correspondence
1. Enteen L, Bauer J, McLean R, et al. Overdose prevention andnaloxone prescription for opioid users in San Francisco. J Urban
Health 2010;87:931-41.
2. Doe-Simkins M, Walley A, Epstein A, Moyer P. Saved by thenose: bystander-administered intranasal naloxone hydrochloride for opioid overdose. Am J Public Health 2009;99:788-91.

3. Role of naloxone in opioid overdose fatality prevention:

public workshop. Silver Spring, MD: Food and Drug Administration, 2012 (http://www.fda.gov/Drugs/NewsEvents/ucm277119.htm).

DOI: 10.1056/NEJMc1209707Four-Year Follow-up after Two-Year Dietary Interventions
To the Editor: Data from trials that compare the workplace-based study, called the Dietary Intereffectiveness of weight-loss diets are frequently vention Randomized Controlled Trial (DIRECT),1,2
limited to the intervention period. In our 2-year we randomly assigned 322 moderately obese
A Weight

B LDL:HDL Ratio
Dietaryintervention

Dietaryintervention

Follow-up
0.8

Mean Change in LDL:HDL Ratio

Mean Change in Weight (kg)210−1

Low fat*−2*Low carb−3−4Med−5−6−7−8

Follow-up0240.6
Low fat0.40.2*−0.2

Low carb−0.4−0.672

Med0.0024Months

C Triglycerides

D Total Cholesterol
Dietaryintervention

Follow-up

20

Mean Change in Total Cholesterol(mg/dl)Mean Change in Triglycerides (mg/dl)

Dietaryintervention

100Low fat−10*
Low carb

−20*
Med

−30
−40−50072

Months2472

Follow-up

1050
Low fat−5−10*
Low carb *−15Med*−200Months

2472

MonthsFigure 1. Changes from Baseline in Diet-Related Measures.
Shown are mean changes from baseline in weight (Panel A), the ratio of low-density lipoprotein (LDL) cholesterol tohigh-density lipoprotein (HDL) cholesterol (Panel B), triglyceride levels (Panel C), and total cholesterol levels (Panel D)
in 322 moderately obese participants who were assigned to one of three weight-loss plans: a low-fat, restricted-calorie
diet (Low fat); a Mediterranean, restricted-calorie diet (Med); or a low-carbohydrate diet without calorie restriction(Low carb). The duration of the original study was 2 years (as indicated by the shaded portion of the graph). Fouryear follow-up analyses were conducted in 259 of the original participants. LDL and HDL were measured in milligrams
per deciliter. Asterisks denote P<0.05 for the difference from baseline at 6 years. The I bars indicate standard deviations.

n engl j med 367;14

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correspondence

participants to one of three weight-loss plans: alow-fat, restricted-calorie diet; a Mediterranean,restricted-calorie diet; or a low-carbohydrate dietwithout calorie restriction. The mean age of theparticipants was 52 years, and the mean body-massindex (the weight in kilograms divided by thesquare of the height in meters) was 31; 86% ofthe participants were men. We provided nutrition
labeling and diet-group color coding daily in theworkplace cafeteria. We also performed a spousal
education program.3
At 2 years, the adherence rate was 85%, withevidence of distinct dietary patterns in the three
diet groups. After 2 years,1 the mean weight loss
was 2.9 kg in the low-fat group, 4.4 kg in theMediterranean group, and 4.7 kg in the lowcarbohydrate group. In addition, we found that
there was a significant diet-induced regression involume in the carotid-vessel wall.4 After the 2-year
intervention was completed, we followed the participants for 4 more years. (Details are provided in
the Supplementary Appendix, available with thefull text of this letter at NEJM.org.)
We next performed an intention-to-treat analysis across the assigned diets, with 4-year followup among 259 participants (80.4% of the originalgroup and 95.2% of those who had completed the2-year trial). At 6 years after study initiation, 67%of the participants had continued with their originally assigned diet, 11% had switched to anotherdiet, and 22% were not dieting (P = 0.36 for allcomparisons). During this follow-up period, participants had regained 2.7 kg of weight lost in thelow-fat group, 1.4 kg in the Mediterranean group,and 4.1 kg in the low-carbohydrate group (P = 0.004for all comparisons).
For the entire 6-year period, the total weightloss was 0.6 kg in the low-fat group, 3.1 kg in
the Mediterranean group, and 1.7 kg in the lowcarbohydrate group (P = 0.01 for all comparisons)(Fig. 1A). There was a significant difference intotal weight loss between the low-fat group and theMediterranean group (P = 0.01) but not between
the low-fat group and the low-carbohydrate group(P = 0.44) or between the Mediterranean group andthe low-carbohydrate group (P = 0.22). Overall, as
compared with the weight at baseline, the 6-year
weight loss was significant for the Mediterraneangroup (P<0.001) and the low-carbohydrate group(P = 0.02) but not for the low-fat group (P = 0.28).
At 6 years, changes from baseline in the ratio

