Rx Nutrition Resource Center
Rx Nutrition Resource Center
Issue: April 2020
Source/Disclosures
Disclosures: Uelmen reports no relevant financial disclosures. Klein reports he holds stock in Aspire Bariatrics and has received research support from Centene, Janssen and Pershing Square Foundation, consultant fees from Dannon-Yakult, Lobesity, Merck, Novo Nordisk and Pfizer and endowments from the Atkins Philanthropic Trust and the Kilo Foundation. Taub reports she consults for Amarin, Amgen, Boehringer Ingelheim, Janssen, Novo Nordisk, Pfizer and Sanofi/Regeneron and is a stockholder of Cardero Therapeutics. Varady reports she has received funding from Nestle and authors fees from Hachette Book Group.
April 22, 2020
11 min read
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Ketogenic diet, intermittent fasting lead popular eating plans for obesity, diabetes

Issue: April 2020
Source/Disclosures
Disclosures: Uelmen reports no relevant financial disclosures. Klein reports he holds stock in Aspire Bariatrics and has received research support from Centene, Janssen and Pershing Square Foundation, consultant fees from Dannon-Yakult, Lobesity, Merck, Novo Nordisk and Pfizer and endowments from the Atkins Philanthropic Trust and the Kilo Foundation. Taub reports she consults for Amarin, Amgen, Boehringer Ingelheim, Janssen, Novo Nordisk, Pfizer and Sanofi/Regeneron and is a stockholder of Cardero Therapeutics. Varady reports she has received funding from Nestle and authors fees from Hachette Book Group.
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Lifestyle interventions are the recommended first steps for treatment of diabetes and other cardiometabolic disorders. Changes to diet and physical activity can ultimately lead to weight loss and its proven benefits.

As evidence from the Look AHEAD and Diabetes Prevention Program trials have shown, losing 5% of body weight is when benefits really start to emerge, according to Caroline M. Apovian, MD, professor of medicine and director of Nutrition and Weight Management at the Boston University School of Medicine and an Endocrine Today Editorial Board Member.

“The 5% weight loss will improve insulin sensitivity in some of the organs, not quite in adipose tissue, but certainly in muscle and liver, so that blood sugar drops pretty quickly and insulin requirements go down,” Apovian told Endocrine Today. “Any other medications that patients are on for diabetes will be reduced as well.”

Intensive weight loss can even lead to diabetes remission and restoration of some beta-cell function. In a study published in Diabetic Medicine in September 2019, adults with type 2 diabetes who lost 10% of their baseline body weight in 1 year were almost twice as likely to reach diabetes remission as those who lost 2.5% or less (RR = 1.77; 95% CI, 1.32-2.38).

People often incorporate elements of popular diets rather than make full-scale changes to their eating pattern, according to Sacha Uelmen, RDN, CDE.

Photo courtesy of Sacha Uelmen. Printed with permission.

For all the good weight loss can do, finding the best way to achieve it is difficult. From a dietary perspective, there are a host of options, including some recently popular strategies that focus on macronutrient makeup or fasting. But choosing the right eating plan is more than just picking the one that promises the most weight loss.

“We don’t evaluate diets based on weight loss at all. Weight loss has nothing to do with whether or not a diet is considered healthy,” Apovian told Endocrine Today. “A healthy diet is one that would naturally lower lipids, lower glucose and improve metabolic health; but if you look at calories and you lower your caloric intake, no matter what you eat, you can lose weight.”

A healthy eating plan

The clinical abnormalities of cardiometabolic disorders are a physician’s primary focus rather than the number on the scale, according to Samuel Klein, MD, the William H. Danforth professor of medicine and nutritional science and director of the Center for Human Nutrition at Washington University School of Medicine in St. Louis.

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“Some diets have shown benefits that are weight-loss independent,” Klein told Endocrine Today. “One prime example is the Mediterranean diet, which is not necessarily associated with a lot of weight loss, but has substantial effects in reducing the risks for developing diabetes and heart disease. Another example is the ketogenic diet, which can improve blood sugar control in people with diabetes by decreasing the dietary load of carbohydrates.”

