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  COMBINATION OF ANTI-OBESITY DRUGS IN CLINICAL DEVELOPMENT As obesity occurs via multifactorial pathways, a single drug might exhibit limit...


COMBINATION OF ANTI-OBESITY DRUGS IN CLINICAL DEVELOPMENT As obesity occurs via multifactorial pathways, a single drug might exhibit limited efficacy. Thus, a high dose might be required, which often causes unacceptable side effects. Combination therapy comprising multiple anti-obesity drugs with complementary modes of action is warranted to broaden the target energy regulatory systems via actions on distinct mechanisms, which could maximize the effect on weight management while maintaining safety and tolerability [72]. To date, however, there has been no approved combination agent for obesity management, besides phentermine/ topiramate and naltrexone/bupropion. Other co-administered medications have been investigated to elucidate their long-term efficacy and adverse events [15,16].

 Most combinations primarily focus on both controlling hunger/appetite/satiety and inhibiting peripheral calorie absorption (i.e., phentermine/sodium glucose co-transporter 2 [SGLT-2] inhibitor, a GLP-1 agonist/other gut hormones, or an SGLT-2 inhibitor). SGLT-2 inhibitors, such as dapagliflozin, empagliflozin, and canagliflozin, block glucose reabsorption from the renal tubules and result in glycosuria. Therefore, they are primarily used by diabetic patients for blood sugar control [73]. Interestingly, these drugs are effective, to some extent, in individuals without diabetes [74]. Theoretically, the amount of glucose loss in urine is approximately 75 g/d (300 kcal energy deficit). Resultantly, 7–8 kg of weight loss owing to these medications can be expected in patients with diabetes over 6–12 months. However, in previous clinical studies with diabetic patients, only 2–3 kg weight loss was achieved with such agents; this was attributed to compensatory hyperphagia/increased appetite [75]. Thus, combining an appetite suppressor, such as phentermine, with a SGLT-2 inhibitor can serve as a good option for weight management. In a recent clinical trial that examined canagliflozin in combination with phentermine, additional weight loss was achieved (6.9%, canagliflozin 300 mg+phentermine 15 mg vs. 1.3%, canagliflozin 300 mg vs. 3.5%, phentermine 15 mg) [76]. Similarly, SGLT-2 inhibitors combined with a GLP-1 agonist caused a greater weight reduction than individual administration of each agent [77]. 216 INITIATING AND TERMINATING PHARMACOTHERAPY FOR OBESITY Despite the marked availability, anti-obesity drugs are reported to be underused by healthcare providers [3,78]. Only 2% of obese adults who are eligible for obesity pharmacotherapy receive prescriptions for these agents from their doctor [79]. As a highly stigmatized disease, there remains a misconception that obesity is mainly due to a lack of willpower and representative of laziness; thus, these patients are considered undeserving of proper treatment with medications or surgery [80]. The high cost of these medications also prevents adequate prescription for long periods. Weight loss is extremely challenging to achieve and sustain, and longterm management of obesity often requires adjunctive pharmacological interventions. 

Today, practitioners have access to several FDA-approved options. Moreover, as there is growing evidence that these drugs can delay the onset of obesity-related complications and improve metabolic and cardiovascular parameters, they should be considered in a timely manner. The decision to initiate drug therapy in an obese individual should be made after the risks and benefits are considered. Importantly, health providers should determine the risk-benefit profile of a given anti-obesity drug on a patient-by-patient basis. Further, the treatment goals should be clear. Patient preferences based on tolerability markedly affect adherence and can cause poor adherence or discontinuation, thereby negating the treatment effects [13,14]. At every visit, physicians should discuss the adverse events that accompany a given drug and evaluate the drug’s effect on weight loss. The goal of treatment with anti-obesity drugs in obese individuals should be long-term maintenance of weight reduction and improvement in overall health. In most clinical trials that evaluated pharmacologic interventions for more than 12 months, a weight loss of 4% to 8% was typical [56]; however, this is rather disappointing considering the high prices of these drugs. Therefore, upon initiation of an anti-obesity medication, health providers must communicate several important messages to their patients. First, not every drug will produce effective results in patients and individual responses will vary widely. Second, when the maximal therapeutic effect of a drug is achieved, a plateau will be reached. Lastly, when drug therapy is discontinued, weight regain is normally expected. Treatment response to most of these drugs should be evaluated at around 12 weeks using the maintenance dose. A trial period of 3 to 4 months is essential for predicting whether a patient might achieve a clinically significant weight loss at 1 year (classified as responders or non-responders); this is supported by data that early weight loss with any medical intervention is a good indicator of long-term outcomes [62,81-83]. Recently approved anti-obesity drugs have “stopping rules” that are suggested by the FDA and EMA to help clinicians identify patients that might achieve a weight reduction >5% within 1 year.

 Stopping rules can avoid unnecessary exposure and enhance the risk–benefit ratio [27]. If <5% weight loss is achieved after 12 weeks of treatment with a full dose (<4% weight loss at 16 weeks for liraglutide), the medication should be discontinued and other drugs should be considered. However, it can be difficult for practitioners to determine whether to continue the use of a given anti-obesity drug at the twelfth week, if the full dose has not been administered. Additionally, stopping rules are based on the results of the trials that conducted combined interventions involving an anti-obesity drug and intensive lifestyle modifications not medication only. Thus, the decision regarding the further continuation of a given medication should be made according to its effectiveness at reducing weight when diet, exercise, and behavioral modifications are adopted. Without a low-calorie diet and an increase in physical activity, the application of a medication alone could lead to failure to achieve weight reduction of 5% even after 12 weeks of treatment

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