Frontiers in Clinical Drug Research – Diabetes and Obesity is an eBook series that brings updated reviews to readers interested in advances in the development of pharmaceutical agents for the treatment of two metabolic diseases – diabetes and obesity. The scope of the eBook series covers a range of topics including the medicinal chemistry, pharmacology, molecular biology and biochemistry of natural and synthetic drugs affecting endocrine and metabolic processes linked with diabetes and obesity. Reviews in this series also include research on specific receptor targets and pre-clinical / clinical findings on novel pharmaceutical agents. Frontiers in Clinical Drug Research – Diabetes and Obesity is a valuable resource for pharmaceutical scientists and postgraduate students seeking updated and critically important information for developing clinical trials and devising research plans in the field of diabetes and obesity research.
The fourth volume of this series features 7 chapters:
-Pharmacologic Obesity Treatment
-Interplay Between Bile Acid and GLP-1 Receptor Agonist Signaling Informs the Design of Drugs to Combat Obesity and its Metabolic Complications
-Sodium–Glucose Co-Transporters Inhibitors for Type 2 Diabetes Mellitus
-The Effects of Traditional Chinese Medicine on Inflammatory Cytokines in Diabetic Nephropathy
-Through the Perspective of Histology – The Alzheimer’s Disease Promotion by Obesity and Glucose Metabolism: Type 3 Diabetes
-Pharmacological Mechanism of PPARγ Ratio in Diabetes and Obesity
-Hydrogen Sulfide and Carbohydrate Metabolism
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After a thirteen-year hiatus, the FDA approved two new anti-obesity drugs in 2012, lorcaserin (brand-name Belviq®) and a fixed-combination of topiramide and phentermine (brand-name Qsymia®); one new anti-obesity drug was approved in 2014, a fixed-combination of naltrexone and bupropion (brand-name Contrave®), and in 2015 the “high dose” liraglutide (brand-name Saxenda®) was approved for weight loss. During this time, the marketed anti-obesity drug sibutramine was withdrawn due to increase in non-fatal myocardial infarction and stroke incidence , two drugs targeting cannabinoid receptors were not approvable in the United States and the European Union due to concerns regarding suicidality and leptin at pharmacologic doses was not marketed due to disappointing efficacy.
All approved drugs, in conjunction with diet and exercise, achieve more weight gain as compared to placebo. Efficacy between different drugs cannot be directly compared since no head-to-head studies have been performed; however, some drugs/drug combinations appear to provide substantially bigger reductions in weight than others or the respective monotherapies. Cardiovascular parameters, especially systolic blood pressure, triglycerides and HDL-cholesterol respond positively to even small amounts of weight loss; the same holds true for insulin and insulin resistance. Uric acid, an emerging risk factor for type 2 diabetes and cardiovascular disease, also tends to improve in response to weight loss although there is an increased short-term risk of gout.
All drugs have specific side effects and several drugs do have black-box warnings; for example, for female patients, pregnancy needs to be ruled-out before starting topiramate and a negative pregnancy test is required every 4 weeks while on treatment with Qsymia, and buproprion needs to be tapered off slowly and not discontinued abruptly to decrease the risk of seizures. Treating overweight/obese subjects presents an opportunity and a challenge to physicians and patients. To achieve optimal weight loss with least complications, patients need to work on hypocaloric diets and exercise
and physicians need to know the prescribing information of the prescribed weight-loss drugs.
The ability to store excess calories has developed in many species to counteract periods of decreased food availability even for prolonged times of famine and to ensure that progression to fecundity and fertility does not result in excessive mortality for mother and offspring. Excess calories are mostly stored as fat in adipose tissue and to a much smaller degree as protein in muscle. However, the body has few, if any, means to defend it against prolonged excessive oversupply of calories. The extent to which it can generate and maintain adipose tissue is genetically determined. After expanding adipose tissue mass and filling all the available storage space in adipose tissue, fat will be deposited in other tissues resulting in lipotoxicity. Depending on the organ affected by lipotoxicity, fatty liver and hepatic insulin resistance, skeletal muscle insulin resistance and pancreatic beta-cell dysfunction can occur; it is likely that the metabolic consequences of lipotoxicity contribute to the development of diabetes and hypertension, renal hyperfiltration and congestive heart failure. In addition, mechanical issues due to excessive adipose tissue mass may cause problems such as degenerative joint disease and sleep apnea.
