Gastric bypass surgery mimetic approaches

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Gastric bypass surgery mimetic approaches Brian R. Boettcher 247 Ridge St, Winchester, MA 01890, USA

Gastric bypass surgery is effectively a polypharmacological approach for treatment of obesity, type 2 diabetes and nonalcoholic steatohepatitis (NASH). The gastric bypass mimetic approaches reviewed are fixed-dose combinatorial pharmacological approaches. There are two key concepts incorporated into these gastric bypass surgery mimetic approaches. The first key concept is that the combination of glucagon-like peptide 1 (GLP-1) and fibroblast growth factor 21 (FGF21) is essential for success of any gastric bypass surgery mimetic approach. This combination affords the potential for durable weight loss, glycemic control and reduction in liver lipids. The second key concept is that a fixed-dose combination approach is preferred over post-approval combination of the individual components because the individual components alone often lack sufficient efficacy for development. Bariatric surgery is the most effective treatment available for diabetes and obesity producing durable weight loss and remission of diabetes [1,2]. Nonsurgical weight loss trials in obese patients have failed to yield a benefit in terms of cardiovascular event rates [3]. Thus, how weight loss is achieved, rather than weight loss per se, may be critical for providing improved cardiovascular outcomes following any weight loss treatment. Substantial and sustained weight loss is needed to positively impact progression of vascular disease and thereby reduce cardiovascular events [3]. Prospective clinical studies examining bariatric surgery and cardiovascular events were unable to detect a significant association between weight loss and cardiovascular events whereas bariatric surgery is associated with a reduced number of cardiovascular deaths in obese adults as well as favorable outcomes regarding diabetes, nonalcoholic fatty liver disease, quality of life, cancer and mortality [3–6]. Thus, understanding and exploiting the weight lossindependent effects of bariatric surgery [1] may be a critical component of any weight loss therapy. Moreover, pharmacological alternatives to gastric bypass surgery are needed as gastric bypass surgery presents serious surgical complications leading to increased mortality and morbidity risks [1]. A key feature of bariatric surgery is the simultaneous involvement of multiple metabolism-related signaling pathways such as E-mail address: [email protected]. 1359-6446/ã 2017 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.drudis.2017.04.009

increases in GLP-1, oxyntomodulin, peptide YY (PYY), fibroblast growth factor 19 (FGF19), bile acids and improved insulin sensitivity (Fig. 1a) [2,7–10]. In contrast, a decreased resting metabolic rate combined with decreases in leptin, GLP-1, PYY, amylin and cholecystokinin levels and increased ghrelin and gastric inhibitory polypeptide (GIP) levels (which increase hunger, food intake and storage) following diet-induced weight loss is thought to contribute to the weight regain that often occurs following diet-induced weight loss [11]. These physiological changes (decreased energy expenditure and increased hunger) that ‘‘defend” against diet and exercise-induced weight loss have been highlighted in a follow-up study of the contestants in the television show ‘‘The Biggest Loser” [12]. The reduction in the resting metabolic rate (metabolic adaptation) that occurs with these individuals is in marked contrast to bariatric surgery patients who, although initially experiencing a significant reduction in resting metabolic rate, had no detectable decrease in resting metabolic rate after 1 year despite continued weight loss [13].

GLP-1 and FGF21 activities (with FGF21 as a metabolic surrogate for FGF19) are likely to be key to successful implementation of any combination approach to mimic gastric bypass surgery FGF19 and FGF21 have similar metabolic effects at pharmacological doses (both function through the b-klotho/fibroblast growth

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a

Gastric bypass surgery

Bile acids —> GLP-1 Oxyntomodulin PYY FGF19 Insulin sensitivity etc.

• Durable weight loss • Glycemic control • Improved cardiovascular outcomes • Improved nonalcoholic fatty liver disease outcomes etc.

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b

Gastric bypass mimetic approach #1 (Injectable treatment)

GLP-1-FGF21 fusion protein (Single molecule dual agonist) Drug Discovery Today

FIGURE 1

(a) Hormonal and metabolic changes following gastric bypass surgery. Gastric bypass surgery produces an increase in bile acids and metabolism-related hormones (glucagon-like peptide 1 (GLP-1), oxyntomodulin, peptide YY (PYY) and fibroblast growth factor 19 (FGF19)) as well as improved insulin sensitivity. These changes will lead to durable weight loss, enhanced glycemic control as well as improvement in cardiovascular and nonalcoholic fatty liver disease (NAFLD) outcomes [3,4]. GLP-1, oxyntomodulin and PYY are produced by intestinal L-cells in response to TGR5 (also called G protein-coupled bile acid receptor 1 (GPBAR1)) stimulation by bile acids [7,102,103]. FGF19 is also released from the intestine in response to farnesoid X receptor (FXR) stimulation by bile acids [7,104]. (b) Gastric bypass mimetic approach #1. The GLP-1-FGF21 fusion protein. Glucagon-like peptide 1 (GLP-1) and fibroblast growth factor 19 (FGF19) are two hormones that increase following bypass surgery. FGF19 and fibroblast growth factor 21 (FGF21) have similar metabolic effects at pharmacological doses (both function through the b-klotho/fibroblast growth factor receptor 1c (FGFR1c) complex) but FGF21 lacks the mitogenic activity of FGF19 that is likely mediated through FGFR4 activation by FGF19 [14]. Therefore, FGF21 is used in place of FGF19 for multi-component mimetics of gastric bypass surgery. GLP-1 requires free N-terminal amino acids for activity whereas FGF21 requires free C-terminal amino acids for activity. Therefore, linear fusion of the two molecules is feasible. Half-life extension is achieved, for example, either via PEGylation or incorporation of an immunoglobulin Fc domain between the GLP-1 and FGF21 analogs. The GLP-1-FGF21 fusion protein, exhibits enhanced glycemic and body weight control superior to that observed with combination therapy using separate analogs of GLP-1 and FGF21 [44,45].

