Pharmacological Approaches in the Treatment and Maintenance of Weight Loss

Obesity—in particular, abdominal obesity—is a major driver in the development of diabetes and cardiovascular disease (1,2). Weight reduction and maintenance, therefore, are key therapeutic goals in both the management of obesity and its associated comorbidities, type 2 diabetes in particular (3). Unfortunately, several weight loss–induced hormonal changes encourage weight regain and counteract maintained weight loss (4). In the short-term, diet-induced weight loss increases orexigenic hormones ghrelin and gastric inhibitory polypeptide (GIP) and decreases anorexigenic hormones leptin, peptide YY, cholecystokinin, amylin, and glucagon-like peptide 1 (GLP-1) (4,5). As a result, patients feel an increased level of hunger, reduced satiety, and an increased desire to eat (4). These changes persist for a long time, even after weight has stabilized or increased again. In addition, resting metabolic rate and energy expenditure are reduced after diet-induced weight loss—an effect that is also mediated by leptin (6).

Moderate weight reduction of ∼4 kg combined with intensive lifestyle intervention has been shown to reduce the incidence of diabetes by 58% in obese patients in a prediabetes state (7). For individuals with diabetes, large-scale studies have shown that a loss of 5–10% of body weight with increased physical activity can improve fitness, improve cardiovascular disease risk factors, reduce HbA_1c levels, and decrease use of diabetes, hypertension, and lipid-lowering medications (8,9). Additional benefits of weight loss might include reduction of depression symptoms and reduced severity of obstructive sleep apnea (10,11). Greater clinical improvements are observed with greater weight loss (9).

Guidelines recommend lifestyle modifications as the foundation of weight loss. Although intensive lifestyle intervention produces clinically beneficial weight loss for many patients, the reality is that intensive lifestyle intervention is difficult to achieve and maintain over the long-term for most patients. Even in an “optimal” clinical trial setting such as Look AHEAD (Action for Health in Diabetes), a third of all patients were unable to achieve at least 5% weight loss after 1 year (12). Most individuals tend to lose weight over a period of 4–6 months and lose 4–10% of baseline weight before experiencing a plateau in weight loss, generally followed by a weight regain (13). Long-term weight loss—in some studies defined as maintaining 75% of initial weight loss (14)—is still difficult to achieve for many patients, and additional options, such as pharmacotherapy with or without very low-calorie diet (VLCD), should be considered for patients who cannot attain sufficient weight loss with lifestyle modification only.

While several antiobesity agents have been withdrawn from the market due to safety concerns, five are now available in the U.S.—orlistat, lorcaserin, phentermine/topiramate, naltrexone/buprion, and liraglutide 3.0 mg (Table 1)—for chronic weight management. Only orlistat is currently available in Europe, with liraglutide 3.0 mg and naltrexone/buprion having recently received approval from the European Medicines Agency as well. These pharmacotherapies have been demonstrated to show efficacy in weight reduction both in obese patients with comorbidities and in obese patients without comorbidities (15–18).

Orlistat functions as an antiobesity agent by inhibiting gastrointestinal lipases, thereby reducing absorption of dietary fat (19). Orlistat is indicated for obesity management, including weight loss and weight maintenance, when used in conjunction with a reduced-calorie diet, and for reduction of the risk of weight regain after prior weight loss (20). In the XENical in the Prevention of Diabetes in Obese Subjects (XENDOS) trial, obese subjects in the placebo group who adhered to a hypocaloric diet and increased physical exercise regimen lost an average of 6.2 kg after 1 year, whereas those in the orlistat group lost an average of 10.6 kg (21). Orlistat also provided weight loss benefits for patients with type 2 diabetes. After 52 weeks of orlistat treatment (120 mg t.i.d.), in combination with a hypocaloric diet and a weight-management program, obese patients with type 2 diabetes achieved –5.0% reduction in weight from baseline (vs. –1.8% with placebo; P < 0.0001) (15). Retrospective analysis of seven studies on orlistat (120 mg t.i.d.) confirms that orlistat-treated patients had significantly greater decreases in body weight than the placebo group (–3.77 vs. –1.42 kg, P < 0.0001). In addition, compared with placebo, more than twice as many orlistat 120 mg–treated patients lost ≥5% of baseline body weight (34.8 vs. 14.1%; P < 0.0001) or lost ≥10% of baseline body weight (9.7 vs. 3.7%; P < 0.0001) (22). Favorable initial response to orlistat has been shown to be a good prognostic indicator for long-term weight loss. Orlistat was generally well tolerated; gastrointestinal effects were the most commonly reported adverse events (AEs) in 20–30% of patients, but all events were considered either mild or moderate (21).