Approximately one third of the American population is obese and approximately ten percent of the American population is diabetic with another approximately 27% percent being pre-diabetic. Even small amounts of weight loss can prevent or delay the onset of type 2 diabetes. The diabetes prevention program (DPP) and the Look AHEAD studies [2, 3] showed that diet with exercise can achieve up to ten percent of weight loss in a good proportion of subjects. The DPP demonstrated that weight loss achieved by life-style modification decreased the onset of diabetes by nearly 60% when compared to standard of care. In subjects with diabetes, weight loss achieved by diet and exercise can effectively lower glucose levels and reduce the need for medications for lipids, blood pressure and sugar control. However, many overweight and obese subjects struggle to achieve meaningful weight loss and, when weight loss is achieved, to maintain the new lower level of body weight. While bariatric surgery has been demonstrated to lead to large and prolonged reductions in body weight, up to 30% weight loss, and cause remission of diabetes and hypertension and reduce the incidence of cancer and cardiovascular disease [4, 5], it is not available to most subjects.
A first step in weight loss is to have a caloric intake that is lower than the energy needed to maintain body weight. Decreasing hunger, increasing satiety in response to a meal, reduced intestinal food absorption and increased metabolism could all support the goal of weight loss; none of the currently approved drugs increases metabolism and drugs that increase metabolism had serious safety issues and were not developed for clinical use (Fig. 1). High-quality clinical studies of weight loss medications have provided us with good estimates of efficacy and safety including improvements in cardiovascular and metabolic parameters. Most common side effects are related to either the central nervous system and/or the gastro-intestinal tract. Long-term results for cardiovascular safety are only available for lorcaserin .Fig. (1)) Schematic display of variables that affect weight. Current approved weight loss drugs work on the left side of the triangle. Exercise is currently the only accepted and recommended obesity treatment that increases energy expenditure.
Orlistat (brand-names Xenical® and Alli®) is the only available drug for weight loss that interferes with absorption of food resulting in decreased caloric intake; it is taken at 120 mg three times a day with meals. Orlistat reduces fat absorption via inhibition of pancreatic lipase; it is minimally absorbed and does not accumulate in the circulation. Weight loss above that observed with placebo while on a diet and exercise regimen is in the 2-3 kilogram range over a one year time period (for review Hutton&Ferguson ). Compared to placebo, roughly twice as many subjects maintained a weight loss of >5.0% (range 35.5-54.8%) and >10.0% (range 16.4-24.8%) after one year (Table 1a). Orlistat treatment was associated with small beneficial reductions in total and LDL-cholesterol and blood pressure (Table 1b). Orlistat reduced the incidence of new onset diabetes by 42% in subjects with impaired glucose tolerance but only by 8% in subjects with normal glucose tolerance [7, 8]. In overweight subjects with diabetes, orlistat treatment led to better glycemic control; however, there was a higher incidence of hypoglycemia in the treatment group [9, 10]. The main adverse events to orlistat are gastro-intestinal and related to its mechanism of action; oily spotting and fecal incontinence have been reported to occur at a frequency of 26.6% and 7.7%, respectively during the first year of treatment. The frequency of these side effects appears to decrease over time. Orlistat is generally safe but rare serious adverse events have been reported in post marketing surveys and the prescribing physicians should be familiar with the package insert of this drug.
