Since 1860, and more recently, in 1972, low carbohydrate (low-carb) diets have been a strategy for weight loss.  Today, there continues to be an interest in low-carb approaches.  While all low carbohydrate approaches reduce the overall intake of carbohydrates, there is no clear consensus on what defines a low-carb diet.  There are three macronutrients—carbohydrates (4 kcal/gm), fat (9 kcal/gm), and protein (4 kcal/gm) found in food.  Therefore, studies have defined low carbohydrate as a percent of daily macronutrient intake or total daily carbohydrate load.  We will define it here as:

1. Very low-carbohydrate (< 10% carbohydrates) or 20-50 gm/day
2. Low-carbohydrate (<26% carbohydrates) or less than < 130 gm/day
3. Moderate-carbohydrate (26%-44%)
4. High-carbohydrate (45% or greater)

For reference, the Institute of Medicine proposes Americans obtain 45%-65% of calories from carbohydrates.[1]  This article will review the evidence and effectiveness of low-carb approaches in clinical medicine.

Low-carb approaches stem primarily from the hypothesis that lowering insulin, a critical hormone that produces an anabolic, fat-storing state, improves cardiometabolic function, and induces weight loss.[2] This approach has been recently called the carbohydrate-insulin model.[3]   Studies have shown low-carb approaches to be superior to other dietary approaches in producing rapid weight loss for the first 6-12 months.[4][5][6]  While diets inducing weight-loss produce a caloric deficit, the mechanism of low-carb diets remains in debate. When lowering carbohydrates from the diet, the macronutrient intake of fat and protein generally increases to compensate for the reduction of carbohydrates.  One hypothesis of why low-carb approaches produce rapid weight loss compared to other diets is that fats and protein increase satiety and produce less concomitant hypoglycemia. This increase in satiety and less rebound hypoglycemia then reduces hunger and overall food intake and produces a caloric deficit.  Additionally, another hypothesis contends that low-carb diets can produce a higher metabolic burn than high-carb diets.  In recent studies, there appears to be a metabolic advantage of approximately 200 to 300 more calories burned compared to an iso-caloric high-carb diet.[2][7]  However, these theories remain controversial.[8]

The ketogenic (keto) diet, a specific version of low-carb, deserves mention.  Keto diets restrict carbohydrate to induce nutritional ketosis and typically limits carbs to 20-50 gms daily.  Restricting carbs to under 50 gms induces glycogen depletion and ketone production from the mobilization of fat stored in adipose tissue.  Nutritional ketosis produces ketone bodies (acetoacetate, acetone, and beta-hydroxybutyrate) and can is measurable as serum or urinary ketones.  Nutritional ketosis generally increases serum ketones to 1 mmol/L to 7 mmol/L but does not produce metabolic acidosis.  Diabetic ketoacidosis, by definition, includes metabolic acidosis, hyperglycemia, and serum ketones (generally over 20 mmol/L).[9]

Despite the debate, it is clear from numerous systematic reviews that low-carb diets are as effective, if not more effective for weight loss compared to other diets. The evidence for benefits and concerns for low-carb will be further delineated below.

There are several hypothetical concerns of the long-term safety of low-carb diets that deserve mention. Safety concerns of low-carb diets relate to ketosis, long-term cardiovascular safety, lipid, and renal effects.

Ketosis

Nutritional ketosis can be induced in the keto diet, the induction phase, and any time where carb load is limited to <10% of macronutrient intake, or 20 to 50 gm/day of carbohydrates.  However, there is no evidence that very-low-carb intake produces metabolic ketoacidosis and remain safe in patients, even with type 2 diabetes.[9][10]  While there have been cases of diabetic ketoacidosis (DKA) with concomitant SGLT2 inhibitors in patients with type 2 diabetes, it is unclear if the very low carb approach can put increased risk of DKA with SGLT2 use. However, the recommendation is for caution with the use of ketogenic diets with concomitant use of SGLT-2 inhibitors.[11]

Mortality and Cardiovascular Safety

There have been several studies linking low-carb diets to increased mortality.  Epidemiological studies and meta-analysis have shown an increased risk of mortality with carbohydrate intake <40%.[12][13]  However, the recent Prospective Urban Rural Epidemiology (PURE) study, a large prospective nutrition study involving over 135,000 participants across the globe, found a relationship between increased mortality and higher carbohydrate intake, and lower mortality associated with higher fat intake.[14] Until long term, randomized studies can be undertaken, the long-term effect is unclear.

Lipid Response

Incorporating more fat and protein in response to the reduction of dietary carbs has led to concerns on the effect of low-carb dieting on lipids; specifically, LDL cholesterol.  Recent systematic reviews of low-carb diets on lipids demonstrate a neutral to small increase in LDL but a favorable triglycerides reduction and an increase in HDL cholesterol, particularly those assigned to the very low-carb intervention.[15][16] Although not formally studied, there may be a subset of lean individuals who have a hyper LDL response with ketogenic diets, a term coined Lean Mass Hyper-Responders. Due to the varied and individualized response, recommendations are for baseline fasting lipid profile, periodic testing, and shared decision making.

Renal Function

With a potentially higher protein intake on low-carb diets, some have expressed concerns on renal function.  However, depending on specific goals, athletes should ingest protein loads to optimize muscle protein synthesis (1.6 gm/kg) or for endurance sports (0.8 gm/kg).[17][18] Encouraging higher protein loads to support physical activity can also help with improving body composition and metabolic adaptations.  In general, there are no data to associate high protein load with worsening kidney function in those with normal kidneys.[19]  For those with chronic kidney disease, a low or very-low-protein diet (0.2-0.8 gm/kg/day) may be recommended to prevent further renal deterioration.[20]

The study of low-carb diets has centered on weight loss in obese and overweight people as well as patients with or at risk for cardiometabolic diseases such as type 2 diabetes and nonalcoholic fatty liver disease.  Ketogenic diets have also been used for seizure disorders and, more recently, have found use in the athletic population as an alternative fuel for performance and health.

Weight Loss

By far, the most research in low-carb approaches has shown that low-carb diet, and specifically ketogenic approaches, induces rapid induction of weight loss.  Initial weight loss is due partly from water loss, but fat loss occurs with adherence to the low carb approach.  With all dietary intervention, as adherence to the diet wanes, weight loss effect becomes similar to other dietary approaches after one year.[21] It is notable that most of the low-carb studies generally use an ad-libitum approach of caloric intake (limiting carbs instead), while most comparison diets are calorie-restricted.  In general, shared decision making is a valid and person-centered approach in determining nutritional approaches to weight loss.

Type 2 Diabetes

Before medications, carbohydrate control has been the cornerstone of glycemic control in both type 1 and type 2 diabetes. Dietary carbohydrates increase insulin needs, and reduction of carbohydrate intake can improve glycemic control.[22] A recent study demonstrated a significant reduction of insulin and oral medications and hemoglobin A1c reduction with ketogenic approaches while demonstrating a high adherence to the intervention at 12 months.[23][24] Also, markers of cardiometabolic risk factors improved.[25] Approaches to nutritional lifestyle approaches to diabetes (medical nutrition therapy) have included low carb as an option in recent guidelines.[26][27] Recent prospective and randomized controlled trials have demonstrated a consistent benefit in glycemic control, weight loss, and sustained medication reduction using a very low carb approach (< 14% of energy from carbohydrates).[28][29][30]

Cardiovascular Risk Factors

As mentioned above, the effect of low-carb diets on cardiovascular risk factors continue to be controversial. While a few studies have demonstrated an increase in LDL cholesterol with low-carb diets, others showed negligible changes. However, other metabolic markers, such as lowering triglycerides, increases in HDL, have been demonstrated with low-carb diets.[4][25][16]

Ketogenic diets have been used successfully since 1920 before the existence of medications for epilepsy.[9][31] Recent studies have shown that acne, cancer, non-alcoholic fatty liver disease, polycystic ovary syndrome, and Alzheimer disease may improve with ketogenic diets.[9][32] Recently use of keto diets to provide sustained, and steady fuel for endurance sports in athletic individuals and the optimization of body composition in high-intensity training for the recreational population have also undergone testing.[33][34]