Regulatory challenges for new drugs to treat obesity and comorbid metabolic disorders

Authors


Professor David Heal, RenaSci Consultancy Ltd, BioCity, Pennyfoot Street, Nottingham NG1 1GF, UK.
Tel: +44 115 912 4260
Fax: +44 115 912 4263
E-mail: david.heal@renasci.co.uk

Abstract

Obesity is a major cause of morbidity and mortality through cardio- and cerebrovascular diseases and cancer. The metabolic consequences of obesity include dyslipidaemia, hypertension, proinflammatory atherogenesis, pre-diabetes and Type 2 diabetes. For a significant proportion of patients, pharmacotherapy to tackle obesity is required as adjunctive support to diet, exercise and lifestyle modification. To this end, the pharmaceutical industry is pursuing many novel drug targets. Although this view is probably not justified, the recent tribulations of rimonabant have created a perception that the regulatory bar for the approval of antiobesity drugs has been raised. Although >5% of placebo-subtracted weight loss maintained over 1 year is the primary efficacy end-point, it is improvements in cardiovascular risk factors that the Food and Drug Administration (FDA) and European Medicines Agency (EMEA) require to grant approval. Safety aspects are also critical in this indication. Many companies are now switching development of their antiobesity drug candidates into other metabolic disorders. Type 2 diabetes is accepted by the industry and FDA, but not EMEA, as the most appropriate alternative. On the other hand, improvements in plasma lipids produced by antiobesity drugs are moderate compared with established therapies, suggesting dyslipidaemia is not a viable development option. Metabolic Syndrome is not accepted by FDA or EMEA as a discrete disease and the agencies will not licence antiobesity drugs for its treatment. The regulatory environment for antiobesity drugs and the spectrum of indications for which they can be approved could change dramatically if positive data for sibutramine emerge from the SCOUT outcome trial.

Introduction

Amongst healthcare experts around the world, there is now agreement that the global epidemic of obesity will be one of the leading causes of morbidity and mortality for current and future generations, unless the inexorable rise in the prevalence of this disorder is reversed. Once considered to be a problem mainly in Western cultures, developing nations have now joined the ranks of countries burdened by obesity. A 1999 United Nations study found obesity to be present in all developing regions and growing rapidly, even in countries where hunger also existed. Obesity is defined by the World Health Organization (WHO) as a subject who has a body mass index (BMI = weight in kg/height in m2) value of >30 kg m−2 (normal BMI = 20–25 kg m−2).

The estimate by the International Obesity Task Force [1] of the current global prevalence of this problem is that there are over 400 million adults worldwide who are classified as clinically obese. This figure is projected to increase to 700 million by 2015. The USA has the highest prevalence in the world with >30% of the adult population categorized as obese, which is predicted to rise to >50% by 2025 [1]. The dramatic increase of worldwide obesity is a very recent phenomenon. For example, in the UK levels of adult obesity remained relatively low and constant at 5–10% of the population until 1990. However, in the subsequent 18 years, the prevalence of obesity in both men and women has more than doubled. Even more concerning is that obesity is rapidly becoming a serious problem in children. Data for the period 2000–2006 indicate that childhood obesity is estimated to afflict 20–25% of boys and 25–30% of girls, equating to least 20 million children worldwide [1].

The health implications of the obesity epidemic are so serious that they may reverse the intergenerational increase in life expectancy, with the current generation of children now being the first who can expect to live significantly less long than their parents [2]. The metabolic consequences of obesity, particularly central adiposity, are drivers of other life-threatening disorders, including dyslipidaemia [elevated plasma concentrations of triglycerides plus low-density lipoprotein (LDL)-cholesterol and decreased plasma concentrations of high-density lipoprotein (HDL)-cholesterol], hypertension, proinflammatory atherogenesis, pre-diabetes (insulin resistance and impaired glucose tolerance) and Type 2 diabetes [3–7]. The co-existence of this cluster of cardio-metabolic risk factors in subjects is often described as the Metabolic Syndrome [4, 8, 9]. All of the above metabolic disorders have been demonstrated to increase the risk of serious macrovascular events, including myocardial infarction, stroke and angina [4, 10–16]. In addition to the morbidity and mortality risks associated with cardio- and cerebrovascular events, obesity is also a predisposing factor in ≤30% of cases of cancer of the colon, breast, kidney and digestive tract [1]. As well as the life-threatening consequences of obesity, there are other chronically debilitating conditions associated with this metabolic disorder, including sleep apnoea, aggravated arthritis, gout, gallstones, and also low self-esteem and increased incidence of affective disorders [17–20].

