Excess body weight, from overweight to overt obesity, is associated with adverse health outcomes [
The current first-line strategy includes several treatment options and dietary interventions to be implemented together with an exercise program [
In this scenario, alternative treatment options are warranted. About 40 years ago, after the introduction of protein-sparing modified fast (PSMF) achieved through the use of oral high-protein foods or liquid formula diets by Blackburn and Bistrian, several studies evaluated its effectiveness and safety [
The purpose of the present study was to investigate the potential role of a 2-week course of enteral treatment with a very low-calorie protein-based formula in the management of severe obesity.
The rationale of this treatment option rests on the following considerations: (1) VLCDs appear to be able to reduce cardiovascular risk rapidly and effectively [
Before being proposed for clinical use, a new WL program should be scientifically evaluated [
This is an open-label interventional study in severely obese, adult out-patients.
All subjects consecutively (from April 2010 to February 2013) attending the Clinical Nutrition Unit of our institution for a WL program were screened for inclusion into the study. Patients had to fulfill the following criteria to be eligible: age ≥ 18 years, severe obesity (body mass index (BMI) ≥ 40 kg/m2) [
Patients were prescribed a homemade very low-calorie (~6 kcal/kg of ideal body weight/day) protein-based formula (2000 mL per day) by enteral route for 14 days. A polyurethane 8-French nasogastric tube was inserted on day 1 and removed at the end (day 15) of the cycle. The nutritional formula was administered continuously (24 hours a day) by means of a small, light, and rechargeable peristaltic feeding pump (Flocare Infinity, Nutricia, Italy) equipped with phthalates and latex-free infusion line. All patients received the enteral nutrition bags at home every day. The enteral nutrition bag and the pump were supplied in a backpack, thus enabling patients to continue to lead a normal life, pursuing their activities of daily living as usual.
The intervention formula was made up of a fixed amount of amino acids (arginine, ornithine-alpha-ketoglutarate, taurine, cysteine, tryptophan, hydroxyproline, and citrulline) and a variable quantity of high-quality (milk whey) proteins (Nepisond; Gefaldiet Service srl, Italy) in order to reach a total protein content of 1.2 g per kilogram of ideal body weight [
Composition of the intervention formula provided daily by enteral route.
Component | Amount |
---|---|
Total volume, mL | 2000 |
Total protein content |
1.2 |
Milk whey proteins (as necessary) | |
Arginine, g | 2.25 |
Ornithine-alpha-ketoglutarate, g | 2.25 |
Taurine, g | 0.45 |
Cysteine, g | 0.45 |
Tryptophan, g | 0.75 |
Hydroxyproline, g | 0.45 |
Citrulline, g | 0.45 |
Lipids (linseed oil), g | 10 |
Alpha-linolenic acid, g | 5.5 |
L-Carnitine, mg | 300 |
Coenzyme Q10, mg | 30 |
Policosanols, mg | 500 |
Fructooligosaccharides, g | 15 |
Sodium, mg | 500 |
Potassium, mg | 3000 |
Chlorum, mg | 3000 |
IBW: ideal body weight.
Patients were allowed to drink water or unsweetened drinks freely (not tea or coffee) during the day. A minimum intake of 2 liters daily was recommended. In patients with a history of kidney stones, the amount was increased to 3 liters.
Before the course, all treatments with hypoglycemic agents and diuretics were discontinued to avoid unintended hypoglycaemia and electrolyte imbalance. Other treatments with anti-hypertensive medications and uric acid and lipid-lowering drugs were left unchanged. Finally, a bowel preparation protocol was adopted for dinner two days before the start of intervention: on day 1, 500 mL of probiotic fermented skimmed milk + vegetable side dish seasoned with olive oil + herbal laxative syrup; on day 2, 500 mL of probiotic fermented skimmed milk + vegetable side dish seasoned with olive oil. During the intervention, no use of laxatives was allowed in order to avoid potassium and bicarbonate loss.