Caroline M. Apovian

Unsaturated fats make up 30% to 45% of the macronutrient content of a Mediterranean eating pattern, with approximately 20% coming from protein and 35% to 50% coming from carbohydrates. Fat content typically consists of olive oil, with lean proteins, nuts, low-fat dairy, vegetables and complex carbohydrates accounting for the rest of the macronutrient makeup.

“A Mediterranean diet is simply a diet that is high in good fats, so it tends to be more moderate in carbohydrates. You’re replacing some of the carbohydrates in your diet with a little bit more unsaturated fat,” Apovian said.

If followed properly, a Mediterranean-style diet can address factors outside of simple weight loss. In a study published in The New England Journal of Medicine in 2018, researchers found that eating a Mediterranean diet led to a 30% reduction in major cardiovascular event risk. A study published in Nutrition & Diabetes in March showed a 22% diabetes risk reduction over 22 years between participants from the Atherosclerosis Risk in Communities (ARIC) study prospective cohort who had the highest and lowest Mediterranean diet adherence scores.

Cutting carbohydrates

A common mistake Americans make when adopting a Mediterranean diet is simply adding olive oil without changing the rest of what they eat, Apovian said. They end up adding calories without reducing carbohydrates.

“The reason to even consider replacing carbohydrates is because the Western diet is high in processed simple carbohydrates,” Apovian said. “Even if you don’t need to lose weight, those carbohydrates are just not good for you. Replacing those with either protein or healthy oil or, for that matter, complex carbohydrates is a better idea.”

Low-carbohydrate eating plans are among the dietary recommendations from the American Diabetes Association, the European Association for the Study of Diabetes and several others. These diets require a reduction in carbohydrates supplemented by an increase in fats and generally fall into one of two approaches. The first is a more conventional low-carbohydrate diet that typically calls for 25% or less of daily calories to come from carbohydrates. The second is a very low-carbohydrate, or ketogenic, diet that requires less than 10% of daily calories to come from carbohydrates.

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“We now recognize that reducing carbohydrate intake and increasing the proportion of calories from fat intake is not a bad thing and can be therapeutic,” Klein said.

Samuel Klein

Low-carbohydrate plans offer potential benefits for several chronic health risk factors, particularly for people with diabetes. In a systematic review and meta-analysis published in Diabetic Medicine in 2018, researchers found that cutting carbohydrate intake to 50 g to 130 g per day — less than 25% of daily calories — reduced HbA1c (weighted mean difference of –0.49%; 95% CI, –0.75 to –0.23) and body weight (weighted mean difference of –0.43 kg; 95% CI, –0.74 to 0.12) among adults with type 2 diabetes.

A ketogenic plan can offer more dramatic benefits for adults with type 2 diabetes. In the Indiana Diabetes Reversal study, a 5-year prospective, nonrandomized trial with an estimated completion date in 2021, 55% of participants experienced diabetes remission after following a ketogenic diet for 2 years, according to Sarah Hallberg, DO, MS, ACSM-CEP, FNLA, FOMA, medical director and founder of Medically Supervised Weight Loss Indiana and medical director of Virta Health, who presented preliminary findings at the 2019 World Congress on Insulin Resistance, Diabetes and Cardiovascular Disease.

“When it comes to diabetes, we know that lowering carbohydrate intake for most people is going to improve their glycemia across all eating patterns, whether they’re eating specifically low-carb, a ketogenic or Mediterranean diet,” Sacha Uelmen, RDN, CDE, director of diabetes education and prevention programs for the Association of Diabetes Care & Education Specialists, told Endocrine Today.

People often incorporate elements of popular diets rather than make full-scale changes to their eating pattern, so a health care provider should ask patients to describe exactly what they mean when they undertake a low-carbohydrate or ketogenic diet, Uelmen said.