A possible explanation for the rapid increase in obesity is that it is being driven by a combination of genetic, social and environmental factors. The ‘thrifty genotype’ has ensured the survival of humans during alternating periods of glut and famine. However, this thrifty genotype is not suited to a modern Western diet where there is almost unrestricted access to an abundance of low-cost calorie-dense foods. This factor is exacerbated when combined with a relatively sedentary modern lifestyle, dominated by office work and reliance on cars [21–23]. Although a significant proportion of people manage very successfully to maintain a healthy bodyweight by following a careful diet and having a reasonable level of physical exercise, for many others this plan has not resulted in the desired healthy outcome. For some of the obese population, pharmacotherapy will be required to provide the requisite adjunctive support to diet, exercise and lifestyle modification that will deliver a clinically beneficial bodyweight reduction of >5%.

Anti-obesity drugs – current status and future prospects

Over the last 15 years, only four new drugs, i.e. dexfenfluramine (Redux®), sibutramine (Meridia®, Reductil®), orlistat (Xenical®) and rimonabant (Acomplia®), have been registered for the treatment of obesity. Of these drugs, only three, dexfenfluramine, sibutramine and orlistat, have achieved global (with the exception of Japan) registration. Rimonabant was approved for clinical use in Europe and several other territories, but the New Drug Application was withdrawn after a Food and Drug Administration (FDA)-appointed expert advisory panel recommended that the product should not be approved for clinical use in the USA. The reason for the non-approval recommendation was because treatment with rimonabant had been linked with severe psychiatric adverse events, e.g. anxiety, depression and suicidal ideation. It was these same side-effects that resulted in rimonabant being suspended by European Medicines Agency (EMEA). On 5 November 2008, Sanofi-Aventis, which discovered, developed and marketed rimonabant, announced in a press conference that all further research on the compound was to be halted immediately [24]. The adverse event problems linked to rimonabant and its ultimate suspension have resulted in termination of the clinical development of three other cannabinoid CB1 receptor antagonists, i.e. Merck's taranabant, Pfizer's otenabant and Solvay/BMS's SLV-319, while the future of several others, including AZD-2207 (AstraZeneca), V-23434 (Vernalis) and E-6776 (Esteve), looks uncertain.

The withdrawal of rimonabant is the latest in a long line of health scares involving antiobesity drugs. In the 1950s and early 1960s, dexamphetamine was widely used as a short-term appetite suppressant, but its use was severely restricted following its frequent diversion and abuse. A second generation of monoamine-releasing agents, including phentermine and fenfluramine, was then developed as centrally-acting, antiobesity drugs with a lower liability for psychostimulant abuse than dexamphetamine. Subsequently, fenfluramine and its isomer, dexfenfluramine, were implicated in the induction of primary pulmonary hypertension (PPH) [25, 26] and cardiac valvulopathy [27, 28], the latter adverse event leading to the global withdrawal of both drugs. In Europe, EMEA went further by withdrawing the licences for a range of other older products on the basis that their clinical benefit was not proven (see Table 1).

Table 1. 
Current status of marketed antiobesity drugs in Europe and the USA
DrugTrade nameAvailable EUAvailable USA
  • Licence suspended in EU and New Drug Application withdrawn in USA.

  • ‡Withdrawn in EU and USA.

OrlistatXenical
SibutramineMeridia, Reductil
PhentermineIonamin, Duromine
d-AmphetamineDurophet, Dexedrine
MethamphetamineDesoxyn
BenzphetamineDidrex
PhendimetrazineBontril
DiethylpropionTenuate, Apisate
RimonabantAcomplia
FenfluraminePonderax, Pondimin
d-FenfluramineRedux
MazindolTeronac

In mechanistic terms, currently available antiobesity drugs can be classified under two broad headings, i.e. centrally-acting drugs that decrease food intake, and a peripherally-acting fat absorption blocker. Sibutramine belongs to the former category. It is a serotonin (5-hydroxytryptamine) and noradrenaline reuptake inhibitor [29] that decreases food intake by enhancing satiety [30, 31]. Orlistat is an irreversible inhibitor of gastric and pancreatic lipases that prevents the absorption of ∼30% of digested fat from the gut [32]. The status of currently approved antiobesity drugs in the USA and Europe is summarized in Table 1.

With this history, it will come as no surprise to learn that the regulatory hurdles for new antiobesity drug candidates very closely reflect the problems that have been associated with the older agents. Table 2 provides a list of antiobesity drug candidates that are in clinical development. These include the centrally-acting monoaminergic food intake regulators, e.g. locaserin, tesofensine, ATHX-105 and PRX-07034, and the peripheral lipase inhibitor, cetilistat. Also listed are candidates targeted at hypothalamic neuropeptides, e.g. obinepitide, gut hormones, e.g. TKS 1225, and various combination products, e.g. Qnexa®, Empatic®, Contrave® and pramlintide/metreleptin.

