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Review of current evidence and clinical recommendations on the effects of low-carbohydrate and very-low-carbohydrate (including ketogenic) diets for the management of body weight and other cardiometabolic risk factors: A scientific statement from the National Lipid Association Nutrition and Lifestyle Task Force

Open AccessPublished:September 13, 2019DOI:https://doi.org/10.1016/j.jacl.2019.08.003

      Highlights

      • Low- and very-low-carbohydrate diets are not superior to other weight loss diets.
      • May have advantages on appetite and reduced triglyceride and diabetes medication.
      • Mixed effects on low-density lipoprotein cholesterol levels.
      • No clear evidence for advantages related to other cardiometabolic risk markers.

      Abstract

      Historically, low-carbohydrate (CHO) and very-low-CHO diets have been used for weight loss. Recently, these diets have been promoted for type 2 diabetes (T2D) management. This scientific statement provides a comprehensive review of the current evidence base available from recent systematic reviews and meta-analyses on the effects of low-CHO and very-low-CHO diets on body weight, lipoprotein lipids, glycemic control, and other cardiometabolic risk factors. In addition, evidence on emerging risk factors and potential safety concerns of low-CHO and very-low-CHO diets, especially for high-risk individuals, such as those with genetic lipid disorders, was reviewed. Based on the evidence reviewed, low-CHO and very-low-CHO diets are not superior to other dietary approaches for weight loss. These diets may have advantages related to appetite control, triglyceride reduction, and reduction in the use of medication in T2D management. The evidence reviewed showed mixed effects on low-density lipoprotein cholesterol levels with some studies showing an increase. There was no clear evidence for advantages regarding effects on other cardiometabolic risk markers. Minimal data are available regarding long-term (>2 years) efficacy and safety. Clinicians are encouraged to consider the evidence discussed in this scientific statement when counseling patients on the use of low-CHO and very-low-CHO diets.

      Keywords

      Introduction

      Historically, dietary strategies that restrict carbohydrate (CHO) have been used for weight loss.
      • Abbasi J.
      Interest in the ketogenic diet grows for weight loss and type 2 diabetes.
      • Brouns F.
      Overweight and diabetes prevention: is a low-carbohydrate-high-fat diet recommendable?.
      • Paoli A.
      • Rubini A.
      • Volek J.S.
      • et al.
      Beyond weight loss: a review of the therapeutic uses of very-low-carbohydrate (ketogenic) diets.
      • Paoli A.
      Ketogenic diet for obesity-friend or foe.
      There is growing interest in low-CHO and very-low-CHO diets for patients with prediabetes and type 2 diabetes (T2D) to improve glycemic control and other cardiometabolic risk factors (eg, high blood pressure and atherogenic dyslipidemia).
      • Abbasi J.
      Interest in the ketogenic diet grows for weight loss and type 2 diabetes.
      • Brouns F.
      Overweight and diabetes prevention: is a low-carbohydrate-high-fat diet recommendable?.
      • Paoli A.
      • Rubini A.
      • Volek J.S.
      • et al.
      Beyond weight loss: a review of the therapeutic uses of very-low-carbohydrate (ketogenic) diets.
      • Paoli A.
      Ketogenic diet for obesity-friend or foe.
      • Harvey C.J.D.C.
      • Schofield G.M.
      • Zinn C.
      • Thornley S.J.
      • Crofts C.
      • Merien F.L.R.
      Low-carbohydrate diets differing in carbohydrate restriction improve cardiometabolic and anthropometric markers in healthy adults: a randomised clinical trial.
      • Hyde P.N.
      • Sapper T.N.
      • Crabtree C.D.
      • et al.
      Dietary carbohydrate restriction improves metabolic syndrome independent of weight loss.
      There are proposed benefits of these diets for other conditions (eg, acne, cancer, neurological diseases, and polycystic ovary syndrome)
      • Paoli A.
      • Rubini A.
      • Volek J.S.
      • et al.
      Beyond weight loss: a review of the therapeutic uses of very-low-carbohydrate (ketogenic) diets.
      and performance enhancement in athletes.
      • Burke L.M.
      • Hawley J.A.
      Swifter, higher, stronger: What's on the menu?.
      There have been anecdotal reports of improved mood, cognitive function, and energy levels with the use of low-CHO and very-low-CHO diets for weight loss, which have not generally been supported by findings from controlled studies.
      • Brinkworth G.D.
      • Buckley J.D.
      • Noakes M.
      • Clifton P.M.
      • Wilson C.J.
      Long-term effects of a very low-carbohydrate diet and a low-fat diet on mood and cognitive function.
      • Brinkworth G.D.
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      • Thompson C.H.
      • et al.
      Long-term effects of very low-carbohydrate and high-carbohydrate weight-loss diets on psychological health in obese adults with type 2 diabetes: randomized controlled trial.
      • El Ghoch M.
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      The effects of low-carbohydrate diets on psychosocial outcomes in obesity/overweight: a systematic review of randomized, controlled studies.
      • Iacovides S.
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      • Meiring R.M.
      Three consecutive weeks of nutritional ketosis has no effect on cognitive function, sleep, and mood compared with a high-carbohydrate, low-fat diet in healthy individuals: a randomized, crossover, controlled trial.
      In addition, very-low-CHO diets have become popular because of the perception they are healthier than currently recommended dietary patterns.
      • Clarke C.
      • Best T.
      Low-carbohydrate, high-fat dieters: characteristic food choice motivations, health perceptions and behaviours.
      There are several types of CHO-restricted diets, some of which restrict CHO to very low levels without restricting dietary protein and fat (eg, Atkins-style diet), whereas others allow moderate CHO intake with moderate protein and fat intake (eg, South Beach, Zone). Contemporary very-low-CHO diets limit protein to moderate levels to induce ketosis without restricting fat or total calories.
      • Abbasi J.
      Interest in the ketogenic diet grows for weight loss and type 2 diabetes.
      A very-low-CHO ketogenic diet (KD) has been used for the treatment of intractable epilepsy since the 1920s. The classic KD is precisely calculated to induce ketosis while providing adequate nutrition to prevent malnutrition and promote normal growth and development in children.
      • Kossoff E.H.
      • Zupec-Kania B.A.
      • Auvin S.
      • et al.
      Optimal clinical management of children receiving dietary therapies for epilepsy: updated recommendations of the International Ketogenic Diet Study Group.
      • Roehl K.
      • Sewak S.L.
      Practice paper of the academy of nutrition and dietetics: classic and modified ketogenic diets for treatment of epilepsy.
      Some individuals participate in medically supervised low-CHO and very-low-CHO diets for weight loss and/or T2D management; however, many follow these diets without medical supervision. In a 2018 survey of Americans between 18 and 80 years of age (n = 1009), 16% reported following some type of low-CHO eating pattern in the past year.
      International Food Information Council Foundation
      Food & Health Survey.
      There is some evidence that low-CHO and very-low-CHO diets elicit weight loss with ad libitum intake and without feelings of deprivation and hunger.
      • Abbasi J.
      Interest in the ketogenic diet grows for weight loss and type 2 diabetes.
      In addition, reduced CHO intake results in decreased insulin levels, which has been hypothesized to produce cardiometabolic benefits.
      • Paoli A.
      • Rubini A.
      • Volek J.S.
      • et al.
      Beyond weight loss: a review of the therapeutic uses of very-low-carbohydrate (ketogenic) diets.
      • Paoli A.
      Ketogenic diet for obesity-friend or foe.
      • Ludwig D.S.
      • Ebbeling C.B.
      The carbohydrate-insulin model of obesity: beyond “calories in, calories out.”.
      However, low-CHO and very-low-CHO diets that are high in saturated fatty acid (SFA)-rich foods and low in nutrient-dense CHO foods are inconsistent with evidence-based dietary strategies recommended by professional organizations.
      • Arnett D.K.
      • Blumenthal R.S.
      • Albert M.A.
      • et al.
      2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines.
      • Grundy S.M.
      • Stone N.J.
      • Bailey A.L.
      • et al.
      2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
      • Jacobson T.A.
      • Maki K.C.
      • Orringer C.E.
      • et al.
      National Lipid Association Recommendations for Patient-Centered Management of Dyslipidemia: Part 2.
      U.S. Department of Health and Human Services and U.S. Department of Agriculture
      2015–2020 Dietary Guidelines for Americans. 8th Edition.
      This National Lipid Association (NLA) Scientific Statement reviews the characteristics of low- and very-low-CHO diets and their impacts on metabolic pathways, examines the evidence on the effects of these diets on weight loss, dyslipidemia, and other cardiometabolic risk factors, and makes recommendations for clinicians about the use of these diets in adults in clinical practice. The specific content of this scientific statement includes:
      • a description of CHO-restricted diets;
      • a brief review of very-low-calorie KDs;
      • the impact of nutritional ketosis on energy and cholesterol metabolism;
      • the differential effects of CHO-restricted diets on the determinants of energy balance and body weight;
      • the evidence base for short- and long-term effects on weight loss, body composition, and cardiometabolic risk factors;
      • safety concerns and adverse effects; and
      • points to consider for the clinician-patient discussion on the use of low-CHO and very-low-CHO diets.

      Definition of CHO-restricted diets

      The terminology and definitions used for CHO-restricted diets vary considerably and are often defined based on the proportion of total daily energy (TDE) from CHO and/or absolute CHO intake. In this review, a CHO-restricted diet is defined as CHO intake below the lower boundary of the acceptable macronutrient distribution range for healthy adults (45–65% TDE).
      U.S. Department of Health and Human Services and U.S. Department of Agriculture
      2015–2020 Dietary Guidelines for Americans. 8th Edition.
      Institute of Medicine
      Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids.
      A moderate-CHO diet is defined as 26–44% TDE from CHO (130–225 grams CHO/d for a reference 2000 kcal diet), a low-CHO diet as 10–25% TDE from CHO (50–130 grams CHO/d), and a very-low-CHO diet as <10% TDE from CHO (<50 grams CHO/d) (Table 1).
      Table 1Diet classification based on amount of TDE and grams per day from CHO
      U.S. Department of Health and Human Services and U.S. Department of Agriculture
      2015–2020 Dietary Guidelines for Americans. 8th Edition.
      • Feinman R.D.
      • Pogozelski W.K.
      • Astrup A.
      • et al.
      Dietary carbohydrate restriction as the first approach in diabetes management: critical review and evidence base.
      • Chang J.
      • Kashyap S.R.
      The protein-sparing modified fast for obese patients with type 2 diabetes: what to expect.
      • Wylie-Rosett J.
      • Aebersold K.
      • Conlon B.
      • et al.
      Health effects of low-carbohydrate diets: where should new research go?.
      Diet descriptionKetogenicCalories/dCHO % TDEProtein % TDEFat % TDE
      VLCHF/KDYes>1000<10
      Typically the amount of CHO required to induce ketosis in most people.22
      (<20–50 g/d)
      ∼10% TDE (1.2–1.5 g/kg)70–80% TDE
      Low-CHONo>100010–25
      Based on 1500 calories/d, an energy intake considered hypocaloric for most individuals.
      (38–97 g/d)
      10–30% TDE25–45% TDE
      Moderate-CHONo>100026–44
      Based on 1500 calories/d, an energy intake considered hypocaloric for most individuals.
      (98–168 g/d)
      10–30% TDE25–35% TDE
      High-CHONo>100045–65
      Based on 1500 calories/d, an energy intake considered hypocaloric for most individuals.
      (169–244 g/d)
      10–30% TDE25–35% TDE
      Very-high-CHONo>1000>65
      Based on 1500 calories/d, an energy intake considered hypocaloric for most individuals.
      (>244 g/d)
      10–30% TDE25–35% TDE
      VLCalD
      VLCalDs vary in macronutrient composition—some may be ketogenic if CHO content is low enough; others may not be if CHO content is >50 g/d. The PSMF is a subset of VLCalDs and is typically higher in protein to spare LBM with a macronutrient composition of <20 to 50 g CHO/d, 1.2 to 1.5 g/kg protein/d, and <10 to 15% TDE fat.
      Varies<800VariesVariesVaries
      Classic KDYesVaries3790
      CHO, carbohydrate; VLCHF/KD, very-low-CHO, high-fat ketogenic diet; VLCalD, very-low-calorie diet; PSMF, protein sparing modified fast; TDE, total daily energy.
      Typically the amount of CHO required to induce ketosis in most people.
      • Feinman R.D.
      • Pogozelski W.K.
      • Astrup A.
      • et al.
      Dietary carbohydrate restriction as the first approach in diabetes management: critical review and evidence base.
      Based on 1500 calories/d, an energy intake considered hypocaloric for most individuals.
      VLCalDs vary in macronutrient composition—some may be ketogenic if CHO content is low enough; others may not be if CHO content is >50 g/d. The PSMF is a subset of VLCalDs and is typically higher in protein to spare LBM with a macronutrient composition of <20 to 50 g CHO/d, 1.2 to 1.5 g/kg protein/d, and <10 to 15% TDE fat.