Phentermine (brand-names Adipex® and Fastin®) has been used for weight management for almost 50 years. It acts at the trace amine-associated receptor 1 (TAAR1); this receptor is intracellular and located at the presynaptic end of the neuron. Phentermine enters the presynaptic neuron via a transport protein and activates TAAR1 which causes the release of norepinephrine; no effects on serotonin have been found. Increased CNS epinephrine levels account for the effects and side effects of this drug. It has been approved as monotherapy for short-term treatment (a few weeks) of obesity as adjunct to diet, exercise and behavioral modification. The reasons for the indication for only short term use include potential long-term adverse effects on the cardiovascular system such as tachycardia, hypertension, primary pulmonary hypertension, valvular heart disease and possible myocardial infarction and stroke. In addition, there is tachyphylaxis over time and the risk of drug dependence. Until recently, few high-quality clinical studies had been conducted with phentermine monotherapy and no dose response data for weight loss or appetite were available; and most of the older studies had small patient populations. Phentermine used to be combined with fenfluramine or dexfenfluramine when these drugs were available. The best data for phentermine monotherapy come from the development program for the combination of topiramate (see below) and phentermine . In this study, all patients received counseling to decrease caloric intake by 500 cal/day and to increase physical activity as tolerated.
Phentermine monotherapy at doses of 7.5 and 15.0 mg/day over 28 weeks lead to a weight reduction of 6.7% and 7.4% respectively; weight loss in response to placebo was 1.7%. Systolic blood pressure (SBP) decreased slightly by ~3.5 mmHg in either treatment group; SBP decreased by ~2 mmHg in the placebo group. Changes in diastolic blood pressure (DBP) were small and, compared to placebo, not clinically meaningful. Heart rate did not change significantly from baseline. There was no change from baseline in fasting glucose and HbA1c in either treatment group.
No cardiovascular outcome studies have been performed to assess the long-term safety of phentermine.
Topiramate (brand-name Topomax®) is approved for the treatment of epileptic seizures and for migraine prophylaxis. The mechanism(s) by which topiramate works are not fully elucidated and may involve action on the GABA and the glutamate receptors as well as inhibition of carbonic anhydrase. The effect of topiramate on weight was first reported in 1996. Further dedicated weight loss studies in obese subjects without epilepsy studies showed robust weight loss; doses up to 384 mg per day were evaluated . In this study by Bray et al. , topiramate was uptitrated every other week until the final target doses were achieved; all participants also participated in a commercially available weight loss program and were provided with a diet that was 600 calories lower per day than the estimated energy expenditure. The average weight loss (intention to treat, last observation carried forward analysis) at 24 weeks was 2.6% for placebo and 5.0%, 4.8%, 6.3%, and 6.3%, respectively, for groups treated with 64, 96, 192, and 384 mg/d topiramate (corresponding to mean decreases of 2.8 kg for placebo and of 5.2, 5.0, 6.4, and 6.6 kg, respectively, for the 64-, 96-, 192-, and 384-mg/d TPM groups.) For subjects who completed the 24 -week study, those receiving placebo experienced 3.6% weight loss compared with losses of 5.8%, 6.5%, 8.2%, and 8.5%, respectively, for those receiving 64, 96, 192, and 384 mg/d topiramate. There were no significant changes in glucose, insulin and lipids compared to placebo. However, all topiramate groups exhibited significantly greater decreases in SBP as compared to placebo. Due to a very high frequency of side effects leading to drop outs of the study, the highest dose was dropped in studies evaluating the effects of topiramate on weight-loss associated changes in glucose control [13, 14] and blood pressure . The study by Stenlöf et al. showed a reduction in body weight of 2.5, 6.6 and 9.1%, respectively, in the placebo and the 96 mg and 192 mg topiramate groups . In the study by Eliasson et al., diabetics on placebo lost no weight whereas patients on topiramate 192 mg per day lost on average 7.2 kg (baseline weight 108.4 kg) .
