Rationale:
Complicated obesity: In weight loss-targeted treatment of obesity, current therapeutic choices include lifestyle modification, drug therapy, and bariatric surgery. For uncomplicated obesity, all the above comprise legitimate means. Attempted weight loss is traditionally initiated by targeting lifestyle, but unfortunately, the long term effect of this approach is limited as regards success rate, the extent of the achieved weight loss and the ability to sustain the achieved weight loss. The use of drugs is mostly reserved for cases where a limited weight loss of 5-10% is considered satisfactory. The safety of drug-assisted weight loss in older obese subjects with co-morbidities such as fluid retention, nephropathy, and heart failure remains insufficiently studied. Even for older subjects without such dominant conditions, data is scarce. For example, two trials (using phentermine/topiramate and liraglutide) have documented efficacy analyses between older adults and their younger, but enrolled only 7% (n= 5254) and 6.9% (n= 5232) older adults, respectively, among their study subjects. It is now well established that in non-elderly subjects, bariatric surgery is followed by substantial weight loss and leads to the cure of obesity and at least to a temporary amelioration/delay/cure of its sequels, including diabetes and hypertension.
However, weight loss is often most critically needed in subjects with complicated obesity, in whom an overall poor health state precludes bariatric surgery altogether. Individuals with long-standing obesity complicated by previous cardiovascular events, diabetes, renal impairment, fluid retention due to renal disease, the use of vasodilator drugs needed to control hypertension (alpha-blockers, calcium channel blocker), left ventricular diastolic dysfunction, respiratory dysfunction including obstructive sleep apnea, pulmonary hypertension, and restrictive lung disease. Such patients are generally too sick to be considered for bariatric surgery. In such patients concomitant weight loss from two body compartments could be extremely beneficial: reduction in fat mass and, often more critical in immediate terms, rapid loss of excess body fluids. In obesity complicated by clinically significant fluid retention, most of the excessive fluid volume is extra-vascular, residing in the extracellular tissue compartment, with only a small, though critical excess, occupying the intracellular compartment. Diuretics are the key tool to reduce volume overload, but they acutely lower the volume of the intravascular fluid compartment, which leads to impairment in renal, myocardial and general tissue arterial perfusion, thus often exacerbating renal failure and overall tissue hypoperfusion, including cerebral, myocardial and hepatic blood supply.
Most older and significantly obese subjects have had sustained obesity for several decades, which has allowed the cumulative evolution of at least some additional comorbidities such as the metabolic syndrome, diabetes, hyperlipidemia coronary heart disease, carotid artery stenosis and/or uncontrolled hypertension, congestive heart failure and renal disease. Paradoxically, then, those older subjects with a complex disease profile, who obviously comprise poor candidates for bariatric surgery, are also the group with the greatest immediate need to lose weight. It is therefore noteworthy that in Israel, individuals over the age of 65 cannot undergo bariatric surgery on the basis of obesity per se, unless approved by a special committee. Although European guidelines for the treatment of obesity in the elderly have concluded that the elderly should not be denied bariatric surgery solely on age grounds, long-term evidence in support of this statement is lacking such that both patients and physicians often consider bariatric surgery at this stage as too risky. Thus, current standard medical practice has little to offer to the complicated older obese patient who, on one hand is burdened with incapacitating obesity and its complications, and, on the other hand, is beyond the reach of the only tool to permanently alleviate obesity, i.e., bariatric surgery.
Intermittent and or short term fasting in humans: There is truly a lack of solid work on the safety and efficacy of fasting as a tool to lose weight in humans. The largest medical database on fasting has been collected on subjects practicing religious fast, such as the Ramadan. However, these forms of fasting are almost uniformly compensated for by excessive feeding either in the beginning or the end of the fast, or both. Insights on the effects of true fasting, longer than 24h, under medical supervision in humans is hard to find in published reports. In one study where caloric restriction for most of the week was combined with one day/week of nearly complete fasting (125Kcal), the intervention was deemed effective and unassociated with untoward effects in 54 obese women over a period of 24 weeks. A recent review included 16 studies of intermittent fasting in humans, of which 11 were carried out in overweight or obese subjects. Duration of the trials varied from 24h to 6 months. In two studies, fasting was daily and lasted from 11 and 16 hours within each day. There were 7 studies lasting 8-12 weeks, with alternate-day fasting, in which fasting was defined as consuming 20-30% of the required caloric intake on the fasting day. In two studies, caloric restriction was defined as consuming 25% less calories on the fasting day. As compared to a variety of more standard dietary measures, intermittent fasting appears to result in some modestly larger weight reduction. Among 16 intervention trials included in review, 11 reported statistically significant weight loss. However, in most of the reviewed intervention trials, complete fasting was either not attempted or restricted to 16 hours only, or less.
Complete intermittent fasting (excluding water) in humans: Despite the lack of data on the effects of complete intermittent fasting, however, a day of fasting is semi/non-intentionally practiced in many subjects undergoing investigative diagnostic procedures such as combined endoscopy and colonoscopy conducted in the afternoon or surgery unexpectedly postponed to the evening hours and many other medical conditions. Unfortunately, this unwanted form of fasting was never studied in depth. However, as early as the late 50s and early 60s of the previous century, it was noted that 5-7 days of complete fasting was associated with diuresis, natriuresis, and weight loss and appeared an effective mode of treatment of the failing heart, in otherwise treatment-refractory subjects who were, at that time, already "fully digitalized". An unexpected finding was the observation that water and salt excretion was enhanced during fasting: one of the fasting patients with heart failure lost 7.3 kg in 5 days, and the average daily weight loss of his 10 original subjects 0.85 kg to 1.5 kg per day, way above what might have been expected by the effect of negative caloric balance on fat and lean tissue loss alone.
Fasting diuresis and fasting as an ancillary tool to lower fluid overload Although it is well known that fasting in obese subjects is associated with natriuresis and development of cumulative negative sodium balance, the mechanism of increased urinary sodium excretion remains largely obscure. The leading hypothesis in recent decades was that reduction in insulin ameliorated increased insulin-driven re-absorption of sodium in the kidney, but overall, following the initial discovery of this phenomenon, it has attracted little research. It is also well established that the obese state, even uncomplicated by renal disease or congestive heart failure, is accompanied by a diminished ability to excrete salt.
During starvation, there appears to be an obligatory sodium loss in linkage to the metabolically generated organic anions, which further enhances fasting related natriuresis. Notably, unlike the action of diuretics and the tubular inhibition of sodium reabsorption, which lowers intravascular volume, the formation of organic anions during starvation takes place in the extravascular compartment, particularly in fat tissue, and would therefore allow the recruitment of tissue sodium (coupled to organic anions formed during lipolysis, and water), followed by the shift of sodium and water from the extravascular compartment to the intravascular compartment, and only then, excretion via the kidney. The latter process, therefore, does not lower intravascular fluid volume and should not impair renal perfusion and function. In support of this concept is the apparent dissociation between sodium and chloride excretion that has been reported with a relatively minimal increase in chloride excretion during the first week of fasting when sodium excretion is rapidly increasing. In fact, during the initial 3 days of fast in obese humans, natriuresis was proportional to urinary 3beta hydroxybutyrate excretion while urinary ammonium had not yet increased, thus indicating that the organic acids generated during lipolysis are the driving force in the shift of sodium from the body, outwards through the kidneys.