Table 2. 
Antiobesity drugs – clinical development pipeline
CompoundStatusMode of actionCompany
CetilistatPhase IIILipase inhibitorAlizyme/Takada
LocaserinPhase III5-HT2C agonistArena
QrnexaPhase IIITopiramate + phentermineVivus
TesofensinePhase IIITriple uptake inhibitorNeurosearch
ContravePhase IIINaltexone SR + bupropion SROrexigen
EmpaticPhase IIbZonisimide SR + bupropion SROrexigen
S-2367Phase IIbNeuropeptide Y5 inhibitorShionogi
ObinepitidePhase IIaY2+ Y4 agonist7TM
TM30339Phase IIaY4 agonist7TM
ATHX-105Phase II (on hold)5-HT2C agonistAthersys
Pramlintide/metreleptinPhase IIAmylinomimetic/leptinAmylin
KRP-204Phase IISelective β3-agonistKyorin
SLx-4090Phase IIMitochondrial transfer protein inhibitorSurface Logix
PRX-07034Phase Ib5-HT6 antagonistEpix
Remogloflozinetabonate (GSK 189075)Phase ISodium glucose transporter-2 (SGLT-2) antagonistGSK
V24343Phase ICB1 antagonistVernalis
Amylin analoguePhase IAmylinomimeticAmylin
AZD 1175/2207Phase I/IICB1 antagonistsAstraZeneca
AZD 1656Phase IGlucokinase activatorAstraZeneca
TKS 1225Phase IOxyntomodulin analogueThiakis

Criteria for regulatory approval

Efficacy

Revised guidance notes for the development of antiobesity drugs have been issued in draft form by the FDA [33] and in final form by EMEA [34]. In both territories, the primary clinical end-point for the approval of a new antiobesity drug is weight reduction and, just as importantly, the maintenance of that weight loss after 1 year's treatment. Clinically meaningful weight reduction after 1 year of treatment is defined as ≥5% (placebo-subtracted and statistically significant) in the USA and >10% of baseline weight, which is also ≥5% greater than that observed with placebo, in Europe. Although weight reduction is the primary end-point of efficacy for antiobesity drug candidates, in the absence of commensurate improvements in a wide range cardiovascular risk factors, weight reduction would be considered by either FDA or EMEA as being a cosmetic outcome with no medical benefit. Consequently, any drug candidate exhibiting this clinical profile would be non-approvable in the USA or Europe. The FDA mandates that an effective weight-management product should provide improvements in blood pressure, lipids, glycaemia, or other beneficial outcomes that are commensurate with the degree of weight loss. To this end, common weight-related comorbidities need to be factored into clinical trials to assess the efficacy of such products. In Europe, EMEA lists ‘secondary end-points’ of efficacy for antiobesity drug candidates as improvements in lipid and glucose metabolism, blood pressure, cardiac function, waist–hip ratio, waist circumference, ultrasensitive C-reactive protein, sleep apnoea episodes and quality of life parameters. EMEA also cites maintenance of weight loss or the prevention of weight regain as an important ‘secondary end-point’ for antiobesity drug candidates.

Safety

The safety criteria for antiobesity drug candidates are particularly onerous because of the poor track record of approved drugs in this therapeutic indication. Furthermore, in the eyes of many healthcare professionals obesity is a risk factor for serious cardiovascular and metabolic diseases including hypertension, Type 2 diabetes and dyslipidaemia, rather than a disease in its own right.

Both regulatory agencies state that antiobesity drugs should not adversely affect cardiovascular function. A subtle difference between the USA and Europe is the focus of these concerns. In the USA, cardiac valvulopathy is highlighted because of their experience with dexfenfluramine and the fenfluramine/phentermine (fen/phen) combination. In Europe, dexfenfluramine and fenfluramine were only approved for use for ≤12 weeks, and as a consequence cardiac valvulopathy was not a safety issue. In addition, the use of dexfenfluramine or fenfluramine together with another centrally-acting anorectic agent was ‘contraindicated’ in the European Summary of Product Characteristics (SPC), thereby circumventing the fen/phen issue also. On the other hand, the fenfluramines have been linked to the rare, but potentially fatal, adverse event of PPH in Europe [25, 26] and it is therefore a focus of safety monitoring and evaluation for current and future antiobesity drugs. For centrally-acting drug candidates, psychiatric adverse events, abuse, dependence and withdrawal side-effects are explicitly noted by FDA and EMEA as potential safety issues to be investigated. In its draft guidance, the FDA also states that it wishes to see drug-mediated weight reduction demonstrated to result from a loss of body fat, rather than lean body mass, using dual energy x-ray absorptiometry or other scanning techniques.

Benefit–risk evaluation

The criteria listed above are the factors on which the benefit–risk evaluation for drug approval is performed, but there is no indication in either guidance document of the relative weight ascribed to each of them. In Europe, ‘hard’ cardiovascular end-points, i.e. myocardial infarction, stroke, morbidity and mortality, are considered to be of far greater relevance than reductions in risk factors like blood pressure, LDL-cholesterol or HbA1c. Although clinically meaningful improvements in these end-points are sufficient to gain European approval for an antiobesity drug candidate, a commitment to a Phase IV outcome trial is a prerequisite for market authorization, cf the Sibutramine Cardiovascular OUTcome (SCOUT) [35] and Comprehensive Rimonabant Evaluation Study of Cardiovascular ENDpoints and Outcomes (CRESCENDO) [36] studies. In the USA, on the other hand, a benign risk profile is the predominant factor in the FDA evaluation of benefit–risk for an antiobesity drug candidate. This emphasis on safety is based not only on the US experience with dexfenfluramine and fen/phen, but also on the recent high-profile safety scares with other drugs, e.g. rofecoxib (Vioxx®) and rosiglitazone (Avandia®).

Emerging issues for antiobesity drug development

It is now well accepted outside the confines of a clinical trial setting, where patients receive substantial behavioural and dietetic support, that the weight-reducing effects of antiobesity drugs are generally considerably lower than those reported in pivotal clinical trials. Estimates from meta-analyses indicate mean weight reductions of 4–5 kg for sibutramine and rimonabant, with orlistat delivering slightly smaller reductions [37–39]. As shown in Table 3, this magnitude of weight reduction is not sufficient to return the average male or female subject with a BMI of 30 kg m−2 to the upper end of the normal weight range (BMI = 25 kg m−2). When taken together with the relatively shallow increase in mortality at higher BMI levels [40–42], the data raise the question of whether current antiobesity drugs will actually deliver long-term improvements in cardiovascular morbidity and mortality. The Swedish Obese Subjects outcome trial demonstrated the long-term benefit of bariatric surgery in morbidly obese subjects [43–45], and this European outcome trial has undoubtedly given significant impetus for EMEA to demand similar proof of efficacy for sibutramine and rimonabant in large Phase IV outcome trials, i.e. SCOUT and CRESCENDO, respectively. Both SCOUT and CRESCENDO are being performed in obese subjects with a high degree of comorbid cardiovascular risk. Ultimately, it is probably SCOUT that will define whether the metabolic benefits of antiobesity drug therapy translate long-term into a reduction of cardiovascular morbidity and mortality.

Table 3. 
Weight reductions needed to normalize body weight in men and women with varying degrees of obesity
 BMI (kg m−2)Weight (kg)Weight loss to achieve BMI = 25
Male2062
1.77 m2578
3094Δ 16 kg
35110Δ 32 kg
40125Δ 47 kg
Female2053
1.63 m2566
3080Δ 14 kg
3593Δ 27 kg
40107Δ 41 kg

Although it is not a regulatory consideration, nonetheless failure to gain widespread reimbursement is another major hurdle for antiobesity development. For this reason, many pharmaceutical companies are actively switching their drug candidates from trials in obesity to Type 2 diabetes, the latter being universally recognized as a serious metabolic disease and one where drug treatment is generally reimbursed.

The recent experience with rimonabant has also created considerable scepticism within the pharmaceutical and biotech industry about the feasibility of obtaining market authorization for novel antiobesity drugs in the USA. The reluctance of the FDA to approve this compound was based on significant concerns about its psychiatric adverse event profile. It was also a problem that appeared to be exacerbated as clinical exposure to the drug increased. Clinical evaluation of Merck's taranabant suggested that these psychiatric adverse events may be a class effect of the CB1 antagonists [46]. Without doubt, the decision to halt the development of several other CB1 antagonists, including taranabant, otenabant and SLV-319, indicates that it was a significant concern for many pharmaceutical companies. If this assessment is correct, the hurdles for registering an antiobesity drug in the USA have not changed substantially for a novel, centrally-acting drug candidate, provided it is effective and has a good safety profile. Moreover, the raft of peripherally-acting compounds now in clinical development, e.g. KRP-204, SLx-4090, AZD 1656 and remogloflozinetabonate, are unlikely to suffer any significant fallout from the withdrawal of rimonabant.

In the search for greater weight-loss efficacy with a reduced liability to adverse events, several pharmaceutical companies have adopted the strategy of combining drugs for the treatment of obesity that have potentially additive or synergistic mechanisms. Although such combination products generally employ drugs that have been registered for a different therapeutic indication, e.g. topiramate (antiepileptic), zonisamide (antiepileptic) and bupropion (antidepressant), it is not always the case, e.g. the pramlintide/metreleptin combination being developed by Amylin. Examples of other combination antiobesity drug candidates include Empatic® (zonisimide + bupropion) and Contrave® (naltrexone + bupropion) being developed by Orexigen, and Qnexa® (topiramate + phentermine) by Vivus. However, the development of fixed-dose combination products puts an additional layer of complexity into the clinical trial programme because the Sponsor will have to demonstrate the superiority of the combination product not only vs. placebo, but also vs. relevant doses of the individual drugs used in the combination. Figure 1 shows Phase II results recently reported by Vivus where Qnexa produces substantially more weight loss than either phentermine or topiramate, in addition to being more effective than placebo. The observed weight loss obtained with Qnexa shows that the pharmacological actions of the two components are approximately additive in the combination product.