1374

n engl j med 367;14

of low-density lipoprotein cholesterol to highdensity lipoprotein cholesterol were similar in thethree groups (P = 0.62 for all comparisons), although the change in the ratio was significant in
the low-carbohydrate group (a reduction of 0.16,
P = 0.04) (Fig. 1B). Reductions in triglyceride levels
from baseline were significant in the Mediterranean group (21.4 mg per deciliter [0.24 mmolper liter], P = 0.03) and the low-carbohydrate group(11.3 mg per deciliter (0.13 mmol per liter],
P = 0.02), with no significant difference among
the three groups (P = 0.12) (Fig. 1C). Overall, there
were persistent and significant reductions frombaseline in total cholesterol levels in all threestudy groups, with reductions of 7.4 mg per deciliter (0.19 mmol per liter) in the low-fat group(P = 0.03), 13.9 mg per deciliter (0.36 mmol perliter) in the Mediterranean group (P = 0.001), and10.4 mg per deciliter (0.27 mmol per liter) in the
low-carbohydrate group (P = 0.02; P = 0.71 for allcomparisons) (Fig. 1D).
In conclusion, a 2-year workplace intervention
trial involving healthy dietary changes had longlasting, favorable postintervention effects, particularly among participants receiving the Mediterranean and low-carbohydrate diets, despite a partial
regain of weight.
Dan Schwarzfuchs, M.D.
Nuclear Research Center Negev
Dimona, Israel
dan.nurit@gmail.com

Rachel Golan, R.D., M.P.H.
Iris Shai, R.D., Ph.D.
Ben Gurion University of the Negev
Beer-Sheva, Israel
Supported by the Nuclear Research Center Negev; the Chief
Scientist Office of the Israeli Ministry of Health (Project No.
300000-4850); and the Dr. Robert C. and Veronica Atkins Research Foundation. This foundation was not involved in any
stage of the design, conduct, or analysis of the study and had noaccess to the study results before publication.
Disclosure forms provided by the authors are available withthe full text of this letter at NEJM.org.
1. Shai I, Schwarzfuchs D, Henkin Y, et al. Weight loss with

low-carbohydrate, Mediterranean, or low-fat diets. N Engl J Med
2008;359:229-41. [Erratum, N Engl J Med 2009;361:2681.]
2. Blüher M, Rudich A, Klöting N, et al. Two patterns of adipokine and other biomarker dynamics in a long-term weight lossintervention. Diabetes Care 2012;35:342-9.
3. Golan R, Schwarzfuchs D, Stampfer MJ, Shai I. Halo effectof a weight-loss trial on spouses: the DIRECT-Spouse study. Public Health Nutr 2010;13:544-9.
4. Shai I, Spence DJ, Schwarzfuchs D, et al. Dietary intervention
to reverse carotid atherosclerosis. Circulation 2010;121:1200-8.
DOI: 10.1056/NEJMc1204792
Correspondence Copyright © 2012 Massachusetts Medical Society.

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