Lorcaserin is a selective small-molecule agonist of the 5-hydroxytryptamine 2C serotonin receptor (5HT2C), which regulates mechanisms related to satiety, ingestive behavior, glucose tolerance, and hepatic insulin sensitivity (16). Unlike previously available antiobesity agents, lorcaserin has low affinity for the 5HT2B receptor subtype, whose activation has been linked to the development of valvular heart disease (17). Lorcaserin is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial BMI of ≥30 kg/m² (obese) or ≥27 kg/m² in the presence of at least one weight-related comorbid condition, such as hypertension, dyslipidemia, or type 2 diabetes (17). In overweight or obese patients without diabetes, lorcaserin treatment provided −5.81% reduction from baseline body weight after 1 year (vs. −2.16% with placebo; P < 0.001) (18). The Behavioral Modification and Lorcaserin Second Study for Obesity Management (BLOSSOM) compared lorcaserin 10 mg b.i.d. versus once daily (QD) versus placebo. Lorcaserin b.i.d. was associated with significantly greater weight loss than lorcaserin QD (−5.8 kg vs. −4.7 kg). Significantly more patients receiving lorcaserin BID and lorcaserin QD lost at least 5% body weight at 1 year (47.2% and 40.2%) than in the placebo group (25.0%). Similarly, significantly more patients achieved at least 10% weight loss in the lorcaserin groups compared with placebo (22.6% b.i.d. vs. 17.4% QD vs. 9.7% placebo). In a phase 3 study of subjects with type 2 diabetes (treated either with metformin or a sulfonylurea), lorcaserin treatment resulted in mean weight changes of −4.5% (b.i.d.) and −5.0% (QD) compared with −1.5% with placebo at week 52 (16). No evidence of increased depression, suicidal thoughts, or echocardiogram-detected valvular regurgitations was found in the lorcaserin treatment arms. Overall, the most common AEs with lorcaserin were headache, back pain, nasopharyngitis, and nausea.

Phentermine is a norepinephrine- and dopamine-releasing agent (with a lower effect with dopamine vs. norepinephrine) approved for the short-term treatment of obesity (23). Topiramate, a registered antiepileptic drug, has several pharmacological mechanisms of action. The exact mechanisms by which the combination phentermine plus topiramate produces weight loss still remain unknown. A phase 3 study examined the efficacy of the combination of phentermine 7.5 mg/topiramate 46.0 mg or phentermine 15.0 mg/topiramate 92.0 mg on weight loss after 56 weeks (24). Patients who completed 1 year of treatment had significantly (P < 0.0001) higher absolute body weight change of –9.9 kg (–9.6%) with phentermine 7.5 mg plus topiramate 46.0 mg vs. –12.9 kg (12.4%) with phentermine 15.0 mg plus topiramate 92.0 mg compared with –1.8 kg (1.6%) in the placebo group (24). Patients with type 2 diabetes (a subgroup of 388 subjects in this study) achieved weight reductions of −6.8% and −8.8% with phentermine 7.5 mg/topiramate 46.0 mg and phentermine 15.0 mg/topiramate 92.0 mg, respectively (vs. placebo, −1.9%). Phentermine/topiramate was well tolerated; constipation, paresthesia, and dry mouth were the most commonly reported treatment-emergent AEs (25). However, the U.S. Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy for phentermine/topiramate to educate prescribers and patients on the increased risk of orofacial clefts in infants exposed to phentermine/topiramate during the first trimester of pregnancy (26).

