Pharmacotherapy for Obesity

Peripherally Acting Agents

Gut-related Peptides Affecting Obesity

Several anorectic peptides are released from the gut postprandially and there has been interest in developing therapeutics to mimic this effect. Investment in gut hormone research as effectors of appetite regulation and also energy expenditure has been encouraged by the recent success of bariatric surgery. Certain evidence suggests that surgically induced weight loss, seen particularly after gastric bypass surgery, might be, at least in part, the result of an increased postprandial gut hormone response of several gut peptides, including GLP-1, PYY and oxyntomodulin.^[82–84] Analogs of these hormones were discussed in the section on centrally acting agents, but it is important to remember that they are also likely to have peripheral effects.

CB1 Antagonists

A new generation of antagonists have been designed to antagonize peripherally expressed CB1 receptors but not to penetrate the blood–brain barrier and thus to avoid the behavioral effects of centrally active agents. Peripheral CB1 receptor antagonists may be useful for inducing weight loss as peripheral CB1 agonism increases food intake.^[114] Peripheral CB1 antagonism is also thought to have beneficial effects on energy expenditure.^[115] This approach has been pursued by 7TM Pharma, whose TM38837 has been shown to be a peripherally restricted CB1 antagonist and has completed a Phase I clinical trial.^[217] Other similar agents such as Northeastern University's AM6545 are also in development and have shown promising results in preclinical studies.^[116] It remains to be shown if clinically relevant weight loss can be achieved without the central appetite-suppressant effects of blood–brain barrier-penetrant CB1 antagonists.

Gut-related Peptides to Treat Obesity & the Metabolic Syndrome

Similarly to the GLP-1R agonists, other new agents, which not only affect weight control but also improve metabolic and cardiovascular disorders, are attracting growing interest. The critical therapeutic end point in the treatment of obesity is not only the reduction in bodyweight, but the reduction in morbidity and mortality from associated comorbidities.

Pramlintide (Symlin®; Amylin Pharmaceuticals), an analog of the pancreatic hormone amylin, is one of these drugs. The agent has been approved as an adjunct to mealtime insulin in patients with Type 1 and 2 diabetes mellitus, but is also associated with a reduction in appetite and food intake through a delayed gastrointestinal motility. In a first dose-escalation randomized trial testing pramlintide for obesity treatment, a mean weight loss of 3.7% was reported after 16 weeks (with a dose of 240 μg) and at least 31% of participants achieved a 5% or greater weight loss.^[117] A subsequent dose-escalation study (with 120, 240 and 360 μg administered two-to-three-times daily) showed a progressive weight reduction at 12 months, with a placebo-subtracted weight loss of 6.1 kg (120 μg) and 7.2 kg (360 μg), respectively.^[118] Two amylin-based analogs are currently undergoing development for obesity treatments: a second-generation amylin analog davalintide^[119] and a combination of pramlintide and metreleptin (a recombinant human leptin).^[120] The combination of the leptin recombinant with pramlintide was expected to restore the leptin sensitivity in obese patients. Indeed, the combined treatment over 20 weeks has been demonstrated to produce greater weight loss than pramlintide or metreleptin administered alone.^[120]

The most common pramlintide-related adverse events are hypoglycemia and nausea, followed by anorexia and vomiting.^[121]

Pramlintide did not show an increase in the overall event rate of severe hypoglycemia in long-term placebo-controlled studies. However, during the first 4 weeks of pramlintide therapy, there was an increase in severe hypoglycemia, particularly in patients with Type 1 diabetes,^[122–125] where the event rate per patient-year ranged between 2.0 and 4.0. As demonstrated in subsequent studies, titrating pramlintide and initially reducing mealtime insulin minimizes the risks of insulin-induced severe hypoglycemia, with improved HbA1C and weight loss.^[126,127] That way, the event rate per patient year for severe hypoglycemia for the first 3-month period of the open-label clinical practice study could be reduced to 0.29 for patients with Type 1 diabetes and to 0.05 for patients with Type 2 diabetes.