      Description of CHO-restricted and ketogenic diets

      Low- and moderate-CHO diets can be moderate or high in fat and moderate or high in protein and do not result in nutritional ketosis due to higher contents of both CHO and protein.
      • Paoli A.
      Ketogenic diet for obesity-friend or foe.
      • Feinman R.D.
      • Pogozelski W.K.
      • Astrup A.
      • et al.
      Dietary carbohydrate restriction as the first approach in diabetes management: critical review and evidence base.
      Ketosis can be predicted for a CHO-restricted diet based on its ketogenic ratio (the ratio of the sum of ketogenic factors to the sum of anti-ketogenic factors):
      KR = (0.9 F + 0.46 P)/(1.0 C + 0.58 P + 0.1 F), where F is grams of fat, P is grams of protein, and C is grams of CHO.
      • Zilberter T.
      • Zilberter Y.
      Ketogenic ratio determines metabolic effects of macronutrients and prevents interpretive bias.
      The ratio that consistently induces ketogenesis is ≥2,
      • Zilberter T.
      • Zilberter Y.
      Ketogenic ratio determines metabolic effects of macronutrients and prevents interpretive bias.
      with 1.5 typically being the lower ketogenic threshold.
      • Zilberter T.
      • Zilberter Y.
      Ketogenic ratio determines metabolic effects of macronutrients and prevents interpretive bias.
      • Talbot F.B.
      • Metkalf K.M.
      • Moriarty M.E.
      Epilepsy: chemical investigations of rational treatment by production of ketosis.
      Zilberter and Zilberter
      • Zilberter T.
      • Zilberter Y.
      Ketogenic ratio determines metabolic effects of macronutrients and prevents interpretive bias.
      reviewed 62 studies that reported on prescribed dietary interventions described as “ketogenic” and found that only 25 of the 62 studies had a ketogenic ratio >1.5, which illustrates the complexity of interpreting the available evidence on KDs, much of which appears to be from investigations that did not truly assess KDs.
      Low- and moderate-CHO diets allow the consumption of CHO-containing foods that are components of cardioprotective dietary patterns, including vegetables, fruits, whole grains, nuts, seeds, and legumes.
      • Arnett D.K.
      • Blumenthal R.S.
      • Albert M.A.
      • et al.
      2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines.
      • Grundy S.M.
      • Stone N.J.
      • Bailey A.L.
      • et al.
      2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
      • Jacobson T.A.
      • Maki K.C.
      • Orringer C.E.
      • et al.
      National Lipid Association Recommendations for Patient-Centered Management of Dyslipidemia: Part 2.
      U.S. Department of Health and Human Services and U.S. Department of Agriculture
      2015–2020 Dietary Guidelines for Americans. 8th Edition.
      • Mozaffarian D.
      Dietary and policy priorities for cardiovascular disease, diabetes, and obesity: a comprehensive review.
      These foods are important sources of fiber, magnesium, B-vitamins, and bioactive compounds, such as polyphenols, all of which have been associated with lower risks for dyslipidemia, atherosclerotic cardiovascular disease (ASCVD) events, and incident T2D.
      • Arnett D.K.
      • Blumenthal R.S.
      • Albert M.A.
      • et al.
      2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines.
      • Grundy S.M.
      • Stone N.J.
      • Bailey A.L.
      • et al.
      2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
      • Jacobson T.A.
      • Maki K.C.
      • Orringer C.E.
      • et al.
      National Lipid Association Recommendations for Patient-Centered Management of Dyslipidemia: Part 2.
      U.S. Department of Health and Human Services and U.S. Department of Agriculture
      2015–2020 Dietary Guidelines for Americans. 8th Edition.
      • Mozaffarian D.
      Dietary and policy priorities for cardiovascular disease, diabetes, and obesity: a comprehensive review.
      • Sikand G.
      • Kris-Etherton P.
      • Boulos N.M.
      Impact of functional foods on prevention of cardiovascular disease and diabetes.
      Contemporary very-low-CHO KDs have become popular among the lay public,
      • Clarke C.
      • Best T.
      Low-carbohydrate, high-fat dieters: characteristic food choice motivations, health perceptions and behaviours.
      • Evans M.
      Keto diets: good, bad or ugly?.
      as well as some clinicians and nutrition scientists.
      • Abbasi J.
      Interest in the ketogenic diet grows for weight loss and type 2 diabetes.
      • Evans M.
      Keto diets: good, bad or ugly?.
      The current popular version is very low in CHO (∼20–50 g/d or 5–10% TDE), high in fat (70–80% TDE),
      • Feinman R.D.
      • Pogozelski W.K.
      • Astrup A.
      • et al.
      Dietary carbohydrate restriction as the first approach in diabetes management: critical review and evidence base.
      and emphasizes the replacement of CHO with fat; thus, it is a very-low-CHO, high-fat (VLCHF) diet,
      • Brouns F.
      Overweight and diabetes prevention: is a low-carbohydrate-high-fat diet recommendable?.
      which results in ketosis.
      • Paoli A.
      Ketogenic diet for obesity-friend or foe.
      • Feinman R.D.
      • Pogozelski W.K.
      • Astrup A.
      • et al.
      Dietary carbohydrate restriction as the first approach in diabetes management: critical review and evidence base.
      Achieving ketosis is highly individualized
      • Adam-Perrot A.
      • Clifton P.
      • Brouns F.
      Low-carbohydrate diets: nutritional and physiological aspects.
      and less than 20 g/d of CHO may be needed in some people.
      • Miller V.J.
      • Villamena F.A.
      • Volek J.S.
      Nutritional ketosis and mitohormesis: potential implications for mitochondrial function and human health.
      In addition, at a given level of CHO intake, protein quantity appears to influence the degree of ketosis because some amino acids are used for gluconeogenesis and stimulate insulin secretion,
      • Paoli A.
      Ketogenic diet for obesity-friend or foe.
      which may reduce hepatic ketone production.
      • Adam-Perrot A.
      • Clifton P.
      • Brouns F.
      Low-carbohydrate diets: nutritional and physiological aspects.
      Therefore, current VLCHF/KDs are typically moderate in protein intake (1.2–1.5 g/kg/d).
      • Paoli A.
      Ketogenic diet for obesity-friend or foe.
      • Feinman R.D.
      • Pogozelski W.K.
      • Astrup A.
      • et al.
      Dietary carbohydrate restriction as the first approach in diabetes management: critical review and evidence base.
      Typically, there is little emphasis on the type of fat that replaces CHO in VLCHF/KDs, which may result in a high intake of SFAs and cholesterol. Furthermore, the severe restriction of CHO in a VLCHF/KD limits CHO intake to nonstarchy vegetables
      • Miller V.J.
      • Villamena F.A.
      • Volek J.S.
      Nutritional ketosis and mitohormesis: potential implications for mitochondrial function and human health.
      and eliminates fiber-rich starchy vegetables, as well as most fruits, legumes, and whole grains,
      • Adam-Perrot A.
      • Clifton P.
      • Brouns F.
      Low-carbohydrate diets: nutritional and physiological aspects.
      which are foods that have been associated with reduced cardiometabolic risk.
      • Mozaffarian D.
      Dietary and policy priorities for cardiovascular disease, diabetes, and obesity: a comprehensive review.

      Medically supervised very-low-calorie ketogenic diets for the treatment of obesity

      Medically supervised very-low-calorie diets (VLCalDs) have been used for over 40 years for the treatment of obesity (body mass index [BMI] ≥30 kg/m2 or a BMI of ≥27 kg/m2 with one or more comorbidities).
      • Chang J.
      • Kashyap S.R.
      The protein-sparing modified fast for obese patients with type 2 diabetes: what to expect.
      • Blackburn G.L.
      • Bistrian B.R.
      • Flatt J.P.
      Role of a protein-sparing fast in a comprehensive weight reduction program.
      • Tsai A.G.
      • Wadden T.A.
      The evolution of very-low-calorie diets: an update and meta-analysis.
      The energy level of a VLCalD has been defined as <800 kcal/d
      • Tsai A.G.
      • Wadden T.A.
      The evolution of very-low-calorie diets: an update and meta-analysis.
      • Jensen M.D.
      • Ryan D.H.
      • Apovian C.M.
      • et al.
      2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society.
      The macronutrient composition of VLCalDs is typically 0.8–1.5 g protein/kg ideal body weight to induce rapid weight loss and preserve lean body mass (LBM) and 15–30 g fat/d. An important point is that the CHO content in some VLCalDs is 20–50 g/d, which may induce ketosis, but can be as high as 80 g/d
      • Tsai A.G.
      • Wadden T.A.
      The evolution of very-low-calorie diets: an update and meta-analysis.
      ; thus, not all VLCalDs are ketogenic
      • Chang J.
      • Kashyap S.R.
      The protein-sparing modified fast for obese patients with type 2 diabetes: what to expect.
      (Table 1). The protein-sparing modified fast (PSMF) is a medically supervised VLCalD with 500–800 kcal/d, primarily from protein (1.2–1.5 g/kg ideal body weight). Fat is restricted to only that found in the protein foods allowed on the diet, such as lean meat, fish and seafood, and poultry. CHO is restricted to 20–50 g/d, resulting in ketosis.
      • Chang J.
      • Kashyap S.R.
      The protein-sparing modified fast for obese patients with type 2 diabetes: what to expect.
      • Tsai A.G.
      • Wadden T.A.
      The evolution of very-low-calorie diets: an update and meta-analysis.
      • Palgi A.
      • Read J.L.
      • Greenberg I.
      • Hoefer M.A.
      • Bistrian B.R.
      • Blackburn G.L.
      Multidisciplinary treatment of obesity with a protein-sparing modified fast: results in 668 outpatients.
      VLCalDs or PSMFs should be prescribed only in limited circumstances by trained clinicians. Patients must be medically supervised due to rapid weight loss and possible health complications, including possible medication adjustments to avoid hypoglycemia and hypotension.
      • Chang J.
      • Kashyap S.R.
      The protein-sparing modified fast for obese patients with type 2 diabetes: what to expect.
      Although some medically supervised programs utilize VLCalDs or PSMFs that are very low in CHO, they are not the focus of this scientific statement. Readers interested in the specific details of VLCalDs and PSMFs for adults are encouraged to read relevant articles.
      • Chang J.
      • Kashyap S.R.
      The protein-sparing modified fast for obese patients with type 2 diabetes: what to expect.
      • Blackburn G.L.
      • Bistrian B.R.
      • Flatt J.P.
      Role of a protein-sparing fast in a comprehensive weight reduction program.
      • Tsai A.G.
      • Wadden T.A.
      The evolution of very-low-calorie diets: an update and meta-analysis.
      • Palgi A.
      • Read J.L.
      • Greenberg I.
      • Hoefer M.A.
      • Bistrian B.R.
      • Blackburn G.L.
      Multidisciplinary treatment of obesity with a protein-sparing modified fast: results in 668 outpatients.

      The impact of nutritional ketosis on energy metabolism

      Glucose is typically the sole fuel for the human brain because fatty acids (FA) cannot cross the blood-brain barrier. When CHO intake is adequate, insulin promotes lipogenesis and suppresses ketone production; thus, ketone concentration is very low (<0.3 mmol/L) vs glucose (∼ 4 mmol/L).
      • Paoli A.
      Ketogenic diet for obesity-friend or foe.
      After a few days of severe CHO restriction (<20 g/d), the body's glucose production from gluconeogenesis becomes insufficient and the central nervous system (CNS) requires an additional energy source. During restricted CHO intake, insulin levels decrease and glucagon levels increase, which impact metabolic pathways in the liver resulting in decreased lipogenesis and increased mitochondrial FA oxidation.
      • Adam-Perrot A.
      • Clifton P.
      • Brouns F.
      Low-carbohydrate diets: nutritional and physiological aspects.
      • McGarry J.D.
      • Foster D.W.
      Regulation of hepatic fatty acid oxidation and ketone body production.
      The increased FA oxidation causes overproduction of acetyl-CoA and the production of ketone bodies in the hepatic mitochondria. Acetoacetate is the main ketone body produced and is converted to β-hydroxybutyrate and acetone. Ketosis is typically defined as a blood level of β-hydroxybutyrate ≥0.3 mmol/L.
      • Sumithran P.
      • Prendergast L.A.
      • Delbridge E.
      • et al.
      Ketosis and appetite-mediating nutrients and hormones after weight loss.
      • Gibson A.A.
      • Seimon R.V.
      • Lee C.M.
      • et al.
      Do ketogenic diets really suppress appetite? A systematic review and meta-analysis.
      Ketone bodies are used as a source of energy for all tissues, especially skeletal and cardiac muscle, after conversion back to acetyl-CoA, which is used in the tricarboxylic acid cycle.
      • Paoli A.
      Ketogenic diet for obesity-friend or foe.
      Because ketone bodies have a similar binding affinity (a.k.a., Michaelis-Menten [kM] constant) as glucose for transport to the brain, the CNS begins to use ketone bodies for energy at a plasma concentration of ∼4 mmol/L. Ketone levels in healthy people do not generally exceed 8 mmol/L because the CNS efficiently uses these molecules for energy in place of glucose.
      • Paoli A.
      • Rubini A.
      • Volek J.S.
      • et al.
      Beyond weight loss: a review of the therapeutic uses of very-low-carbohydrate (ketogenic) diets.
      • Paoli A.
      Ketogenic diet for obesity-friend or foe.
      • Paoli A.
      • Bosco G.
      • Camporesi E.M.
      • Mangar D.
      Ketosis, ketogenic diet and food intake control: a complex relationship.
      In ketogenesis, glucose levels remain within normal levels via gluconeogenesis from glucogenic amino acids and glycerol from hydrolyzed triglycerides (TG). During the first 3 to 4 days of a KD, the main source of glucose is via gluconeogenesis from amino acids. If the circumstances that promote ketogenesis continue, the contribution of amino acids decreases and the amount of glucose derived from glycerol increases.
      • Paoli A.
      Ketogenic diet for obesity-friend or foe.
      Based on research examining the effects of fasting and very-low-CHO diets, metabolic adaptation to ketosis takes two weeks or longer to achieve a steady-state ketone level.
      • Ludwig D.S.
      • Ebbeling C.B.
      The carbohydrate-insulin model of obesity: beyond “calories in, calories out.”.
      • Owen O.E.
      • Caprio S.
      • Reichard Jr., G.A.
      • Mozzoli M.A.
      • Boden G.
      • Owen R.S.
      Ketosis of starvation: a revisit and new perspectives.
      • Yang M.U.
      • Van Itallie T.B.
      Composition of weight lost during short-term weight reduction. Metabolic responses of obese subjects to starvation and low-calorie ketogenic and nonketogenic diets.

      The impact of nutritional ketosis on cholesterol metabolism

      Low-CHO and very-low-CHO/KDs appear to have variable effects on low-density lipoprotein cholesterol (LDL-C) levels (discussed in a later section) due, in part, to the hepatocellular effects of low insulin levels. A higher CHO intake increases insulin levels, which activates HMG-CoA reductase and increases hepatic cholesterol synthesis.
      • Paoli A.
      • Rubini A.
      • Volek J.S.
      • et al.
      Beyond weight loss: a review of the therapeutic uses of very-low-carbohydrate (ketogenic) diets.
      • Paoli A.
      Ketogenic diet for obesity-friend or foe.
      A lower CHO intake decreases insulin levels and inhibits HMG-CoA reductase activation and cholesterol synthesis while activating HMG-CoA lyase, an enzyme involved in ketone body production, thus favoring ketogenesis.
      • Adam-Perrot A.
      • Clifton P.
      • Brouns F.
      Low-carbohydrate diets: nutritional and physiological aspects.
      There are secondary effects on lipoprotein lipase (and co-factors), as well as LDL-receptor and PCSK9 expression affecting very-low-density lipoprotein (VLDL) and LDL clearance and lipoprotein remodeling. The net impact on serum LDL-C levels is thus mediated by complex mechanisms. It has been proposed that, by lowering insulin levels, low-CHO diets may inhibit hepatic cholesterol synthesis.
      • Paoli A.
      • Rubini A.
      • Volek J.S.
      • et al.
      Beyond weight loss: a review of the therapeutic uses of very-low-carbohydrate (ketogenic) diets.
      • Paoli A.
      Ketogenic diet for obesity-friend or foe.
      • Adam-Perrot A.
      • Clifton P.
      • Brouns F.
      Low-carbohydrate diets: nutritional and physiological aspects.
      Unless this is counteracted by other mechanisms, the expected result would be decreased total cholesterol (total-C) and LDL-C,
      • Paoli A.
      • Rubini A.
      • Volek J.S.
      • et al.
      Beyond weight loss: a review of the therapeutic uses of very-low-carbohydrate (ketogenic) diets.
      • Paoli A.
      Ketogenic diet for obesity-friend or foe.
      • Adam-Perrot A.
      • Clifton P.
      • Brouns F.
      Low-carbohydrate diets: nutritional and physiological aspects.
      especially when intakes of SFA and dietary cholesterol are not increased
      • Paoli A.
      Ketogenic diet for obesity-friend or foe.
      when CHO consumption is lowered. Thus, LDL-C response cannot be predicted in the individual, and should be evaluated in those who choose to follow a low-CHO or very-low-CHO/KD.

