Intermittent Fasting Trial Comes Out (Partly) Positive, but CV Impact Mixed

Intermittent fasting, with eating concentrated within an 8-hour window early in the day, increased weight loss and improved diastolic blood pressure and mood compared with eating over 12 hours or more throughout the day in a 14-week randomized trial.

Weight loss was only one of two co-primary endpoints, however, and there was not a significant effect on the other—fat loss—or on several additional cardiometabolic risk factors beyond blood pressure, lead author Humaira Jamshed, PhD (University of Alabama at Birmingham), and colleagues report.

Among the two-thirds of participants who fully completed the trial, the benefits seen in the overall population were joined by significant reductions in body fat and trunk fat.

The findings, published online this week in JAMA Internal Medicine, indicate that “the early time-restricted eating intervention may therefore be an effective treatment for both obesity and hypertension,” the investigators write.

Senior author Courtney Peterson, PhD (University of Alabama at Birmingham), acknowledged that the effects observed in the trial were not as great as might have been expected based on earlier studies, noting that the difference in weight loss between study arms was about 5 lbs, or the equivalent of cutting 214 calories per day out of one’s diet.

Nevertheless, she told TCTMD, “It’s still an exciting result to say . . . people actually got a benefit and were able to lose weight faster and they were able to eat about 200 calories less a day.”

The trial is interesting but not a game changer, commented Pam Taub, MD (UC San Diego Health, La Jolla, CA), who conducts research on intermittent fasting and participated in the first pilot study of time-restricted eating in patients with metabolic syndrome.

“My general feeling is time-restricted eating is going to have the most benefit in patients with underlying abnormalities like elevated blood pressure, elevated hemoglobin A1c, and elevated LDL,” she told TCTMD.

That said, the significant weight loss seen in this trial over just 14 weeks is “very promising because there is a huge epidemic of obesity, and obesity is the gateway to many diseases like diabetes and coronary disease.”

The findings are also noteworthy because time-restricted eating is a cheap strategy, Taub said, noting that medications to treat obesity are expensive. “I think we need more studies like this to look at the impact of a lifestyle intervention, and it has an important clinical significance because if these studies are substantiated in larger studies then this is something that we as clinicians can be recommending as an evidence-based strategy for our patients.”

Uncertain Effects of Intermittent Fasting

These findings come on the background of a literature filled with mixed results regarding the impact of intermittent fasting, as well as another trial published earlier this year showing that time-restricted eating did not boost weight loss among patients who had cut their daily caloric intake by 25%. Still, there is evidence from other studies that time-restricted eating can reduce body weight, increase fat oxidation, and improve cardiometabolic measures like insulin sensitivity and blood pressure compared with eating during a wider window of time during the day, even when caloric intake is similar.

For the current trial, which is one of the largest of intermittent fasting to date, the investigators enrolled 90 adults with obesity, but without diabetes or a severe/unstable chronic medical condition, who were receiving treatment through the Weight Loss Medicine Clinic at the University of Alabama at Birmingham Hospital. Mean age was 43, and mean body mass index was 39.6 kg/m². Most of the participants (80%) were women.

Participants were randomized to time-restricted eating—allowing consumption between 7 AM and 3 PM—or to a control situation in which they could eat during a window of 12 or more hours each day; they were asked to adhere to their assignments for at least 6 days each week. All received weight-loss counseling that involved recommendations for caloric restriction and physical activity.

My general feeling is time-restricted eating is going to have the most benefit in patients with underlying abnormalities like elevated blood pressure, elevated hemoglobin A1c, and elevated LDL. Pam Taub

Only 59 (66%) of the participants completed all aspects of the trial; 22% dropped out and in another 12% outcome data couldn’t be collected because of the COVID-19 pandemic.

There was significant weight loss in both arms of the trial, although the amount lost over 14 weeks was greater with time-restricted eating—6.3 vs 4.0 kg (13.9 vs 8.8 lbs; P = 0.002). Fat mass also dropped, with no significant difference between groups in the intention-to-treat analysis (P = 0.09); an advantage on this endpoint for time-restricted eating became apparent in an analysis of those who completed the trial (P = 0.047).