AMP-activated Protein Kinase & Peroxisome Proliferator-activated Receptor Modulators

AMP-activated protein kinase (AMPK) is a key enzyme in the regulation of energy metabolism that has pleiotropic effects in multiple tissues. AMPK is activated under fasting conditions and causes increased fatty acid oxidation, glucose uptake and glycolysis, and the inhibition of fatty acid and glycogen synthesis. Recently, AMPK has also emerged as a regulator of appetite, contributing to the control of energy metabolism at both the cell and whole-body levels.^[128] 5-amino-1-β-D-ribofuranosylimidazole-4-carboxamide (AICAR), a cell-permeable adenosine analog that can be phosphorylated to form 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranosyl-5'-monophosphate, stimulates AMPK activity and glucose uptake in both muscle and adipose tissues.^[129–131] AMPK activation by AICAR administration into the third ventricle or directly into the paraventricular nucleus of the hypothalamus has been shown to significantly increase food intake.^[132] By contrast, the expression of dominant negative AMPK in the hypothalamus was sufficient to reduce food intake and bodyweight, whereas constitutively active AMPK increased both.^[128] These experimental studies suggest that while activation of AMPK in the periphery may be beneficial to obese patients by increasing energy expenditure, in the brain, suppression of AMPK would be desirable to inhibit appetite. Peroxisome proliferator-activated receptor (PPAR)-γ antagonism has also been considered as a possible target for obesity treatment, even though the concept is relatively new.^[133] PPAR-γ is known to regulate fatty acid storage and glucose metabolism. The genes activated by PPAR-γ stimulate lipid uptake and adipogenesis by fatty cells, while PPAR-γ-knockout mice fail to generate adipose tissue when fed a high-fat diet.^[134] Treatment for 10 weeks with SR-202, a PPAR-γ antagonist, has been shown to reduce weight gain, white adipose tissue accumulation and brown fat mass in a mouse model.^[135] Several other PPAR-γ antagonists have recently been reported including GW-0072 (GlaxoSmithKline Pharmaceuticals) and LG-100641 (Ligand Pharmaceuticals, Inc), which antagonize thiazolidinedione-induced adipocyte differentiation.^[136,137] These early results suggest that PPAR-γ antagonists may have clinical potential for obesity treatment.

G-protein-coupled Receptor 119

The success of GLP-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in diabetes treatment^[138] has also awakened interest in G-protein-coupled receptor 119 (GPR119) as another target for the treatment of diabetes and obesity. GPR119 or glucose-dependent insulinotropic receptors are predominantly expressed in the islet β-cells and the GI tract. Ethanolamides are proposed to be the endogenous ligands for GPR119, with oleoylethanolamide as the most potent endogenous GPR119 agonist identified to date. Stimulation of GPR119 receptors is an attractive target for treating Type 2 diabetes as they have been shown to play a role in glucose homeostasis through modulation of insulin secretion^[139–143] and direct stimulation of GLP-1 and glucose-dependent insulinotropic peptide secretion.^[144,145] These endogenous antidiabetic hormones stimulate glucose-dependent insulin secretion and improve glycemic control. Stimulation of GPR119 has the benefit of stimulating a multihormonal response, which mimics the physiological response to elevated glucose. In addition to its antidiabetic control, GPR119 agonists also seem to provide a major beneficial effect on bodyweight.^[146] However, the mechanisms underlying these effects on energy homeostasis remain to be demonstrated.

Sodium–Glucose Transporter 2 Inhibitors

Another new class of antidiabetic drugs with potential impact on bodyweight involves the sodium–glucose cotransporter (SGLT2) inhibitors. Glucose is reabsorbed from primary urine via the high-capacity, low-affinity SGLT2 on the luminal surface of the renal cells in the proximal tubules. Selective inhibitors of SGLT2 reduce glucose reabsorption, causing excess glucose to be eliminated in the urine, which results in a decrease in plasma glucose levels. The glucosuria produced by SGLT2 inhibitors is associated with weight loss and reduced blood pressure.

Orally active SGLT2 inhibitors currently in clinical development include BI 10733, canagliflozin (TA7284)^[147] and dapagliflozin.^[148,149] It has been reported that in obese diabetic rodents, these agents induced significant urinary glucose excretion, and reduced blood glucose and bodyweight. To date, clinical data have only been published for dapagliflozin as monotherapy^[150,151] and for combination therapy with metformin,^[152] glimepiride^[153] and insulin plus oral antidiabetic agents.^[154] In a randomized placebo-controlled trial over 12 weeks, dapagliflozin (dosed at 2.5–50 mg/day) produced a 1.3–2.0 kg higher weight loss compared with metformin (1500 mg/day) alone.^[151] Long-term weight loss is consistent with the calories lost due to ongoing glucose elimination in the urine. A common side effect seen in this class of drugs is an increased risk of genitourinary infections. In summary, SGLT2 inhibitors illustrate a novel and interesting class of antidiabetic and anti-obesity drug, but long-term clinical trials are needed to confirm their safety in patients with diabetes. SGLT1 inhibitors (e.g., LX4211 [Lexicon Pharmaceuticals]) block glucose absorption in the gut and increase the release of the satiety-inducing gut hormones GLP1 and PYY.

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