Obesity, type 2 diabetes and hypertension represent a major health problem. These conditions are components of the metabolic syndrome affecting every fifth adult worldwide [1]. Although it is now acknowledged that type 2 diabetes and hypertension mostly result from lifestyle factors but medical treatment continues to rely on drugs [2]. Symptoms of the metabolic syndrome typically show up in mid-life but the number of co-morbidities are increasing through later years. Typically, symptoms are controlled with an increasing number of drugs. In parallel side effects are also increasing and are usually controlled with additional medications. It is a vicious circle. Currently, a major proportion of elderly in the western world is overmedicated [3]. In sharp contrast with this diseases of civilization are virtually absent in contemporary hunter-gatherer societies [4]. It is suggested that chronic diseases of civilization result from an evolutionary mismatch between our ancient and current diet [5]. It was also suggested that a return to an evolutionary adapted diet may be beneficial for health [5]. The paleolithic diet has previously been shown to confer metabolic benefits in healthy as well as in patients with metabolic syndrome [6] [7] [8] [9] [10]. Voegtlin, first proponent of the human evolutionary diet, suggested an animal fat-meat based diet as being evolutionary adapted [11]. Recently, we reported successful treatment of patients with epilepsy [12] and type 1 diabetes [13] with the paleolithic ketogenic diet. The diet we refer to as the paleolithic ketogenic diet is close to the meat-fat based diet originally proposed by Voegtlin [11]. Herein, we report on a patient with obesity, type 2 diabetes and hypertension whose excessive medication could be discontinued and clinical parameters associated with the metabolic syndrome markedly improved.

Previous medical history
The patient's previous medical history included gallbladder surgery in 1987 due to choledocholithiasis and chronic cholecystitis. Hyperglycemia and impaired glucose tolerance was first demonstrated on 24 February 2004. Due to bloody stool Weber test was performed on 25 August 2006 which showed positivity. Therefore, colonoscopy was performed on 19 September 2006 which indicated a 2-cm polyp in the sigmoid colon. Irrigoscopy performed on 25 September 2006 confirmed the above mentioned polyp and also indicated dilation of the colon as well as sigmoid diverticulosis. The polyp was removed on 6 November 2006. Histopathology from this specimen showed tubulovillous adenocarcinoma in polyp (Grade 1). Resection margins were negative. Gastroscopy performed on 21 September 2006 indicated reflux esophagitis and erosive gastritis. Gastroscopy follow-up, three years later, on 26 January 2009 indicated reflux esophagitis but no evidence of gastritis. A next gastroscopy follow-up on 26 January 2011, showed reflux esophagitis and a 5-mm gastric polyp which was removed. Histopathology from this sample showed no abnormalities. A subsequent gastroscopy performed on 14 March 2013 showed reflux esophagitis. Colonoscopy follow-up on 26 January 2007 demonstrated dilation of colon. Subsequent colonoscopy examinations on 27 August 2007, 25 August 2008, 31 August 2009 and 15 April 2013 were able to examine the colon until the transversus lienalis and showed no alterations. A computed tomography (CT) colonography on 27 April 2011 was negative too.

On 10 December 2009, she experienced pressing pain behind the sternum. Echocardiography on 14 December 2009 showed impaired left ventricular diastolic function as well as aortic and mitral insufficiency.

A routine ophthalmological examination on 01 June 2006 showed crossing phenomenon and hyperemic macula, ocular signs of hypertonia and diabetes. Follow- up ophthalmology examination on 20 May 2009 and on 21 May 2010 showed angiopathy while follow-up examinations on 18 May 2012 and 30 July 2013 indicated angiopathy as well as retinopathy.

Medications
Due to elevated blood glucose parameters and high blood pressure from 01 March 2005 onwards the patient was treated with acarbose, ramipril and hydrochlorothiazide. On 02 November 2006 pantoprazole was added because of reflux esophagitis revealed by gastroscopy. Due to increases in blood glucose from 23 August 2007, the patient was also taking metformin. On 14 December 2009 bisoprolol was added because of high blood pressure. Following the cardiological event acetylsalicylic acid was prescribed on 15 April 2010. From 28 October 2010, the patient was prescribed amlodipine due to high blood pressure. The number and the names (active substance) of the medications taken through the course of the disease and the associated 90-min glucose are indicated in Figure 1.