factor receptor 1c (FGFR1c) complex) but FGF21 lacks the mitogenic activity of FGF19 that is likely mediated through FGFR4 activation by FGF19 [14]. Therefore, FGF21 is used in place of FGF19 for multi-component mimetics of gastric bypass surgery. The GLP-1 and FGF21 mechanisms of action are complementary as seen in a variety of rodent animal models. GLP-1 enhances satiety, insulin secretion and pancreatic b-cell proliferation and inhibits gastric emptying, glucagon release, liver lipid accumulation and b-cell apoptosis [15,16]. FGF21 is an insulin sensitizer that increases energy expenditure, adiponectin levels and lifespan and decreases liver lipid levels [17–21]. In addition, FGF21 protects pancreatic b-cells by both a direct mechanism [22] and an indirect mechanism as an insulin sensitizer in a human clinical study [23]. FGF21 improves the plasma lipid profile by increasing high-density lipoprotein cholesterol (HDLc) and by decreasing low-density lipoprotein cholesterol (LDLc) and triglycerides in monkeys and humans thereby providing cardiovascular benefits [20,24]. Both GLP-1 and FGF21 are cardioprotective as seen in animal models of myocardial injury [25–30]. These cardiovascular benefits observed in animal models have translated to humans based on results of the LEADER trial with the GLP-1 analog, liraglutide [31]. Major adverse cardiac events (MACE) were significantly reduced by 13% with liraglutide treatment versus placebo. Finally, FGF21 links the metabolic and immune systems and regulates peripheral T-cell homeostasis by preventing age-related thymic degeneration. Thus, 2

FGF21 prevents age-induced loss of naive T cells and delays immune senescence in mice [32]. GLP-1 and FGF21, when combined, may also be mutually protective against two potential adverse effects (pancreatitis and bone loss) that have been reported, thereby providing improved adverse effect margins. Although controversial [33,34], reports suggest that GLP-1 therapies may present an increased risk of pancreatitis [35]. However, FGF21 has been shown to be protective in rodent models of pancreatitis [36,37]. FGF21 causes bone loss in mice by increasing bone marrow-derived mesenchymal stem cell (MSC) peroxisome proliferator-activated receptor gamma (PPARg) activity thereby increasing adipocyte formation and decreasing osteoblast formation [38]. FGF21 also enhances bone resorption by induction of hepatic insulin-like growth factor binding protein 1 (IGFBP1) which promotes osteoclastogenesis [39]. However, these results have been contested [40]. On the other hand, changes in bone biomarkers that indicate bone loss have been reported in a human clinical study with a long-acting FGF21 analog [41]. Therefore, additional long-term studies in humans are required to determine the role of FGF21 in human skeletal biology [21]. However, GLP-1 decreases PPAR-g activity in human bone marrow-derived MSCs and prevents differentiation into adipocytes [42]. Moreover, GLP-1 receptor (GLP-1R) agonists are bone protective in humans [43]. Therefore, including GLP-1 activity in any FGF21-based therapy insures minimal potential bone loss, as well

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as maximizing weight loss, glycemic control, cardioprotection and reduction in liver lipids.

Gastric bypass mimetic approach #2 (oral treatment)

The first gastric bypass surgery mimetic approach described is the GLP-1-FGF21 fusion protein (Fig. 1b). Given the weak glycemic control seen in human clinical trials with FGF21 analogs, it appears less likely that FGF21 will be developed as an independent anti-diabetic therapy [21]. Consequently, combination therapies will likely be needed to achieve the full therapeutic potential of FGF21 biology. The GLP-1-FGF21 fusion protein exhibits enhanced glycemic and body weight control superior to that observed with combination therapy using separate analogs of GLP-1 and FGF21 [44,45]. The enhanced efficacy (potentially through altered receptor trafficking and/or cross-talk) and potency (possibly through entropic/avidity effects) of the fusion protein may be obtained through multivalent receptor interactions in cells coexpressing the GLP-1R and the b-klotho/FGFR1c complex. Furthermore, the addition of a second disulfide bond (glutamine to cysteine at position 55 and glycine to cysteine at position 148) into FGF21 improves its thermodynamic stability and pharmacokinetic profile [46]. A second approach to mimic gastric bypass surgery involves the fixed-dose combination of a DPP-4/fibroblast activation protein (FAP) dual inhibitor plus cevoglitazar (PPAR-a/g dual agonist/ LBM642) (Fig. 2). FAP has been identified as an inactivator of FGF21 through a C-terminal decapeptide cleavage analogous to DPP-4 inactivation of GLP-1 [47–50]. DPP-4 and FAP are highly homologous and share a similar active site. Moreover, FAP inhibitors that also inhibit DPP-4 and related proteases have been described [51]. Therefore, a DPP-4/FAP dual inhibitor should be feasible that enhances both FGF21 and GLP-1 activities. Cevoglitazar is an atypical PPAR-a/g dual agonist that does not cause weight gain and edema due to its non-adipose tissue targeting [52]. Additive anti-diabetic and anti-obesity benefits have been observed with the cevoglitazar plus DPP-4 inhibitor combination in Zucker fa/fa rats (LBM642 (cevoglitazar) Non-confidential Project Summary, Novartis Pharma AG, Business Development and Licensing (BD&L), Basel, Switzerland). This approach should increase both GLP-1 (via DPP-4 inhibition) and FGF21 (the PPAR-a activity of cevoglitazar increases hepatic expression of FGF21 and FAP inhibition prevents FGF21 proteolytic inactivation). The combination of GLP-1 and FGF21 has additive/supra-additive antiobesity and anti-diabetic efficacies [44,53]. Entresto is a fixed-dose combination of valsartan and sacubitril that has proven very effective in treatment of heart failure [54,55]. The fixed-dose combination strategy was required for intellectual property (IP) protection as the patent for sacubitril expired in 1997 [56]. A similar fixed-dose combination approach could be taken with cevoglitazar and a DPP-4/FAP dual inhibitor in order to develop a single pill format and provide IP protection as the patent for cevoglitazar expired in 2015 [57]. The third approach to mimic gastric bypass surgery is the fixeddose combination of GLP-1, glucagon (GCG), PYY3-36 (neuropeptide Y Y2 receptor (Y2R) ligand) and/or pancreatic polypeptide (PP; neuropeptide Y Y4 receptor (Y4R) ligand), i.e. the GLP-1R/GCGR/ Y4R tri-agonist or GLP-1R/GCGR/Y2R/Y4R tetra-agonist (Fig. 3).