“As a dietitian, a lot of us will hear ‘ketogenic diet’ and we get panicked because we’re thinking someone has cut out all carbs, which could be dangerous,” Uelmen said.

“Most people are not following a specific eating pattern that has been studied in research,” Uelmen said. “They are taking the components that they agree with or think seem reasonable within their circumstances and trying to make it work.”

Constipation, dehydration and hypoglycemia are all possible with carbohydrate-restrictive diets, according to Uelmen. To address these issues, she recommends evaluating pre-diet eating and physical activity habits and carefully monitoring insulin, SGLT2 inhibitors and other glucose-lowering medications, as well as medications for hypertension, depression and anxiety.

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Intermittent fasting

In contrast to eating plans that prescribe a specific macronutrient balance, intermittent fasting patterns regulate the timing of meals during the day or over a week.

Krista A. Varady, PhD, professor of nutrition in the department of kinesiology and nutrition at the University of Illinois at Chicago, has spent 15 years studying intermittent fasting to address the difficulties inherent in diets that call for intensive calorie restriction.

“I noticed that people had a really hard time adhering to daily calorie restriction,” Varady told Endocrine Today. “I thought, ‘Do people actually have to diet every day to lose weight? Why don’t we create this protocol where you basically just have different alternating days of fast day, feast day, and see if that can help people lose weight?”

A variety of intermittent fasting regimens are possible, Varady said. Among the most common are alternate-day fasting, in which participants consume very little — usually 500 kcal — or even nothing on one day and then follow that with a “feast day” in which they may eat without restrictions; the 5:2 diet, which features fasting 2 days each week while eating normally on the other five; and time-restricted eating, which allows calorie consumption within a certain window — typically 6, 8 or 10 hours — each day.

“We ran our first [alternate-day fasting] study in 2008 and found that people actually really liked it,” Varady said. “They can stick to it pretty well in the short term ... with 90% of their fast days, they stick to that 500-calorie goal for up to about 3 months or so. After that, people find it a little bit harder.”

Pam R. Taub

Amount of weight loss varies from person to person, Varady said, with ranges from 3% to 15% of body weight from 2 to 12 months.

In a study published in Obesity in 2019, Varady and colleagues showed that alternate-day fasting led to a greater reduction in fasting insulin (52% vs. 14%; P < .05) and insulin resistance (53% vs. 17%; P < .05) at 1 year compared with daily calorie restriction.

“The two diets don’t produce different amounts of weight loss,” Varady said. “In terms of lipids and blood pressure, they seem to produce the same decreases in those risk markers as long as the people are losing the same amount of weight.”

Similarly, time-restricted eating can lead to weight loss and weight-related health improvements. In findings published in 2018 in Nutrition and Healthy Aging, Varady and colleagues demonstrated that participants with obesity who ate without restriction during an 8-hour window had a 2.6% greater reduction in body weight (P < .001), a 341 kcal per day greater reduction in energy intake (P = .04), a 1 kg/m2 greater reduction in BMI (P < .001) and a 7 mm Hg greater reduction in systolic BP (P = .02) vs. participants with obesity who did not change their eating pattern.

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“One thing we always need to keep in mind is the safety of this regimen because some of the longer fasting [window] regimens are not safe for patients that are on medications such as antihypertensive medications,” Pam R. Taub, MD, FACC, director of the Step Family Foundation Cardiovascular Rehabilitation and Wellness Center and associate professor of medicine at University California, San Diego, told Endocrine Today.

In a 12-week, single-arm study, published in February in Cell Metabolism, Taub and colleagues found that adults with metabolic syndrome or prediabetes — most of whom were prescribed statin and antihypertensive medications — who ate during a 10-hour window experienced reductions in weight (–3.3 kg; P = .00028), BMI (–1.09 kg/m2; P = .00011), percent body fat (–1.01%; P = .00013), waist circumference (–4.46 cm; P = .0097), visceral fat rating (–0.58; P = .004), systolic BP (–5.12 mm Hg; P =.041), diastolic BP (–6.47 mm Hg; P = .004), total cholesterol (–13.16 mg/dL; P = .03), LDL cholesterol (–11.94 mg/dL; P = .016) and non-HDL cholesterol (–11.63 mg/dL; P = .04) from baseline.