      Effects of low-CHO and very-low-CHO diets on determinants of energy balance and body weight

      CHO-restricted diets have significant effects on factors that influence energy expenditure (EE) and intake. Results from well-controlled studies have shown that substitution of fat for CHO results in a higher EE. Hall et al.
      • Hall K.D.
      • Chen K.Y.
      • Guo J.
      • et al.
      Energy expenditure and body composition changes after an isocaloric ketogenic diet in overweight and obese men.
      examined changes in EE in 17 men with overweight or obesity consuming an isocaloric habitual high-CHO diet (50% TDE CHO, 15% TDE protein, 35% TDE fat) for 4 weeks followed by a VLCHF/KD (5% TDE CHO, 15% TDE protein, 80% TDE fat) for 4 weeks. Participants spent two consecutive days each week in a metabolic chamber to measure changes in EE using the doubly labeled water method during the last two weeks of each dietary phase. During the VLCHF/KD phase, EE was 57 kcal/d higher as measured by the metabolic chamber and 151 kcal/d higher as measured by the doubly labeled water method.
      In a randomized controlled trial (RCT), participants who had lost an average of 12% of body weight were randomly assigned to weight maintenance diets varying in dietary CHO, i.e., low (20% TDE), moderate (40% TDE), or high (60% TDE).
      • Ebbeling C.B.
      • Feldman H.A.
      • Klein G.L.
      • et al.
      Effects of a low carbohydrate diet on energy expenditure during weight loss maintenance: randomized trial.
      Protein intake was held constant and energy from fat was substituted for CHO. Total EE measured with doubly labeled water was 91 kcal/d higher with the moderate-CHO group and 209 kcal/d higher in the low-CHO group compared with the high-CHO group, with a linear trend of 52 kcal/d per 10% reduction in dietary CHO.
      • Ebbeling C.B.
      • Feldman H.A.
      • Klein G.L.
      • et al.
      Effects of a low carbohydrate diet on energy expenditure during weight loss maintenance: randomized trial.
      Although EE appears to be higher with low-CHO diets and very-low-CHO/KDs, the mechanisms contributing to this are incompletely understood. It has been proposed that changes in catecholamines and thyroid hormone levels influence the EE of individuals following these diets, but associated changes have not been observed in all studies. In the trial by Hall et al.
      • Hall K.D.
      • Chen K.Y.
      • Guo J.
      • et al.
      Energy expenditure and body composition changes after an isocaloric ketogenic diet in overweight and obese men.
      (discussed previously), there was a significant increase in thyroid-stimulating hormone and free thyroxine (T4) levels, significantly decreased free and total tri-iodothyronine levels, and significantly decreased levels of leptin and norepinephrine in the 17 participants during the VLCHF/KD phase of their study.
      Results from controlled investigations have suggested a reduced appetite also occurs with CHO restriction, due to various mechanisms, and contributes to weight loss.
      • Paoli A.
      Ketogenic diet for obesity-friend or foe.
      • Gibson A.A.
      • Seimon R.V.
      • Lee C.M.
      • et al.
      Do ketogenic diets really suppress appetite? A systematic review and meta-analysis.
      • Paoli A.
      • Bosco G.
      • Camporesi E.M.
      • Mangar D.
      Ketosis, ketogenic diet and food intake control: a complex relationship.
      • Johnstone A.M.
      • Horgan G.W.
      • Murison S.D.
      • Bremner D.M.
      • Lobley G.E.
      Effects of a high-protein ketogenic diet on hunger, appetite, and weight loss in obese men feeding ad libitum.
      • Westman E.C.
      • Feinman R.D.
      • Mavropoulos J.C.
      • et al.
      Low-carbohydrate nutrition and metabolism.
      Westman et al.
      • Westman E.C.
      • Feinman R.D.
      • Mavropoulos J.C.
      • et al.
      Low-carbohydrate nutrition and metabolism.
      reported that there was a “spontaneous reduction in calorie intake” in studies that examined the effects of low-CHO diets and very-low-CHO/KDs on appetite and satiety, which may be partly mediated through effects of nutritional ketosis on appetite. Participants report less hunger when they are in ketosis, although the mechanisms of action of ketosis on hunger and appetite suppression are not completely understood and evidence suggests both direct and indirect actions of ketone bodies and their oxidation.
      • Paoli A.
      • Rubini A.
      • Volek J.S.
      • et al.
      Beyond weight loss: a review of the therapeutic uses of very-low-carbohydrate (ketogenic) diets.
      • Adam-Perrot A.
      • Clifton P.
      • Brouns F.
      Low-carbohydrate diets: nutritional and physiological aspects.
      • Gibson A.A.
      • Seimon R.V.
      • Lee C.M.
      • et al.
      Do ketogenic diets really suppress appetite? A systematic review and meta-analysis.
      • Paoli A.
      • Bosco G.
      • Camporesi E.M.
      • Mangar D.
      Ketosis, ketogenic diet and food intake control: a complex relationship.
      The degree to which ketosis contributes to appetite reduction, independent of other variables, such as the quantities of CHO and protein consumed and oxidized, is uncertain.
      • Gibson A.A.
      • Seimon R.V.
      • Lee C.M.
      • et al.
      Do ketogenic diets really suppress appetite? A systematic review and meta-analysis.
      Protein appears to provide greater satiety than CHO.
      • Feinman R.D.
      • Pogozelski W.K.
      • Astrup A.
      • et al.
      Dietary carbohydrate restriction as the first approach in diabetes management: critical review and evidence base.
      • Adam-Perrot A.
      • Clifton P.
      • Brouns F.
      Low-carbohydrate diets: nutritional and physiological aspects.
      • Gibson A.A.
      • Seimon R.V.
      • Lee C.M.
      • et al.
      Do ketogenic diets really suppress appetite? A systematic review and meta-analysis.
      • Westman E.C.
      • Feinman R.D.
      • Mavropoulos J.C.
      • et al.
      Low-carbohydrate nutrition and metabolism.
      • Rains T.M.
      • Leidy H.J.
      • Sanoshy K.D.
      • Lawless A.L.
      • Maki K.C.
      A randomized, controlled, crossover trial to assess the acute appetitive and metabolic effects of sausage and egg-based convenience breakfast meals in overweight premenopausal women.
      However, well-controlled studies that matched protein intake found that a ketogenic, high-protein diet suppressed appetite more than a high-protein diet that was not ketogenic, suggesting that circulating ketone levels have an impact, independent of protein intake.
      • Gibson A.A.
      • Seimon R.V.
      • Lee C.M.
      • et al.
      Do ketogenic diets really suppress appetite? A systematic review and meta-analysis.
      Longer-term, well-controlled studies are needed to assess the degree to which appetite suppression occurs with CHO restriction above the threshold for ketosis, which would allow a higher intake of nutrient-dense CHO foods (eg, vegetables, fruits, whole grains, and legumes) that reflect evidence-based cardioprotective dietary patterns.
      • Gibson A.A.
      • Seimon R.V.
      • Lee C.M.
      • et al.
      Do ketogenic diets really suppress appetite? A systematic review and meta-analysis.
      Low-CHO diets may reduce hunger by influencing circulating levels of hormones that impact hunger and appetite control, including ghrelin, leptin, and cholecystokinin, but study results have been inconsistent.
      • Sumithran P.
      • Prendergast L.A.
      • Delbridge E.
      • et al.
      Ketosis and appetite-mediating nutrients and hormones after weight loss.
      • Gibson A.A.
      • Seimon R.V.
      • Lee C.M.
      • et al.
      Do ketogenic diets really suppress appetite? A systematic review and meta-analysis.
      • Paoli A.
      • Bosco G.
      • Camporesi E.M.
      • Mangar D.
      Ketosis, ketogenic diet and food intake control: a complex relationship.
      • Ebbeling C.B.
      • Feldman H.A.
      • Klein G.L.
      • et al.
      Effects of a low carbohydrate diet on energy expenditure during weight loss maintenance: randomized trial.
      • Johnstone A.M.
      • Horgan G.W.
      • Murison S.D.
      • Bremner D.M.
      • Lobley G.E.
      Effects of a high-protein ketogenic diet on hunger, appetite, and weight loss in obese men feeding ad libitum.
      • Hu T.
      • Yao L.
      • Reynolds K.
      • et al.
      The effects of a low-carbohydrate diet on appetite: A randomized controlled trial.
      Ghrelin and cholecystokinin levels were mildly decreased during ketosis in participants following a low-CHO, VLCalD/KD,
      • Sumithran P.
      • Prendergast L.A.
      • Delbridge E.
      • et al.
      Ketosis and appetite-mediating nutrients and hormones after weight loss.
      whereas ghrelin and leptin were significantly lower in participants assigned to a low-CHO (but non-ketogenic) weight maintenance diet (20% TDE CHO) compared with participants following a moderate-CHO (40% TDE) or high-CHO (60% TDE) weight maintenance diet.
      • Ebbeling C.B.
      • Feldman H.A.
      • Klein G.L.
      • et al.
      Effects of a low carbohydrate diet on energy expenditure during weight loss maintenance: randomized trial.
      Hu et al.
      • Hu T.
      • Yao L.
      • Reynolds K.
      • et al.
      The effects of a low-carbohydrate diet on appetite: A randomized controlled trial.
      found no difference in change in ghrelin levels or self-reported change in appetite between the participants consuming a very-low-CHO diet (<40 g/d) or a low-fat (<30% TDE), high-CHO (∼55% TDE) diet over 12 months. These results illustrate the many potential factors that influence EE and appetite during weight loss with low-CHO diets and very-low-CHO/KDs.
      Other possible effects of low-CHO and very-low-CHO diets on energy balance and body weight are: 1) diuretic effects of ketosis
      • Frigolet M.E.
      • Ramos Barragán V.E.
      • Tamez González M.
      Low-carbohydrate diets: a matter of love or hate.
      • Husain A.M.
      • Yancy Jr., W.S.
      • Carwile S.T.
      • et al.
      Diet therapy for narcolepsy.
      and reduced insulin concentration
      • Brands M.W.
      Role of insulin-mediated antinatriuresis in sodium homeostasis and hypertension.
      ; 2) increased adipose tissue lipolysis
      • Paoli A.
      Ketogenic diet for obesity-friend or foe.
      • Frigolet M.E.
      • Ramos Barragán V.E.
      • Tamez González M.
      Low-carbohydrate diets: a matter of love or hate.
      • Cahill Jr., G.F.
      Fuel metabolism in starvation.
      • Kather H.
      • Wieland E.
      • Scheurer A.
      • Vogel G.
      • Wildenberg U.
      • Joost C.
      Influences of variation in total energy intake and dietary composition on regulation of fat cell lipolysis in ideal-weight subjects.
      ; 3) reduction in resting respiratory quotient, reflecting a higher proportion of fat being oxidized for energy
      • Paoli A.
      Ketogenic diet for obesity-friend or foe.
      • Paoli A.
      • Cenci L.
      • Fancelli M.
      • et al.
      Ketogenic diet and phytoextracts comparison of the efficacy of Mediterranean, Zone and Tisanoreica diet on some health risk factors.
      • Paoli A.
      • Grimaldi K.
      • Bianco A.
      • Lodi A.
      • Cenci L.
      • Parmagnani A.
      Medium term effects of a ketogenic diet and a mediterranean diet on resting energy expenditure and respiratory ratio.
      • Tagliabue A.
      • Bertoli S.
      • Trentani C.
      • Borrelli P.
      • Veggiotti P.
      Effects of the ketogenic diet on nutritional status, resting energy expenditure, and substrate oxidation in patients with medically refractory epilepsy: a 6-month prospective observational study.
      ; and 4) increased metabolic costs of gluconeogenesis and the thermic effect of protein.
      • Paoli A.
      Ketogenic diet for obesity-friend or foe.
      • Blackburn G.L.
      • Bistrian B.R.
      • Flatt J.P.
      Role of a protein-sparing fast in a comprehensive weight reduction program.
      • Frigolet M.E.
      • Ramos Barragán V.E.
      • Tamez González M.
      Low-carbohydrate diets: a matter of love or hate.
      • Fine E.J.
      • Feinman R.D.
      Thermodynamics of weight loss diets.

      Key points

      • Low-CHO diets and very-low-CHO/KDs appear to increase EE. The mechanisms contributing to this effect are incompletely understood.
      • Changes in catecholamines and thyroid hormone levels may influence the EE of individuals following low-CHO diets and very-low-CHO/KDs.
      • Individuals following low-CHO diets and very-low-CHO/KDs in RCTs reported reduced appetite and hunger. The mechanisms that contribute to this are not clear but may include changes in gastrointestinal hormones.