DPP-4/FAP dual inhibitor + cevoglitazar (non-adipose PPAR-α/γ dual agonist)

GLP-1 and FGF21 + Triglycerides and non-HDLc + hsCRP and fibrinogen + Blood pressure + Ghrelin and hepatic SR-BI + Respiratory quotient (RQ)

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Three fixed-dose combination approaches to mimic gastric bypass surgery

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FIGURE 2

Gastric bypass mimetic approach #2. The fixed-dose combination of a DPP4/FAP dual inhibitor plus cevoglitazar. Dual inhibition of dipeptidyl peptidase 4 (DPP-4) and fibroblast activation protein (FAP) will lead to an increase in endogenous levels of glucagon-like peptide 1 (GLP-1) and fibroblast growth factor 21 (FGF21) by increasing their metabolic stability, while the peroxisome proliferator-activated receptor alpha (PPAR-a) activity of cevoglitazar will increase hepatic expression of FGF21. Cevoglitazar is an atypical PPAR-a/g dual agonist that does not cause weight gain and edema due to its non-adipose tissue targeting [52]. Additive anti-diabetic and anti-obesity benefits have been observed with the cevoglitazar plus DPP-4 inhibitor combination in Zucker fa/fa rats. Cevoglitazar treatment produces an improvement in markers of cardiovascular benefits including decreased triglyceride, non high-density lipoprotein cholesterol (non-HDLc), high-sensitivity C-reactive protein (hsCRP) and fibrinogen levels in humans as well as decreased blood pressure in ZSF1 rats. Cevoglitazar treatment should also have cardiovascular benefits based on increased ghrelin levels [86–91] and the probable increase in hepatic scavenger receptor BI (SR-BI) in humans. Increased hepatic SR-BI will increase macrophage reverse cholesterol transport thereby reducing coronary heart disease [99]. Cevoglitazar treatment also decreases the respiratory quotient (RQ) in humans and the shift to fat utilization may be indicative of long-term weight loss [92]. Although the patent for cevoglitazar expired in 2015, it is possible to obtain intellectual property (IP) protection as the fixed-dose combination of cevoglitazar with a DPP-4/FAP dual inhibitor.

GLP-1R/GCGR dual agonists (e.g. TT-401 and HM12525A) and PYY3-36/PP (Y2R/Y4R) dual agonists (e.g. TM30338/obinepitide) have advanced into clinical trials. However, thus far, none have advanced into Phase 3 trials. In fact, TT-401 completed Phase 2 trials and Lilly decided not to advance TT-401 into Phase 3 trials [31,58]. PP (Y4R) activity is included, even though PP levels don’t change following bypass surgery, since improved efficacy and gastrointestinal (GI) tolerability has been observed versus PYY336 activity alone. Although peripherally administered PYY is emetic, neither Y4R (PP) nor Y2R/Y4R dual agonists cause emesis or evidence of GI-tract side effects in cynomolgus monkeys [59]. TM30338/obinepitide (Y2R/Y4R dual agonist) inhibited food intake in humans up to 9 h post dosing (Edwin T Parlevliet, PhD. thesis, Leiden University, 2010, Chapter 6). PP also causes a sustained decrease in both appetite and food intake [60,61] and decreases hepatic insulin resistance [62,63] in humans. The combination of a GLP-1R/GCGR dual agonist (oxyntomodulin) or a GLP-1R agonist with PYY3-36 has additive/supra-additive efficacies based on studies in both humans [64,65] and mice [66,67].

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Gastric bypass mimetic approach #3 (injectable treatment)

FGF21 GLP-1R/GCGR/Y4R (single molecule tri-agonist)

FGF21 or

GLP-1R/GCGR/Y2R/Y4R (single molecule tetra-agonist) Drug Discovery Today

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FIGURE 3

Gastric bypass mimetic approach #3. The GLP-1R/GCGR/Y4R tri-agonist or the GLP-1R/GCGR/Y2R/Y4R tetra-agonist. The combination of a glucagon-like peptide 1 receptor (GLP-1R)/glucagon receptor (GCGR) dual agonist (oxyntomodulin) or a GLP-1R agonist with peptide YY3-36 (PYY3-36) has additive/supra-additive efficacies based on studies in both humans [64,65] and mice [66,67]. Endogenous levels of fibroblast growth factor 21 (FGF21) are increased by the GCGR activity of the tri- or tetra-agonist [69–71]. PYY3-36 is a neuropeptide Y receptor Y2 (Y2R) agonist and pancreatic polypeptide (PP) is a neuropeptide Y receptor Y4 (Y4R) agonist. Although PP levels do not increase following bypass surgery, Y4R activity is included to improve efficacy and gastrointestinal (GI) tolerability [59].

Furthermore, in humans, combined blockade of GLP-1 and PYY actions increased food intake after bypass surgery supporting a role for these hormones in decreased food intake after surgery [68]. GLP-1R/GCGR dual agonism also leads to an increase in FGF21 [69] due to the glucagon activity [70,71]. Synthesis of the GLP-1R/ GCGR/Y4R tri-agonist or GLP-1R/GCGR/Y2R/Y4R tetra-agonist is achievable using chemical methods as outlined in [72,73] (Fig. 4). An alternate approach to the tri- or tetra-agonist is a fixed-dose combination of the GLP-1R/GCGR dual agonist with a Y4R agonist or Y2R/Y4R dual agonist. The single molecule multi-agonist is

SH

preferred since enhanced efficacy (via altered receptor trafficking and/or cross-talk) and/or potency (via entropic/avidity effects) may be obtained through possible multivalent receptor interactions in cells co-expressing the GLP-1R and/or GCGR along with the Y2R and/or Y4R. Enhanced efficacy and potency versus the individual components have been observed with GLP-1-FGF21 fusion proteins [44]. The fixed-dose combination strategy is analogous to that used to develop Entresto and may be the only viable path forward since the individual components alone appear to lack sufficient efficacies for development. Y2R activity has potential for adverse bone effects. Mouse knockout models of Y1 and Y2 receptors and PYY along with transgenic over-expression of PYY support a role of these receptors in regulation of bone metabolism. These animal models have established that bone mass is under the control of the NPY system, indirectly via hypothalamic Y2 receptors and NPY-ergic neurons, as well as directly via osteoblastic Y1 receptors [74]. However, since GLP-1R agonists are bone protective [43], the GLP-1R activity of the GLP-1R/GCGR/Y2R/Y4R tetra-agonist peptide should counteract possible adverse bone effects of Y2R agonism. Also note that potential adverse bone effects due to Y2R activity are not an issue for the GLP-1R/GCGR/Y4R tri-agonist.