The study by Stenlöf et al. showed that hemoglobin A1c (HbA1c) decreased in the topiramate treatment groups (96mg and 192 mg) by ~0.6% (baseline ~6.8%) while HbA1c decreased by 0.2% in the placebo group . Fasting plasma glucose (FPG) decreased by ~18 mg/dL in the topiramate groups while no change was observed in the placebo group. Insulin levels decreased in all groups but there were no differences between placebo and topiramate groups. No significant changes in lipid profiles were found in either group. SBP decreased significantly more in the topiramate treatment groups (-2.0, -6.3 and -7.6 mmHg) in the placebo and the 96 mg and 192 mg topiramate groups, respectively. Albumin excretion was also found to significantly decrease in the topiramate groups but not in the placebo group.
The study by Eliason et al. also showed a more pronounced decrease in HbA1c in the topiramate 192 mg group (1.1% vs. 0.3% at a baseline of ~%) . FPG also was lowered more robustly with topiramate (~ 23mg/dL vs. 10 mg/dL). No between-group differences were observed for lipids and insulin levels. In addition, no differences in insulin sensitivity were found. And no significant changes in blood pressure were observed.
Assessment of topiramate’s effect on blood pressure in a group of obese hypertensive subjects  showed that patients on drug (either 96 mg or 196 mg per day) lost significantly more weight (1.9%, 5.9% and 6.5%, respectively, for placebo or topiramate 96 mg or 196 mg per day). While SBP decreased in all groups, the reduction was not statistically significantly different as compared to placebo. DBP decreased also slightly in all groups and the reduction in the topiramate groups was significantly greater than placebo (2.1, 5.5 and 6.3 mmHg). In subjects who had lost >5.0% body weight induced by a low-calorie diet, topiramate was associated with additional reduction in weight with an efficacy similar to that described above . All topiramate studies showed robust weight loss above placebo and it was speculated that the drug might increase the metabolic rate in addition to affecting food intake. However, a dedicated study by Tremblay et al. was unable to substantiate any effect on metabolic rate ; therefore, all weight loss in response to topiramate appear to be the result of its effect on appetite and/or satiety.
While topiramate was very effective, the side-effect profile was unfavorable showing mainly central nervous system site effects, especially at high doses. A dedicated dose-response study on topiramate’s effect on cognition showed that these became significantly more frequent and pronounced at studied  doses of greater than 96 mg per day. At the end, due to the side-effect profile, the topiramate monotherapy program for a weight loss indication was discontinued.
No cardiovascular outcome studies have been performed to assess the long-term safety of topiramate.
The effect of the combination of topiramate and phentermine (Qsymia®) on weight has been studied in several studies [11, 19, 20]. A pooled analysis of results  showed that, in non-diabetic obese subjects, the combination leads to weight loss at all available doses. Mean weight loss was 4.7%, 8.2% and 10.4% at doses of 3.75mg/23mg for Phentermine/Topiramide Extended Release (Phen/TpmER), 7.5mg/46mg (Phen/TpmER) and 15mg/92mg (Phen/TpmER), respectively vs. 1.5% in response to placebo. In obese diabetic subjects, the 15mg/92mg(Phen/TpmER) dose lead to a 9.4% weight loss vs. 2.7% with placebo. Combination therapy achieved clinically meaningful weight loss (>5.0% body weight) in approximately 45% of the subjects treated with the lowest dose 3.75mg/23mg (Phen/TpmER), and in approximately 60-70% of subjects treated with the higher doses vs. approximately 20% in the placebo groups (Table 2a).