      Evidence for the effect of low-CHO and very-low-CHO diets on weight loss

      Weight loss in adults with overweight or obesity

      Despite favorable effects of low-CHO and very-low-CHO diets on EE and intake, long-term effects on weight loss may not be superior to more conventional strategies. According to the 2013 American Heart Association/American Cardiology/The Obesity Society (AHA/ACC/TOS) Guideline for the Management of Overweight and Obesity in Adults,
      • Jensen M.D.
      • Ryan D.H.
      • Apovian C.M.
      • et al.
      2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society.
      research has not demonstrated any advantage of a very-low-CHO diet on weight loss at 6 months compared with a calorie-restricted, low-fat diet. More recently, several systematic reviews and meta-analyses of RCTs have examined the effectiveness of low-CHO, high-fat (LCHF) (>30% TDE fat) vs high-CHO, low-fat (HCLF) diets (<30% TDE fat) for weight loss in individuals with overweight or obesity at 3 to 6 months
      • Naude C.E.
      • Schoonees
      • Senekal M.
      • Young T.
      • Garner P.
      • Volmink J.
      Low carbohydrate versus isoenergetic balanced diets for reducing weight and cardiovascular risk: a systematic review and meta-analysis.
      or 1 to 2 years.
      • Naude C.E.
      • Schoonees
      • Senekal M.
      • Young T.
      • Garner P.
      • Volmink J.
      Low carbohydrate versus isoenergetic balanced diets for reducing weight and cardiovascular risk: a systematic review and meta-analysis.
      • Bueno N.B.
      • de Melo I.S.
      • de Oliveira S.L.
      • da Rocha Ataide T.
      Very-low-carbohydrate ketogenic diet v. low-fat diet for long-term weight loss: a meta-analysis of randomised controlled trials.
      • Schwingshackl L.
      • Hoffmann G.
      Comparison of effects of long-term low-fat vs high-fat diets on blood lipid levels in overweight or obese patients: a systematic review and meta-analysis.
      • Mansoor N.
      • Vinknes K.J.
      • Veierød M.B.
      • Retterstøl K.
      Effects of low-carbohydrate diets v. low-fat diets on body weight and cardiovascular risk factors: a meta-analysis of randomised controlled trials.
      Participants assigned to both LCHF and HCLF diets achieved clinically meaningful weight loss (Table 2, Fig. 1). However, weight loss was significantly greater with LCHF diets vs HCLF diets when the prescribed diets were hypocaloric,
      • Schwingshackl L.
      • Hoffmann G.
      Comparison of effects of long-term low-fat vs high-fat diets on blood lipid levels in overweight or obese patients: a systematic review and meta-analysis.
      when the prescribed ad libitum LCHF diets were hypocaloric (even though not required or encouraged),
      • Mansoor N.
      • Vinknes K.J.
      • Veierød M.B.
      • Retterstøl K.
      Effects of low-carbohydrate diets v. low-fat diets on body weight and cardiovascular risk factors: a meta-analysis of randomised controlled trials.
      and the study duration was less than 2 years.
      • Bueno N.B.
      • de Melo I.S.
      • de Oliveira S.L.
      • da Rocha Ataide T.
      Very-low-carbohydrate ketogenic diet v. low-fat diet for long-term weight loss: a meta-analysis of randomised controlled trials.
      Table 2Effect of low-CHO and very-low-CHO diets compared with HCLF diets on weight, lipids, HbA1c, and blood pressures at 1–2 years follow-up reported in meta-analyses
      Author# of RCTsWeight WMD (95% CI), kgLDL-C, WMD (95% CI), mg/dLHDL-C, WMD (95% CI), mg/dLTG, WMD (95% CI), mg/dLHbA1c WMD (95% CI), %SBP, WMD (95% CI), mm/HgDBP, WMD (95% CI), mm/Hg
      Meta-analyses of studies of adults with overweight and/or obesity
       Naude et al. 2014
      • Naude C.E.
      • Schoonees
      • Senekal M.
      • Young T.
      • Garner P.
      • Volmink J.
      Low carbohydrate versus isoenergetic balanced diets for reducing weight and cardiovascular risk: a systematic review and meta-analysis.
      14−0.48 (−1.44 to 0.49)2.71 (−0.39 to 6.19)1.55 (0.39 to 3.09)−5.31 (−12.4 to 2.66)NR−2.00 (−5.00 to 1.00)−0.03 (−1.68 to 1.62)
       Bueno et al. 2013
      • Bueno N.B.
      • de Melo I.S.
      • de Oliveira S.L.
      • da Rocha Ataide T.
      Very-low-carbohydrate ketogenic diet v. low-fat diet for long-term weight loss: a meta-analysis of randomised controlled trials.
      13−0.91 (−1.65 to −0.17)4.64 (1.55 to 7.73)3.48 (2.32 to 4.64)−15.9 (−23.9 to −7.09)−0.24 (−0.55 to 0.06)−1.47 (−3.44 to 0.50)−1.43 (−2.49 to −0.37)
       Schwingshackl & Hoffmann 2013
      • Schwingshackl L.
      • Hoffmann G.
      Comparison of effects of long-term low-fat vs high-fat diets on blood lipid levels in overweight or obese patients: a systematic review and meta-analysis.
      320.15 (−0.50 to 0.80); −0.59
      For hypocaloric diet comparisons only.
      (−1.04 to −0.15)
      3.11 (1.71 to 4.51)2.35 (1.29 to 3.42)−8.38 (−13.5 to −3.25)NRNRNR
       Mansoor et al. 2016
      • Mansoor N.
      • Vinknes K.J.
      • Veierød M.B.
      • Retterstøl K.
      Effects of low-carbohydrate diets v. low-fat diets on body weight and cardiovascular risk factors: a meta-analysis of randomised controlled trials.
      11−2.17 (−3.36 to −0.99)6.19 (0.12 to 12.8)5.41 (3.48 to 7.35)−23.0 (−32.8 to −13.3)NR−1.02 (−2.98 to 0.94)−1.01 (−2.75 to 0.74)
       Gjuladin-Hellon et al. 2019
      • Gjuladin-Hellon T.
      • Davies I.G.
      • Penson P.
      • Amiri Baghbadorani R.
      Effects of carbohydrate-restricted diets on low-density lipoprotein cholesterol levels in overweight and obese adults: a systematic review and meta-analysis.
      5
      In the Gjuladin-Hellon et al.61 meta-analysis, 8 RCTs were included in the full meta-analysis, but only 5 RCTs were included in the 12 mo + meta-analysis for LDL-C, HDL-C, and TG.
      NR1.55 (−1.55 to 4.64)3.48 (0.77 to 5.80)−9.74 (−15.9 to −2.66)NRNRNR
       Sackner-Bernstein et al. 2016
      • Sackner-Bernstein J.
      • Kanter D.
      • Kaul S.
      Dietary intervention for overweight and obese adults: comparison of low-carbohydrate and low-fat diets. A meta-analysis.
      17−2.04
      The decimal places reported reflect those reported in the published article.
      (−3.15, −0.93)
      8.6
      The decimal places reported reflect those reported in the published article.
      (3.6 to 13.7)
      5.1
      The decimal places reported reflect those reported in the published article.
      (3.5 to 6.7)
      −28.8
      The decimal places reported reflect those reported in the published article.
      (−39.1 to −18.5)
      NR−1.7
      The decimal places reported reflect those reported in the published article.
      (−3.5 to 0.2)
      NR
      Meta-analyses of studies of adults with overweight and/or obesity with pre-diabetes and/or type 2 diabetes
       Naude et al. 2014
      • Naude C.E.
      • Schoonees
      • Senekal M.
      • Young T.
      • Garner P.
      • Volmink J.
      Low carbohydrate versus isoenergetic balanced diets for reducing weight and cardiovascular risk: a systematic review and meta-analysis.
      50.91 (−2.08 to 3.89)3.87 (−2.32 to 10.44)0.00 (−3.48 to 3.09)−7.09 (−43.4 to 23.0)0.01 (−0.28 to 0.30)0.31 (−3.1 to 3.72)0.09 (−1.95 to 2.13)
       Schwingshackl & Hoffmann 2014
      • Schwingshackl L.
      • Hoffmann G.
      Comparison of the long-term effects of high-fat v. low-fat diet consumption on cardiometabolic risk factors in subjects with abnormal glucose metabolism: a systematic review and meta-analysis.
      14
      In the Schwingshackl & Hoffmann63 meta-analysis, the authors included RCTs of high-fat diets (>30% TDE total fat) of which 6 studies were classified as low-CHO and 4 were classified as moderate-CHO.
      −0.47 (−1.85 to 0.92)1.55 (−5.41 to 8.89)1.55 (0.00 to 3.09)−15.9 (−21.3 to −11.5)−0.17 (−0.39 to 0.06)−1.35 (0.35 to 2.35)−1.35 (−1.79 to −0.92)
       Meng et al. 2017
      • Meng Y.
      • Bai H.
      • Wang S.
      • Li Z.
      • Wang Q.
      • Chen L.
      Efficacy of low carbohydrate diet for type 2 diabetes mellitus management: A systematic review and meta-analysis of randomized controlled trials.
      9−0.24 (−2.18 to 1.70)1.55 (−3.09 to 6.19)2.71 (1.16 to 4.25)−29.2 (−39.9 to −18.6)−0.44 (−0.61 to −0.26)NRNR
       Snorgaard et al. 2017
      • Snorgaard O.
      • Poulsen G.M.
      • Andersen H.K.
      • Astrup A.
      Systematic review and meta-analysis of dietary carbohydrate restriction in patients with type 2 diabetes.
      100.20 (−0.97 to 1.36)−0.39 (−3.87 to 2.71)NRNR0.04 (−0.04 to 0.13)NRNR
       Huntriss et al. 2018
      • Huntriss R.
      • Campbell M.
      • Bedwell C.
      The interpretation and effect of a low-carbohydrate diet in the management of type 2 diabetes: a systematic review and meta-analysis of randomised controlled trials.
      5–7
      In the Huntriss et al.66 meta-analysis, 18 RCTs were included in the full meta-analysis, but only 7 RCTs were included in the 12 mo + meta-analysis for HDL-C, TG, HbA1c, SBP, and DBP, 6 RCTs were included for weight, and 5 RCTs were included for LDL-C.
      0.28 (−1.37 to 1.92)1.93 (−3.87 to 7.35)2.32 (1.55 to 3.48)−21.3 (−31.0 to −11.5)−0.28 (−0.53 to −0.02)−2.74 (−5.27 to −0.20)−0.99 (−2.24 to 0.25)
       Korsmo-Haugen et al. 2019
      • Korsmo-Haugen H.K.
      • Brurberg K.G.
      • Mann J.
      • Aas A.M.
      Carbohydrate quantity in the dietary management of type 2 diabetes: a systematic review and meta-analysis.
      7–10
      In the Korsmo-Haugen et al.67 meta-analysis, 23 RCTs were included in the full meta-analysis, but the number of RCTs varied in the 12 mo + meta-analyses, which is what is reported in Table 2: 7 RCTs were included for DBP, 8 RCTs were included for SBP, 9 RCTs were included for LDL-C and TG, and 10 were included for weight, HDL-C, and HbA1c.
      0.14 (−0.29 to 0.57)1.16 (−3.87 to 6.19)2.32 (−0.39 to 5.03)−8.86 (−20.4 to 2.66)0.00 (−0.10 to 0.09)−1.39 (−3.20 to 0.43)−0.55 (−2.17 to 1.06)
       Sainsbury et al. 2018
      • Sainsbury E.
      • Kizirian N.V.
      • Partridge S.R.
      • Gill T.
      • Colagiuri S.
      • Gibson A.A.
      Effect of dietary carbohydrate restriction on glycemic control in adults with diabetes: a systematic review and meta-analysis.
      25−0.43 (−0.93 to 0.07)NRNRNR−0.09 (−0.21 to 0.03)NRNR
       van Zuuren et al. 2018
      • van Zuuren E.J.
      • Fedorowicz Z.
      • Kuijpers T.
      • Pijl H.
      Effects of low-carbohydrate- compared with low-fat-diet interventions on metabolic control in people with type 2 diabetes: a systematic review including GRADE assessments.
      2–3
      In the van Zuuren et al.69 meta-analysis, 33 RCTs and 3 clinical control trials were included in the full meta-analysis, but the number of RCTs varied in the 12 mo + meta-analyses, which is what is reported in Table 2: 2 RCTs were included for weight, LDL-C, HDL-C, TG, SBP, and DBP, and 3 RCTs were included for HbA1c.
      −0.14 (−1.64 to 1.35)2.32 (−3.09 to 8.12)4.64 (2.71 to 6.57)−16.8 (−28.3 to −4.43)−0.02 (−0.37 to 0.41)1.60 (−1.50 to 4.70)0.88 (−1.25 to 3.02)
      HCLF, high-carbohydrate, low-fat; RCT, randomized control trials; WMD, weight mean difference; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; TG, triglycerides; HbA1c, hemoglobin A1c; SBP, systolic blood pressure; DBP, diastolic blood pressure; NR, not reported.
      If all values in the confidence interval are on the same side of zero (either all positive or all negative), the findings are significant.
      In this meta-analysis, 14 RCTs were included in the full meta-analysis, but the number of RCTs varied in the analyses involving only participants with T2D: 5 RCTs were included for SBP, 6 RCTs were included for DBP, 7 RCTs were included for LDL-C, 8 RCTs were included for weight, 9 RCTs were included for HDL-C, and 10 RCTs were included for TG and HbA1c.
      For hypocaloric diet comparisons only.
      In the Gjuladin-Hellon et al.
      • Gjuladin-Hellon T.
      • Davies I.G.
      • Penson P.
      • Amiri Baghbadorani R.
      Effects of carbohydrate-restricted diets on low-density lipoprotein cholesterol levels in overweight and obese adults: a systematic review and meta-analysis.
      meta-analysis, 8 RCTs were included in the full meta-analysis, but only 5 RCTs were included in the 12 mo + meta-analysis for LDL-C, HDL-C, and TG.
      The decimal places reported reflect those reported in the published article.
      § In the Schwingshackl & Hoffmann
      • Schwingshackl L.
      • Hoffmann G.
      Comparison of the long-term effects of high-fat v. low-fat diet consumption on cardiometabolic risk factors in subjects with abnormal glucose metabolism: a systematic review and meta-analysis.
      meta-analysis, the authors included RCTs of high-fat diets (>30% TDE total fat) of which 6 studies were classified as low-CHO and 4 were classified as moderate-CHO.
      In the Huntriss et al.
      • Huntriss R.
      • Campbell M.
      • Bedwell C.
      The interpretation and effect of a low-carbohydrate diet in the management of type 2 diabetes: a systematic review and meta-analysis of randomised controlled trials.
      meta-analysis, 18 RCTs were included in the full meta-analysis, but only 7 RCTs were included in the 12 mo + meta-analysis for HDL-C, TG, HbA1c, SBP, and DBP, 6 RCTs were included for weight, and 5 RCTs were included for LDL-C.
      In the Korsmo-Haugen et al.
      • Korsmo-Haugen H.K.
      • Brurberg K.G.
      • Mann J.
      • Aas A.M.
      Carbohydrate quantity in the dietary management of type 2 diabetes: a systematic review and meta-analysis.
      meta-analysis, 23 RCTs were included in the full meta-analysis, but the number of RCTs varied in the 12 mo + meta-analyses, which is what is reported in Table 2: 7 RCTs were included for DBP, 8 RCTs were included for SBP, 9 RCTs were included for LDL-C and TG, and 10 were included for weight, HDL-C, and HbA1c.
      ∗∗ In the van Zuuren et al.
      • van Zuuren E.J.
      • Fedorowicz Z.
      • Kuijpers T.
      • Pijl H.
      Effects of low-carbohydrate- compared with low-fat-diet interventions on metabolic control in people with type 2 diabetes: a systematic review including GRADE assessments.
      meta-analysis, 33 RCTs and 3 clinical control trials were included in the full meta-analysis, but the number of RCTs varied in the 12 mo + meta-analyses, which is what is reported in Table 2: 2 RCTs were included for weight, LDL-C, HDL-C, TG, SBP, and DBP, and 3 RCTs were included for HbA1c.
      Table 32015 ACC/AHA clinical practice guideline recommendation classification system
      • Kolanowski J.
      • Bodson A.
      • Desmecht P.
      • Bemelmans S.
      • Stein F.
      • Crabbe J.
      On the relationship between ketonuria and natriuresis during fasting and upon refeeding in obese patients.
      Modified from the 2015 ACC/AHA Clinical Practice Guideline Recommendation Classification System
      Figure thumbnail gr1
      Figure 1Effects of low-CHO and very-low-CHO diets vs high-CHO, low-fat diets on cardiometabolic risk markers at 1–2 years follow-up.
      • Naude C.E.
      • Schoonees
      • Senekal M.
      • Young T.
      • Garner P.
      • Volmink J.
      Low carbohydrate versus isoenergetic balanced diets for reducing weight and cardiovascular risk: a systematic review and meta-analysis.
      • Bueno N.B.
      • de Melo I.S.
      • de Oliveira S.L.
      • da Rocha Ataide T.
      Very-low-carbohydrate ketogenic diet v. low-fat diet for long-term weight loss: a meta-analysis of randomised controlled trials.
      • Schwingshackl L.
      • Hoffmann G.
      Comparison of effects of long-term low-fat vs high-fat diets on blood lipid levels in overweight or obese patients: a systematic review and meta-analysis.
      • Mansoor N.
      • Vinknes K.J.
      • Veierød M.B.
      • Retterstøl K.
      Effects of low-carbohydrate diets v. low-fat diets on body weight and cardiovascular risk factors: a meta-analysis of randomised controlled trials.
      • Gjuladin-Hellon T.
      • Davies I.G.
      • Penson P.
      • Amiri Baghbadorani R.
      Effects of carbohydrate-restricted diets on low-density lipoprotein cholesterol levels in overweight and obese adults: a systematic review and meta-analysis.
      • Sackner-Bernstein J.
      • Kanter D.
      • Kaul S.
      Dietary intervention for overweight and obese adults: comparison of low-carbohydrate and low-fat diets. A meta-analysis.
      • Schwingshackl L.
      • Hoffmann G.
      Comparison of the long-term effects of high-fat v. low-fat diet consumption on cardiometabolic risk factors in subjects with abnormal glucose metabolism: a systematic review and meta-analysis.
      • Meng Y.
      • Bai H.
      • Wang S.
      • Li Z.
      • Wang Q.
      • Chen L.
      Efficacy of low carbohydrate diet for type 2 diabetes mellitus management: A systematic review and meta-analysis of randomized controlled trials.
      • Snorgaard O.
      • Poulsen G.M.
      • Andersen H.K.
      • Astrup A.
      Systematic review and meta-analysis of dietary carbohydrate restriction in patients with type 2 diabetes.
      • Huntriss R.
      • Campbell M.
      • Bedwell C.
      The interpretation and effect of a low-carbohydrate diet in the management of type 2 diabetes: a systematic review and meta-analysis of randomised controlled trials.
      • Korsmo-Haugen H.K.
      • Brurberg K.G.
      • Mann J.
      • Aas A.M.
      Carbohydrate quantity in the dietary management of type 2 diabetes: a systematic review and meta-analysis.
      • Sainsbury E.
      • Kizirian N.V.
      • Partridge S.R.
      • Gill T.
      • Colagiuri S.
      • Gibson A.A.
      Effect of dietary carbohydrate restriction on glycemic control in adults with diabetes: a systematic review and meta-analysis.
      • van Zuuren E.J.
      • Fedorowicz Z.
      • Kuijpers T.
      • Pijl H.
      Effects of low-carbohydrate- compared with low-fat-diet interventions on metabolic control in people with type 2 diabetes: a systematic review including GRADE assessments.
      LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; T2D, type II diabetes; TG, triglycerides; HbA1c, hemoglobin A1c; SBP, systolic blood pressure; DBP, diastolic blood pressure. *No significant difference between diet groups. **Mixed results on significant difference between diet groups—some meta-analyses found a significant difference between diet groups, while others did not. ***Significant difference between diet groups.
      Results for patients with prediabetes
      • Schwingshackl L.
      • Hoffmann G.
      Comparison of the long-term effects of high-fat v. low-fat diet consumption on cardiometabolic risk factors in subjects with abnormal glucose metabolism: a systematic review and meta-analysis.
      and T2D
      • Naude C.E.
      • Schoonees
      • Senekal M.
      • Young T.
      • Garner P.
      • Volmink J.
      Low carbohydrate versus isoenergetic balanced diets for reducing weight and cardiovascular risk: a systematic review and meta-analysis.
      • Meng Y.
      • Bai H.
      • Wang S.
      • Li Z.
      • Wang Q.
      • Chen L.
      Efficacy of low carbohydrate diet for type 2 diabetes mellitus management: A systematic review and meta-analysis of randomized controlled trials.
      • Snorgaard O.
      • Poulsen G.M.
      • Andersen H.K.
      • Astrup A.
      Systematic review and meta-analysis of dietary carbohydrate restriction in patients with type 2 diabetes.
      • Huntriss R.
      • Campbell M.
      • Bedwell C.
      The interpretation and effect of a low-carbohydrate diet in the management of type 2 diabetes: a systematic review and meta-analysis of randomised controlled trials.
      • Korsmo-Haugen H.K.
      • Brurberg K.G.
      • Mann J.
      • Aas A.M.
      Carbohydrate quantity in the dietary management of type 2 diabetes: a systematic review and meta-analysis.
      were similar, with no significant difference for weight loss between the low-CHO and HCLF diet groups in long-term studies (Table 2, Fig. 1). Sainsbury et al.
      • Sainsbury E.
      • Kizirian N.V.
      • Partridge S.R.
      • Gill T.
      • Colagiuri S.
      • Gibson A.A.
      Effect of dietary carbohydrate restriction on glycemic control in adults with diabetes: a systematic review and meta-analysis.
      found a significant decrease in weight with low-CHO vs HCLF diets at 3 months (weighted mean difference [WMD] −1.08 kg, 95% CI: −1.93, −0.23, n = 12 studies), but no difference at >6 months (WMD −0.14 kg, 95% CI: −0.94, 0.65, n = 9 studies). van Zuuren et al.
      • van Zuuren E.J.
      • Fedorowicz Z.
      • Kuijpers T.
      • Pijl H.
      Effects of low-carbohydrate- compared with low-fat-diet interventions on metabolic control in people with type 2 diabetes: a systematic review including GRADE assessments.
      reported a significantly greater weight loss at 8–16 weeks (WMD −2.04 kg, 95% CI: −3.23, −0.85; P = .0008; n = 4 studies) with low-CHO vs HCLF diets, but no difference at any other time. In addition, Snorgaard et al.
      • Snorgaard O.
      • Poulsen G.M.
      • Andersen H.K.
      • Astrup A.
      Systematic review and meta-analysis of dietary carbohydrate restriction in patients with type 2 diabetes.
      reported no difference in BMI and waist circumference in their meta-analysis.