Synthetic approaches for preparation of multi-agonist stapled peptides The disulfide insertion approach may be used to ‘‘staple” a GLP1R/GCGR dual agonist, a Y2R/Y4R dual agonist and a Y4R agonist [72,73] (Fig. 4). With a-helical peptides it is possible to link two cysteine residues that are separated by 6, 10 or 13 intervening amino acids using methods described by Schultz’s group [73]. It should also be possible to link two cysteine residues separated by

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1,3-dichloroacetone

O

H2N-X-L-PL

N

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S N S

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PLA

PLB

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GLP-1R/GCGR/Y4R tri-agonist or GLP-1R/GCGR/Y2R/Y4R tetra-agonist Drug Discovery Today

FIGURE 4

Synthetic scheme for preparation of GLP-1R/GCGR/Y4R tri-agonists and GLP-1R/GCGR/Y2R/Y4R tetra-agonists (adapted from Ref. [72]). A disulfide insertion approach is used to ``staple” a-helical peptides and conjugate with a coupling reagent. PLA and PLB are complementary coupling groups (``Payload”); e.g. PLA + PLB = azide + alkyne, sulfhydryl + maleimide, etc. X represents oxygen (O) and L represents a linker. An alternate strategy to crosslink 2 cysteines separated by 6 amino acids (2 helical turns) utilizes a cross-linker based on N,N’-butane-1,4-diyl bis(bromoacetamide) [73]. Possible disulfide insertion sites are positions 18 and 22 or 15 and 22 of the Y2R/Y4R dual agonist or Y4R agonist [80]. Half-life extension could be achieved using a mini-pump device, e.g. ITCA 650 [31]. The mini-pump device improves compliance (6–12 months drug delivery), reduces the nausea side effect by lowering peak drug exposure and the NDA for delivery of exenatide (ITCA 650) has been filed with an FDA regulatory decision expected in late 2017 [83]. 4

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3 intervening amino acids using 1,3-dichloroacetone [72]. A Y2R/ Y4R dual agonist or Y4R agonist [75–78] and (Simmi Jolly, PhD. thesis, King’s College London, 2013 and Edwin T Parlevliet, PhD. thesis, Leiden University, 2010, Chapter 6) can be coupled to the GLP-1R/GCGR dual agonist [58] using click chemistry (e.g. azidealkyne cycloaddition) [72]. C-terminal dipeptide cleavage of PYY336 by a tissue-based protease produces the inactive PYY3-34 in humans [79]. Consequently, it may be possible to improve metabolic stability through peptide modification to block the C-terminal cleavage. Possible disulfide insertion sites are positions 18 and 22 or 15 and 22 of the Y2R/Y4R dual agonist or Y4R agonist [80]. Half-life extension could be achieved using (1) a mini-pump device, e.g. ITCA 650 [31]; (2) a sustained-release polymer approach, e.g. either a microsphere [81] or hydrogel [82] formulation; (3) the MicroCor transdermal delivery system [73]; or (4) by coupling an immunoglobulin Fc domain or albumin binder through the linker connecting the two peptides. The mini-pump device may be preferred as it improves compliance (6–12 months drug delivery), reduces the nausea side effect by lowering peak drug exposure and the NDA for delivery of exenatide (ITCA 650) has been filed with an FDA regulatory decision expected in late 2017 [83].

Fixed-dose combination gastric bypass mimetic approaches are preferred Entresto is a fixed-dose combination therapy of valsartan, an angiotensin II receptor antagonist, and sacubitril, a neutral endopeptidase (NEP) inhibitor. When compared to standard angiotensin-converting enzyme (ACE) inhibitor therapy, Entresto lowered the risk of cardiovascular death by 20% and the risk of hospitalization by 21% for patients suffering from chronic heart failure. Proper use of Entresto is expected to prevent 28,000 deaths per year in the U.S. [55]. The sacubitril component of Entresto was never developed alone because it lacked sufficient efficacy for full development. Sacubitril was originally synthesized in the early 1990’s and its patent expired in 1997 [56]. Cevoglitazar has faced similar development hurdles, as did sacubitril. In clinical trials cevoglitazar showed good efficacy for dyslipidemia but did not show sufficient efficacy for type 2 diabetes and obesity due to the short nature of the initial trials (1 month) and its poor distribution into adipose tissue and, therefore, reduced short term glycemic control efficacy (LBM642 (cevoglitazar) Non-confidential Project Summary, Novartis Pharma AG, BD&L, Basel, Switzerland). However, as designed and desired, the side effects of weight gain and edema, seen in other PPAR-g or PPAR-a/g agonists, were not observed. Nevertheless, based on preclinical studies, it was expected that combination with a DPP-4 inhibitor would substantially enhance both its anti-diabetic and anti-obesity efficacies. However, the decision to out-license the molecule was made in 2007 and no further clinical studies were carried out. Subsequently, its patent expired in 2015 [57]. A similar fixed-dose combination approach should also be applied to the development of a DPP-4/FAP dual inhibitor as a DPP-4/FAP dual inhibitor alone may not have sufficient efficacy to support Phase 3 development. The ultimate therapy is the combination of a DPP-4/FAP dual inhibitor with cevoglitazar in order to obtain the maximal efficacies of the combination of GLP-1 plus FGF21 activities. Thus, the fixed-dose combination of a DPP-4/FAP

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dual inhibitor and cevoglitazar should be pursued in parallel with development of the DPP-4/FAP dual inhibitor. The fixed-dose combination approach should also be utilized for the combination of a GLP-1R/GCGR dual agonist with a Y4R agonist or Y2R/Y4R dual agonist. It is very likely that one or both of these therapeutic approaches will not be developed for regulatory approval due to commercial reasons, i.e. insufficient efficacy alone relative to current therapies. This occurred with sacubitril in the case of Entresto and therefore the fixed-dose combination approach (GLP-1R/GCGR/Y4R or GLP-1R/GCGR/Y2R/Y4R multiagonists) may be the only viable path forward for these combinations.