Taub and colleagues are investigating the mechanisms underlying the benefits of time-restricted eating regimens.

“More than 10 hours of fasting results in a low-grade state of ketosis, and ketosis results in lipolysis — break down of fat into free fatty acids, which can function as a high energy fuel for cells,” Taub said. “We believe this mobilization of fat stores may be responsible for the weight loss and other metabolic benefits we saw in our study.”

As with very low-carbohydrate diets, plans that call for intermittent fasting — whether each day or each week — may require medication adjustments for people with diabetes.

Krista A. Varady

“No matter what the regimen is, no matter how benign it seems, a physician does need to be involved,” Taub said. “For our patients with metabolic syndrome ... when parameters got better, I lowered medication. If they stayed on higher levels of their antihypertensives, they may have gotten hypotensive.”

Consulting with a health care provider is important for anyone with diabetes who considers an intermittent fasting strategy. These regimens have not been studied with people with diabetes requiring insulin.

“Patients with diabetes who require insulin have to be very careful with an intermittent feeding diet plan,” Klein said. “They have to regulate their diabetes medications very carefully to avoid having hypoglycemia.”

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Sticking with a plan

Adherence is crucial for evaluating a diet because potential benefits mean nothing if the plan is too difficult to follow, Uelmen said.

She suggests that for at least some people, intermittent fasting may be easier than making constant food choices as with calorie restriction or macronutrient-based diets.

“Let’s face it, food is everywhere and the more food options we have around us, the harder it is to manage. Eating patterns that take an elimination approach seem a lot easier than figuring out all the details,” Uelmen said.

“I always council on macronutrient content of the food, and if somebody wants to do time-restricted feeding, I don’t think it’s a bad idea,” Apovian said, specifically advising an 8-to-9-hour eating window from the early morning to early evening.

The first 10 days of intermittent fasting are the most difficult, according to Varady, and there is no evidence that gradually introducing these plans could lead to an easier transition. These regimens can lead to headaches and irritability initially, although Varady said drinking plenty of water can help counteract these effects.

“We always give people exit surveys, and for alternate-day fasting, only about 20% of people say they’re going to continue the diet, whereas with time-restricted feeding, 80% to 90% of people say that they’d be happy to continue this because they find it so easy,” Varady said.

“In the next 10 years, we’re going to have a lot more information about what factors or characteristics in which people might make them more susceptible to benefit with one diet approach vs. another,” Klein said, noting that this could help foster more “precision medicine” and individualization.

Ultimately, the most effective eating plan must be determined at the individual patient level.

“I personally think that there is no magic formula nor will there be, as the perfect study from a nutrition standpoint would take years and years to complete and likely tell us exactly what we know: Everyone is different,” Uelmen said. “Research needs to be focused less on the ‘perfect macronutrient balance’ and more on the behavioral, cultural and environmental characteristics that help people succeed in building healthier lives.” – by Phil Neuffer and Jill Rollet with additional reporting by Darlene Dobkowski

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Disclosures: Uelmen reports no relevant financial disclosures. Klein reports he holds stock in Aspire Bariatrics and has received research support from Centene, Janssen and Pershing Square Foundation, consultant fees from Dannon-Yakult, Lobesity, Merck, Novo Nordisk and Pfizer and endowments from the Atkins Philanthropic Trust and the Kilo Foundation. Taub reports she consults for Amarin, Amgen, Boehringer Ingelheim, Janssen, Novo Nordisk, Pfizer and Sanofi/Regeneron and is a stockholder of Cardero Therapeutics. Varady reports she has received funding from Nestle and authors fees from Hachette Book Group.