All the subjects had height (to the nearest 0.5 cm) and body weight (to the nearest 0.1 Kg) measured by the same calibrated flat scales equipped with a telescopic, vertical steel stadiometer according to standard procedures. The BMI was derived accordingly (weight [kg] and height [m] squared; kg/m2). Waist and hip circumferences (WC and HC, resp.) were assessed (to the nearest 0.5 cm) using a plastic flexible tape. Placing the tape perpendicular to the long axis of the body and parallel to the floor, WC and HC were measured at the midpoint between the lowest rib and the iliac crest and around the largest portion of the buttocks, respectively. The waist-hip ratio (WHR) was also calculated [
Venous blood samples were drawn after 8 to 12 hours of fasting and the following parameters were assessed on the same day by our institutional laboratory using conventional automated analyzers and commercial kits: hemoglobin, total lymphocyte count, blood urea nitrogen (BUN), creatinine, uric acid, glucose, insulin, C-peptide, glycated hemoglobin, growth hormone (GH), insulin-like growth factor 1 (IGF-1), total cholesterol, high-density and low-density lipoprotein cholesterol (HDL and LDL, resp.), triglycerides, apolipoproteins A-I and B (ApoA-I and ApoB, resp.), albumin, serum enzymes (cholinesterase, aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamyl transferase (
Systolic and diastolic blood pressure (SBP and DBP, resp.) were measured by appropriately sized standard sphygmomanometers after having the patient seated for at least 5 minutes in a chair, with feet on the floor and arm supported at heart level. The average of three measurements, obtained at 2-minute intervals, was used for the analysis [
Patients were also screened for the presence of cholestatic liver disease (overt cholelithiasis or biliary sludge).
Data on these parameters were collected at baseline (day 0; tube placement) and at the end (day 15; tube removal) of the intervention, before any pharmacological treatment was reintroduced. Patients were also asked to check their ketosis status daily by means of urine sample spot checks.
It was defined by the necessity to discontinue the intervention. The causes of the discontinuation were to be recorded.
Patients were asked to report the onset of any of the following side effects daily, using a self-administered questionnaire: asthenia, headache, dizziness, fainting, orthostatic hypotension, heartburn, nausea, vomiting, palpitations, muscle cramps, hunger, and constipation. Safety was also assessed by the evaluation of changes in the following hematological and biochemical parameters and, for those presenting with normal values, by the excursion outside of the reference ranges of our laboratory (new cases): hemoglobin, total lymphocyte count, BUN, creatinine, uric acid, albumin, serum enzymes (cholinesterase, AST, ALT,
It was defined by the changes (increase (HDL, ApoA-I, and GH) or more frequently the reduction (all the others)) in the following study parameters: body weight, BMI, WC, HC, WHR, uric acid, glucose, insulin, HOMA-IR, C-peptide, glycated hemoglobin, IGF-1, total cholesterol, HDL, LDL, triglycerides, triglyceride/HDL ratio, ApoB, ApoB/ApoA-I ratio, AST, ALT, and
All statistical analyses were performed using the software MEDCALC for Windows, Version 11.3.0.0 (MedCalc Software, Mariakerke, Belgium). The level of significance was set at the two-tailed
Safety parameters were analyzed in and reported for the per-protocol (PP) population. However, the analysis of efficacy parameters was conducted according to the intention-to-treat (ITT) principle. Accordingly, all patients who had been assessed at baseline were included in the ITT population. The value observed at baseline was used in the analyses for dropouts.
Data were presented as mean and standard deviation (SD) or counts and percentage, as appropriate.