Cevoglitazar/LBM642 (Phase 2) is the preferred combination partner for an orally available multicomponent gastric bypass mimetic Cevoglitazar not only increases hepatic expression of FGF21 but also has additional attributes that make it an attractive partner for fixed-dose combination with DPP-4/FAP dual inhibitors. Cevoglitazar has limited adipose exposure [52] and does not cause weight gain and edema like typical PPAR-g or PPAR-a/g agonists that target adipose tissue (e.g. Roche’s aleglitazar [84]). Nevertheless, cevoglitazar does retain the beneficial insulin sensitizing effects of PPAR-g activation possibly through PPAR-g effects in non-adipose tissue, e.g. liver, muscle or macrophages as demonstrated by Hevener et al. [85]. Moreover, cevoglitazar increases ghrelin levels in humans (LBM642 (cevoglitazar) Non-confidential Project Summary, Novartis Pharma AG, BD&L, Basel, Switzerland) and this may have cardiovascular benefits as ghrelin improves endothelial function in metabolic syndrome patients [86], increase heart function and exercise capacity in patients with heart failure [87], prevents arrhythmias and reduces mortality in the acute phase after myocardial infarction [88] and attenuates pressure overload-induced cardiac hypertrophy [89,90]. Increased ghrelin levels may also contribute to the beneficial effects of exercise on chronic inflammatory diseases of the elderly [91]. Cevoglitazar treatment also decreases the respiratory quotient (RQ) in both mice and humans and the shift to fat utilization may be indicative of long-term weight loss based on human clinical results [92]. A signal for decreased food intake (even in the presence of increased ghrelin levels which should lead to increased food intake) was also observed in humans with high baseline food intake following cevoglitazar treatment, consistent with similar observations in rodent and monkey animal models. The effect on food intake may involve a novel intestinal mechanism of action, in which cevoglitazar acts as a mimetic of oleylethanolamide, an endogenous intestinal satiety hormone [52,93]. Additional cardiovascular benefits from cevoglitazar treatment may be achieved through an improved lipid profile, i.e. decreased triglycerides and non-HDLc in humans, decreased blood pressure in ZSF1 rats which are obese, diabetic and hypertensive, and decreased high sensitivity C-reactive protein (hsCRP) and fibrinogen levels in cynomolgus monkeys and humans. An additional advantage is that, in dogs, cevoglitazar exhibits additive efficacy in combination with simvastatin without a drug-drug interaction and, in humans, has no clinically significant drug–drug interaction with simvastatin and midazolam [94]. In marked contrast to the hyperbolic HDLc dose-response changes observed in rodent and monkey animal models, HDLc

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changes with cevoglitazar treatment in humans are bell-shaped. HDLc increases at low doses due to cevoglitazar’s PPAR-a activity and decreases at high doses due to PPAR-g activity, which, for cevoglitazar, is less potent than its PPAR-a activity
HDLc decreases have been observed clinically for the combination of fibrates (PPAR-a agonists) and thiazolidinediones (TZDs; PPAR-g agonists) [95]. It is interesting to note that the PPAR-a/g dual agonist, aleglitazar, did not cause decreased HDLc at the doses tested [96], further attesting to the unique behavior of cevoglitazar in humans perhaps due to its non-adipose tissue targeting. Weight gain and edema mediated by the adipose PPAR-g activity of aleglitazar may be dose limiting and preclude it from achieving a sufficiently high liver exposure to activate hepatic PPAR-g activity. Decreased HDLc at high doses is consistent with cevoglitazar treatment leading to an increase in hepatic scavenger receptor BI (SR-BI) mediated by PPAR-g [97,98]. If true, this will improve HDL function and cholesterol flux leading to a reduction in coronary heart disease based on human genetic results with SR-BI loss-offunction variant P376L [99] and results with SR-BI gene manipulation in mice [100,101]. It is important to note that enhanced macrophage reverse cholesterol transport mediated by hepatic SRBI should occur at lower doses of cevoglitazar that don’t cause a decrease in HDLc from its original level since cevoglitazar’s more

potent PPAR-a activity will lead to increased apolipoprotein A1 (apoA1) and HDLc.

Conclusion Gastric bypass surgery mimetic approaches are described that afford the possibility of superior weight loss and glycemic control along with cardiovascular benefits and improved treatments for nonalcoholic steatohepatitis (NASH). One key concept to the success of these approaches is the fixed-dose combination of GLP-1 and FGF21 activities, either directly or indirectly. One such fixed-dose combination approach is the GLP-1-FGF21 fusion protein that exhibits enhanced glycemic and body weight control superior to combination therapy using separate analogs of GLP-1 and FGF21. A second approach is based on enhancement of endogenous levels of FGF21 and GLP-1 through the fixed-dose combination of a DPP-4/FAP dual inhibitor with the PPAR-a/g dual agonist, cevoglitazar. The third approach involves a single molecule GLP-1R/GCGR/Y4R tri-agonist or GLP-1R/GCGR/Y2R/ Y4R tetra-agonist. The GCGR activity of these multi-agonists induces hepatic expression of FGF21. These approaches are focused on targets with strong human and rodent genetic and pharmacological validation and are therefore expected to have a high probability of success in translation to the clinic.

References 1 Rubino, F. et al. (2010) Metabolic surgery to treat type 2 diabetes: clinical outcomes and mechanisms of action. Annu. Rev. Med. 61, 393–411 2 Hage, M.P. et al. (2012) Role of gut-related peptides and other hormones in the amelioration of type 2 diabetes after Roux-en-Y gastric bypass surgery. ISRN Endocrinol. http://dx.doi.org/10.5402/2012/504756 https://www.hindawi.com/ journals/isrn/ ¨ stro ¨ m, L. et al. (2012) Bariatric surgery and long-term cardiovascular events. JAMA 3 Sjo 307, 56–65 4 Mummadi, R.R. et al. (2008) Effect of bariatric surgery on nonalcoholic fatty liver disease: systematic review and meta-analysis. Clin. Gastroenterol. Hepatol. 6, 1396– 1402 ¨ stro ¨ m, L. et al. (2007) Effects of bariatric surgery on mortality in Swedish obese 5 Sjo subjects. N. Engl. J. Med. 357, 741–752 ¨ stro ¨ m, L. et al. (2009) Effects of bariatric surgery on cancer incidence in obese 6 Sjo patients in Sweden (Swedish Obese Subjects Study): a prospective, controlled intervention trial. Lancet Oncol. 10, 653–662 7 Abdeen, G. and Le Roux, C.W. (2016) Mechanism underlying the weight loss and complications of Roux-en-Y gastric bypass. Review. Obes. Surg. 26, 410–421 8 Meek, C.L. et al. (2016) The effect of bariatric surgery on gastrointestinal and pancreatic peptide hormones. Peptides 77, 28–37 9 Choudhury, S.M. et al. (2016) Gastrointestinal hormones and their role in obesity. Curr. Opin. Endocrinol. Diabetes Obes. 23, 18–22 10 Holst, J.J. (2016) Gut hormones and gastric bypass. Cardiovasc. Endocrinol. 5, 69–74 11 Sumithran, P. et al. (2011) Long-term persistence of hormonal adaptations to weight loss. N. Eng. J. Med. 365, 1597–1604 12 Fothergill, E. et al. (2016) Persistent metabolic adaptation 6 years after The Biggest Loser competition. Obesity 24, 1612–1619 13 Knuth, N.D. et al. (2014) Metabolic adaptation following massive weight loss is related to the degree of energy imbalance and changes in circulating leptin. Obesity 22, 2563–2569 14 Adams, A.C. et al. (2012) Fundamentals of FGF19 & FGF21 action in vitro and in vivo. PLoS One http://dx.doi.org/10.1371/journal.pone.0038438 http://www.plosone.org 15 Baggio, L.L. and Drucker, D.J. (2007) Biology of incretins: GLP-1 and GIP. Gastroenterology 132, 2131–2157 16 Gupta, N.A. et al. (2010) Glucagon-like peptide-1 receptor is present on human hepatocytes and has a direct role in decreasing hepatic steatosis in vitro by modulating elements of the insulin signaling pathway. Hepatology 51, 1584–1592

