Pharmacotherapy
Historically, anti-obesity pharmacotherapy has been improperly managed due to (a) the too short-term drug prescriptions [16, 28, 29, 48], (b) lack of weight maintenance follow-up [16, 27, 29, 49, 50], (c) lack of pharmacological combinations [16–18, 30], and (d) undertreatment [16, 51], since only 2% of patients with obesity are prescribed pharmacological treatments [51]. Obesity involves multiple central and peripheral mechanisms to prevent weight loss and induce weight regain after a period of weight loss, such as decreased resting metabolic rate and enhanced food-reward circuit sensitivity [16, 27, 29, 49]. Thus, a combination of multiple drugs, whenever there are no harmful interactions, is more adequate and effective than monotherapy, as demonstrated in several studies [16–25]. Likewise, long-term therapy tends to be more successful, particularly, for weight-regain prevention [48], given the fact that metabolic adaptations after weight loss tend to persist for several years afterwards [27, 29, 52], which makes weight loss maintenance challenging [16, 27–29, 49, 50]. Indeed, the AACE obesity guidelines recommend the avoidance of short-term therapy (less than 6 months) due to the proven safety profile and superiority of the long-term use of all the available anti-obesity drugs. The guidelines also recommend a combination of drugs [24], as “appetite regulation involves multiple pathways, and targeting more than one pathway concurrently may have additive or synergistic effects” [24].
The proposed pharmacotherapy protocol in the present study, therefore, relied on the long-term prescription of a combination of many medications. The prescribed non-centrally acting drugs (medications that do not alter neurotransmitter production or signaling) were as follows:
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(1)
Liraglutide, a GLP-1 analogue, which has been approved for long-term obesity treatment [33, 48], and has wide peripheral and central actions, including a central action on newly discovered GLP-1 pathways [53–55];
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(2)
Orlistat, a lipase inhibitor, has been extensively proven to be safe and effective, and has exhibited other benefits besides weight loss, such as effects on non-alcoholic steatohepatitis (NASH) [55] and glycemic control [56–58];
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(3)
SGLT2 inhibitors, which are anti-diabetic drugs that promote weight loss due to glycosuria and calorie loss through urine; they were used here as off-label therapy for obesity. Additionally, the SGLT2 inhibitor empagliflozin has been shown to reduce cardiovascular risks [59], an effect that is expected to be common to this entire class of drugs [60]. SGLT2 inhibitors are also effective for weight loss in non-diabetic patients [61], and have probable synergistic effects with GLP-1 analogues on both glycemic control and weight loss [61]. SGLT2 inhibitors induce gluconeogenesis and increase glucagon and GLP-1 levels, which may contribute to fat loss [62]. In fact, it is been found that SGLT2 inhibitors can be effective as monotherapy for non-diabetic subjects and can enhance weight loss as an add-on therapy to GLP-1 analogues [63];
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(4)
Metformin, a muscle and liver insulin sensitizer, can promote weight loss, especially when insulin resistance is found [64, 65]; and
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(5)
Testosterone was prescribed whenever its deficiency was detected and there were no contraindications, as it has been shown to promote fat loss when hypogonadism and obesity are present together, and improves several metabolic parameters, particularly, in men [66, 67].
Among centrally acting drugs, the proposed medications used in this study were as follows:
Sibutramine, a noradrenaline and serotonin reuptake inhibitor, has been prohibited in some countries, but its use is still allowed, under strict control, in Brazil. The prohibition of sibutramine in some countries was due to the SCOUT study [68], which showed an 11% increase in cardiovascular events with sibutramine use. However, several issues were found in regards to the design of this trial: (a) subjects who were at a high risk of cardiovascular disease were included, which is questionable since a high cardiovascular disease risk is a relative contraindication to sibutramine use; (b) the medication was maintained in patients who did not exhibit weight loss, despite the standardized recommendation of interruption of sibutramine in case of non-responsiveness; (c) subgroup analysis, although not the primary objective, showed that among subjects who were at a high risk of cardiovascular disease, weight loss was associated with a decrease in this risk, whereas among subjects who were not at a high risk of cardiovascular disease, no correlation was detected between weight loss and cardiovascular disease risk. Indeed, further studies involving post-hoc analysis [69] and studies with large populations [70] showed that the wide prohibition of sibutramine marketing might have been inappropriate for patients without cardiovascular disease;
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(1)
Topiramate, originally developed as an anti-epileptic agent, had its use extended to obesity management, when combined with phentermine [20]. This is a safe drug combination [71] that reduces carbohydrate craving and calorie intake [72]. Topiramate also reduces insulin [20] and leptin [73] resistances, and has been shown to exert direct lipolytic effects [74]. Topiramate as an add-on therapy to sibutramine was a plausible alternative in our practice, as phentermine is still not approved in Brazil.
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(2)
Bupropion with naltrexone, which is a combination of a noradrenaline and dopamine reuptake inhibitor and an opioid receptor antagonist with synergistic effects, has been approved as an anti-obesity therapy. It has been shown to induce even greater weight loss than previously predicted (−9.2 kg versus −6.6 kg in previous studies) [75]. Additionally, it reduces CRP and WC, and increases HDLc [75].
Lorcaserin, a 5-HT2c receptor agonist, was not included in our protocol, since this drug is not officially approved in Brazil, despite its proven safety and efficacy in different studies [35, 76, 77] and a possible effect on BED [78–81]. We recently included lisdexamfetamine in our protocol, even though the current study does not have any subject in whom the drug was used. Lisdexamfetamine has been shown to be effective against BED [82, 83], which has been confirmed by a systematic review of randomized controlled trials [84]. Several newly discovered brain pathways that induce obesity [85–89] reinforce the importance of centrally acting drugs in obesity, preferably targeting more than one mechanism.
Diet
A personalized diet plan was employed for each subject, according to their food preferences and social environment. Studies have shown that non-adherence to diets occurs when individual aspects are not taken into account [26, 27, 31]. The addition of whey protein was based on the findings of several studies that showed that this source of protein can prevent fat gain with high-fat diets, enhance fat loss with hypocaloric diets and considerably improve metabolic parameters [90–93].
We did not require 100% diet adherence to classify the subjects as adherents to the proposed diet plans. It has been observed that intermittent diets, such as alternate day fasting and intermittent fasting diet, allow periods of free meals and have no negative impact on weight loss [37–40] when the rest of the diet plan is strictly followed. These diets also help to decrease long-term BED [40]. When 100% diet adherence is not required, social events and travels become feasible, as both situations induce diet escapes and further loss of adherence to food recommendations.
BED is an expected disorder among patients with obesity, particularly, in patients with BMI > 35 kg/m2, more than 50% of whom are affected by compulsive eating disorders [27]. The active search for BED in these patients is supported by AACE obesity guidelines [24].
Exercise
Although exercises may not be the best approach to promote weight loss in obesity, they do improve fat loss, help avoid muscle loss and prevent weight regain by increasing energy expenditure and decreasing BED symptoms [27]. Intensive surveillance of adherence to physical activity was critical for the success of the proposed interventions.
Behavioral therapy
The role of behavioral therapy in obesity management is well established [29–31], especially for weight maintenance, when motivation decreases, as behavior plays a critical role in the pathophysiology of obesity. Conversely, psychological modalities of obesity management are being decreasingly used [15], possibly due to the lack of professional education on obesity [31]. Among the various types of psychotherapies, the behavioral cognitive approach is the most studied strategy for weight loss and has therefore been standardized for obesity management [30, 31].
The lack of adherence to regular follow-up with psychotherapists was possibly the result of a misbelief that the behavioral approach is not necessary nor effective, despite strong evidence of its efficacy [31]. We did not require a psychotherapist who specialized in obesity, since it is not feasible to conduct large-scale obesity therapy with obesity specialists due to the high prevalence of this disorder. The only requirement was that subjects be followed up with CBT approaches, based on the evidence of this strategy of obesity management.
Surveillance
This study proposed three types of surveillance: the assisted body analysis monthly surveillance, the regular phone calls and the weekly self-surveillance. They were employed independently in order to provide more intense oversight. The importance of surveillance on the efficacy of weight loss and maintenance strategies has been broadly studied [94–98] and is a key aspect in the success of both weight loss and maintenance.
Weekly self-surveillance was recommended to be performed on Tuesdays, and not on Mondays, since weekends are the periods when patients are more likely to increase carbohydrate and sodium intakes, with consequent accumulation of glycogen (in the liver and muscles) and retention of water, respectively. The excessive carbohydrate and sodium intakes can add up to 3–4 kg of extra weight, but this is quickly lost on the first day of adequate diet, usually on Mondays [99]. Phone calls have also been reported play a significant role in ensuring long-term adherence to obesity therapy [100], which was confirmed by us.
Assessments of responses to obesity-management therapies
The assessment of responses to obesity therapy should go beyond mere BW measurements, and include evaluations of metabolic parameters, WC, and FW, which are accurate predictors of cardiovascular and metabolic risks [27, 29]. BMI may not be an accurate parameter and can mislead interventions [101–103]. One of the best ways to evaluate the response to obesity-management therapies is to analyze markers of glucose and lipid metabolism and inflammatory markers, as these will more directly predict risk reductions. Good clinical methods, such as body composition analysis and WC measurements, also improve the accuracy of response assessments. For example, the prevention of lean mass loss is an important goal of obesity management, and this parameter is underestimated when BW is the only outcome analyzed. Lean mass can be determined using body composition analysis and estimated using WC. Approaches that preserve muscle mass, such as resistive exercises, tend to be underappreciated when weighing scales are the only tool employed. Furthermore, the effectiveness of strategies that induce intensive loss, such as bariatric procedures, is overestimated by weighing scale measurements, owing to intense muscle loss.
To ensure the quality of the methodology and the accuracy of the results, it was important to exclude from the metabolic analysis subjects who received medications that improved metabolic markers. These improvements were not related to the proposed intervention protocol, and could falsely improve the final results. However, patients receiving on- and off-label drugs for obesity that also improve metabolic markers were included in the metabolic analysis, as they were prescribed these drugs regardless of their baseline metabolic levels.
Metabolic and clinical outcomes
After the intervention, impressive improvements were seen in markers of liver function, lipid metabolism, glucose metabolism, and inflammation, and were better than the improvements previously described in the literature [16–22, 33–35]. It is important to note that none of the medications used in this study is indicated for the correction of liver dysfunction. Therefore, the improvements observed were secondary to FW loss and the beneficial side effects of some of the drugs. The significant clinical and metabolic improvements observed in this study will probably reduce overall risks [27], an effect which is enhanced by the inherent protective cardiovascular effects of some of the medications used in this protocol, such as liraglutide [32], SGLT inhibitors [59], metformin [65] and orlistat [19, 29].
Although anti-hyperglycemic medications were prescribed, HbA1c dropped more than expected. The initial HbA1c was less than 6.0%, and it is known that the lower the HbA1c level, the harder it is to decrease. The reduction in inflammatory markers, such as CRP and uric acid, was also attributable to general metabolic changes, as no specific drugs were prescribed for these markers. The improvements observed in this study were greater than the sum of the previously described improvements attributable to each of the prescribed drugs [20, 33–35]. Thus, synergistic effects of the different drugs used in this study may explain these surprising positive findings.
Normalization of liver transaminases was seen in most patients, suggesting that clinical obesity management may be attempted prior to specific etiological investigations and therapies for NASH. This approach may also prevent unnecessary invasive procedures (such as liver biopsy). Further studies investigating the quantitative imaging and classification of NASH before and after anti-obesity therapy, together with biochemical liver-function analysis are recommended.
The highly selective loss of fat mass was possibly due to the intensive body constitution surveillance and consequent adjustments in terms of diet and exercise plans (and also due to testosterone therapy in patients with hypogonadism), which probably led to more significant changes in metabolic parameters and WC.
Finally, this study showed that patients do not necessarily need to follow up with all three non-pharmacological interventions (CBT, physical therapy and diet plan) and do not have to specifically follow certain therapies, since there were no differences in results among the various therapy groups, regardless of whether two or three interventions were regularly followed, or between different combinations. Despite being the ideal approach, follow-up with all three modalities can be tiring and time-consuming, and patients are therefore less likely to adhere all of these treatments in the long run.
Changes in anti-obesity strategies
Instead of introducing one intervention at a time and evaluating the response to each intervention, we optimized all the key aspects of the proposed protocol at once, given that: (1) obesity is a complex, hard-to-manage disease, (2) its prevalence and severity are quickly increasing, and (3) many issues have been identified regarding the proposed current therapies. Furthermore, aggressive approaches induce greater weight loss, which can positively predict long-term weight loss and maintenance [104].
In our opinion, obesity is a too severe a disorder for step-by-step approaches. It has several long-term consequences, including a more than 500% increase in cardiovascular disease, 260% increase in overall mortality after 18 years of obesity [105], and increased public health costs in more than 50% of subjects [106]. Owing to these reasons, we considered an aggressive approach to obesity management to be more suitable. Once the proposed combination of interventions is demonstrated to be effective, then we suggest that the number, intensity and agressiveness of the interventions be slowly decreased until an optimal protocol that remains chronically effective is found.
Besides developing an aggressive therapeutic protocol combining on and off-label medications, we were also concerned with determining the optimal time period for which medications should be taken as well as designing a suitable discontinuation plan. We could not find any information in the literature about when and how obesity drugs should be weaned off. We therefore developed a protocol based on the mechanisms of action and safety profiles of the proposed drugs.
Although previous studies [10, 15, 24, 29] have recommended a two-step approach (weight loss and weight maintenance) to obesity management (Fig. 5), there is a crucial period between these two steps that cannot be part of either of these periods. Herein, we named this in-between period as weight stabilization. This step starts right after the achievement of the final body weight, and the length of the weight-stabilization period will depend on the amount of weight loss and duration of previous obesity. The longer obesity was present, the longer it takes to stabilize the new weight. It is important to point out that duration of this period is estimated and therefore not precise, as there is no accurate predictor of how long a weight-stabilization period would be necessary in each case. Our strategy has been illustrated in Figs. 6, 7, 8 and 9 to provide an easier understanding of the proposed therapy. The intervention was continued after the end of the first year (the period of this study) by 42 of the 43 subjects (one subject moved out), once they understood the importance of long-term therapy, and with whom we are currently applying the proposed steps for weight loss, stabilization and supervised maintenance.
Rescue therapy was performed in two patients during the study. One of them had lost 26.7 kg but regained 6.9 kg during the weaning-off process, after his mother’s death; all the medications were re-prescribed in their full doses. The other subject had an exacerbation of BED, and consequently regained 9.3 kg of the 22.0 kg of previously lost weight. We reintroduced all the medications and added lisdexamfetamine at a daily dose of 50 mg. Both patients were able to fully lose the regained weight in a period of less than 3 months, which reinforces the importance of a prompt approach once weight regain is detected.
We consider it important to maintain as many aspects of real life as possible during the proposed intervention, for example by including programmed interruptions in physical activity, allowing vacations and not having an obligation for 100% adherence to diet. We consider that there is a theoretically higher chance of long-term success when individuals with obesity do not stand apart from their realities while undergoing obesity therapies. All 43 subjects had tried to lose weight medically at least twice, with medications, diet and exercises. However, the amounts of the previous weight losses were less intense and the duration of the weight losses were short, usually less than 3 months (in 38 of 43 subjects).
The cost of the proposed therapy for a 2-year period is five times less than the expected increase in costs due to obesity complications [107–109]. Once effective weight loss occurs, the protocol would be able to decrease costs by more than US$600 billion over the next 20 years [110]. Even though current approaches are still unable to provide long-term reduction in health costs due to weight regain, which is observed with most approaches and enforces the rationale for the current lack of health insurance coverage for obesity treatments [110].
Herein, we proposed a different way to express weight loss: controlled obesity, not ex-obesity, similar to diabetic patients in whom glucose is normalized or to hypertensive patients in whom blood pressure is controlled. The practical difference in terms of naming the weight-maintenance period as “controlled obesity” is that it helps support the notion of long-term therapy, regardless of the types of intervention, as obesity is seen as a current disease even in weight-controlled subjects.
Weight maintenance
Obesity approaches are often successful in inducing weight loss, but not in preventing weight regain [29, 49], due to several reasons: (1) no protocols or guidelines are available on drug weaning-off strategies; (2) a standardized optimal period of drug use is lacking; pharmacological strategies vary according to the clinical judgment of the treating physician, and are not based on any previous protocol or studies; (3) there is a loss of motivation after the achievement of the final weight, when the positive reward of losing fat fades away; and (4) there is a lack of long-term studies with currently approved interventions.
The need of effective clinical approaches to obesity management
The high prevalence of moderate and severe obesity [41], particularly among lower income and scholarship subjects [41] turns unfeasible to provide proper bariatric surgery and follow-up to the whole population that has formal indication for this procedure. Given this fact, an effective clinical approach could be an alternative to help millions of subjects with obesity.
Therefore, the objective of this study was to develop an effective, holistic, clinical protocol for obesity management that can be implemented before bariatric surgery. We developed this protocol by correcting the historical mistakes in obesity interventions generally observed in clinical studies, such as the dissociation between pharmacological and non-pharmacological strategies, and the lack of combination drug therapies. We speculated that these reasons could explain why clinical therapy for obesity often fails.
Clinical management vs. bariatric surgery
To our knowledge, this is the first study to analyze an intensive clinical approach to obesity management, incorporating combined pharmacotherapy and non-pharmacological modalities as well as the systematic evaluation of clinical and metabolic parameters. Indeed, the commitment of the whole team to the protocol, the quality of the diet plans, the monitoring of the adherence to exercise regimens and psychotherapy combined with continuous body surveillance allowed this clinical protocol to serve as an alternative to bariatric surgery.
Although we did not perform a head-to-head comparison, the outcomes of this protocol are comparable to those of bariatric surgeries, especially to sleeve gastrectomy, and indicate that clinical strategies can be effective in obesity management, especially when optimal and synergistic strategies are selected. Our search for an effective strategy to avoid bariatric surgery was an attempt to cease and possibly reverse the recent trend of the trivialization of bariatric surgery. This trend is worrisome because post-bariatric surgery patients must take lifelong precautions that are not required from non-surgical ex-obese subjects [13, 14, 30]. In our medical practice, we found that many post-bariatric surgery patients were not always aware of the possible complications of the surgery and indeed, of the patients responsibilities, which is corroborated by previous studies [13, 14].
Limitations of this study
We are aware that the proposed protocol is not easily reproducible, not due to biological issues, but due to social and financial conditions of obesity therapy centers and affected subjects. The drugs used are expensive and are not usually covered by health insurance in the USA and in Brazil. Furthermore, pharmaceutical industries produce each of the proposed medications in separate packages, which hampers the conducting of studies with potential drug combinations. In fact, several issues in fighting obesity with pharmacotherapy were highlighted by a study [16], such as not treating obesity as a chronic disease, lack of availability of other clinical strategies for weight loss, culturally unacceptable adverse effects of anti-obesity agents, low sales performance of obesity medications (which weakens the research for new molecules), and lack of drugs covered by health insurance.
Besides the difficulty in reproducing this study, other important limitations of our paper are the lack of a control group, possibility of enhanced effects due to the placebo effect, small number of subjects, and the retrospective nature of the analysis, although none of the patients were lost to follow-up. Despite these limitations, the impressive results observed in the subjects are hardly questionable, and support the hypothesis that anti-obesity interventions should be aggressive, although this must be further evaluated in controlled trials in future.
Final discussion
The results of this protocol highlight the feasibility of clinical anti-obesity therapies in patients with moderate-to-severe obesity as well as the need for a multidisciplinary and aggressive clinical approach to the patient with obesity prior to bariatric surgery, as this has been shown to be more effective than isolated treatments. Anti-obesity therapy, regardless of the type of practice, should be offered as a combination of different strategies, and pharmacotherapy must be a part of this therapy in order to provide effecrtive management. Our anti-obesity approach is not easy to be implemented, as it requires several professionals, and strict and continuous contact with patients; however, as the results show, our approach may be a good alternative for patients prior to bariatric procedures. Secondary findings are also important to note, such as remission of altered liver profile and improvements in several metabolic disorders, which confirm the efficacy of the proposed approach.