Paleolithic ketogenic diet
We first met the 65-year-old female on 30 January 2013. She was overweight (BMI 37.1, height 160 cm, weight 95 kg), had high blood sugar and frequent high blood pressure spikes despite antidiabetic and antihypertensive medication. At this time her systolic blood pressure was between 130 and 160 mmHg and diastolic blood pressure between 70 and 85 mmHg. Her fasting glucose level was between 144 and 162 mg/dL. Altogether she was taking eight medicines. The patient was motivated in weight loss and in the reduction of her medication. She was advised to start the paleolithic ketogenic diet. She was suggested a diet consisting of at least 70% animal-based food with a fat : protein ratio of at least 2:1. Fat and red meats were preferred over lean meats. Offals meat were encouraged to ensure adequate intake of vitamins. No more than 30% of the diet was suggested as plant-derived food including root vegetables and small amounts of fruit. Dairy, cereals, grains, legumes, solanaceous vegetables, plant oils (including coconut oil), artificial sweeteners and foods with additives were not allowed. In addition to the paleolithic ketogenic diet, she was taking 2000 IU of vitamin D3 for four months then it was stopped. No other vitamin or mineral supplements were used. Typical foods the patient was eating include broth, stew, fried bacon, beef steak, stewed calf liver, braised pork marrow, greaves. Vegetables consumed as garnish were limited and typically included root vegetables, onion and cabbage.

Upon diet commencement (on the third day of the diet) all medications were stopped promptly except for bisoprolol which was discontinued within two weeks. The patient was controlled tightly during the first weeks of the diet. In case of high blood pressure, she was advised to take captopril, a short-acting antihypertensive. Laboratory workup was performed regularly (eight times during 22 months on the diet) in order to control adherence to the diet and to give feedback to the patient (Table 1). All urinary analyses were positive for ketones. While on the paleolithic ketogenic diet blood glucose level, 90-min glucose on the glucose tolerance test, HgA1c and total cholesterol levels decreased as compared to previous measurements. Triglyceride levels also dropped markedly as well as inflammatory markers including erythrocyte sedimentation rate. A statistical analysis (t-test) comparing laboratory measures during the two years of the paleolithic ketogenic diet and during the previous nine years on a normal diet revealed a significant decrease for HgA1c (p=0.02), cholesterol (p=0.01) and triglyceride (p=0.003). Typically, the patient had two meals a day. She tracked glucose levels daily both preprandially and postprandially before and after the first meal of the day. The patient reported to strictly adhere to the diet insofar not consuming non-paleolithic food at all. At the same time she admitted having some difficulties with fruit restriction and reported that her spikes in blood sugar (Figure 2) and blood pressure to be associated with these events of excess fruit intake. Nevertheless home monitoring of glucose showed a clear decreasing trend both preprandially and postprandially between February 2013 and June 2014 (Figure 2). Then due to the normalization of blood glucose she measured blood glucose levels only occasionally. While on the diet she also reported a decreasing tendency in the frequency of high blood pressure spikes. At the time of writing this case report, she had no high blood pressure spike for six months. Despite no vitamin D supplementation, her winter time vitamin D level (on 05 March 2014) was in the normal range (85 nmol/L). The patient did not perform exercise while on the paleolithic diet.

Currently, she is on the diet for 22 months. While on the diet her weight changed from 95 kg to 81 kg and she is still losing weight. Her BMI changed from 37.1 to 31.6. She reported increased physical fitness and to be free of symptoms. The patient gave written informed consent for publication of her case.

Recent clinical studies show that low-carbohydrate diets including the paleolithic diet are beneficial in conditions associated with the metabolic syndrome [6] [7] [8] [9] [10]. In the current medical practice, patients with metabolic syndrome are generally treated with numerous drugs. Yet studies available on the paleolithic diet does not give clues how to deal with preexisting medications when shifting towards the paleolithic diet. Our experience indicate that upon the shift towards the paleolithic ketogenic diet most drugs become unnecessary and should be discontinued [14].

Herein, we analyzed past medical history of a patient with metabolic syndrome to reveal how her medication might have contributed to the worsening of her disease and how disease was influenced by the paleolithic ketogenic diet.