Figure 1.


Qnexa – weight-loss in a Phase II study. The results are from a randomized, double-blind, placebo-controlled Phase II trial performed by Vivus Pharmaceuticals to evaluate Qnexa® (phentermine + topiramate). The trial was conducted on 200 obese (body mass index >30) subjects (159 women and 41 men). The figure shows the completers data at week 24; 92% of enrolled patients on Qnexa vs. 62% on placebo. Using an intention to treat-last observation carried forward (ITT-LOCF) analysis, the percentages of patients achieving 5, 10 and 15% weight loss on Qnexa® were 83% (P < 0.0001), 50% (P < 0.0001) and 20% (P < 0.0007) vs. on placebo 14, 8 and 0%. Data taken from the Vivus website (http://www.vivus.com) and presentations at scientific symposia. Placebo (—○—); Phentermine (inline image); Topiramate (—▴—); Qnexa (—◊—)

Approval of antiobesity drugs for other metabolic disorders

As already mentioned, in the benefit–risk assessment that is performed by the regulatory agencies, the efficacy of antiobesity drugs is assessed on improvements in cardiovascular risk factors. Thus, there is a strong rationale, reflected in the product labelling, for approving the use of antiobesity drugs in overweight and obese patients with comorbid Type 2 diabetes and/or dyslipidaemia. This was especially so for rimonabant's SPC, where EMEA recognized that part of the improvement in HbA1c and HDL-cholesterol evoked by the drug was independent of its action to cause weight loss [47]. However, in spite of evidence to demonstrate the contribution of prolonged, drug-induced weight reduction to the prevention of other metabolic disorders, e.g. the Xendos Type 2 diabetes prevention study with orlistat [48], no antiobesity drug has yet received market authorization for the treatment of such metabolic disorders. The reasons for this are discussed below.

The Metabolic Syndrome

One of the most contentious areas in terms of drug development has been the status of the Metabolic Syndrome as a therapeutic indication suitable for the market authorization of new drugs. The syndrome was first described by Reaven in his 1988 Banting Medal award lecture [49]. In his groundbreaking lecture, Reaven postulated that insulin resistance and the compensatory hyperinsulinanaemia predisposed patients to hypertension, hyperlipidaemia and diabetes, and thus was the underlying cause of much cardiovascular disease. Although obesity was not included in Reaven's primary list of disorders caused by insulin resistance, he acknowledged that obesity was correlated with insulin resistance and hyperinsulinaemia. Thus, reducing bodyweight and increasing physical activity would be predicted to have a beneficial effect on what he called ‘syndrome X’. An illustration of the key factors of what we now call the Metabolic Syndrome is shown in Figure 2.

Figure 2.


The components of the Metabolic Syndrome

It should be noted that as originally envisaged by Reaven, the essential driver of the Metabolic Syndrome was insulin resistance. However, several groups of clinical experts (often with a therapeutic bias, e.g. diabetologists, cardiologists and endocrinologists) have since revisited the definition of the Metabolic Syndrome either to refine or fundamentally alter its diagnostic criteria. Such groups have included the WHO and National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III and the International Diabetes Federation (IDF). Each of these highly respected and authoritative bodies has drawn different conclusions about what cardiovascular risk factors should be included in the definition of the Metabolic Syndrome, whether there is an essential core symptom that is a prerequisite for the diagnosis of the syndrome, and finally, what are the cut-off criteria for reaching a decision on whether or not a patient can be diagnosed as having the Metabolic Syndrome. The WHO produced the first revised definition of the Metabolic Syndrome in 1999 [50] and this definition most closely adheres to Reaven's original hypothesis [51]. This was followed by the NCEP ATP III guidelines published in 2001 [52]. Recently, the IDF published its ‘consensus worldwide definition of the Metabolic Syndrome’ in 2005 [9] and this definition of the syndrome was a major deviation from Reaven's original hypothesis because central obesity was not only included as a risk factor for diagnosis, but also classified as being a prerequisite. The individual definitions of the Metabolic Syndrome according to the WHO, NCEP ATP III and IDF guidelines are reported in Table 4.

Table 4. 
Different criteria for a diagnosis of Metabolic Syndrome
 WHONCEP ATP IIIIDF
T2D, IGT, glucose intolerance and/or IR +≥2 others≥3 risk factorsCentral obesity +≥2 other risk factors
  1. T2D, Type 2 diabetes; IGT, impaired glucose tolerance; IR, insulin resistance; BMI, body mass index; M, males; F, females.