6

17 Xu, J. et al. (2009) Fibroblast growth factor 21 reverses hepatic steatosis, increases energy expenditure, and improves insulin sensitivity in diet-induced obese mice. Diabetes 58, 250–259 18 Kliewer, S.A. and Mangelsdorf, D.J. (2010) Fibroblast growth factor 21: from pharmacology to physiology. Am. J. Clin. Nutr. 91 (Suppl), 254S–257S 19 Zhang, Y. et al. (2012) The starvation hormone, fibroblast growth factor-21, extends lifespan in mice. eLife http://dx.doi.org/10.7554/eLife.00065 http://www. elifesciences.org 20 Kharitonenkov, A. and DiMarchi, R. (2015) FGF21 revolutions: recent advances illuminating FGF21 biology and medicinal properties. Trends Endocrinol. Metab. 26, 608–617 21 Kharitonenkov, A. and DiMarchi, R. (2016) Fibroblast growth factor 21 night watch: advances and uncertainties in the field (Review). J. Intern. Med. http://dx.doi.org/ 10.1111/joim.12580 http://onlinelibrary.wiley.com/journal/10.1111/(ISSN) 1365-2796 22 Wente, W. et al. (2006) Fibroblast growth factor-21 improves pancreatic b-cell function and survival by activation of extracellular signal-regulated kinase 1/2 and Akt signaling pathways. Diabetes 55, 2470–2478 23 Buchanan, T.A. et al. (2002) Preservation of pancreatic b-cell function and prevention of type 2 diabetes by pharmacologic treatment of insulin resistance in high-risk Hispanic women. Diabetes 51, 2796–2803 24 Kharitonenkov, A. et al. (2007) The metabolic state of diabetic monkeys is regulated by fibroblast growth factor-21. Endocrinology 148, 774–781 25 Okerson, T. and Chilton, R.J. (2012) The cardiovascular effects of GLP-1 receptor agonists. Cardiovasc. Ther. 30, e146–e155.http://dx.doi.org/10.1111/j.17555922.2010.00256.x http://onlinelibrary.wiley.com/journal/10.1111/(ISSN) 1755-5922 26 Liu, S.Q. et al. (2013) Endocrine protection of ischemic myocardium by FGF21 from the liver and adipose tissue. Sci. Rep. 3, 2767.http://dx.doi.org/10.1038/srep02767 http://www.nature.com/srep/index.html 27 Planavila, A. et al. (2013) Fibroblast growth factor 21 protects against cardiac hypertrophy in mice. Nat. Commun. 4, 2019.http://dx.doi.org/10.1038/ ncomms3019 http://www.nature.com/ncomms/index.html 28 Planavila, A. et al. (2015) Fibroblast growth factor 21 protects the heart from oxidative stress. Cardiovasc. Res. 106, 19–31 29 Zhang, C. et al. (2015) Fibroblast growth factor 21 protects the heart from apoptosis in a diabetic mouse model via extracellular signal-regulated kinase 1/2-dependent signalling pathway. Diabetologia 58, 1937–1948

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DRUDIS-2005; No of Pages 8

30 Di Lisa, F. and Itoh, N. (2015) Cardiac Fgf21 synthesis and release: an autocrine loop for boosting up antioxidant defenses in failing hearts. Cardiovasc. Res. 106, 1–3 31 Dove, A.E. et al. (2016) Diabetes news. J. Diabetes 8, 748–752 32 Youm, Y.-H. et al. (2016) Prolongevity hormone FGF21 protects against immune senescence by delaying age-related thymic involution. Proc. Natl. Acad. Sci. U. S. A. 113, 1026–1031 33 Holst, J.J. and Deacon, C.F. (2013) Is there a place for incretin therapies in obesity and prediabetes? Trends Endocrinol. Metab. 24, 145–152 34 Drucker, D.J. et al. (2011) The safety of incretin-based therapies—review of the scientific evidence. J. Clin. Endocrinol. Metab. 96, 2027–2031 35 Singh, S. et al. (2013) Glucagonlike peptide 1-based therapies and risk of hospitalization for acute pancreatitis in type 2 diabetes mellitus. JAMA Intern. Med. 173, 534–539 36 Johnson, C.L. et al. (2009) Fibroblast growth factor 21 reduces the severity of cerulean-induced pancreatitis in mice. Gastroenterology 137, 1795–1804 37 Johnson, C.L. et al. (2014) Silencing of the fibroblast growth factor 21 gene is an underlying cause of acinar cell injury in mice lacking MIST1. Am. J. Physiol. Endocrinol. Metab. 306, E916–E928 38 Wei, W. et al. (2012) Fibroblast growth factor 21 promotes bone loss by potentiating the effects of peroxisome proliferator-activated receptorg. Proc. Natl. Acad. Sci. U. S. A. 109, 3143–3148 39 Wang, X. et al. (2015) A liver-bone endocrine relay by IGFBP1 promotes osteoclastogenesis and mediates FGF21-induced bone resorption. Cell Metab. 22, 811–824 40 Li, X. et al. (2016) FGF21 is not a major mediator for bone homeostasis or metabolic actions of PPARa and PPARg agonists. J. Bone Miner. Res. http://dx.doi.org/10.1002/ jbmr.2936 http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1523-4681 41 Talukdar, S. et al. (2016) A long-acting FGF21 molecule, PF-05231023, decreases body weight and improves lipid profile in non-human primates and type 2 diabetic subjects. Cell Metab. 23, 427–440 42 Sanz, C. et al. (2010) Signaling and biological effects of glucagon-like peptide 1 on the differentiation of mesenchymal stem cells from human bone marrow. Am. J. Physiol. Endocrinol. Metab. 298, E634–E643 43 Iepsen, E.W. et al. (2015) GLP-1 receptor agonist treatment increases bone formation and prevents bone loss in weight-reduced obese women. J. Clin. Endocrinol. Metab. 100, 2909–2917 44 Boettcher, B.R. et al. (2016) Novartis AG. Dual function fibroblast growth factor 21 proteins, US9458214 B2. 45 Hong, H.N. et al. (2016) YH25724, a novel long-acting GLP-1/FGF21 dual agonist provides potent and sustained glycaemic control, body weight loss and lipid profile improvement in animal models. EASD 2016 Munich, Abstract #111. 46 Boettcher, B.R. et al. (2016) Novartis AG. Methods of treating metabolic disorders with an FGF21 variant, US9266935 B2. 47 Zhen, E.Y. et al. (2016) Circulating FGF21 proteolytic processing mediated by fibroblast activation protein. Biochem. J. 473, 605–614 48 Dunshee, D.R. et al. (2016) Fibroblast activation protein cleaves and inactivates Fibroblast Growth Factor 21. J. Biol. Chem. 291, 5986–5996 49 Sanchez-Garrido, M.A. et al. (2016) Fibroblast activation protein (FAP) as a novel metabolic target. Mol. Metab. 5, 1015–1024 50 Coppage, A.L. et al. (2016) Human FGF-21 is a substrate of fibroblast activation protein. PLoS One http://dx.doi.org/10.1371/journal.pone.0151269 http://www. plosone.org 51 Tsai, T.-Y. et al. (2010) Substituted 4-carboxymethylpyroglutamic acid diamides as potent and selective inhibitors of fibroblast activation protein. J. Med. Chem. 53, 6572–6583 52 Chen, H. et al. (2010) Cevoglitazar, a novel peroxisome proliferator-activated receptor-a/g dual agonist, potently reduces food intake and body weight in obese mice and cynomolgus monkeys. Endocrinology 151, 3115–3124 53 Coskun, T., and Glaesner, W. (2013) Eli Lilly and Company. Co-administration of FGF-21 and GLP-1 to treat diabetes and lower blood glucose. US8557769 B2. 54 Ksander, G.M., and Webb, R.L. (2014) Novartis AG. Methods of treatment and pharmaceutical composition, US8796331 B2. 55 Fonarow, G.C. et al. (2016) Potential mortality reduction with optimal implementation of angiotensin receptor neprilysin inhibitor therapy in heart failure. JAMA Cardiol. http://dx.doi.org/10.1001/jamacardio.2016.1724 56 Ksander, G. (1993) Ciba-Geigy Corporation. Biaryl substituted 4-amino-butyric acid amides, US5217996A. 57 Bach, A.T. et al. (2007) Novartis AG. Heterocyclic compounds and methods of use, US7183304 B2. ¨ p, M.H. et al. (2016) Unimolecular polypharmacy for treatment of diabetes 58 Tscho and obesity. Cell Metab. 24, 51–62 59 Schwartz, T. et al. (2010) 7TM Pharma A/S. Y-receptor agonists, US20100160226 A1.