This case represents a typical disease career of a patient with metabolic syndrome. Her medical history included elevated glucose parameters and hypertension initially controlled with oral antidiabetics and antihypertensives in 2005. Then with the emergence of new diagnostic findings pantoprazole was added. Two years later metformin was added to support glucose metabolism. Nevertheless glucose control deteriorated again in 2011 following the addition of three new drugs. These included bisoprolol, acetylsalicylic acid and amlodipine. Bisoprolol and amlodipine, which belong to beta-blocker and calcium channel blocker type antihypertensives, respectively, are known for their effect to adversely affect glucose metabolism [15] [16]. Glucose parameters further deteriorated in 2012.

Current guidelines first advise lifestyle changes and exercise to treat the metabolic syndrome and to induce weight loss [1]. Yet these dietary advices usually remain without effect [17]. Also, overweight people are unable to exert considerable physical activity. Therefore, patients are prescribed medications. A main problem is that in current medical practice each component of the metabolic syndrome is treated separately even though targeting one symptom by a drug may worsen another symptom also associated with the metabolic syndrome. Therefore, the number of drugs as well as side effects are increasing.

Our patient was overweight and was taking eight medicines. When shifting towards the paleolithic ketogenic diet she was able to discontinue all medications. Her weight begin to decrease along with improving glucose parameters and lowered blood pressure. Our experience with patients on the paleolithic ketogenic diet indicate that the use of antihypertensive drugs hinder the normalization of glucose levels and weight loss [14]. Also, antihypertensive drugs become unnecessary since the paleolithic ketogenic diet efficiently lowers high blood pressure. In this case, antihypertensive drugs could be discontinued because the patient had no atherosclerosis. In those cases, with atherosclerosis antihypertensives may be discontinued only within a longer time period. The blood pressure lowering effect of the paleolithic ketogenic diet is due to the fact that the paleolithic ketogenic diet limits those food components which result in elevated blood pressure. These components mainly include fruits and foods with added fructose. Drop in blood pressure was also reported in previous studies with the paleolithic diet [6] [8]. Our experience with patients with hypertension indicate that as compared to the paleolithic diet which does not limit fruits and vegetables, the paleolithic ketogenic diet more efficiently normalize blood pressure. Given that in the paleolithic ketogenic diet carbohydrate intake is strongly limited less insulin is required for normoglycemia and therefore oral antidiabetics become unnecessary.

While on the paleolithic ketogenic diet home monitoring of glucose in our patient showed a decreasing tendency both preprandially and postprandially. Laboratory measurements also showed a decreasing tendency in glucose parameters and triglyceride normalized too. Total cholesterol and LDL cholesterol tended to decrease while HDL cholesterol remained relatively unchanged. Uric acid remained in the normal range while on the paleolithic ketogenic diet. These laboratory parameters are similar to those in our two previous cases on the paleolithic ketogenic diet [12][13]. All six urinary tests were positive for ketones indicating a good adherence to the diet. The patient admitted to occasionally exceed the advised limit for fruit. She also linked excessed fruit intake to high blood pressure spikes which is in accordance with literature data showing high blood pressure to be associated with fructose [18]. Nevertheless our patient reported a decreasing tendency of blood pressure across the 22 months.

Those patients who underwent gallbladder surgery are advised against eating fatty foods and the ketogenic diet too. Our patient, however, reported no gastrointestinal side effects while on the paleolithic ketogenic diet. Of note, her winter-time vitamin D level was normal in spite of no vitamin D supplementation indicating that a regular intake of offal, animal fat and meat may ensure normal vitamin D status. Also, no signs of vitamin or mineral deficiency emerged despite of the lack of supplementation.

Currently, the patient is on the paleolithic ketogenic diet for 22 months. No side effects emerged and she is free of symptoms. She is resoluted to continue the diet.

The paleolithic ketogenic diet proved to be a safe, feasible and effective therapy in this patient with metabolic syndrome. Medications could be discontinued and components of the metabolic syndrome improved continuously. We used the paleolithic ketogenic diet in a patient without a gallbladder indicating that, contrary to the widely held notion, this organ is not a prerequisite for maintaining a diet rich in animal fat. Neither vitamin nor other supplements was used indicating the effectiveness of the paleolithic ketogenic diet as a sole therapy.

1. International Diabetes Federation: The IDF consensus worldwide definition of the metabolic syndrome. Available at: http://www.idf.org/metabolic-syndrome Accessed December 8, 2014.    
2. Perez-Pastor EM, Metcalf BS, Hosking J, Jeffery AN, Voss LD, Wilkin TJ. Assortative weight gain in mother-daughter and father-son pairs: An emerging source of childhood obesity. Longitudinal study of trios (EarlyBird 43). Int J Obes (Lond) 2009 Jul;33(7):727–35.   [CrossRef]   [Pubmed]    
3. Hofer-Dückelmann C. Gender and polypharmacotherapy in the elderly: A clinical challange. In: Sex and Gender Differences in Pharmacology (Ed: Regitz-Zagrosek V) 2002. pp. 169–82.    
4. Lindeberg S. Food and western disease: Health and nutrition from an evolutionary perspective. Chichester: Wiley-Blackwell 2009.    
5. Cordain L. The paleo diet: Lose weight and get healthy by eating the food you were designed to eat. New York: Wiley 2002.    
6. Österdahl M, Kocturk T, Koochek A, Wändell PE. Effects of a short-term intervention with a paleolithic diet in healthy volunteers. Eur J Clin Nutr 2008 May;62(5):682–5.   [CrossRef]   [Pubmed]    
7. Jönsson T, Granfeldt Y, Ahrén B, et al. Beneficial effects of a Paleolithic diet on cardiovascular risk factors in type 2 diabetes: A randomized cross-over pilot study. Cardiovasc Diabetol 2009 Jul 16;8:35.   [CrossRef]   [Pubmed]    
8. Frassetto LA, Schloetter M, Mietus-Synder M, Morris RC Jr, Sebastian A. Metabolic and physiologic improvements from consuming a paleolithic, hunter-gatherer type diet. Eur J Clin Nutr 2009 Aug;63(8):947–55.   [CrossRef]   [Pubmed]    
9. Mellberg C, Sandberg S, Ryberg M, et al. Long-term effects of a Palaeolithic-type diet in obese postmenopausal women: A 2-year randomized trial. Eur J Clin Nutr 2014 Mar;68(3):350–7.   [CrossRef]   [Pubmed]    
10. Boers I, Muskiet FA, Berkelaar E, et al. Favourable effects of consuming a Palaeolithic-type diet on characteristics of the metabolic syndrome: A randomized controlled pilot-study. Lipids Health Dis 2014 Oct 11;13:160.   [CrossRef]   [Pubmed]    
11. Voegtlin WL. The stone age diet: Based on in-depth studies of human ecology and the diet of man. New York: Vantage Press 1975.    
12. Clemens Z, Kelemen A, Fogarasi A, Tóth C. Childhood Absence Epilepsy Successfully Treated with the Paleolithic Ketogenic Diet. Neurology and Therapy 2013;2(1-2):71–6.   [CrossRef]    
13. Tóth C, Clemens Z. Type 1 diabetes mellitus successfully managed with the paleolithic ketogenic diet. Int J Case Rep Images 2014;5(10):699–703.   [CrossRef]    
14. Tóth C. Paleolithic medicine (Paleolit orvoslás). Budapest: Jaffa 2012.    
15. Blackburn DF, Wilson TW. Antihypertensive medications and blood sugar: Theories and implications. Can J Cardiol 2006 Mar 1;22(3):229–33.   [CrossRef]   [Pubmed]    
16. Levine M, Boyer EW, Pozner CN, et al. Assessment of hyperglycemia after calcium channel blocker overdoses involving diltiazem or verapamil. Crit Care Med 2007 Sep;35(9):2071–5.   [CrossRef]   [Pubmed]    
17. Accurso A, Bernstein RK, Dahlqvist A, et al. Dietary carbohydrate restriction in type 2 diabetes mellitus and metabolic syndrome: Time for a critical appraisal. Nutr Metab (Lond) 2008 Apr 8;5:9.   [CrossRef]   [Pubmed]    
18. Madero M, Perez-Pozo SE, Jalal D, Johnson RJ, Sánchez-Lozada LG. Dietary fructose and hypertension. Curr Hypertens Rep 2011 Feb;13(1):29–35.   [CrossRef]   [Pubmed]