The investigators also evaluated the impact on several cardiometabolic measures, including blood pressure, heart rate, glucose and insulin levels, insulin sensitivity, beta-cell function, glycated hemoglobin level, and plasma lipids, but the only one significantly improved by time-restricted eating was diastolic blood pressure. That fell by 5 mm Hg in the intervention arm and by 1 mm Hg in the control arm (P = 0.04).

Mood disturbances, particularly those related to fatigue-inertia, vigor-activity, and depression-dejection, were improved by the intervention, but there were no impacts on food intake, physical activity, or sleep outcomes.

Differences Across Studies

The researchers provide an explanation for why their study showed a significant improvement in weight loss with time-restricted eating and the trial published earlier this year in NEJM did not, noting that “our study had better post hoc statistical power owing to less variability in weight loss.”

In addition, “our 95% CI was narrower than and wholly contained within the other trial’s 95% CI,” they point out. “Therefore, our results are not incompatible. Furthermore, our early time-restricted eating group extended their daily fasting by twice as much, fasting an extra 4.8 hours per day versus only a modest 2.3-hour change in the [prior] study.”

Regarding the blood pressure effect observed in the current trial, the researchers note that the magnitude is similar to what has been seen with the Dietary Approaches to Stop Hypertension (DASH) diet and endurance exercise. A comparable change in systolic blood pressure occurred, although it didn’t reach statistical significance due to larger variance, they add.

I don’t think we have definitive-enough evidence to recommend that people do intermittent fasting. I don’t think the field is there yet. Courtney Peterson

The reduction in diastolic blood pressure “suggests that intermittent fasting may be an effective approach for treating high blood pressure and for treating hypertension,” Peterson said, noting that the finding is consistent with some—but not all—prior studies. Although “there’s probably something there,” she said, “we don’t have a definitive answer yet.”

The lack of effects on other cardiometabolic outcomes differs from other studies of time-restricted eating, which have shown improvements in levels of glucose and fasting insulin, as well as insulin sensitivity, Jamshed et al write.

“We acknowledge the limitation that we did not measure glycemic endpoints in the postprandial state, which are more responsive to dietary interventions,” they say. “We also had larger variability in fasting insulin level relative to our previous trial. For plasma lipid levels, our results are consistent with most studies on time-restricted eating, which report no effects.”

Need for More Evidence

In an accompanying editorial, Shalender Bhasin, MBBS (Brigham and Women’s Hospital, Boston, MA), says the two recent trials—the current one and the one published in NEJM—“are notable because they demonstrate the feasibility of implementing time-restricted eating of calorically restricted diets in community-living adults. The scientific premise and the preclinical data . . . are promising, but the inconsistency among studies renders it difficult to draw strong inferences from these well-conducted but relatively small trials.”

Despite the lack of solid evidence, time-restricted eating remains popular around the world, Bhasin notes. “Substantially larger randomized clinical trials of longer duration are needed to comprehensively evaluate the hypothesized benefits and risks of long-term time-restricted eating of calorically restricted diets in adults,” he says, saying the eating pattern “is a promising idea in need of stronger clinical trial evidence to support its benefits and long-term safety.”

Peterson agreed. “I don’t think we have definitive-enough evidence to recommend that people do intermittent fasting. I don’t think the field is there yet. I think the field will be there probably in 10 years,” she said, suggesting studies of 300 to 500 participants might be needed to get a clear answer, at least in terms of weight loss. “We are not close to being able to say intermittent fasting definitely does or does not help with weight loss and improving overall health.”

Taub said she already recommends time-restricted eating for some of her patients, most of whom have diabetes or coronary disease. The patients who will get the most benefit are those who have the most abnormalities or who have the longest daily eating windows.

But the intermittent fasting has to be applied carefully after assessing a patient’s medications and health status, Taub advised, urging caution around volume depletion or hypotension, for example. “There’s some things that you have to educate patients about. You can’t just blindly tell everybody to do this.”

The science behind intermittent fasting, particularly from animal studies, is solid, but it’s difficult to do behavioral interventions in humans, Taub added. “In terms of clinical trials, you have to pick the right population. With anything, there’s a sweet spot.”

For that reason, “you’re not going to see benefits in everybody,” Taub said about time-restricted eating. “It’s figuring out the right people, and I think the right patients are those with metabolic syndrome and diabetes and hypertension.”