Group comparisons were performed using Fisher’s exact test (categorical variables) and Student’s
Changes in study parameters were investigated by Student’s
In total, 364 patients (59% females; BMI (mean ± SD),
Overall, the intervention was well tolerated. Twenty-six patients (7%; 13 men and 13 women) had to discontinue the intervention within 48 hours. Discontinuation was only due to nasogastric tube intolerance (physical discomfort or social reasons). The features of dropouts were similar to those of completers (Supplementary Table 1, available online at
No serious adverse events occurred during the intervention. Throughout the intervention period, constipation was the most frequently reported side effect (8.6% and 10.9% during the first and the second week, resp.). Other frequent (>10%) side effects reported during the first week were headache and hunger. However, their frequency was significantly reduced during the second week of the study. The same applied to other symptoms, with the exception of muscle cramps. Nonetheless, prevalence was almost below 5%. The frequency of self-reported side effects throughout the study is reported in detail in Table
Self-reported side effects throughout the study (per-protocol population;
Side effect | Days 1–7 | Days 8–14 |
---|---|---|
|
|
|
Asthenia | 17 (5.1) | 6 (1.8) |
Headache | 34 (10.0) | 3 (0.9) |
Dizziness | 2 (0.6) | 1 (0.3) |
Fainting | 4 (1.2) | 1 (0.3) |
Orthostatic hypotension | 25 (7.4) | 12 (3.6) |
Heartburn | 23 (6.8) | 11 (3.3) |
Nausea | 13 (3.8) | 3 (0.9) |
Vomiting | 6 (1.8) | 2 (0.6) |
Palpitations | 4 (1.2) | 2 (0.6) |
Muscle cramps | 7 (2.1) | 13 (3.8) |
Hunger | 34 (10.1) | 12 (3.6) |
Constipation | 29 (8.6) | 37 (10.9) |
In respect to hematological and biochemical variables (Table
Changes in hematological and biochemical safety parameters after the intervention (per-protocol population;
Variable | Baseline | Day 14 | Mean difference |
|
Laboratory range | New cases | |
---|---|---|---|---|---|---|---|
|
|
|
Below the lower limit |
Above the upper limit |
|||
Hemoglobin, g/L | 14.0 (1.5) | 14.1 (1.4) | 0.1 |
0.005 | 12.0–15.5 (13.5–17.0) | 12 (3.6) | 5 (1.5) |
Lymphocytes, |
2334 (651) | 1946 (587) | −388 |
<0.001 | 1300–3600 | 23 (6.8) | 2 (0.6) |
Blood urea nitrogen, mg/dL | 31 (8) | 26.7 (7.5) | −3.9 |
<0.001 | 10–50 | 0 | 1 (0.3) |
Creatinine, mg/dL | 0.71 (0.15) | 0.77 (0.16) | 0.06 |
<0.001 | 0.55–1.2 | 7 (2.1) | 1 (0.3) |
Uric acid, mg/dL | 5.6 (1.2) | 8.1 (2.3) | 2.5 |
<0.001 | 3.5–7.0 | 0 | 178 (52.7) |
Albumin, g/L | 44.4 (0.5) | 45.9 (0.5) | 1.5 |
<0.001 | 35.0–52.0 | 2 (0.6) | 8 (2.4) |
Cholinesterase, UI/dL | 9839 (1906) | 9617 (1893) | −222 |
<0.001 | 4250–11250 | 2 (0.6) | 21 (6.2) |
AST, UI/dL | 23 (10) | 34 (17) | 11 |
<0.001 | 6–39 | 0 | 34 (10.1) |