      Points to consider regarding the effects of low-CHO and very-low-CHO diets on weight loss

      The results from the meta-analyses discussed previously support the view that low- and very-low-CHO diets are not superior for weight loss compared with diets with a higher quantity of CHO and are difficult to maintain in clinical trials of adults with overweight and obesity, with or without prediabetes or diabetes.
      • Naude C.E.
      • Schoonees
      • Senekal M.
      • Young T.
      • Garner P.
      • Volmink J.
      Low carbohydrate versus isoenergetic balanced diets for reducing weight and cardiovascular risk: a systematic review and meta-analysis.
      • Bueno N.B.
      • de Melo I.S.
      • de Oliveira S.L.
      • da Rocha Ataide T.
      Very-low-carbohydrate ketogenic diet v. low-fat diet for long-term weight loss: a meta-analysis of randomised controlled trials.
      • Schwingshackl L.
      • Hoffmann G.
      Comparison of effects of long-term low-fat vs high-fat diets on blood lipid levels in overweight or obese patients: a systematic review and meta-analysis.
      • Mansoor N.
      • Vinknes K.J.
      • Veierød M.B.
      • Retterstøl K.
      Effects of low-carbohydrate diets v. low-fat diets on body weight and cardiovascular risk factors: a meta-analysis of randomised controlled trials.
      • Schwingshackl L.
      • Hoffmann G.
      Comparison of the long-term effects of high-fat v. low-fat diet consumption on cardiometabolic risk factors in subjects with abnormal glucose metabolism: a systematic review and meta-analysis.
      • Snorgaard O.
      • Poulsen G.M.
      • Andersen H.K.
      • Astrup A.
      Systematic review and meta-analysis of dietary carbohydrate restriction in patients with type 2 diabetes.
      • Huntriss R.
      • Campbell M.
      • Bedwell C.
      The interpretation and effect of a low-carbohydrate diet in the management of type 2 diabetes: a systematic review and meta-analysis of randomised controlled trials.
      • Korsmo-Haugen H.K.
      • Brurberg K.G.
      • Mann J.
      • Aas A.M.
      Carbohydrate quantity in the dietary management of type 2 diabetes: a systematic review and meta-analysis.
      • Sainsbury E.
      • Kizirian N.V.
      • Partridge S.R.
      • Gill T.
      • Colagiuri S.
      • Gibson A.A.
      Effect of dietary carbohydrate restriction on glycemic control in adults with diabetes: a systematic review and meta-analysis.
      • van Zuuren E.J.
      • Fedorowicz Z.
      • Kuijpers T.
      • Pijl H.
      Effects of low-carbohydrate- compared with low-fat-diet interventions on metabolic control in people with type 2 diabetes: a systematic review including GRADE assessments.
      In the studies included in the meta-analyses, mean CHO intake in the low- and very-low-CHO diet groups at the end of follow-up exceeded 50 g/d in all except one study.
      • Brinkworth G.D.
      • Noakes M.
      • Buckley J.D.
      • Keogh J.B.
      • Clifton P.M.
      Long-term effects of a very-low-carbohydrate weight loss diet compared with an isocaloric low-fat diet after 12 mo.
      Mean CHO intake in the remaining studies was between 33–47% TDE by study end.
      • Bueno N.B.
      • de Melo I.S.
      • de Oliveira S.L.
      • da Rocha Ataide T.
      Very-low-carbohydrate ketogenic diet v. low-fat diet for long-term weight loss: a meta-analysis of randomised controlled trials.
      • Schwingshackl L.
      • Hoffmann G.
      Comparison of effects of long-term low-fat vs high-fat diets on blood lipid levels in overweight or obese patients: a systematic review and meta-analysis.
      • Mansoor N.
      • Vinknes K.J.
      • Veierød M.B.
      • Retterstøl K.
      Effects of low-carbohydrate diets v. low-fat diets on body weight and cardiovascular risk factors: a meta-analysis of randomised controlled trials.
      Attrition was ∼30% for both the LCHF and HCLF diet groups in some studies.
      • Mansoor N.
      • Vinknes K.J.
      • Veierød M.B.
      • Retterstøl K.
      Effects of low-carbohydrate diets v. low-fat diets on body weight and cardiovascular risk factors: a meta-analysis of randomised controlled trials.
      Gardner et al.
      • Gardner C.D.
      • Trepanowski J.F.
      • Del Gobbo L.C.
      • et al.
      Effect of low-fat vs low-carbohydrate diet on 12-month weight loss in overweight adults and the association with genotype pattern or insulin secretion: The DIETFITS Randomized Clinical Trial.
      found that when individuals are educated to consume foods with high dietary quality for both low-fat and low-CHO diets, weight loss was similar in both groups. Sacks et al.
      • Sacks F.M.
      • Bray G.A.
      • Carey V.J.
      • et al.
      Comparison of weight-loss diets with different compositions of fat, protein, and carbohydrates.
      found that satisfaction was similar among study completers assigned to four different hypocaloric diets (n = 645): low-fat, average-protein; low-fat, high-protein; high-fat, average-protein; and high-fat, high-protein. However, there was substantial variation in weight loss achieved with each of the diet conditions with some individuals in each showing well-above-average weight loss, suggesting that personal preference in the selection of a weight loss diet is important and should be considered.