REVIEWS

60 Batterham, R.L. et al. (2003) Pancreatic polypeptide reduces appetite and food intake in humans. J. Clin. Endocrinol. Metab. 88, 3989–3992 61 Neary, N.M. et al. (2008) No evidence of an additive inhibitory feeding effect following PP and PYY3-36 administration. Int. J. Obes. (Lond.) 32, 1438–1440 62 Brunicardi, F.C. et al. (1996) Pancreatic polypeptide administration improves abnormal glucose metabolism in patients with chronic pancreatitis. J. Clin. Endocrinol. Metab. 81, 3566–3572 63 Rabiee, A. et al. (2011) Pancreatic polypeptide administration enhances insulin sensitivity and reduces the insulin requirements of patients on insulin pump therapy. J. Diabetes Sci. Technol. 5, 1521–1528 64 Field, B.C.T. et al. (2010) PYY3-36 and oxyntomodulin can be additive in their effect on food intake in overweight and obese humans. Diabetes 59, 1635–1639 65 Schmidt, J.B. et al. (2014) Effects of PYY3-36 and GLP-1 on energy intake, energy expenditure and appetite in overweight men. Am. J. Physiol. Endocrinol. Metab. 306, E1248–E1256 66 Talsania, T. et al. (2005) Peripheral exendin-4 and peptide YY3-36 synergistically reduce food intake through different mechanisms in mice. Endocrinology 146, 3748– 3756 67 Paulik, M. et al. (2011) Combined long-acting PYY and GLP-1 agonism synergistically normalizes weight and glucose in obese and diabetic mice. Diabetes 60 (224-OR), A61 68 Svane, M.S. et al. (2016) Peptide YY and glucagon-like peptide-1 contribute to decreased food intake after Roux-en-Y gastric bypass surgery. Int. J. Obes. (Lond.) 40, 1699–1706 69 Park, Y.J. et al. (2014) Lipolytic and insulinotropic effects of HA, a novel long-acting GLP-1/glucagon dual agonist. Diabetes 63 (Suppl. 1), M12525 116-LB 70 Habegger, K.M. et al. (2013) Fibroblast growth factor 21 mediates specific glucagon actions. Diabetes 62, 1453–1463 71 Cyphert, H.A. et al. (2014) Glucagon stimulates hepatic FGF21 secretion through a PKA- and EPAC-dependent posttranscriptional mechanism. PLoS One http://dx.doi. org/10.1371/journal.pone.0094996 http://www.plosone.org 72 Hu, Q-Y., and Imase, H. (2015) Novartis AG. Methods for oxime conjugation to ketone-modified polypeptides, US20150150998 A1. 73 Yang, P.-Y. et al. (2016) Engineering a long-acting, potent GLP-1 analog for microstructure-based transdermal delivery. Proc. Natl. Acad. Sci. U. S. A. 113, 4140– 4145 74 Wong, I.P.L. et al. (2012) Peptide YY regulates bone remodeling in mice: A link between gut and skeletal biology. PLoS One http://dx.doi.org/10.1371/journal. pone.0040038 http://www.plosone.org 75 Schwartz, T. (2008) 7TM Pharma A/S. Y2/Y4 selective receptor agonists for therapeutic interventions, US20080261871 A1. 76 Schwartz, T. et al. (2009) 7TM Pharma A/S. Y4 selective receptor agonists for therapeutic interventions, US20090118178 A1. 77 Bellmann-Sickert, K. et al. (2011) Long-acting lipidated analogue of human pancreatic polypeptide is slowly released into circulation. J. Med. Chem. 54, 2658– 2667 78 Thieme, V. et al. (2016) High molecular weight PEGylation of human pancreatic polypeptide at position 22 improves stability and reduces food intake in mice. Br. J. Pharmacol. 173, 3208–3221 79 Tora¨ng, S. et al. (2016) In vivo and in vitro degradation of peptide YY3-36 to inactive peptide YY3-34 in humans. Am. J. Physiol. Regul. Integr. Comp. Physiol. 310, R866– R874 80 Pedragosa-Badia, X. et al. (2014) Pancreatic polypeptide is recognized by two hydrophobic domains of the human Y4 receptor binding pocket. J. Biol. Chem. 289, 5846–5859 81 DeYoung, M.B. et al. (2011) Encapsulation of exenatide in poly-(d,l-lactide-coglycolide) microspheres produced an investigational long-acting once-weekly formulation for type 2 diabetes. Diabetes Technol. Ther. 13, 1145–1154 82 Li, K. et al. (2013) A long-acting formulation of a polypeptide drug exenatide in treatment of diabetes using an injectable block copolymer hydrogel. Biomaterials 34, 2834–2842 83 Marathe, P.H. et al. (2017) American Diabetes Association standards of medical care in diabetes 2017. J. Diabetes http://dx.doi.org/10.1111/1753-0407.12524 http:// onlinelibrary.wiley.com/journal/10.1111/(ISSN)1753-0407 84 Lincoff, A.M. et al. (2014) Effect of aleglitazar on cardiovascular outcomes after acute coronary syndrome in patients with type 2 diabetes mellitus. JAMA 311, 1515–1525 85 Hevener, A.L. et al. (2007) Macrophage PPARg is required for normal skeletal muscle and hepatic insulin sensitivity and full antidiabetic effects of thiazolidinediones. J. Clin. Invest. 117, 1658–1669 86 Tesauro, M. et al. (2005) Ghrelin improves endothelial function in patients with metabolic syndrome. Circulation 112, 2986–2992

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87 Nagaya, N. et al. (2004) Effects of ghrelin administration on left ventricular function, exercise capacity, and muscle wasting in patients with chronic heart failure. Circulation 110, 3674–3679 88 Mao, Y. et al. (2014) Ghrelin as a treatment for cardiovascular diseases. Hypertension 64, 450–454 89 Mao, Y. et al. (2015) Endogenous ghrelin attenuates pressure overload-induced cardiac hypertrophy via a cholinergic anti-inflammatory pathway. Hypertension 65, 1238–1244 ¨ ter, K.-D. (2015) Pressure overload, sympathetic drive and inflammation. Is 90 Schlu Ghrelin the link? Hypertension 65, 1158–1159 91 Markofski, M.M. et al. (2014) Exercise training modifies ghrelin and adiponectin concentrations and is related to inflammation in older adults. J. Gerontol. A Biol. Sci. Med. Sci. 69, 675–681 92 Zurlo, F. et al. (1990) Low ratio of fat to carbohydrate oxidation as predictor of weight gain: study of 24-h RQ. Am. J. Physiol. Endocrinol. Metab. 259, E650–E657 93 Fu, J. et al. (2003) Oleylethanolamide regulates feeding and body weight through activation of the nuclear receptor PPAR-a. Nature 425, 90–93 94 Sun, H. et al. (2006) Drug-drug interaction potential of LBM642, a PPAR-a and PPAR-g dual agonist, with midazolam and simvastatin. J. Clin. Pharmacol. 46, 1074 (Abstract #59) 95 Linz, P.E. et al. (2014) Paradoxical reduction in HDL-c with fenofibrate and thiazolidinedione therapy in type 2 diabetes: The ACCORD lipid trial. Diabetes Care 37, 686–693 96 Henry, R.R. et al. (2009) Effect of the dual peroxisome proliferator-activated receptor-a/g agonist aleglitazar on risk of cardiovascular disease in patients with

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98

99 100 101

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type 2 diabetes (SYNCHRONY): a phase II, randomised, dose-ranging study. Lancet 374, 126–135 Ahmed, R.A.M. et al. (2009) Human scavenger receptor class b type 1 is regulated by activators of peroxisome proliferators-activated receptor-g in hepatocytes. Endocrine 35, 233–242 Zhang, Y. et al. (2011) Upregulation of scavenger receptor BI by hepatic nuclear factor 4a through a peroxisome proliferator-activated receptor g-dependent mechanism in liver. PPAR Res. http://dx.doi.org/10.1155/2011/164925 https:// www.hindawi.com/journals/ppar/ Zanoni, P. et al. (2016) Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease. Science 351, 1166–1171 Trigatti, B.L. et al. (2003) Influence of the HDL receptor SR-BI on lipoprotein metabolism and atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 23, 1732–1738 Zhang, Y. et al. (2005) Hepatic expression of scavenger receptor class B type I (SRBI) is a positive regulator of macrophages reverse cholesterol transport in vivo. J. Clin. Invest. 115, 2870–2874 Ullmer, C. et al. (2013) Systemic bile acid sensing by G protein-coupled bile acid receptor 1 (GPBAR1) promotes PYY and GLP-1 release. Br. J. Pharmacol. 169, 671–684 Gutierrez-Aguilar, R. and Woods, S.C. (2011) Nutrition and L and Kenteroendocrine cells. Curr. Opin. Endocrinol. Diabetes Obes. 18, 35–41 Gerhard, G.S. et al. (2013) A role for fibroblast growth factor 19 and bile acids in diabetes remission after Roux-en-Y gastric bypass. Diabetes Care 36, 1859–1864

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