SBP decreased from baseline in all the combination therapy groups which was significantly different from the placebo group where a lesser drop in blood pressure was observed; greater weight loss was associated with greater reductions in pressure. DBP, compared to placebo, decreased more with the two higher doses of the combination. Fasting insulin levels decreased more in the combination therapy groups which was even slightly more pronounced in a subgroup of pre-diabetic subjects; no overall changes were seen in glucose levels except in pre-diabetic and diabetic subgroups. In the pre-diabetic subgroup, glucose decreased by approximately 5-6 mg/dL in the combination therapy groups vs. approximately 2.5 mg/dL in the placebo group; the annualized incidence of progression from prediabetes to diabetes was lower in the combination therapy groups and this decrease in incidence was related to the degree of weight loss. In the diabetic subgroup, glucose decreased by approximately 5-10 mg/dL in the combination therapy groups vs. approximately 5 mg/dL in the placebo group. Furthermore, in the diabetic subgroup [13, 22], glycated hemoglobin decreased by 0.4% vs. 0.1% in the combination vs. the placebo groups, respectively. Triglycerides and HDL-cholesterol improved slightly with combination therapy compared to placebo. LDL-cholesterol may improve slightly as compared to placebo (Table 2b).
A subgroup analysis  of subjects with prediabetes and/or the metabolic syndrome suggests clinical meaningful reduction in the rate of progression to diabetes of 80-90% with the highest dose of Phen/TpmER combination.
No cardiovascular outcome studies have been performed to assess the long-term safety of the combination therapy of phentermine and topiramate.
Lorcaserin (Belviq®) is a highly selective and potent 5-hydroxy tryptamine 2c (5-HT2c) agonist. It works on receptors in the central nervous system, particularly in the hypothalamus. It activates 5-HT2c receptors on the pro-opiomelanocortin (POMC) neurons in the arcuate nucleus which leads to the release of alpha-melanocortin-stimulating hormone (alpha-MSH). MSH acts on melanocortin-4 receptors in the paraventricular nucleus to suppress appetite. The mode of action is similar to fenfluramine and dexfenfluramine; however, the latter drugs had metabolites with activity on 5-HT2A and 5-HT2B receptors which mediate hallucinations and cardiovascular side effects such as valvulopathy and pulmonary hypertension. Lorcaserin, due to its selectivity for 5-HT2c receptors, appears to be void of any effects on the 5-HT2A and 5HT-2B receptors. The FDA recommends to monitor for worsening and emergence of suicidal thoughts and behaviors and there is a black-box warning that refers to this potential side-effect.
A small 12-week dose-finding study  showed weight loss of 1.8 kg. 2.6 kg and 3.6 kg, respectively, at doses of 10 mg qd. 15 mg qd and 10 mg bid compared to a 0.3 kg weight loss with placebo. The BLOSSOM trial  evaluated the effect of lorcaserin at doses of 10 mg qd and 10 mg bid over one year; it showed a weight loss of 5.8 kg and 4.7 kg at doses of 10 mg qd and 10 mg bid, respectively, compared to 2.9 kg weight loss with placebo. The BLOOM trial  evaluated weight loss in response to 10 mg bid over two years; at one year, the weight loss was 5.8 kg with lorcaserin versus 2.2 kg with placebo. During year two, part of the subjects randomized to lorcaserin were changed to placebo as per protocol; around week 72, weight in the subjects changed to placebo became indistinguishable to that of subjects who had been on placebo from the beginning of the study. Subjects who continued on locarserin for the whole two-year period maintained more weight loss as compared to the placebo group(s) although the between-group difference in weight loss became smaller.
The BLOOM-DM  trial was a dedicated, one-year weight-loss study in a type 2 diabetic population that evaluated the response to lorcarserin 10 mg qd and 10 mg bid versus placebo. The two lorcaserin treatment groups experienced similar weight loss of ~5.5 kg while the placebo group lost ~2.0 kg over the one year period. Results for the proportion of subjects achieving clinically meaningful weight loss are in (Table 3a).
BLOSSOM  showed no changes in HbA1c in response to either dose of lorcaserin and glucose and insulin levels were not reported. Small decreases in LDL-cholesterol were observed with either dose of lorcaserin; these changes were not different from placebo. Similarly, no changes in either SBP or DBP were observed. In the BLOOM  trial, significant but tiny reductions were observed in HbA1c, glucose and insulin levels. Reductions in blood SBP and DBP were small and not different from placebo Table (3b).
The results of the trial (CAMELIA-TIMI) to assess long-term cardiovascular safety with locaserin were recently published ; rates of cardiovascular events were not different from placebo.
The combination of naltrexone and bupropion (Contrave®) was approved for the treatment of obesity in 2014. Interestingly, none of these drugs is FDA-approved as monotherapy for weight loss. Both drugs have been on the market for several decades with indications to treat depression and smoking cessation (bupropion) and as an antidote to opioid overdoses (naltrexone). Most monotherapy (early) studies for either component were small and limited to patients with depression or other behavioral problems. The FDA recommends to monitor for worsening and emergence of suicidal thoughts and behaviors and there is a black-box warning that refers to this potential side-effect.
Naltrexone is an opioid receptor antagonist with affinity to all three opioid receptor subtypes; it acts most potently on mu and delta receptor subtypes and works on central and peripheral opioid receptors. Its mechanism on weight is not well understood; it is thought to be mediated via receptors in the mesolimbic system that affect the dopaminergic reward- and learning center. It is thought that opioid antagonist remove an inhibitory feedback on pro-opiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus that are involved in energy balance and eating behavior; studies in mice do support this concept . The effect of removing POMC neuron inhibition becomes evident mostly when measuring the frequency of action currents in isolated neurons (mouse-brain slice). If the proposed mechanism of naltrexone action is correct, naltrexone might also enhance the efficacy of lorcaserin; however, there are no studies to refute or support the combination of naltrexone and lorcaserin.
Studies with naltrexone showed little or no effect on weight [28, 29]. In normal subjects (not taking any opioids), administration of naltrexone has no significant cardio-vascular effects. It also has no effect on energy expenditure.
In the two studies [28, 29] with high quality data of monotherapy with naltrexone, naltrexone 50 mg qd showed an adjusted weight loss of 2% vs. 1.0% for placebo after 16 weeks of treatment; in the second study, naltrexone 48 mg qd (immediate release) showed 1.2% weight vs. a 0.8% weight loss with placebo. Weight loss of >5.0% was reported in 15.0% and 12.0% of subjects taking naltrexone 50 mg or placebo, respectively. No subject in the naltrexone group achieved a >10.0% weight loss. Similarly, subjects taking the immediate release formulation of naltrexone 48 mg did not achieve better weight loss outcomes compared to placebo. Changes from baseline in blood pressure, fasting insulin and glucose and lipids were small and not different between naltrexone and placebo groups.
Bupropion acts centrally on norepinephrine transporters, on the vesicular monoamine transporter and possibly also on dopamine transporters. It inhibits norepinephrine and dopamine reuptake. In subjects with depression, it had been recognized to induce mild weight loss, which was in contrast to other classes of antidepressants that were associated with weight gain. Weight loss for bupropion monotherapy 300 mg qd was 3.6% vs. 1.0% in the placebo group and 400 mg daily resulted in 2.7% vs. 0.8% weight loss. Changes from baseline in blood pressure, fasting insulin and glucose and lipids were small and not different between bupropion and placebo groups.
For the combination therapy with naltrexone and bupropion, most results have been obtained with the 32 mg daily dose sustained release formulation of naltrexone and the 360 mg daily dose of sustained release bupropion; different daily doses of naltrexone (16 mg or 48 mg) were studied in combination with bupropion 360 mg daily dose and the results were overall not meaningfully different from the 32 mg naltrexone dose [11, 30]. In obese, non-diabetic subjects, weight loss in response to the combination therapy was slightly more than 6.0% versus approximately 1.5% in the placebo groups. Combination therapy achieved clinically meaningful weight loss (>5.0% body weight) in approximately 50%the treated subjects vs. approximately 15% in the placebo groups.
Blood pressure did not change from baseline in the combination therapy groups which was significantly different from the placebo group where, despite less weight loss, blood pressure slightly decreased. Fasting insulin levels decreased more in the combination therapy groups; no overall changes were seen in glucose levels. Triglycerides and HDL-cholesterol improved slightly with combination therapy compared to placebo. LDL-cholesterol may improve slightly as compared to placebo.
In obese subjects with type 2 diabetes  treatment resulted in a 5.0% vs. a 1.8% weight loss in the combination therapy group and the placebo group, respectively. Combination therapy achieved clinically meaningful weight loss (>5.0% body weight) in approximately 45%the treated subjects vs. approximately 20% in the placebo group (Table 4a).
Blood pressure tended to be slightly decreased from baseline in both groups with no significant between-group differences. HbA1c decreased significantly more in the combination group (0.6% vs. 0.1%). Fasting glucose levels tended to improve more in the combination group but the difference missed statistical significance. Fasting insulin levels decreased similarly in both groups. Triglycerides and HDL-cholesterol improved slightly with combination therapy compared to placebo. LDL-cholesterol did not change in either group (Table 4b).
A cardiovascular study was under way but was discontinued due to inappropriately disclosed interim analyses. At the time the study was closed, there did not appear to be an increased cardiovascular risk with the combination therapy.
Liraglutide (brand-name Victoza® for the treatment of diabetes and Saxenda® for weight management) is a glucagon-like peptide-1 (GLP-1) analog that is resistant to degradation by the enzyme dipeptidyl-peptidase-4 (DPP-4) and acts on several organ systems including the brain where is decreases appetite, the stomach where it delays gastric emptying and the pancreas where it increases insulin secretion in a glucose-dependent fashion. In humans, the effect of liraglutide on weight is due to decreasing food intake and increasing satiety [32, 33]. In rodents, it may increase energy expenditure but this observation appears to be dependent on which obesity model is used. Liraglutide is administered daily via subcutaneous injection. Liraglutide levels are in steady state approximately 12 hours after injection and more than 10-fold higher than native GLP-1. A dose-response study  demonstrated significant weight loss vs. placebo at doses of 1.8 mg per per day and higher; the dose-response study and pharmacokinetic modeling  indicated that the 3.0 mg dose would be optimal for weight loss. Liraglutide needs to be slowly up-titrated over a four-week period to administer the full daily dose of 3.0 mg which reduces the gastro-intestinal side-effects. There is a black box warning that liraglutide is contraindicated in subjects with a personal or family history of medullary thyroid carcinoma or in patients with multiple endocrine neoplasia syndrome 2; this black box warning is based on animal data. In addition, there is concern about a potential association between incretin-based therapies and pancreatitis; however, the current data are inconclusive and a recently completed large, placebo-controlled and randomized study using 1.8 mg of liraglutide did not demonstrate any increased risk.
In obese, non-diabetic subjects, weight loss in response to liraglutide was 8.0% versus approximately 2.6% in the placebo group . Liraglutide therapy achieved clinically meaningful weight loss (>5.0% body weight) in approximately 60% of the treated subjects vs.approximately 27% in the placebo group (Table 5a). Subgroup analyses suggested that liraglutide may be less effective is subjects with body mass index >=40. A study by Wadden et al. , showed that the effect of liraglutide on weight loss was additive to that achieved after a 12-week low calorie (1200-1400 cal/day) diet; in addition to the 5.9% of body weight lost due to diet, subjects on liraglutide lost another 6.2% vs. a 0.2% loss in the placebo group. In diabetic subjects , liraglutide 3.0 mg qd reduced weight by 6.0% vs. 2.0% observed in the placebo group. Clinically meaningful weight loss (>5.0% body weight) was observed in approximately 55% of the treated subjects in the liraglutide group vs. approximately 20% in the placebo group (Table 5a).
In type 2 diabetic subjects, the reduction in HbA1c was 1.3% vs. 0.3%, respectively, in the liraglutide and placebo group. SBP decreased slightly more in the liraglutide vs. the placebo group (2.8 mmHg vs. 0.4 mmHg); no between-group differences were seen for the decrease in DBP Table (5b).
SBP and DBP decreased from baseline in the liraglutide and the placebo groups; the decrease was more pronounced with liraglutide. Heart rate increased by approximately 2.5 beats per minute with liraglutide while there was no change in the placebo group.
In non-diabetic obese subjects, fasting glucose and fasting insulin levels decreased more in response to liraglutide. In non-diabetic obese subjects, fasting glucose levels decreased by 7.1 mg/dL and 0.1 mg/dl, respectively, in the liraglutide and placebo groups, respectively Table (5b), and HbA1c decreased significantly more in the liraglutide group (0.6% vs. 0.1%). Fasting insulin levels decreased by 12.6% and 4.4%, respectively, in the liraglutide and placebo groups. Interestingly, the decrease in C-peptide was similar in both groups.
All lipid parameters (LDL, HDL-, VLDL-, non-HDL-, total cholesterol and triglycerides) improved in the liraglutide group and the changes were significantly more pronounced vs. placebo (Table 5b).
No cardiovascular-outcomes results are available for the 3.0 mg dose of liraglutide in obese non-diabetic subjects; however, a study in high-risk, obese diabetic subjects  showed that subjects receiving liraglutide (~80% on the 1.8 mg dose) experienced ~13% lower incidence of the primary composite endpoint (consisting of first occurrence of death from any cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke).
Over the last 40 years, based on the work of Jules Hirsch, Rudolph Leibel, Jeffrey Friedman, Michael Nauck and Jens Holst and many others, progress has been made in unraveling mechanisms of control of appetite, satiety and feeding that appears to be involved in generating unhealthy amounts of adipose tissue. Their work has provided evidence for cross talk between adipocytes and the brain (e.g. leptin – not developed for commercial use) and for cross talk between the gut and the brain (e.g. GLP-1 – liraglutide which is marketed for weight loss). Their work has led to identification of neuronal pathways and neuro-transmitters that present potential targets for weight management drugs. Work is underway to coax (fat) cells into being metabolically more active and thus aide weight management.
Currently available weight-loss drugs are moderately effective, although not as effective as gastric sleeve or Roux-en-Y bariatric surgery. Neither surgery nor drug treatment work without diet; all patients can gain weight while on drug or after surgery when high-density, high-calorie food items are consumed.
Side effects often limit the dosing of the drugs; this problem can be overcome in part by combining lower doses of drugs that affect different targets. For example, one might combine and GLP-1 agonist with one or two drugs described in this chapter; this would be off-label use requiring vigilance for side effects and ideally conducted in randomized and blinded fashion as part of clinical research and drug development.
The authors confirm that they have no conflict of interest to declare for this publication.
For more than a century the physiological role of bile acids was considered limited to their actions in cholesterol metabolism and lipid absorption from the gastrointestinal tract. Evidence emerging over the past 20 years has greatly changed this perspective. It is now apparent that these complex molecules play an integral signaling function within the gut and have extra-intestinal hormonal actions. Bile acid interaction with plasma membrane G protein-coupled receptors (e.g. TGR5, M3R) and nuclear receptors (e.g. FXR) expressed on intestinal epithelial cells modulates post-receptor signaling and gene transcription. Herein, we review the fundamentals of how bile acid structure governs the interaction of these molecules with cell receptors and transport proteins (e.g. ASBT), and how these interactions are important for nutritional balance. We focus on bile acid interaction with TGR5, a receptor whose activation stimulates release of glucagon-like peptide-1 (GLP-1) from enteroendocrine L cells; GLP-1, an intestinal incretin, is important for glucose homeostasis. Drugs that mimic the actions of GLP-1 or retard its degradation are effective treatments for diabetes, obesity, and their metabolic complications (e.g
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