      Key points

      Tabled 1
      Key recommendations for weight loss in adults with overweight or obesity
      The NLA grading system adopted the methodology and classification system used in the 2015 ACC/AHA Clinical Practice Guideline Recommendation Classification System73 (Table 3). All recommendations were graded by the Class of the Recommendation (COR) and by the Levels of the Evidence (LOE) supporting the Recommendation.
      CORLOE
      Because a specific distribution of CHO, protein, and fat has not been shown to be superior for weight loss, it is reasonable to counsel patients on achieving a calorie reduction by limiting the intake of multiple energy sources (ie, CHO, fat) vs limiting calories from a single energy source (ie, CHO).
      • Jensen M.D.
      • Ryan D.H.
      • Apovian C.M.
      • et al.
      2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society.
      • Naude C.E.
      • Schoonees
      • Senekal M.
      • Young T.
      • Garner P.
      • Volmink J.
      Low carbohydrate versus isoenergetic balanced diets for reducing weight and cardiovascular risk: a systematic review and meta-analysis.
      • Bueno N.B.
      • de Melo I.S.
      • de Oliveira S.L.
      • da Rocha Ataide T.
      Very-low-carbohydrate ketogenic diet v. low-fat diet for long-term weight loss: a meta-analysis of randomised controlled trials.
      • Schwingshackl L.
      • Hoffmann G.
      Comparison of effects of long-term low-fat vs high-fat diets on blood lipid levels in overweight or obese patients: a systematic review and meta-analysis.
      • Mansoor N.
      • Vinknes K.J.
      • Veierød M.B.
      • Retterstøl K.
      Effects of low-carbohydrate diets v. low-fat diets on body weight and cardiovascular risk factors: a meta-analysis of randomised controlled trials.
      • Schwingshackl L.
      • Hoffmann G.
      Comparison of the long-term effects of high-fat v. low-fat diet consumption on cardiometabolic risk factors in subjects with abnormal glucose metabolism: a systematic review and meta-analysis.
      • Meng Y.
      • Bai H.
      • Wang S.
      • Li Z.
      • Wang Q.
      • Chen L.
      Efficacy of low carbohydrate diet for type 2 diabetes mellitus management: A systematic review and meta-analysis of randomized controlled trials.
      • Snorgaard O.
      • Poulsen G.M.
      • Andersen H.K.
      • Astrup A.
      Systematic review and meta-analysis of dietary carbohydrate restriction in patients with type 2 diabetes.
      • Huntriss R.
      • Campbell M.
      • Bedwell C.
      The interpretation and effect of a low-carbohydrate diet in the management of type 2 diabetes: a systematic review and meta-analysis of randomised controlled trials.
      • Korsmo-Haugen H.K.
      • Brurberg K.G.
      • Mann J.
      • Aas A.M.
      Carbohydrate quantity in the dietary management of type 2 diabetes: a systematic review and meta-analysis.
      • Sainsbury E.
      • Kizirian N.V.
      • Partridge S.R.
      • Gill T.
      • Colagiuri S.
      • Gibson A.A.
      Effect of dietary carbohydrate restriction on glycemic control in adults with diabetes: a systematic review and meta-analysis.
      • van Zuuren E.J.
      • Fedorowicz Z.
      • Kuijpers T.
      • Pijl H.
      Effects of low-carbohydrate- compared with low-fat-diet interventions on metabolic control in people with type 2 diabetes: a systematic review including GRADE assessments.
      • Gardner C.D.
      • Trepanowski J.F.
      • Del Gobbo L.C.
      • et al.
      Effect of low-fat vs low-carbohydrate diet on 12-month weight loss in overweight adults and the association with genotype pattern or insulin secretion: The DIETFITS Randomized Clinical Trial.
      • Sacks F.M.
      • Bray G.A.
      • Carey V.J.
      • et al.
      Comparison of weight-loss diets with different compositions of fat, protein, and carbohydrates.
      IIaB-R
      A low-CHO diet (50–130 g CHO/d) or very-low-CHO/KD (∼20–49 g CHO/d) is a reasonable option for some patients for a limited period of time (2–6 months) to induce weight loss.
      • Naude C.E.
      • Schoonees
      • Senekal M.
      • Young T.
      • Garner P.
      • Volmink J.
      Low carbohydrate versus isoenergetic balanced diets for reducing weight and cardiovascular risk: a systematic review and meta-analysis.
      • Sainsbury E.
      • Kizirian N.V.
      • Partridge S.R.
      • Gill T.
      • Colagiuri S.
      • Gibson A.A.
      Effect of dietary carbohydrate restriction on glycemic control in adults with diabetes: a systematic review and meta-analysis.
      • van Zuuren E.J.
      • Fedorowicz Z.
      • Kuijpers T.
      • Pijl H.
      Effects of low-carbohydrate- compared with low-fat-diet interventions on metabolic control in people with type 2 diabetes: a systematic review including GRADE assessments.
      IIaB-R
      Because low-CHO diets or very-low-CHO/KDs are difficult to maintain long-term, a more moderate CHO intake (>130–225 g/d) is reasonable for longer-term (>6 months) weight loss and maintenance.
      • Naude C.E.
      • Schoonees
      • Senekal M.
      • Young T.
      • Garner P.
      • Volmink J.
      Low carbohydrate versus isoenergetic balanced diets for reducing weight and cardiovascular risk: a systematic review and meta-analysis.
      • Bueno N.B.
      • de Melo I.S.
      • de Oliveira S.L.
      • da Rocha Ataide T.
      Very-low-carbohydrate ketogenic diet v. low-fat diet for long-term weight loss: a meta-analysis of randomised controlled trials.
      • Schwingshackl L.
      • Hoffmann G.
      Comparison of effects of long-term low-fat vs high-fat diets on blood lipid levels in overweight or obese patients: a systematic review and meta-analysis.
      • Mansoor N.
      • Vinknes K.J.
      • Veierød M.B.
      • Retterstøl K.
      Effects of low-carbohydrate diets v. low-fat diets on body weight and cardiovascular risk factors: a meta-analysis of randomised controlled trials.
      • Schwingshackl L.
      • Hoffmann G.
      Comparison of the long-term effects of high-fat v. low-fat diet consumption on cardiometabolic risk factors in subjects with abnormal glucose metabolism: a systematic review and meta-analysis.
      • Snorgaard O.
      • Poulsen G.M.
      • Andersen H.K.
      • Astrup A.
      Systematic review and meta-analysis of dietary carbohydrate restriction in patients with type 2 diabetes.
      • Huntriss R.
      • Campbell M.
      • Bedwell C.
      The interpretation and effect of a low-carbohydrate diet in the management of type 2 diabetes: a systematic review and meta-analysis of randomised controlled trials.
      • Korsmo-Haugen H.K.
      • Brurberg K.G.
      • Mann J.
      • Aas A.M.
      Carbohydrate quantity in the dietary management of type 2 diabetes: a systematic review and meta-analysis.
      • Sainsbury E.
      • Kizirian N.V.
      • Partridge S.R.
      • Gill T.
      • Colagiuri S.
      • Gibson A.A.
      Effect of dietary carbohydrate restriction on glycemic control in adults with diabetes: a systematic review and meta-analysis.
      • van Zuuren E.J.
      • Fedorowicz Z.
      • Kuijpers T.
      • Pijl H.
      Effects of low-carbohydrate- compared with low-fat-diet interventions on metabolic control in people with type 2 diabetes: a systematic review including GRADE assessments.
      IIaB-R
      The NLA grading system adopted the methodology and classification system used in the 2015 ACC/AHA Clinical Practice Guideline Recommendation Classification System
      • Halperin J.L.
      • Levine G.N.
      • Al-Khatib S.M.
      • et al.
      Further evolution of the ACC/AHA clinical practice guideline recommendation classification system: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
      (Table 3). All recommendations were graded by the Class of the Recommendation (COR) and by the Levels of the Evidence (LOE) supporting the Recommendation.

      Evidence for the effect of low-CHO and very-low-CHO diets, including ketogenic diets, on body composition changes

      Body water loss

      The initial weight loss that occurs with low-CHO diets and very-low-CHO/KDs is largely attributable to the loss of body water, not fat loss.
      • Adam-Perrot A.
      • Clifton P.
      • Brouns F.
      Low-carbohydrate diets: nutritional and physiological aspects.
      This body water loss occurs due to at least two major mechanisms, ketonuria-induced natriuresis and glycogen-depletion, although other mechanisms may also play some role.
      • Frigolet M.E.
      • Ramos Barragán V.E.
      • Tamez González M.
      Low-carbohydrate diets: a matter of love or hate.
      • Kolanowski J.
      • Bodson A.
      • Desmecht P.
      • Bemelmans S.
      • Stein F.
      • Crabbe J.
      On the relationship between ketonuria and natriuresis during fasting and upon refeeding in obese patients.
      • Gomez-Arbelaez D.
      • Bellido D.
      • Castro A.I.
      • et al.
      Body composition changes after very-low-calorie ketogenic diet in obesity evaluated by 3 standardized methods.
      Renal losses of sodium and water are also promoted by lower average insulin levels during low-CHO diets, because insulin promotes renal reabsorption of sodium.
      • Kolanowski J.
      Influence of glucose, insulin, and glucagon on sodium balance in fasting obese subjects.
      Glycogen depletion to maintain blood glucose levels results in a loss of body water (3 grams of water per 1 gram stored glycogen).
      • Brouns F.
      Overweight and diabetes prevention: is a low-carbohydrate-high-fat diet recommendable?.
      • Adam-Perrot A.
      • Clifton P.
      • Brouns F.
      Low-carbohydrate diets: nutritional and physiological aspects.
      • Frigolet M.E.
      • Ramos Barragán V.E.
      • Tamez González M.
      Low-carbohydrate diets: a matter of love or hate.
      • Husain A.M.
      • Yancy Jr., W.S.
      • Carwile S.T.
      • et al.
      Diet therapy for narcolepsy.
      • Gomez-Arbelaez D.
      • Bellido D.
      • Castro A.I.
      • et al.
      Body composition changes after very-low-calorie ketogenic diet in obesity evaluated by 3 standardized methods.
      Gomez-Arbelaez et al.
      • Gomez-Arbelaez D.
      • Bellido D.
      • Castro A.I.
      • et al.
      Body composition changes after very-low-calorie ketogenic diet in obesity evaluated by 3 standardized methods.
      found that the peak amount of water loss (as measured by multifrequency-bioelectrical impedance) coincided with the phase of maximum ketosis in study participants and, as ketosis decreased, body water was recovered.

      Lean body mass or fat-free mass and body fat mass

      A concern with any weight loss intervention is the potential to decrease LBM while decreasing fat mass as individuals lose weight.
      • Paoli A.
      Ketogenic diet for obesity-friend or foe.
      VLCalDs and protein-sparing–modified fast interventions were intended to promote rapid weight loss while preserving LBM.
      • Tsai A.G.
      • Wadden T.A.
      The evolution of very-low-calorie diets: an update and meta-analysis.
      Results from RCTs suggest that a higher protein intake has a protective effect for preserving LBM during weight loss. Adam-Perrot et al.
      • Adam-Perrot A.
      • Clifton P.
      • Brouns F.
      Low-carbohydrate diets: nutritional and physiological aspects.
      reviewed studies that demonstrated when participants consumed a LCHF diet vs a hypocaloric low-fat diet, they achieved equivalent or higher fat mass loss, but also a higher loss of LBM, unless accompanied by higher protein intake. A hypocaloric high-protein, low-fat diet vs an isocaloric HCLF diet resulted in less LBM loss, suggesting a high-protein diet was more effective at preserving LBM.
      • Adam-Perrot A.
      • Clifton P.
      • Brouns F.
      Low-carbohydrate diets: nutritional and physiological aspects.
      • Layman D.K.
      • Boileau R.A.
      • Erickson D.J.
      • et al.
      A reduced ratio of dietary carbohydrate to protein improves body composition and blood lipid profiles during weight loss in adult women.
      Krieger et al.
      • Krieger J.W.
      • Sitren H.S.
      • Daniels M.J.
      • Langkamp-Henken B.
      Effects of variation in protein and carbohydrate intake on body mass and composition during energy restriction: a meta-regression 1.
      conducted a meta-regression analysis of RCTs (n = 87) to examine the effects of varying amounts of protein and CHO intake on body composition during energy restriction (minimum of 1000 kcal/d). After controlling for energy intake, diets with <41.4% TDE from CHO (mean intake 79–97 g/d) were associated with 6.56 kg more body mass loss, 1.74 kg more fat-free mass (FFM) loss, and 5.57 kg more fat mass loss at >12 weeks. When protein intake was >1.05 g/kg/d, there was 1.21 kg more FFM retained compared with protein intake ≤1.05 g/kg/d at >12 weeks.
      • Krieger J.W.
      • Sitren H.S.
      • Daniels M.J.
      • Langkamp-Henken B.
      Effects of variation in protein and carbohydrate intake on body mass and composition during energy restriction: a meta-regression 1.
      Thus, low-CHO diets that have a higher protein content from partially replacing CHO with protein rather than fat alone appear to promote fat mass loss and result in a lower percentage of LBM lost.
      • Willoughby D.
      • Hewlings S.
      • Kalman D.
      Body composition changes in weight loss: strategies and supplementation for maintaining lean body mass, a brief review.
      Other RCTs with small sample sizes found a greater loss of FFM with very-low-CHO/KDs compared with moderate-CHO (35% TDE; 30% TDE protein)
      • Johnstone A.M.
      • Horgan G.W.
      • Murison S.D.
      • Bremner D.M.
      • Lobley G.E.
      Effects of a high-protein ketogenic diet on hunger, appetite, and weight loss in obese men feeding ad libitum.
      or high-CHO (50% TDE; 15% TDE protein)
      • Hall K.D.
      • Chen K.Y.
      • Guo J.
      • et al.
      Energy expenditure and body composition changes after an isocaloric ketogenic diet in overweight and obese men.
      diets.

      Key points

      Tabled 1
      Key recommendation for body weight and composition
      The NLA grading system adopted the methodology and classification system used in the 2015 ACC/AHA Clinical Practice Guideline Recommendation Classification System73 (Table 3). All recommendations were graded by the Class of the Recommendation (COR) and by the Levels of the Evidence (LOE) supporting the Recommendation.
      CORLOE
      In patients choosing to lose weight using a CHO-restricted diet, it is reasonable to recommend a higher protein intake (1.0–1.5 g/kg/d) to preserve LBM during weight loss.
      • Layman D.K.
      • Boileau R.A.
      • Erickson D.J.
      • et al.
      A reduced ratio of dietary carbohydrate to protein improves body composition and blood lipid profiles during weight loss in adult women.
      • Krieger J.W.
      • Sitren H.S.
      • Daniels M.J.
      • Langkamp-Henken B.
      Effects of variation in protein and carbohydrate intake on body mass and composition during energy restriction: a meta-regression 1.
      IIaB-R
      LBM, lean body mass.
      The NLA grading system adopted the methodology and classification system used in the 2015 ACC/AHA Clinical Practice Guideline Recommendation Classification System
      • Halperin J.L.
      • Levine G.N.
      • Al-Khatib S.M.
      • et al.
      Further evolution of the ACC/AHA clinical practice guideline recommendation classification system: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
      (Table 3). All recommendations were graded by the Class of the Recommendation (COR) and by the Levels of the Evidence (LOE) supporting the Recommendation.

