

Clinical bottom line

From these three studies, the patient and provider are able to make an informed decision. The low-carbohydrate diet that this patient is motivated to try is likely to result in weight loss with no apparent increase in key cardiovascular risk factors. She should note, however, that the weight loss is not likely to be permanent and that regular exercise combined with a healthy diet high in fruits, vegetables, and whole grains and low in saturated fats will yield the best long-term health benefits. Furthermore, low-carbohydrate diets are associated with potential health risks, such as orthostatic hypotension, dehydration, poor athletic performance, osteoporosis, renal problems, and an unbalanced diet.

Even with evidence from three randomized, controlled trials, the small enrollments and limited duration of these studies do not allow for strong conclusions about the efficacy and effects of a low-carbohydrate diet. Given the small number of participants in these studies, statistical power to detect differences may be lacking. In addition, biomarkers of disease do not always predict outcome; thus, the overall effect of a low-carbohydrate diet compared with a conventional diet on cardiovascular risk factors is uncertain.

REFERENCES

1. Serdula MK, Mokdad AH, Williamson DF, et al. Prevalence of attempting weight loss and strategies for controlling weight. JAMA. 1999;282:1353-1358.

2. Flegal KM, Carroll MD, Ogden CL, Johnson CL. Prevalence and trends in obesity among US adults, 1999-2000. JAMA. 2002;288:1723-1727.

3. The truth about dieting. Consum Rep. June 2002;67:26-31.

4. The Atkins diet. Med Lett Drugs Ther. June 12,2000;42:52.

5. Foster GD, Wyatt HR, Hill JO, et al. A randomized trial of a low-carbohydrate diet for obesity. N Engl J Med. 2003;348:2082-2090.

6. Brehm BJ, Seeley RJ, Daniels SR, D'Alessio DA. A randomized trial comparing a very low carbohydrate diet and a calorie-restricted low fat diet on body weight and cardiovascular risk factors in healthy women. J Clin Endocrinol Metab. 2003;88:1617-1623.

7. Samaha FF, Iqbal N, Seshadri P, et al. A low-carbohydrate as compared with a low-fat diet in severe obesity. N Engl J Med. 2003;348:2074-2081.