Naltrexone is an opioid receptor antagonist, while bupropion is a norepinephrine and dopamine reuptake inhibitor (27); the combination increases proopiomelanocortin neuronal firing, which may have anorectic effects. The combination provides greater weight loss than monotherapy with either agent or placebo (27). Multiple 56-week multicenter, double-blind, placebo-controlled trials (CONTRAVE Obesity Research, or COR-I, COR-II, COR-BMOD, and COR-Diabetes) were conducted to evaluate the effect of bupropion/naltrexone in conjunction with lifestyle modification in a placebo-controlled cohort. In COR-I and COR-II, mean change in body weight after 1 year was –6.1% and −6.4% in the naltrexone 32 mg plus bupropion (NB) group, respectively, and –1.3% and −1.2% in the placebo group (28,29). In COR-I, 48% of participants assigned to NB had a decrease in body weight of ≥5% compared with 16% assigned to placebo (28). In COR-Diabetes, patients on bupropion/naltrexone lost significantly more weight compared with those on placebo (−5.0% vs. −1.8%). In COR-BMOD, intensive behavior modification was added to all treatment arms, resulting in better results, with a weight loss of 9.3% in the NB group vs. 5.1% in the placebo group. Compared with placebo, treatment with NB was associated with a higher incidence of nausea, constipation, and vomiting but was not associated with increased depression, suicidal thoughts, or hypoglycemia. While NB may represent a novel pharmacological approach for the treatment of obesity, further studies are required to assess its effects on cardiovascular outcomes, as systolic blood pressure and pulse rate have been found to be higher with NB than with placebo (17).

The underlying mechanisms that mediate the effects of weight reduction of liraglutide are most probably a combination of effects on the gastrointestinal tract and the brain. Native GLP-1 suppresses appetite and energy intake in both normal-weight and obese individuals, as well as in people with type 2 diabetes, and delays gastric emptying. GLP-1 receptors are expressed in several brain stem nuclei involved in appetite regulation, and subcutaneously administered liraglutide might also reach these sites (30).The weight-reducing effect of liraglutide was already noted in studies using the lower doses of 1.2 and 1.8 mg, indicated for the treatment of type 2 diabetes. Liraglutide (3.0 mg QD) has been shown to provide weight-reduction benefits for obese patients; after 20 weeks, the placebo-subtracted reduction in weight from baseline with liraglutide (3.0 mg) treatment was –4.4 kg (P = 0.003) (30,31). The SCALE maintenance trial assessed the efficacity of liraglutide in maintaining weight loss achieved with a low-calorie diet after 1 year. After a diet-induced weight loss, subjects on liraglutide lost an additional 6.2% vs. 0.2% with placebo. Fifty percent of subjects on liraglutide achieved ≥5% weight loss vs. 21.8% in the placebo group. Results were similar in patients with type 2 diabetes (SCALE Diabetes trial) and prediabetes (SCALE Obesity and Prediabetes) (32,33). The weight reductions observed with liraglutide (3.0 mg QD) primarily result from reductions in fat mass and body fat percentage (including visceral fat) rather than lean tissue mass (31,34). In the SCALE Obesity and Prediabetes trial, there seemed to be a slightly reduced weight loss response in patients with a BMI >40 kg/m², but this was not confirmed in the SCALE Diabetes trial (32,33). Similar to liraglutide 1.8 mg treatment in patients with diabetes, the most common AEs with liraglutide 3.0 mg treatment were gastrointestinal, which is also consistent with the known physiological effects of GLP-1 receptor agonists (31). Of note, heart rate was slightly but significantly increased in liraglutide-treated patients versus placebo by 4 bpm (31). In the liraglutide group, three individuals were diagnosed with a malignancy (breast, colon, and prostate) versus no individuals in the placebo group.