      Evidence for the effect of low-CHO and very-low-CHO diets on traditional cardiometabolic risk factors

      Effects on blood lipids and lipoproteins

      Recent systematic reviews and meta-analyses of RCTs of adults with overweight or obesity without diabetes have reported conflicting results on the effects of low-CHO and very-low-CHO diets on total-C and LDL-C
      • Naude C.E.
      • Schoonees
      • Senekal M.
      • Young T.
      • Garner P.
      • Volmink J.
      Low carbohydrate versus isoenergetic balanced diets for reducing weight and cardiovascular risk: a systematic review and meta-analysis.
      • Bueno N.B.
      • de Melo I.S.
      • de Oliveira S.L.
      • da Rocha Ataide T.
      Very-low-carbohydrate ketogenic diet v. low-fat diet for long-term weight loss: a meta-analysis of randomised controlled trials.
      • Schwingshackl L.
      • Hoffmann G.
      Comparison of effects of long-term low-fat vs high-fat diets on blood lipid levels in overweight or obese patients: a systematic review and meta-analysis.
      • Mansoor N.
      • Vinknes K.J.
      • Veierød M.B.
      • Retterstøl K.
      Effects of low-carbohydrate diets v. low-fat diets on body weight and cardiovascular risk factors: a meta-analysis of randomised controlled trials.
      • Gjuladin-Hellon T.
      • Davies I.G.
      • Penson P.
      • Amiri Baghbadorani R.
      Effects of carbohydrate-restricted diets on low-density lipoprotein cholesterol levels in overweight and obese adults: a systematic review and meta-analysis.
      • Sackner-Bernstein J.
      • Kanter D.
      • Kaul S.
      Dietary intervention for overweight and obese adults: comparison of low-carbohydrate and low-fat diets. A meta-analysis.
      (Table 2). In a meta-analysis of 14 RCTs that examined the differences in blood lipids between low-CHO and isocaloric balanced diets, there was a trend in the low-CHO diet groups for a higher total-C (WMD 3.09 mg/dL, 95% CI: −0.77, 6.57, n = 12 studies) and LDL-C (WMD 3.48 mg/dL, 95% CI: 0.0, 6.96, n = 12 studies) at 3–6 months follow-up and 1–2 years follow-up (total-C WMD 2.32 mg/dL, 95% CI: −1.16, 6.19, n = 6 studies; LDL-C WMD 2.71 mg/dL, 95% CI: −0.39, 6.19, n = 6 studies).
      • Naude C.E.
      • Schoonees
      • Senekal M.
      • Young T.
      • Garner P.
      • Volmink J.
      Low carbohydrate versus isoenergetic balanced diets for reducing weight and cardiovascular risk: a systematic review and meta-analysis.
      A meta-analysis of 8 large RCTs (each n > 100) over 6–24 months examined the effects of CHO-restricted diets vs low-fat (LF) diets on LDL-C and other lipid markers in adults with overweight or obesity.
      • Gjuladin-Hellon T.
      • Davies I.G.
      • Penson P.
      • Amiri Baghbadorani R.
      Effects of carbohydrate-restricted diets on low-density lipoprotein cholesterol levels in overweight and obese adults: a systematic review and meta-analysis.
      The CHO-restricted diets were divided into two subgroups: moderate-CHO (4 trials; 35–40% TDE CHO or 130–225 g/d) and very-low-CHO (4 trials; <10% TDE CHO or <50 g/d). The LF diets were 50–65% TDE CHO and 20–35% TDE fat, except one study (70% TDE CHO, <10% TDE fat). Overall, significantly higher LDL-C (WMD 2.71 mg/dL; 95% CI, 0.77, 5.03; P = .009; n = 8 studies) was reported in the pooled analysis of CHO-restricted diets vs LF diets. However, a subgroup analysis based on CHO content reported no significant difference in LDL-C levels between CHO-restricted vs LF diets (for very-low-CHO: 2.71 mg/dL; 95% CI: −1.93, 6.96; P = .27, n = 4 studies; for moderate-CHO: 1.93 mg/dL; 95% CI: −0.77, 4.64; P = .16, n = 4 studies).
      • Gjuladin-Hellon T.
      • Davies I.G.
      • Penson P.
      • Amiri Baghbadorani R.
      Effects of carbohydrate-restricted diets on low-density lipoprotein cholesterol levels in overweight and obese adults: a systematic review and meta-analysis.
      Contrary to the results from these two meta-analyses,
      • Naude C.E.
      • Schoonees
      • Senekal M.
      • Young T.
      • Garner P.
      • Volmink J.
      Low carbohydrate versus isoenergetic balanced diets for reducing weight and cardiovascular risk: a systematic review and meta-analysis.
      • Gjuladin-Hellon T.
      • Davies I.G.
      • Penson P.
      • Amiri Baghbadorani R.
      Effects of carbohydrate-restricted diets on low-density lipoprotein cholesterol levels in overweight and obese adults: a systematic review and meta-analysis.
      four other meta-analyses examining the effects of low-CHO diets vs HCLF diets in adults with overweight or obesity found significantly higher LDL-C levels during the CHO-restricted diets.
      • Bueno N.B.
      • de Melo I.S.
      • de Oliveira S.L.
      • da Rocha Ataide T.
      Very-low-carbohydrate ketogenic diet v. low-fat diet for long-term weight loss: a meta-analysis of randomised controlled trials.
      • Schwingshackl L.
      • Hoffmann G.
      Comparison of effects of long-term low-fat vs high-fat diets on blood lipid levels in overweight or obese patients: a systematic review and meta-analysis.
      • Mansoor N.
      • Vinknes K.J.
      • Veierød M.B.
      • Retterstøl K.
      Effects of low-carbohydrate diets v. low-fat diets on body weight and cardiovascular risk factors: a meta-analysis of randomised controlled trials.
      • Sackner-Bernstein J.
      • Kanter D.
      • Kaul S.
      Dietary intervention for overweight and obese adults: comparison of low-carbohydrate and low-fat diets. A meta-analysis.
      Systematic reviews and meta-analyses of RCTs examining the effects of low-CHO and very-low-CHO diets on blood lipids in patients with T2D and prediabetes found no significant difference in total-C
      • Naude C.E.
      • Schoonees
      • Senekal M.
      • Young T.
      • Garner P.
      • Volmink J.
      Low carbohydrate versus isoenergetic balanced diets for reducing weight and cardiovascular risk: a systematic review and meta-analysis.
      • Schwingshackl L.
      • Hoffmann G.
      Comparison of the long-term effects of high-fat v. low-fat diet consumption on cardiometabolic risk factors in subjects with abnormal glucose metabolism: a systematic review and meta-analysis.
      • Meng Y.
      • Bai H.
      • Wang S.
      • Li Z.
      • Wang Q.
      • Chen L.
      Efficacy of low carbohydrate diet for type 2 diabetes mellitus management: A systematic review and meta-analysis of randomized controlled trials.
      • Snorgaard O.
      • Poulsen G.M.
      • Andersen H.K.
      • Astrup A.
      Systematic review and meta-analysis of dietary carbohydrate restriction in patients with type 2 diabetes.
      • Huntriss R.
      • Campbell M.
      • Bedwell C.
      The interpretation and effect of a low-carbohydrate diet in the management of type 2 diabetes: a systematic review and meta-analysis of randomised controlled trials.
      • Korsmo-Haugen H.K.
      • Brurberg K.G.
      • Mann J.
      • Aas A.M.
      Carbohydrate quantity in the dietary management of type 2 diabetes: a systematic review and meta-analysis.
      • van Wyk H.J.
      • Davis R.E.
      • Davies J.S.
      A critical review of low-carbohydrate diets in people with Type 2 diabetes.
      and LDL-C levels
      • Naude C.E.
      • Schoonees
      • Senekal M.
      • Young T.
      • Garner P.
      • Volmink J.
      Low carbohydrate versus isoenergetic balanced diets for reducing weight and cardiovascular risk: a systematic review and meta-analysis.
      • Schwingshackl L.
      • Hoffmann G.
      Comparison of the long-term effects of high-fat v. low-fat diet consumption on cardiometabolic risk factors in subjects with abnormal glucose metabolism: a systematic review and meta-analysis.
      • Meng Y.
      • Bai H.
      • Wang S.
      • Li Z.
      • Wang Q.
      • Chen L.
      Efficacy of low carbohydrate diet for type 2 diabetes mellitus management: A systematic review and meta-analysis of randomized controlled trials.
      • Snorgaard O.
      • Poulsen G.M.
      • Andersen H.K.
      • Astrup A.
      Systematic review and meta-analysis of dietary carbohydrate restriction in patients with type 2 diabetes.
      • Huntriss R.
      • Campbell M.
      • Bedwell C.
      The interpretation and effect of a low-carbohydrate diet in the management of type 2 diabetes: a systematic review and meta-analysis of randomised controlled trials.
      • Korsmo-Haugen H.K.
      • Brurberg K.G.
      • Mann J.
      • Aas A.M.
      Carbohydrate quantity in the dietary management of type 2 diabetes: a systematic review and meta-analysis.
      • van Zuuren E.J.
      • Fedorowicz Z.
      • Kuijpers T.
      • Pijl H.
      Effects of low-carbohydrate- compared with low-fat-diet interventions on metabolic control in people with type 2 diabetes: a systematic review including GRADE assessments.
      • van Wyk H.J.
      • Davis R.E.
      • Davies J.S.
      A critical review of low-carbohydrate diets in people with Type 2 diabetes.
      between low-CHO and HCLF diets (Table 2, Fig. 1).
      None of the meta-analyses discussed previously examined the effect of low-CHO or very-low-CHO diets on VLDL-C, non–high-density lipoprotein cholesterol (non–HDL-C), apolipoprotein B (apoB), or LDL particle number or size in adults with T2D and there is very little evidence from RCTs of adults with overweight or obesity. Gjuladin-Hellon et al.
      • Gjuladin-Hellon T.
      • Davies I.G.
      • Penson P.
      • Amiri Baghbadorani R.
      Effects of carbohydrate-restricted diets on low-density lipoprotein cholesterol levels in overweight and obese adults: a systematic review and meta-analysis.
      identified only three large (n > 100) RCTs that examined the impact of CHO-restricted diets on VLDL-C,
      • Foster G.D.
      • Wyatt H.R.
      • Hill J.O.
      • et al.
      Weight and metabolic outcomes after 2 years on a low-carbohydrate versus low-fat diet: a randomized trial.
      apoB levels,
      • Klemsdal T.O.
      • Holme I.
      • Nerland H.
      • Pedersen T.R.
      • Tonstad S.
      Effects of a low glycemic load diet versus a low-fat diet in subjects with and without the metabolic syndrome.
      or LDL-C particle size.
      • Morgan L.M.
      • Griffin B.A.
      • Millward D.J.
      • et al.
      Comparison of the effects of four commercially available weight-loss programmes on lipid-based cardiovascular risk factors.
      Although the results of these large RCTs showed improvement in these variables for the CHO-restricted diet groups vs the HCLF diets groups, results were limited by the CHO restriction in the diet interventions ranging from ketogenic to nonketogenic and the intensive lifestyle interventions provided to participants may have affected the results.
      Similar to total-C and LDL-C, recent systematic reviews and meta-analyses of RCTs have found varying results on the effects of low-CHO and very-low-CHO diets on TG and HDL-C levels (Table 2, Fig. 1). In their meta-analysis of adults with overweight or obesity (14 RCTs), Naude et al.
      • Naude C.E.
      • Schoonees
      • Senekal M.
      • Young T.
      • Garner P.
      • Volmink J.
      Low carbohydrate versus isoenergetic balanced diets for reducing weight and cardiovascular risk: a systematic review and meta-analysis.
      reported a significant difference for HDL-C at 1–2 years follow-up, but no significant difference for TG between diet groups. Furthermore, both Naude et al.
      • Naude C.E.
      • Schoonees
      • Senekal M.
      • Young T.
      • Garner P.
      • Volmink J.
      Low carbohydrate versus isoenergetic balanced diets for reducing weight and cardiovascular risk: a systematic review and meta-analysis.
      and Korsmo-Haugen et al.
      • Korsmo-Haugen H.K.
      • Brurberg K.G.
      • Mann J.
      • Aas A.M.
      Carbohydrate quantity in the dietary management of type 2 diabetes: a systematic review and meta-analysis.
      reported no significant differences between diet groups for TG and HDL-C levels at 1–2 years follow-up in adults with overweight or obesity and T2D.
      Conversely, other meta-analyses reported significant improvements in both TG and HDL-C levels with low-CHO diets vs HCLF diets at 1–2 years follow-up in adults with overweight and obesity
      • Bueno N.B.
      • de Melo I.S.
      • de Oliveira S.L.
      • da Rocha Ataide T.
      Very-low-carbohydrate ketogenic diet v. low-fat diet for long-term weight loss: a meta-analysis of randomised controlled trials.
      • Schwingshackl L.
      • Hoffmann G.
      Comparison of effects of long-term low-fat vs high-fat diets on blood lipid levels in overweight or obese patients: a systematic review and meta-analysis.
      • Mansoor N.
      • Vinknes K.J.
      • Veierød M.B.
      • Retterstøl K.
      Effects of low-carbohydrate diets v. low-fat diets on body weight and cardiovascular risk factors: a meta-analysis of randomised controlled trials.
      • Gjuladin-Hellon T.
      • Davies I.G.
      • Penson P.
      • Amiri Baghbadorani R.
      Effects of carbohydrate-restricted diets on low-density lipoprotein cholesterol levels in overweight and obese adults: a systematic review and meta-analysis.
      • Sackner-Bernstein J.
      • Kanter D.
      • Kaul S.
      Dietary intervention for overweight and obese adults: comparison of low-carbohydrate and low-fat diets. A meta-analysis.
      and prediabetes or T2D.
      • Schwingshackl L.
      • Hoffmann G.
      Comparison of the long-term effects of high-fat v. low-fat diet consumption on cardiometabolic risk factors in subjects with abnormal glucose metabolism: a systematic review and meta-analysis.
      • Meng Y.
      • Bai H.
      • Wang S.
      • Li Z.
      • Wang Q.
      • Chen L.
      Efficacy of low carbohydrate diet for type 2 diabetes mellitus management: A systematic review and meta-analysis of randomized controlled trials.
      • Huntriss R.
      • Campbell M.
      • Bedwell C.
      The interpretation and effect of a low-carbohydrate diet in the management of type 2 diabetes: a systematic review and meta-analysis of randomised controlled trials.
      • van Zuuren E.J.
      • Fedorowicz Z.
      • Kuijpers T.
      • Pijl H.
      Effects of low-carbohydrate- compared with low-fat-diet interventions on metabolic control in people with type 2 diabetes: a systematic review including GRADE assessments.
      Gjuladin-Hellon et al.
      • Gjuladin-Hellon T.
      • Davies I.G.
      • Penson P.
      • Amiri Baghbadorani R.
      Effects of carbohydrate-restricted diets on low-density lipoprotein cholesterol levels in overweight and obese adults: a systematic review and meta-analysis.
      reported a significantly greater decrease in TG levels and a significantly greater increase in HDL-C levels with CHO-restricted diets vs LF diets at 6 and 12 months in adults with overweight or obesity, but no significant difference at 24 months, except in the very-low-CHO diet group, which maintained significantly higher HDL-C levels than the other diet groups at 24 months.