ALT, UI/dL | 32 (21) | 47 (32) | 15 |
<0.001 | 6–34 | 0 | 90 (26.6) |
30 (31) | 22 (13) | 8 |
<0.001 | 6–42 | 0 | 4 (1.2) | |
CPK, UI/dL | 121 (75) | 134 (88) | 13 |
0.003 | 24–190 | 0 | 37 (10.9) |
LDH, UI/dL | 424 (87) | 438 (98) | 14 |
0.002 | 125–600 | 0 | 21 (6.2) |
Sodium, mEq/L | 139 (2.2) | 138 (2.5) | −1.0 |
<0.001 | 135–153 | 21 (6.2) | 0 |
Potassium, mEq/L | 4.4 (0.3) | 4.5 (0.3) | 0.1 |
<0.001 | 3.5–5.3 | 1 (0.3) | 3 (0.9) |
Magnesium, mg/dL | 1.98 (0.17) | 1.93 (0.18) | −0.05 |
<0.001 | 1.7–2.6 | 5 (1.5) | 0 |
Calcium, mg/dL | 9.3 (0.4) | 9.6 (0.4) | 0.4 |
<0.001 | 8.6–10.5 | 1 (0.3) | 4 (1.2) |
Phosphorus, mg/dL | 3.4 (0.5) | 3.7 (0.5) | 0.3 |
<0.001 | 2.7–4.5 | 3 (0.9) | 15 (4.4) |
BMI: body mass index; AST: aspartate aminotransferase; ALT: alanine aminotransferase;
aBaseline versus end of study (by Student’s
Despite similar age (women, 40.1 [SD, 10.8] versus men, 41.1 [SD, 10.3];
The intervention resulted in significant WL (ITT population, 5.7% [SD, 2.3]; PP population, 6.1% [SD, 1.8]; Table
Changes in anthropometric, clinical, and metabolic features after the intervention (efficacy analysis; intention-to-treat population [
Characteristic | Baseline | Day 14 |
|
---|---|---|---|
[Mean (SD)] | [Mean (SD)] | ||
Body weight, kg | 129.0 (24.2) | 121.7 (23.5) | <0.001 |
BMI, kg/m2 | 46.6 (7.2) | 43.9 (7.1) | <0.001 |
Waist circumference, cm | 134.5 (16.4) | 129.1 (16.1) | <0.001 |
Hip circumference, cm | 139.0 (15.1) | 134.9 (14.8) | <0.001 |
Waist-hip ratio | 0.97 (0.09) | 0.96 (0.09) | 0.068 |
Uric acid, mg/dL | 5.6 (1.2) | 7.9 (2.4) | <0.001 |
Glucose, mg/dL | 98 (27) | 82 (17) | <0.001 |
Insulin, |
23 (19) | 12 (12) | <0.001 |
HOMA-IR | 5.8 (6.0) | 2.6 (3.3) | <0.001 |
C-peptide, ng/mL | 4.3 (2.2) | 2.7 (1.6) | <0.001 |
HbA1C, % | 5.8 (1.0) | 5.6 (0.8) | <0.001 |
Growth hormone, ng/mL | 0.62 (1.39) | 165 (2.93) | <0.001 |
IGF-1, ng/mL | 146 (75) | 124 (76) | <0.001 |
Total cholesterol, mg/dL | 194 (34) | 156 (37) | <0.001 |
HDL cholesterol, mg/dL | 47 (12) | 36 (10) | <0.001 |
LDL cholesterol, mg/dL | 125 (31) | 99 (38) | <0.001 |
Triglycerides, mg/dL | 135 (75) | 100 (38) | <0.001 |
Triglycerides-HDL ratio | 3.3 (2.6) | 3.1 (1.7) | 0.032 |
ApoA-I, mg/dL | 144 (31) | 112 (35) | <0.001 |
ApoB, mg/dL | 103 (43) | 89 (36) | <0.001 |
ApoB/ApoA-I ratio | 0.75 (0.43) | 0.88 (0.56) | <0.001 |
SBP, mmHg | 134 (11) | 126 (9) | <0.001 |
DBP, mmHg | 81 (8.5) | 75 (6.7) | <0.001 |
Heart rate, bpm | 73 (3.6) | 72 (3.3) | <0.001 |
BMI: body mass index; HOMA-IR: homeostasis model assessment of insulin resistance; HbA1C: glycosylated hemoglobin; IGF-1: insulin-like growth factor 1; HDL: high density lipoprotein; LDL: low density lipoprotein; ApoA-I: apolipoprotein A-I; ApoB: apolipoprotein B; SBP: systolic blood pressure; DBP: diastolic blood pressure.
aBaseline versus end of study by Student’s
WL resulted in significant improvement in blood pressure, in all anthropometric variables and most hematological and biochemical parameters. As expected, uric acid and ApoB/ApoA-I ratio showed an increase, while HDL, ApoA-I, and IGF-1 were significantly decreased (Table
In secondary efficacy analyses (multivariable linear regression; Table
Age-adjusted changesa in cardiometabolic and clinical parameters according to gender and diabetes (generalized linear regression analysis in intention-to-treat population
Characteristic | Mean (SD)a | Gender (men versus women) | Diabetes (yes versus no) | ||
---|---|---|---|---|---|
Difference |
|
Difference |
|
||
Weight loss, % | −5.7 (2.3) | −0.4 |
0.109 | 0.1 |
0.853 |
Waist circumference, cm | −5.4 (3.6) | −0.2 |
0.537 | −0.2 |
0.612 |
Hip circumference, cm | −4.1 (3.8) | 0.1 |
0.756 | −0.7 |
0.140 |
Waist-hip ratio | −0.01 (0.02) | 0.001 |
0.657 | 0.003 |
0.268 |
Uric acid, mg/dL | 2.3 (2.1) | 0.1 |
0.714 | −0.02 |
0.942 |
Glucose, mg/dL | −16 (22) | −2 |
0.275 | −19 |
<0.001 |
Insulin, |
−11 (16) | −5 |
0.009 | −5 |
0.016 |
HOMA-IR | −3.2 (4.9) | −1.5 |
0.004 | −2.9 |
<0.001 |
C-peptide, ng/mL | −1.6 (1.9) | −0.4 |
0.037 | −0.6 |
0.013 |
HbA1C, % | −0.2 (0.40) | −0.03 |
0.438 | −0.1 |
0.004 |
Growth hormone, ng/mL | 1.04 (2.32) | −0.1 |
0.722 | −0.2 |
0.527 |
IGF-1, ng/mL | −20 (65) | 23 |
0.005 | −13 |
0.174 |
Total cholesterol, mg/dL | −39 (31) | 5 |
0.137 | 2 |
0.551 |
HDL cholesterol, mg/dL | −11 (10) | 3 |
0.002 | 2 |
0.106 |
LDL cholesterol, mg/dL | −26 (29) | 3 |
0.289 | 7 |
0.068 |
Triglycerides, mg/dL | −35 (61) | −13 |
0.031 | −25 |
0.001 |
Triglycerides-HDL ratio | −0.2 (2.0) | −0.3 |
0.183 | −0.8 |
<0.001 |
ApoA-I, mg/dL | −30 (40) | 8 |
0.116 | −4 |
0.480 |
ApoB, mg/dL | −9 (28) | 3 |
0.472 | 1 |
0.826 |
ApoB/ApoA-I ratio | 0.15 (0.58) | −0.1 |
0.219 | 0.1 |
0.238 |
SBP, mmHg | −7.7 (10.2) | −2.3 |
0.035 | −2.2 |
0.047 |
DBP, mmHg | −5.4 (8.3) | −1.9 |
0.037 | −2.3 |
0.031 |
Heart rate, bpm | −1 (3.8) | −0.05 |
0.906 | −0.5 |
0.327 |
SD: standard deviation; BMI: body mass index; HOMA-IR: homeostasis model assessment of insulin resistance; HbA1C: glycosylated hemoglobin; IGF-1: insulin-like growth factor 1; HDL: high density lipoprotein; LDL: low density lipoprotein; ApoA-I: apolipoprotein A-I; ApoB: apolipoprotein B; SBP: systolic blood pressure; DBP: diastolic blood pressure.
aChanges (in percentage) were computed as follows: final – baseline.
In respect to the improvement of cardiometabolic profile, we report also that the diuretic therapy was no longer deemed necessary while oral hypoglycemic agents were reintroduced at half of the initial dose.
The present study has shown that a 2-week course of PSMF, achieved through the administration of a very low-calorie protein-based formula by enteral route, is a feasible, safe, and effective procedure to be taken into due consideration for a composite weight loss program for the management of severe obesity.
The effectiveness of VLCD has been reported to rest on its appetite-suppressing ketogenic nature, which mimics the anorexia of starvation, and the satiating effect associated with its high-protein content [
In our study, discontinuation of therapy was unrelated to adverse effects and was driven only by intolerance to the tube, either for physical or social reasons. Self-reported side effects were few and mainly limited to the first days of the intervention. Previous studies have reported the occurrence or intensification of emotional disturbances, such as depression and anxiety during intensive WL [
The intervention investigated herein has also proved to be effective in reducing body weight and improving the cardiometabolic risk profile. This was particularly evident in diabetic patients, thus supporting the efficacy of VLCDs in rapidly modifying cardiovascular risk [
Current guidelines [
PSMF and more extensively prolonged VLCDs have raised concerns and criticisms because of the risk of complications, which may occur not only during the intervention but also during the “refeeding” phase and are mainly related to electrolyte disturbances. These include some major problems, such as nephrolithiasis or arrhythmias, and other minor issues (headache, nausea, occasional vomiting, bad breath, fatigue, muscle cramps, and constipation) [
Finally, another concern with VLCDs is weight regain. On the one hand, initial WL appears to predict lower body weight at follow-up. On the other, rapid WL has been also associated with greater regain during the maintenance phase [
The strengths of our study are the large study population, the rigorous selection of the patients, and the standardized and responsible approach.
However, also its limitations should be taken into account. First, this was an observational study and randomized trials including control groups—treated either with standard hypocaloric diet or oral VLCD—should be performed to achieve a more rigorous evaluation among the plethora of available WL interventions. Second, the present report focused only on data addressing a single enteral course of treatment; the impact of this intervention should be clearly evaluated within the broader context of a long-term composite weight management program. Particularly, in order to further support its use in clinical practice, postintervention normalization of safety parameters needs to be addressed. Finally, the evaluation of self-perceived outcome measures (e.g., hunger or wellbeing) by means of visual analogue scales would have been also informative.
In conclusion, a 14-day course of enteral treatment with a very low-calorie protein-based formula appears to be a feasible, likely safe, and efficacious therapeutic option to be taken into consideration for a composite weight loss program for the management of severe obesity.
The study was performed in adherence with the principles established by the Declaration of Helsinki. The study protocol was approved by the Ethics Committee of the A.O.R.N. “San Giuseppe Moscati” (Avellino, Italy).
Dr. G. Castaldo had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
The sponsor of this study had no role in the design and conduct of the study; in the collection, management, analysis, and interpretation of the data; or in the preparation, review, or approval of the paper.
The authors certify that there are no affiliations with or involvement in any organization or entity with a direct financial interest in the subject matter or materials discussed in the paper and indicated no potential conflict of interests.
All authors approved the final version of the paper. G. Castaldo was responsible for study concept and design. G. Castaldo and L. Castaldo were responsible for acquisition of data. G. Castaldo was responsible for analysis and interpretation of data. G. Castaldo was responsible for drafting of the paper. G. Castaldo, L. Monaco, and P. Sorrentino were responsible for critical revision of the paper for important intellectual content. G. Castaldo was responsible for statistical analysis. G. Castaldo obtained funding. G. Castaldo, Monaco, and P. Sorrentino were responsible for administrative, technical, or material support. G. Castaldo was responsible for study supervision.
This work was supported by the A.O.R.N. “San Giuseppe Moscati” (Avellino, Italy) and by unrestricted grants of Nutricia Italia. The authors wish to thank Jennifer S. Hartwig, M.D., for assistance in editing the paper.