In the selection of the best antiobesity drug for a specific patient, the aspects of possible side effects, contraindications, and drug interactions should be taken into consideration. An overview is provided in Table 2. Recent safety concerns about an increased risk of major adverse cardiac events have led either to definitive withdrawal of existing antiobesity medications or a lack of new treatments being approved (35). Assessment of cardiovascular safety has now emerged as a major consideration for all new antiobesity and glucose-lowering agents under current review by the FDA (36). So far, none of the current FDA-approved medications have had a cardiovascular outcome trial. Given the significant need for effective and safe weight loss medication, it is perhaps not surprising that many more antiobesity therapies are in development (see the recent article by Rodgers et al. [20]; these newer therapies are also overviewed below). The potential of these therapies in patients with type 2 diabetes, as well as their cardiovascular safety, will need to be established.

As obesity is considered to be a chronic disease, its treatment necessitates enduring efforts in calorie restriction and increased physical activity. After diet-induced weight loss, several counterregulatory neurohormonal mechanisms aim at maintaining and even reexpanding fat mass (37). Given the importance of obesity and its associated risks as a public health problem, the limited evidence about long-term weight maintenance still remains problematic. Most patients unfortunately regain weight after a weight-management program, whereas individuals continuing in a clinical trial can maintain a weight loss of ∼3% of initial body weight up to 5 years. As identified in the Look AHEAD study, not only greater initial weight losses but also the sustained weight loss during the first year are predictive factors for successful weight loss after 4 years (38). Other predictors of weight loss maintenance include the use of low-calorie diets and increased physical activity and self-monitoring (14).

Maintaining a considerable weight loss requires substantial behavioral efforts. Among cognitive strategies for weight maintenance that Voils et al. (39) listed in a review are the following items: self-regulatory focus, self-efficacy to maintain weight loss, self-efficacy to recover from a relapse, self-monitoring, and social support derived from social networks. Also, eating frequency has been reported to be higher in weight loss maintainers. In a systematic review, meal-replacement strategies, high-protein diets, and antiobesity drugs were associated with weight loss maintenance, mainly after VLCD/low-calorie diet (37).

Long-term medical therapy as an adjunct to sustain weight loss should be taken into consideration (National Institutes of Health, National Heart, Lung, and Blood Institute). Several of the aforementioned agents have been tested as part of a long-term weight-management plan.

Apart from the short-term efficacy of sibutramine (38), the Sibutramine Trial of Obesity Reduction and Maintenance (STORM) study indicated a superiority of sibutramine over placebo to maintain at least 80% of initially achieved weight loss (43% in sibutramine group vs. 16% in placebo group) (40). Eventually, sibutramine was withdrawn by the FDA owing to risk of serious cardiovascular events, as shown in the Sibutramine Cardiovascular Outcomes Trial (SCOUT) report.

Rimonabant, a cannabinoid receptor antagonist, significantly increased weight loss at 1 year of treatment (−3.4 kg for 5 mg and −6.6 kg for 20 mg vs. −1.8 kg for placebo) (41), resulting in a significant increase in patients achieving 5% and 10% weight loss. At 2 years of treatment, the results were comparable with a mean 5.5 kg and 2.9 kg weight reduction for the rimonabant 20 mg and 5 mg group vs. 1.2 kg in the placebo group (42). After 2 years, the advantageous cardiovascular effects were maintained. Due to concerns about psychiatric side effects (mood disturbances and suicidality), rimonabant was withdrawn by the European Medicines Agency in 2009.

Several placebo-controlled randomized trials have investigated the long-term effectiveness of orlistat in weight reduction. After 2 years, 57% of subjects on orlistat 120 mg maintained a weight loss of ≥5% vs. 37.4% in the placebo group (43). In another 2-year study, use of orlistat induced a mean weight loss of 7.6% (orlistat 120 mg) and 6.8% (orlistat 60 mg) vs. 4.5% for placebo after 2 years of treatment (44). In another study, in which orlistat was added after a VLCD-induced weight loss of ≥5%, use of orlistat was associated with maintenance of an extra 2.4-kg weight loss for up to 3 years in obese subjects (45). In a 4-year study, in patients who completed 4 full years of treatment, 52.8% in the treated group and 37.3% in the placebo group lost ≥5% of baseline body weight and 26.2% and 15.6%, respectively, lost ≥10% of baseline body weight (21). This resulted in a greater reduction in the incidence of type 2 diabetes over lifestyle changes alone (6.2% vs. 9.0% [–37.3% reduction], P = 0.0032) (21).

In the BLOOM trial, 3,182 adults who were overweight or obese received lorcaserin 10 mg b.i.d. or placebo for 52 weeks in conjunction with diet and exercise. At week 52, all subjects were rerandomized to either placebo or lorcaserin for an additional year. At 1 year, the average weight loss was 5.8 ± 0.2 kg with lorcaserin and 2.2 ± 0.1 kg with placebo, resulting in 47.5% of patients in the lorcaserin group and 20.3% in the placebo group losing 5% or more body weight. Among patients in the lorcaserin group who had weight loss of 5% or more at year 1, the loss was maintained in a greater proportion of patients who continued to receive lorcaserin in year 2 than in those who were reassigned to receive placebo (67.9% vs. 50.3%) (46).

The 52-week CONQUER trial randomized obese patients to placebo, midtreatment dose (7.5/46 mg), or maximum treatment dose (15/92 mg). At 56 weeks, change in body weight was −10.2 kg, –8.1 kg, and –1.4 kg in the patients assigned to maximum, midtreatment, and placebo, respectively. Five percent and 10% weight loss was achieved in 70% and 48% in the maximum dose group, 62% and 37% in the midtreatment group, and 21% and 7% in the placebo group (47), respectively. An extension of this trial (SEQUEL) showed persistent favorable effects after 2 years, with −10.7%, −9.3%, and −2.2% for the maximum dose, midtreatment, and placebo group, respectively (25). Phentermine/topiramate was clearly effective in all BMI categories. However, a significant treatment effect by baseline BMI was observed. Among all subjects with class II obesity or greater at baseline (i.e., BMI ≥35 kg/m²), mean weight losses after 2 years were significantly greater for phentermine/topiramate compared with placebo. In a prespecified subgroup analysis of weight loss in subjects with type 2 diabetes at baseline, the phentermine/topiramate–treated subjects also showed greater weight loss compared with placebo-treated subjects. At week 108, subjects with type 2 diabetes in the placebo group (n = 55) lost 2.0% of body weight, whereas subjects with type 2 diabetes in both the 7.5/46 mg (n = 26) and 15/92 mg (n = 64) groups lost 9.0% of body weight.

Liraglutide, when given in a dose of 2.4 or 3.0 mg daily during 2 years, results in a mean weight loss of 5.8 kg, which was significantly greater than with orlistat and placebo. At year 2, significantly more subjects on liraglutide 2.4/3.0 mg than on orlistat lost ≥5 and ≥10% weight. Of the 64% who achieved ≥5% weight loss with liraglutide 2.4/3.0 mg at year 1, >85% maintained this at year 2 (31). The use of a low-calorie diet in a recent liraglutide approach indicated how effective this injectable GLP-1 receptor agonist can be (48).

Effects of different maintenance strategies after VLCDs have been evaluated in several trials, including the use of antiobesity agents.

VLCD can be considered a critical enhancer of weight management with antiobesity agents. Given the average weight loss of ∼8–10 kg over 1 year with the majority of antiobesity agents, other additional approaches for more appropriate and optimized weight loss and maintenance have been studied. The use of a VLCD (500–800 kcal/day) is an interesting consideration as initial start-up therapy for such an approach. The use of a VLCD prior to pharmacological treatment has shown excellent results, with successes beyond 10 kg weight loss and with a maintenance lasting for at least 1 year (38).

In the Apfelbaum study, >90% of patients could maintain >50% of the weight loss that was achieved (38). Astrup and colleagues (49) could report a similar successful 52-week outcome, using topiramate after an initial low-calorie approach.

Also with orlistat, in an analysis on maintenance in subjects with abdominal obesity, Richelsen et al. (45) could demonstrate that an extra weight loss of 2.4 kg could be achieved after VLCD and maintained for up to 3 years.

In a crossover study with the lipase inhibitor orlistat, the use of this pharmacological agent on top of a low-calorie diet after an initial 52 weeks of hypocaloric dieting could maintain body weight ∼7–8% up to 120 weeks (42). As to changes in metabolic risk factors, the orlistat patients tended to show better outcomes (45). Using sibutramine (STORM trial), James et al. (40) found a significant drug effect on weight loss maintenance after a 600 kcal–deficit weight loss program. In that same STORM trial, van Baak et al. (50) could demonstrate that on top of a pharmacological treatment, leisure activity could contribute to weight maintenance as well. Similarly, the use of topiramate has shown results comparable with those of sibutramine, confirming the useful strategy of VLCD followed by pharmacotherapy, irrespective of the mechanism of action of the respective agent studied. Also, with lorcaserin similar results could be confirmed in a crossover design.

Using an injectable approach with liraglutide 3 mg, Wadden et al. (48) confirmed the previous findings that treatment with a GLP-1 receptor agonist liraglutide at high doses with lifestyle support could significantly maintain weight loss (>5% of initial body weight) achieved by a low-calorie diet. An almost 6-kg placebo-subtracted weight loss could be observed at week 56, resulting in a total weight loss of ∼12 kg after 1 year.

As was previously consistently shown with other pharmacological agents (20), liraglutide could enhance the benefit of lifestyle intervention on body weight—beyond 10 kg—and additional reduction in cardiovascular disease risk factors.

As our knowledge of the physiology of appetite and energy homeostasis improves, so too will our ability to understand how therapies might be combined to provide effective weight management. This is particularly necessary in patients with type 2 diabetes (51,52).

A new class of antidiabetes therapies that show potential for weight loss (although they are not indicated for weight loss per se) are the sodium–glucose cotransporter (SGLT)-2 inhibitors (53). In individuals with type 2 diabetes, SGLT-2 expression is increased in the renal proximal tubular cells, leading to increased renal glucose reabsorption, which ultimately aggravates hyperglycemia. SGLT-2 inhibitors reduce blood glucose, mainly through increased glycosuria, although indirect mechanisms have also been reported (51,54). Dapagliflozin therapy is associated with modest reduction in body weight and shows a favorable weight profile in comparison with both placebo and metformin. Dapagliflozin-induced body weight has been shown to occur through reductions in fat mass, visceral fat, and subcutaneous fat (55). Also, canagliflozin has demonstrated dose-related reductions in baseline body weight in individuals with diabetes (56,57). Canagliflozin (50–300 mg) has also been reported to have beneficial weight effects in overweight or obese individuals without diabetes (58). While increased glucose excretion contributes to the weight loss observed with SGLT-2 inhibitor treatment, weight reduction is often limited to <4 kg after even 52 weeks of treatment (54). This attenuation of weight loss may occur because SGLT-2 inhibitor–induced glycosuria is accompanied by compensatory hyperphagia, as demonstrated in animal studies (53) and suggested by human studies (59). A potential future option is a SGLT-2 inhibitor/GLP-1 receptor agonist combination (59). The effect of GLP-1 receptor agonists on satiety may weaken the compensatory “overeating” mechanism observed with SGLT-2 inhibition and enhance weight loss by SGLT-2 inhibitors (60). In the CANagliflozin cardioVascular Assessment Study (CANVAS), addition of canagliflozin 100 mg or 300 mg to a background therapy of dipeptidyl peptidase-4 inhibitor or GLP-1 receptor agonist resulted in a weight loss varying between 2.3 and 3.2% after 18 weeks (61). Other combination trials with SGLT-2 inhibitors as background therapy are also underway.

Given the role of leptin and amylin in controlling food intake and energy expenditure and the role of incretins (GLP-1) in glucose and weight control (62,63), it is no surprise that many of the therapies in preclinical development involve these different hormones. Therapies that are currently being studied include the following.

Because results with recombinant human leptin or metreleptin (human leptin analog) have been disappointing in reducing weight for obese patients with type 2 diabetes (62), approaches are now focused on leptin-related synthetic peptides, such as leptin receptor antagonists or leptin-related synthetic peptide analogs or mimetics, and leptin combination therapies (64). Initial preclinical as well as clinical data suggest that leptin and amylin—two hormones involved in the control of satiety—have additive effects (64). In a proof-of-concept randomized controlled trial in overweight/obese subjects, it was shown that combination treatment with pramlintide/metreleptin led to a significant earlier, sustained, and greater weight loss than treatment with pramlintide or metreleptin alone (65). However, a subsequent trial was recently halted because of safety concerns.

PEGylated (PEG) leptin, along with PEG–GLP-1/glucagon, may be another potential combination therapy option (66). This combination is an intriguing potential option, as preclinical data indicate that PEG-leptin and PEG–GLP-1/glucagon coagonism can restore leptin responsiveness, which is often reduced when leptin is used alone. Responsiveness to leptin is associated with decreased food intake, improved glucose tolerance, and insulin sensitivity, as well as decreased triglycerides and lower plasma cholesterol. These may be the contributing factors that lead to the weight loss observed with leptin/GLP-1/glucagon coagonism (66).

Another potential therapy is the combination of amylin analogs and GLP-1 receptor agonists. As both agents can slow gastric emptying, it is possible that these two agents combined may have synergistic effects, but the gastrointestinal tolerance should be evaluated.

Another incretin pathway compound in early-stage development is a peptide that acts as an agonist at both the GLP-1 and GIP receptors (67). Although GIP is orexogenic, GIP-overexpressing mice even show a reduced tendency to develop diet-induced obesity, contradicting the notion that the orexogenic effect of GIP results in an obesogenic effect (68). Dipeptidyl peptidase 4 inhibitors increase endogenous levels of GLP-1 and GIP, resulting in better glycemic control without weight gain. A preclinical study indicates that dual agonism of GLP-1 and GIP has the potential to enhance the antiobesity effects observed with monoagonism, as it affects both adiposity-induced insulin resistance and pancreatic insulin deficiency. Simultaneous administration of a GLP-1 agonist and a peptide YY agonist resulted in decreased food intake in humans that exceeded the effects of the individual compounds (69). Likewise, coadministration of cholecystokinin with either a GLP-1 agonist or amylin produced greater than additive weight loss in rats (70); in a recent study in rodents, a new monomeric peptide triagonist simultaneously acting at three key metabolically related peptide hormone receptors (GLP-1, GIP, and glucagon) was found to provide additional glucose control and weight-reducing benefits over dual coagonism (71). Extensive clinical investigation into the efficacy and safety of coagonist therapy for the treatment of patients with obesity and type 2 diabetes is warranted.

Benefits of weight reduction are irrefutable, and lifestyle interventions aimed at prompting weight loss remain the cornerstone of obesity treatment, but the majority of patients are unable to achieve 10-kg weight loss targets and/or maintenance. Clearly, a shift in paradigm of weight loss management is needed, with the acceptance of pharmacotherapy as a valuable addition. Several interesting drugs are currently approved, but long-term data on efficacy and safety, in particular, cardiovascular safety, remain warranted. Additionally, health care practitioners should consider the weight effects of pharmacotherapy in the management of obesity-related comorbidities and consider weight-neutral or weight-reducing medications that can complement the patient’s desire for a healthier lifestyle (60).

Funding. L.V.G. received grant support from National Research Funds, Belgium, and also received grant support for hepatic research from the European Union consortium (Hepadip and Resolve consortia).

Duality of Interest. L.V.G. is, or has been, a member of the advisory boards and speakers bureaus of AstraZeneca/Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, Janssen, Johnson & Johnson, Merck Sharp & Dohme, Novo Nordisk, and Sanofi (in the period 2010–2014). No other potential conflicts of interest relevant to this article were reported.