Type 2 diabetes (fasting plasma glucose)≥6.1 mmol l−1 (110 mg dl−1)Included by IGT criterion≥6.1 mmol l−1 (110 mg dl−1)
IGT (fasting plasma glucose)≥5.6 mmol l−1 (100 mg dl−1)≥6.1 mmol l−1 (110 mg dl−1)≥5.6 mmol l−1 (100 mg dl−1)
Insulin resistanceHyperinsulinaemic/euglycaemic clamp. Glucose intake below lowest quartileNot includedNot included
ObesityBMI > 30Waist >102 cm (40 in) M;Waist >94 cm (37.4 in) M;
Waist–hip >0.9 M; >0.85 F>88 cm (35 in) F>80 cm (31.8 in) F
Hypertension≥140/90 mmHg≥130/85 mmHg≥130 mmHg or
  ≥85 mmHg
  Hypertension diagnosis or treatment
Serum triglycerides≥1.7 mmol l−1 (150 mg dl−1)≥1.7 mmol l−1 (150 mg dl−1)>1.7 mmol l−1 (150 mg dl−1)
  Drug treatment
HDL-cholesterol<0.9 mmol l−1 (35 mg dl−1) M<1.03 mmol l−1 (40 mg dl−1) M<0.9 mmol l−1 (40 mg dl−1) M
<1.0 mmol l−1 (39 mg dl−1) F<1.29 mmol l−1 (50 mg dl−1) F<1.1 mmol l−1 (50 mg dl−1) F
  Drug treatment
Microalbuminuria≥20 g min−1Not includedNot included
albumin : creatinine ≥30 mg g−1  

A comparison of these very different definitions of the Metabolic Syndrome reveals that there are patients who will meet the criteria for its diagnosis according to one definition, but will fail on both of the others. For example, a man with waist circumference of 90 cm, triglycerides 155 mg dl−1 (1.76 mmol l−1), HDL-cholesterol 35 mg dl−1 (0.9 mmol l−1), blood pressure 135/90 mmHg with a fasting plasma glucose of 105 mg dl−1 (5.82 mmol l−1) would be diagnosed as having the Metabolic Syndrome according to NCEP ATP III, but not WHO or IDF criteria. It might be thought that these differences in classification reflect the perspectives of individual specializations in the metabolic field, but this is also not the case. For example, within a year of the IDF publishing its ‘consensus guidelines on the metabolic syndrome’, two other major diabetes groups, the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD), appeared in print with a damning criticism of the IDF definition [53]. The ADA/EASD critique of the Metabolic Syndrome was much more fundamental than merely questioning the criteria employed for its diagnosis, because it questioned the arbitrary cut-off points applied in all definitions of the syndrome and the lack of a rationale for the exclusion of other significant cardiovascular risk factors, e.g. smoking and a family history of cardiovascular disease. The overall conclusion reached by Kahn and colleagues was that with no irrefutable evidence of any cooperative or synergistic interaction between the risk factors included in the definition of the Metabolic Syndrome, none of the definitions satisfied the requirement for designation as a ‘syndrome’. Moreover, the ADA/EASD recommended that the individual risk factors should be treated in clinical practice, not the Metabolic Syndrome as an entity. Even the IDF did not advocate the use of pharmacological interventions to reduce central obesity, merely citing diet, exercise and a change to a healthy diet to reduce weight by 5–10%. Worse was to come, when Reaven himself stepped into the argument and published a similarly critical review of the IDF consensus guidelines on Metabolic Syndrome [51]. Thus, with competing and divergent definitions of what constituted the Metabolic Syndrome, and internecine warfare breaking out between the respective groups of clinical opinion leaders, the chances of any regulatory agency favouring one definition over all others and using it to register drugs for clinical use in the indication was remote. However, even if a single, agreed definition of the Metabolic Syndrome existed (including one where central obesity was a prerequisite), the fact that a diagnosis of the syndrome is made on the basis of any two (or three, or four) of four (or five) risk factors spanning obesity, Type 2 diabetes, dyslipidaemia and hypertension, means that a diagnosis of Metabolic Syndrome would be clinically meaningless because of the disparate cluster of patients that would be captured under this umbrella definition. Furthermore, in this heterogeneous patient population no single drug would be suitable for treating every patient and the risk of inappropriate prescribing would be significant. When this factor is added into the equation, it is predictable that the regulatory agencies are not prepared currently to consider approving an antiobesity drug as a treatment for the Metabolic Syndrome.

As discussed earlier, long-term clinical outcome trials are an important factor that could alter the status of the Metabolic Syndrome as a therapeutic indication for the registration of new antiobesity drugs. EMEA is very focused on ‘hard’ end-points in outcome trials, and both Abbott and Sanofi-Aventis agreed to perform Phase IV trials, i.e. SCOUT and CRESCENDO, to determine whether antiobesity drug therapy using sibutramine and rimonabant, respectively, together with lifestyle intervention, would significantly reduce cardiovascular morbidity and mortality in overweight/obese subjects with a high degree of high cardiovascular risk, e.g. in overweight or obese patients, plus the presence of coronary, cerebral and/or peripheral arteriopathy, impaired glucose tolerance or Type 2 diabetes, and at least one other established vascular risk factor. Comparing the patient inclusion criteria for these two outcome trials with the various definitions of the Metabolic Syndrome reveals that many of these subjects would be classified as having the Metabolic Syndrome according to the criteria devised by the WHO, NCEP ATP III or IDF. If, in this heterogeneous population, sibutramine is ultimately shown significantly to reduce cardiovascular morbidity and mortality, it is possible that the regulatory agencies will need to reconsider their position on the Metabolic Syndrome as a therapeutic indication, and on the approval of antiobesity drugs for its management.

Type 2 diabetes

The spreading epidemic of obesity is a major driver for the growing number of diabetes sufferers [3, 5, 54–57]. More significantly, there is an exponential relationship between increasing BMI and the relative risk of developing diabetes, e.g. women with a BMI > 35 have a ∼60-fold greater probability of being diagnosed with Type 2 diabetes than women with a BMI < 22 [58].

Improvements in glycaemic control, e.g. plasma glucose and insulin concentrations, insulin resistance and HbA1c, are the appropriate secondary end-points for evaluating the efficacy of antiobesity drug therapy in subjects with Type 2 diabetes. Although improvement in these secondary end-points with accompanying reduction in bodyweight and visceral adiposity is highly beneficial in the management of Type 2 diabetes in overweight or obese patients, a decision on whether to approve any antiobesity drug specifically for the treatment of Type 2 diabetes would require its benefits to be compared with those delivered by current antidiabetic drugs. A reduction in plasma HbA1c is generally accepted as the most appropriate primary end-point for the evaluation of antidiabetic drug candidates, with a reduction ≥0.5% considered to be clinically meaningful. The first generation of antidiabetic drugs, including the sulphonylureas, thiazolidinediones and metformin, generally produce reductions in HbA1c of the order of 1.0–1.5% when administered as monotherapy [59–64]. More recent introductions, including the postprandial glucose regulators, e.g. nateglinide, GLP-1 agonists, e.g. exenatide and liraglutide, and the DPP-IV inhibitors, e.g. sitagliptin, evoke smaller decreases in HbA1c in the region of 0.7–0.8% [65–69].

By comparison, antiobesity drugs evoke clinically meaningful reductions in HbA1c in obese diabetic subjects. Orlistat shows the most consistent effects with additional HbA1c reductions of 0.3–0.5% at 1 year when given in combination with oral antidiabetic agents [70–72]. The effects of sibutramine on plasma HbA1c in obese diabetics are rather more variable, with reported reductions ranging from 0.1% at 26 weeks [73] to 2.2% at 52 weeks [74]. When the data are viewed overall, the HbA1c-reducing action of sibutramine is likely to be of the order of 0.5–0.7% when this drug is given in combination with oral antidiabetic agents [73–75]. Rimonabant has been evaluated both as an adjunct to oral antidiabetic therapy in the 1-year RIO Diabetes trial [76] and as monotherapy in the Study Evaluating Rimonabant Efficacy in drug NAive DiabEtic patients (SERENADE) trial [77]. In the former, rimonabant evoked a highly respectable 0.7% fall in plasma HbA1c when combined with either metformin or a sulphonylurea [76]. When used as monotherapy in newly diagnosed, treatment-naive, obese (average BMI ∼34 kg m−2) Type 2 diabetics, rimonabant produced a mean decrease in plasma HbA1c of 0.5% at week 26 [77]. In a population that is predominantly obese, weight gain is an unwelcome side-effect for a significant proportion of antidiabetic therapies, particularly the sulphonylureas, thiazolidinediones and insulin [78–81]. On the other hand, metformin and some of the newer agents, including pramlintide, exenatide and sitagliptin, are either weight-neutral or induce a small degree of weight loss [67, 68, 80, 82]. As expected, when antiobesity drugs are used to treat Type 2 diabetes in overweight or obese subjects, these drugs produce weight loss [70–77, 83], which, depending on the agent, accounts for all or part of their benefit on glycaemic control. However, subjects with Type 2 diabetes are fairly resistant to the actions of centrally- or peripherally-acting antiobesity drugs. Consequently, the degree of mean weight loss in obese Type 2 diabetics is smaller than that observed in other obese patient populations, e.g. the ‘healthy’ obese (obesity without significant comorbid metabolic disease) or obesity with dyslipidaemia. For example, rimonabant decreased bodyweight by 3.9 kg when used as an adjunct to oral diabetic drugs [76] and 3.8 kg when used as monotherapy [77]. For comparison, in the healthy obese population, the placebo-subtracted reductions in bodyweight were 4.7 kg [84, 85], while in obese subjects with dyslipidaemia it was 5.4 kg [86].

Viewed overall, the antiobesity drugs deliver metabolic benefits in Type 2 diabetes that compare favourably with those of the newer generation of antidiabetic agents. The reason why antiobesity drugs have not until now received serious consideration for treatment of Type 2 diabetes is driven by four factors.

  • 1The lack of pivotal trial data where HbA1c, not weight loss, has been used as the primary end-point of efficacy.
  • 2Until the recent SERENADE trial, no evaluation had been made of an antiobesity drug given as monotherapy in Type 2 diabetes.
  • 3Type 2 diabetes does not occur exclusively in overweight or obese subjects and approval in this therapeutic indication would imply that a drug would be suitable for all categories of patient, irrespective of BMI. The utility of antiobesity drugs as adjunctive treatments or monotherapy in normal-weight subjects with Type 2 diabetes has not been demonstrated.
  • 4Until recently, EMEA and FDA had insisted that any beneficial effect of an antiobesity drug on glycaemic control due to weight loss should be discounted. Only improvements beyond those resulting from reduced bodyweight would be taken into consideration for approval of an antiobesity drug in Type 2 diabetes.

FDA has very recently changed its stance on this issue. In its ‘Draft Guidance for Industry. Diabetes Mellitus: developing drugs and therapeutic biologics for treatment and prevention’[87] it states that ‘The FDA's current thinking is that a sponsor can gain approval for the treatment of Type 2 diabetes for a drug or biologic whose principal mechanism of action appears to be weight loss by showing a clinically meaningful and statistically significant improvement in glycaemia’. To date, there has been no indication of what such a clinical development programme would look like. In Europe, there has not been any communication from EMEA to suggest that it is also considering a similar strategy for the development of antiobesity drugs for the indication of Type 2 diabetes.

Dyslipidaemia

Obesity, a Westernized diet that is high in fat and cholesterol, together with other cardiometabolic risk factors, e.g. smoking and lack of physical exercise, exert a highly deleterious effect on plasma lipid profiles. Hyperlipidaemia is an important modifiable risk factor for the development and progression of cardiovascular disease. The causal link between LDL-cholesterol and coronary heart disease is now firmly established [88]. Compelling evidence also supports an independent link between atherosclerosis and low serum concentrations of HDL-cholesterol [89] with high serum levels of triglycerides [90, 91].

Many people with atherogenic dyslipidaemia would also be diagnosed as having the Metabolic Syndrome according to the WHO, NCEP ATP III or IDF classifications (see Table 4). Treatment aims are to obtain plasma concentrations of LDL-cholesterol <2.58 mmol l−1 (100 mg dl−1), total cholesterol <5.15 mmol l−1 (200 mg dl−1), HDL-cholesterol >1.55 mmol l−1 (60 mg dl−1) and triglycerides <1.7 mmol l−1 (150 mg dl−1) [4]. In common with other related metabolic disorders, e.g. obesity, insulin resistance, Type 2 diabetes and Metabolic Syndrome, it has been shown that dieting, increased physical activity and a switch to a low fat/low cholesterol diet has a major positive impact on all atherogenic, dyslipidaemic and cardiovascular risk factors. Key drugs to treat elevated apolipoprotein-B and/or atherogenic dyslipidaemia are the statins, cholesterol-absorption blockers, bile-acid sequestrants, nicotinic acid and the peroxisome proliferator-activated receptor α agonists (the fibrates). In addition, there are interesting, novel, lipid-regulator, drug candidates in clinical development, the most exciting being the cholesterylester transfer protein (CETP) inhibitors, e.g. R1658 (Roche/Japan Tobacco) and anacetrapib (Merck). The actions of the current crop of drugs and the CETP inhibitors to improve the major components of dyslipidaemia are reported in Table 5. What is immediately apparent is how surprisingly broad their spectrum of beneficial effects is, e.g. the statins are principally known as LDL-cholesterol/VLDL-cholesterol-lowering drugs, but they also substantially increase HDL-cholesterol and reduce serum triglycerides.

Table 5. 
A comparison of the efficacy of various antiobesity drugs vs. lipid regulators as treatments for dyslipidaemia
DrugLDL-CHDL-CTrigsBody weight
  • *

    Després et al. (2005) [86];

  • Dujovne et al. (2001) [97];

  • Muls et al. (2001) [93]; Derosa et al. (2003) [95]; Lucas et al. (2003) [94]; Fillippatos et al. (2005) [96];

  • §

    NCEP ATP III (2002) [4];

  • Knopp et al. (2003) [104];

  • ††

    Ballantyne et al. (2005) [105]; McKenny et al. (2005) [106];

  • ‡‡

    Merck press release (2007) [107].

Rimonabant* (RIO lipids)±8% ↑12% ↓5.4 kg ↓
Sibutramine±6% ↑17% ↓4.3 kg ↓
Orlistat5–18% ↓8% ↑–9% ↓10–14% ↓1–6 kg ↓
Statins§18–55% ↓5–15% ↑7–30% ↓±
Fibrates§5–20% ↓10–35% ↑20–50% ↓±
Bile-acid sequestrants§15–30% ↓3–5% ↑±/↑±
Niaspan®§16% ↓22% ