The keto diet has been widely promulgated as an effective therapy for the treatment of diabetes and weight loss with minimal side effects. The diet may be of benefit for some in select circumstances, but perhaps not for all patients. Many discussions regarding the diet present an unbalanced view, often omitting studies that show harm or lack of a benefit. To balance the narrative, I’ve written this post that I intend to keep maintained for foreseeable future. Below I present the links to references of important studies that are often excluded from the discussion of ketogenic, and by association, low-carbohydrate diets. I invite you to look through them. Personally, I did not expect to find as much as I did (and certainly not so many concerning side effects). If you have other studies or comments, please post them below in the reply section of this page. You can also share them with me on Twitter @sjoshiMD.

1. Claim that the Ketogenic Diet is Beneficial for Diabetes
   1. I’ve excluded non-randomized studies from this discussion for simplicity. Several short-term (<12 months), randomized studies have shown benefit (but keep reading..)
      1. Westman et al.
      2. Saslow et al.
      3. Saslow et al.
   2. As time goes on, the benefit of the ketogenic diet decreases as manifested by a decreasing net difference in glycosylated hemoglobin A1c levels (see table below)
      

      Trial	Duration	Mean Reduction of HbA1c on Ketogenic Diet	Mean Reduction of HbA1c on Control Diet	Difference in Mean HbA1c Between Diets
      Westman et al. 2008	24 weeks	1.5%	0.5%	1.0%
      Saslow et al. 2017	32 weeks	0.8%	0.3%	0.5%
      Saslow et al. 2017	52 weeks	0.5%	0.2%	0.3%

   3. Finally, further illustrating the point of the decreasing difference between glycemic levels as time goes on (likely a result of difficulty of complying with the diet and lack of any effect on the pathophysiology of diabetes), a meta-analysis of randomized-controlled trials lasting a year did not show any benefit in fast plasma glucose or glycosylate hemoglobin levels
      1. Bueno et al.
   4. What is the point to the diet if there is no benefit to it over the long-term for diabetes?
2. Claim that the Ketogenic Diet is Beneficial for Obesity
   1. Meta-analysis of randomized controlled trials lasting more than a year showed a 0.91 kg (95% CI -1.65, -0.17), which is equivalent to 2 pounds of additional weight loss compared to a low-fat strategy
      1. Bueno et al.
   2. The claims of abundant weight loss are not substantiated with high-quality research
   3. What is the point to the diet if there is only 2 pounds of weight loss after one year?
      1. To put this in perspective, this is the amount of weight you would lose if you ate 19 less calories per day for an entire year (roughly).
3. Mutation Among Inuit to Avoid Ketosis
   1. The Inuit of the Arctic consumed a diet high in fat given their dependence on marine mammals with blubber and high amounts of adipose tissue. One would expect that this type of diet, given the lack of carbohydrates, would induce ketosis. However, the Inuit of Greenland and Canada actually have a mutation to avoid ketosis.
   2. The mutation can have deleterious consequences if the Inuit are not able to obtain energy from other sources since ketone bodies are a source of energy. Unsurprisingly, the mutation increases the risk of hypoketotic hypoglycemia, which increases the risk of death, especially in infants.
   3. The plot thickens: Despite the deadly risks of the mutation, more than 80% of Greenland and Canadian Inuit have the mutation. Why? Why would evolution favor the propagation of a deleterious mutation? The only reason is if the alternative was worse.
   4. Some have theorized that ketosis is not likely a wise a long-term strategy for survival. The ketogenic diet can cause metabolic acidosis (see below) from the production of acidic ketones, which lowers the pH. In times of stress (like illness, trauma, starvation, cold weather?, etc.), the blood can become even more acidic (lower pH) and increase the risk of death. Situations like this might have favored the spread of a mutation to circumvent ketosis in the Inuit.
4. Claim that the Ketogenic Diet Drastically Increases Metabolism
   1. Keto enthusiasts often tout the diet as unique because of its ability to significantly increase the metabolic rate. Not only is this not true, in some cases, it is actually the opposite of what was found in scientific studies.
      1. When ketogenic and non-ketogenic low carbohydrate diets were compared to each other, there was no difference in metabolism.
      2. Researchers at the NIH have shown that low-fat diets (like a whole-foods plant-based diet) actually result in more fat loss than low-carb diets (e.g. the keto diet).
         1. The low-carb diet did lose more total weight but this study shows that this weight was from lean tissue (muscle) loss and water loss, and not loss of fat (the opposite of what is generally desired).
         2. Other studies have also shown the sizable amount of water lost with the ketogenic diet, which is regained once the ketogenic diet is stopped.
      3. It has been hypothesized that the ketogenic diet can increase energy expenditure by a whopping 400-600 calories per day. In a scientific study, researchers found that the increase energy expenditure in the ketogenic diet was much smaller and approached the limit of science to detect the increase. In addition, fat loss was less compared to those on a high-carb diet. Finally, those eating a ketogenic diet had more water and lean body mass loss than those eating a low-fat, high-carb diet.
5. Documented Side Effects of the Ketogenic Diet from the Pediatric Epilepsy Literature
   1. Arrhythmias
      1. Best et al.
      2. Freeman et al. 1998
   2. Bone Disorders
      1. Decreased Bone Mass without Fracture
         1. Bergqvist et al. 2012
         2. Hahn et al.
         3. Kang et al.
         4. Mackay et al.
      2. Skeletal Fractures
         1. Bergqvist et al. 2007
         2. Groesbeck et al.
   3. Cardiomyopathy
      1. Best et al.
      2. Kang et al.
   4. Carnitine Deficiency
      1. Mackay et al.
      2. Peterson et al.
      3. Rios et al.
   5.  Constipation
      1. Groesbeck et al.
      2. Kang et al.
      3. Mackay et al.
      4. Rios et al.
      5. Vining et al. 1998
      6. Coppola et al.
   6. Cholesterol Abnormalities (Elevated triglycerides, elevated LDL, elevated apolipoprotein B, and/or decreased HDL)
      1. Ballaban-Gil et al.
      2. Bergqvist et al. 1998
      3. Bergqvist et al. 2012
      4. Chesney et al.
      5. Dekaban
      6. Groesbeck et al.
      7. Kang et al.
      8. Kwiterovich et al.
      9. Mackay et al.
      10. Nizamuddin et al.
      11. Rios et al.
      12. Vining et al. 1999
      13. Coppola et al.
      14. Suo et al.
      15. Retterstol et al.
   7.  Death
      1. Bank et al.
      2. Groesbeck et al.
      3. Kang et al.
      4. Stewart et al.
   8.  Dehydration
      1. Kang et al.
      2. Wheless
   9. Gastrointestinal Disturbance (Nausea, Vomiting, Diarrhea)
      1. Bergqvist et al. 2012
      2. Freeman et al. 1998
      3. Kang et al.
      4. Mackay et al.
      5. Rios et al.
      6. Vining et al. 1998
      7. Coppola et al.
      8. Galvan et al.
      9. Suo et al.
   10. Hematologic Disturbances (Anemia, Bone Marrow Suppression, Neutropenia, Platelet Dysfunction)
       1. Ballaban-Gil et al.
       2. Berry-Kravis et al.
       3. Chin et al.
       4. Goodwell et al.
       5. Kang et al.
       6. Rashidian et al.
       7. Suo et al.
   11. Hepatic Dysfunction
       1. Ballaban-Gil et al.
       2. Kang et al.
       3. Suo et al.
       4. Freeman et al. 2006
   12. Hypoglycemia
       1. Kang et al.
       2. Mackay et al.
       3. Rios et al.
       4. Coppola et al.
   13. Hyponatremia
       1. Kang et al.
   14. Hypoproteinemia
       1. Ballaban-Gil et al.
       2. Kang et al.
       3. Suo et al.
   15. Hypercalciuria
       1. Mackay et al.
   16. Hyperuricemia
       1. Kang et al.
       2. Suo et al.
   17. Infections (Non-Pneumonial)
       1. Kang et al.
       2. Vining et al. 1998
       3. Coppola et al.
       4. Suo et al.
   18. Kidney Stones
       1. Bergqvist et al. 2012
       2. Freeman et al. 1998
       3. Furth et al.
       4. Groesbeck et al.
       5. Hemingway et al.
       6. Kang et al.
       7. Kielb et al.
       8. Livingston
       9. McNally et al.
       10. Rios et al.
       11. Sampath et al.
       12. Suo et al.
   19. Lack of Appetite (Hyporexia/Refusing Food)
       1. Rios et al.
       2. Coppola et al.
       3. Suo et al.
   20. Lipemia Retinalis
       1. Livingston
   21. Metabolic Acidosis
       1. Best et al.
       2. Freeman et al. 1998
       3. Rios et al.
       4. Kang et al.
       5. Vining et al. 1998
       6. Coppola et al.
       7. Suo et al.
   22. Mineral Deficiencies
       1. Calcium
          1. Bergqvist et al. 2007
          2. Hahn et al.
          3. Zupec-Kania et al.
          4. Suo et al.
       2. Chromium
          1. Zupec-Kania et al.
       3.  Copper
          1. Chin et al.
          2. Goodwell et al.
          3. Rashidian et al.
          4. Zupec-Kania et al.
       4.  Iron
          1. Kang et al.
       5. Magnesum (Hypomagnesemia)
          1. Kang et al.
       6.  Manganese
          1. Zupec-Kania et al.
       7.  Molybdenum
          1. Zupec-Kania et al.
       8.  Phosphorus
          1. Bergqvist et al. 2007
          2. Zupec-Kania et al.
       9.  Selenium
          1. Best et al.
          2. Chee et al.
          3. Zupec-Kania et al.
       10.  Zinc
           1. Bergqvist et al. 1999
           2. Zupec-Kania et al.
   23. Optic Neuropathy
       1. Hoyt et al.
   24.  Pancreatitis
       1. Kang et al.
       2. Mackay et al.
       3. Stewart et al.
   25.  Pneumonia
       1. Freeman et al. 1998
       2. Kang et al.
   26. Prolongation of QT Interval
       1. Best et al.
   27. Restricted Growth
       1. Bergqvist et al. 2007
       2. Bergqvist et al. 2012
       3. Groesbeck et al.
       4. Hemingway et al.
       5. Mackay et al.
       6. Peterson et al.
       7. Vining et al. 2002
       8. Williams et al.
   28. Vitamin Deficiencies
       1. Biotin
          1. Zupec-Kania et al.
       2. Folate
          1. Zupec-Kania et al.
       3.  Niacin
          1. Zupec-Kania et al.
       4. Pantothenic Acid
          1. Zupec-Kania et al.
       5.  Riboflavin
          1. Zupec-Kania et al.
       6.  Thiamin
          1. Zupec-Kania et al.
       7. Vitamin B1
          1. Hoyt et al.
       8. Vitamin B6
          1. Zupec-Kania et al.
       9. Vitamin C
          1. Zupec-Kania et al.
       10. Vitamin D
           1. Bergqvist et al. 2007
           2. Hahn et al.
           3. Zupec-Kania et al.
6. Harms of Low-Carbohydrates Diets in General
   1. Birth Defects (Neural Tube Defects)
      1. Desorsiers et al.
   2. All-Cause Mortality
      1. Fung et al.
      2. Lagiou et al.
      3. Li et al.
      4. Noto et al.
      5. Seidelmann et al.
      6. Sjögren et al.
      7. Trichopoulou et al.
      8. Global Burden of Disease Study 2016
         1. Largest dietary risk factor for death is a diet low in whole grains
         2. Of note, previous years have shown similar results
   3. Cancer Mortality
      1. Fung et al.
      2. Trichopoulou et al.
   4. Cardiovascular Mortality
      1. Fung et al.
      2. Lagiou et al.
      3. Li et al.
      4. Sjögren et al.
      5. Trichopoulou et al.
   5. Coronary Artery Calcification
      1. Snell-Bergeon et al.
   6. Cardiovascular risk factors
      1. Mansoor et al,

If you have other studies or comments, please post them below in the reply section of this page. You can also share them with me on Twitter @sjoshiMD.

Last Updated 11/4/18