      Points to consider regarding the effects of low-CHO and very-low-CHO diets on blood lipids and lipoproteins

      The conflicting results of the studies examining the effect of low-CHO and very-low-CHO diets on blood lipids and lipoprotein levels in adults with overweight or obesity with and without T2D may be due to variations in CHO and fat quantity and quality of the diet interventions in the RCTs, and/or differences in adherence to the prescribed diets over the course of the study periods.
      • Naude C.E.
      • Schoonees
      • Senekal M.
      • Young T.
      • Garner P.
      • Volmink J.
      Low carbohydrate versus isoenergetic balanced diets for reducing weight and cardiovascular risk: a systematic review and meta-analysis.
      • Schwingshackl L.
      • Hoffmann G.
      Comparison of the long-term effects of high-fat v. low-fat diet consumption on cardiometabolic risk factors in subjects with abnormal glucose metabolism: a systematic review and meta-analysis.
      • Krieger J.W.
      • Sitren H.S.
      • Daniels M.J.
      • Langkamp-Henken B.
      Effects of variation in protein and carbohydrate intake on body mass and composition during energy restriction: a meta-regression 1.
      • van Wyk H.J.
      • Davis R.E.
      • Davies J.S.
      A critical review of low-carbohydrate diets in people with Type 2 diabetes.
      Participants began with a CHO-restriction that was ketogenic (<20–50 g/d) at study start in very few studies included in the meta-analyses and adherence to the diet was not maintained to the study end, except in the Brinkworth et al.
      • Brinkworth G.D.
      • Noakes M.
      • Buckley J.D.
      • Keogh J.B.
      • Clifton P.M.
      Long-term effects of a very-low-carbohydrate weight loss diet compared with an isocaloric low-fat diet after 12 mo.
      study; thus, at 2-year follow-up, there was little difference between the diets.
      • Naude C.E.
      • Schoonees
      • Senekal M.
      • Young T.
      • Garner P.
      • Volmink J.
      Low carbohydrate versus isoenergetic balanced diets for reducing weight and cardiovascular risk: a systematic review and meta-analysis.
      • Bueno N.B.
      • de Melo I.S.
      • de Oliveira S.L.
      • da Rocha Ataide T.
      Very-low-carbohydrate ketogenic diet v. low-fat diet for long-term weight loss: a meta-analysis of randomised controlled trials.
      • Schwingshackl L.
      • Hoffmann G.
      Comparison of effects of long-term low-fat vs high-fat diets on blood lipid levels in overweight or obese patients: a systematic review and meta-analysis.
      • Mansoor N.
      • Vinknes K.J.
      • Veierød M.B.
      • Retterstøl K.
      Effects of low-carbohydrate diets v. low-fat diets on body weight and cardiovascular risk factors: a meta-analysis of randomised controlled trials.
      • Gjuladin-Hellon T.
      • Davies I.G.
      • Penson P.
      • Amiri Baghbadorani R.
      Effects of carbohydrate-restricted diets on low-density lipoprotein cholesterol levels in overweight and obese adults: a systematic review and meta-analysis.
      • Huntriss R.
      • Campbell M.
      • Bedwell C.
      The interpretation and effect of a low-carbohydrate diet in the management of type 2 diabetes: a systematic review and meta-analysis of randomised controlled trials.
      • Korsmo-Haugen H.K.
      • Brurberg K.G.
      • Mann J.
      • Aas A.M.
      Carbohydrate quantity in the dietary management of type 2 diabetes: a systematic review and meta-analysis.
      In one meta-analysis of RCTs of adults with overweight or obesity without T2D, the TDE SFA in the HCLF diets was ∼9.3%, whereas the low-CHO and comparison control diets were ∼12.5–15% TDE SFA.
      • Schwingshackl L.
      • Hoffmann G.
      Comparison of effects of long-term low-fat vs high-fat diets on blood lipid levels in overweight or obese patients: a systematic review and meta-analysis.
      Thus, the greater SFA in the low-CHO and control diets may have resulted in higher LDL-C levels vs the HCLF diet. The lack of significant difference between the diet groups in RCTs involving adults with T2D or prediabetes may be attributed to similar SFA content between diets,
      • Huntriss R.
      • Campbell M.
      • Bedwell C.
      The interpretation and effect of a low-carbohydrate diet in the management of type 2 diabetes: a systematic review and meta-analysis of randomised controlled trials.
      SFA intake did not increase from baseline in the diet groups,
      • van Wyk H.J.
      • Davis R.E.
      • Davies J.S.
      A critical review of low-carbohydrate diets in people with Type 2 diabetes.
      or CHO was replaced with unsaturated fatty acids in the low-CHO diets.
      • Korsmo-Haugen H.K.
      • Brurberg K.G.
      • Mann J.
      • Aas A.M.
      Carbohydrate quantity in the dietary management of type 2 diabetes: a systematic review and meta-analysis.
      Taken together, the available data suggest that controlling SFA intake is crucial to prevent significant increases in LDL-C and for achieving improved cardiovascular (CV) health with low-CHO diets. Furthermore, improvements in TG and HDL-C levels were achieved at a CHO intake considered low (<130 g/d) or moderate (130–225 g/d), but not ketogenic, which may promote more successful adherence.
      • Huntriss R.
      • Campbell M.
      • Bedwell C.
      The interpretation and effect of a low-carbohydrate diet in the management of type 2 diabetes: a systematic review and meta-analysis of randomised controlled trials.
      In addition to the points discussed previously, weight loss can impact lipids and lipoproteins and modifications in macronutrients can influence the response to some extent. Negative energy balance and weight loss, regardless of the dietary strategy, tend to improve TG, LDL-C, and HDL-C.
      • Jacobson T.A.
      • Maki K.C.
      • Orringer C.E.
      • et al.
      National Lipid Association Recommendations for Patient-Centered Management of Dyslipidemia: Part 2.
      A 3 kg weight loss can decrease TG by at least 15 mg/dL, and a 5 to 8 kg weight loss can decrease LDL-C by ∼5 mg/dL and increase HDL-C by 2 to 3 mg/dL.
      • Jensen M.D.
      • Ryan D.H.
      • Apovian C.M.
      • et al.
      2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society.
      The macronutrient content of the dietary strategy used for weight loss can affect LDL-C levels in that a higher intake of unsaturated fatty acids tends to lower LDL-C, whereas a higher intake of SFA, cholesterol, and trans fatty acids tends to raise LDL-C. Higher protein intake, particularly from plant proteins such as soy protein, tends to lower LDL-C relative to protein from animal sources. Thus, the effect on LDL-C is variable and likely depends in part on the net impact of the various factors discussed previously. Weight loss with a low-CHO diet that is also low in SFA, cholesterol, and trans fatty acids will tend to reduce LDL-C, but LDL-C may increase with a low-CHO diet that is high in SFA, cholesterol, trans fatty acids, and animal proteins.
      • Jacobson T.A.
      • Maki K.C.
      • Orringer C.E.
      • et al.
      National Lipid Association Recommendations for Patient-Centered Management of Dyslipidemia: Part 2.
      In regard to TG levels, reducing dietary CHO will generally lower TG levels with a resultant decrease in VLDL-C, particularly in individuals with elevated TG. The TG-lowering effect will be enhanced by weight loss and negative energy balance. Lowering TG will generally raise HDL-C once weight has stabilized, but HDL-C may go down during weight loss or negative energy balance. Weight stabilization after weight loss also tends to raise HDL-C. The reduction in TG levels due to weight loss, with or without CHO restriction, will also tend to shift toward larger HDL and LDL particles.
      • Jacobson T.A.
      • Maki K.C.
      • Orringer C.E.
      • et al.
      National Lipid Association Recommendations for Patient-Centered Management of Dyslipidemia: Part 2.
      Although the results from some studies may not show a significant difference in lipid and lipoprotein parameters between diet groups, there may be individuals who experience extreme effects of low-CHO and VLCHF diets, which may be related to genetic factors and the variable response to substrate availability and neurohormonal reactivity. Two RCTs
      • Tay J.
      • Brinkworth G.D.
      • Noakes M.
      • Keogh J.
      • Clifton P.M.
      Metabolic effects of weight loss on a very-low-carbohydrate diet compared with an isocaloric high-carbohydrate diet in abdominally obese subjects.
      • Retterstøl K.
      • Svendsen M.
      • Narverud I.
      • Holven K.B.
      Effect of low carbohydrate high fat diet on LDL cholesterol and gene expression in normal-weight, young adults: a randomized controlled study.
      reported considerable variability in LDL-C levels in adults with obesity consuming a VLCHF diet (4% TDE, 61% TDE total fat, 20% TDE SFA)
      • Tay J.
      • Brinkworth G.D.
      • Noakes M.
      • Keogh J.
      • Clifton P.M.
      Metabolic effects of weight loss on a very-low-carbohydrate diet compared with an isocaloric high-carbohydrate diet in abdominally obese subjects.
      or adults with a normal weight following a very-low-CHO diet (<20 g/d; ad libitum with no restriction on fat or protein intake)
      • Retterstøl K.
      • Svendsen M.
      • Narverud I.
      • Holven K.B.
      Effect of low carbohydrate high fat diet on LDL cholesterol and gene expression in normal-weight, young adults: a randomized controlled study.
      compared with a HCLF or control diet. The increase in LDL-C ranged between 5–10% in one RCT
      • Tay J.
      • Brinkworth G.D.
      • Noakes M.
      • Keogh J.
      • Clifton P.M.
      Metabolic effects of weight loss on a very-low-carbohydrate diet compared with an isocaloric high-carbohydrate diet in abdominally obese subjects.
      and 44% (range 5% to 107%) in the other RCT.
      • Retterstøl K.
      • Svendsen M.
      • Narverud I.
      • Holven K.B.
      Effect of low carbohydrate high fat diet on LDL cholesterol and gene expression in normal-weight, young adults: a randomized controlled study.
      In their narrative review on nutrigenetics and blood cholesterol levels, Vazquez-Vidal et al. reviewed gene-nutrient interaction studies that examined inter-individual variability in blood cholesterol responses.
      • Vazquez-Vidal I.
      • Desmarchelier C.
      • Jones P.J.H.
      Nutrigenetics of blood cholesterol concentrations: towards personalized nutrition.
      Some studies have shown significant associations between the APOE4 allele and an increased LDL-C response to dietary interventions while others found no association indicating the LDL-C response varies based on different types of dietary interventions (ie, amount and type of fat and cholesterol) or specific foods.
      • Vazquez-Vidal I.
      • Desmarchelier C.
      • Jones P.J.H.
      Nutrigenetics of blood cholesterol concentrations: towards personalized nutrition.
      • Ordovas J.M.
      Gene-diet interaction and plasma lipid responses to dietary intervention.
      Thus, it is essential to assess the lipid profile of patients who choose to follow low-CHO or very-low-CHO diets and KDs.

      Key points

      • Results from meta-analyses demonstrate a variable total-C and LDL-C response to low-CHO and very-low-CHO diets.
      • A high saturated fatty acid (SFA) content in low-CHO and very-low-CHO diets is a key factor for an increase in LDL-C.
      • Compared with high-CHO, low-fat (HCLF) diets, low-CHO diets generally decrease TG levels.
      • Compared with HCLF diets, low-CHO diets generally result in a short-term increase in HDL-C levels, which is typically not maintained for longer durations.
      • Improvements in TG and HDL-C levels were achieved at low- and moderate-CHO intakes vs very-low-CHO intakes, which may result in better long-term adherence.
      • Genetic factors have been shown to play a role in the individual variability of LDL-C levels with low-CHO and very-low-CHO diets.
      • Baseline and follow-up lipid/lipoprotein assessments are essential for individuals following low-CHO and very-low-CHO diets to identify extreme responses.

      Effects on glucose, hemoglobin A1c, insulin and insulin sensitivity, and hypoglycemic medication use

      Systematic reviews and meta-analyses of low-CHO and very-low-CHO diets compared with HCLF diets in RCTs of adults without T2D
      • Naude C.E.
      • Schoonees
      • Senekal M.
      • Young T.
      • Garner P.
      • Volmink J.
      Low carbohydrate versus isoenergetic balanced diets for reducing weight and cardiovascular risk: a systematic review and meta-analysis.
      • Mansoor N.
      • Vinknes K.J.
      • Veierød M.B.
      • Retterstøl K.
      Effects of low-carbohydrate diets v. low-fat diets on body weight and cardiovascular risk factors: a meta-analysis of randomised controlled trials.
      or that included a small number of adults with T2D
      • Bueno N.B.
      • de Melo I.S.
      • de Oliveira S.L.
      • da Rocha Ataide T.
      Very-low-carbohydrate ketogenic diet v. low-fat diet for long-term weight loss: a meta-analysis of randomised controlled trials.
      found no significant difference for fasting blood glucose (FBG), hemoglobin A1c (HbA1c), and insulin levels between diet groups, although there were trends in favor of the low-CHO diets for these endpoints. However, only one RCT
      • Brinkworth G.D.
      • Noakes M.
      • Buckley J.D.
      • Keogh J.B.
      • Clifton P.M.
      Long-term effects of a very-low-carbohydrate weight loss diet compared with an isocaloric low-fat diet after 12 mo.
      included in the meta-analyses reported CHO intake <50 g/d by the end of study.
      • Bueno N.B.
      • de Melo I.S.
      • de Oliveira S.L.
      • da Rocha Ataide T.
      Very-low-carbohydrate ketogenic diet v. low-fat diet for long-term weight loss: a meta-analysis of randomised controlled trials.
      • Mansoor N.
      • Vinknes K.J.
      • Veierød M.B.
      • Retterstøl K.
      Effects of low-carbohydrate diets v. low-fat diets on body weight and cardiovascular risk factors: a meta-analysis of randomised controlled trials.
      Systematic reviews and meta-analyses of RCTs comparing low-CHO and very-low-CHO diets to HCLF diets in adults with T2D and prediabetes found no significant difference between glucose levels
      • Naude C.E.
      • Schoonees
      • Senekal M.
      • Young T.
      • Garner P.
      • Volmink J.
      Low carbohydrate versus isoenergetic balanced diets for reducing weight and cardiovascular risk: a systematic review and meta-analysis.
      • Meng Y.
      • Bai H.
      • Wang S.
      • Li Z.
      • Wang Q.
      • Chen L.
      Efficacy of low carbohydrate diet for type 2 diabetes mellitus management: A systematic review and meta-analysis of randomized controlled trials.
      or insulin levels.
      • van Wyk H.J.
      • Davis R.E.
      • Davies J.S.
      A critical review of low-carbohydrate diets in people with Type 2 diabetes.
      In short-term (≤6 months) studies, HbA1c was significantly lower with low-CHO diets compared with HCLF diets.
      • Schwingshackl L.
      • Hoffmann G.
      Comparison of the long-term effects of high-fat v. low-fat diet consumption on cardiometabolic risk factors in subjects with abnormal glucose metabolism: a systematic review and meta-analysis.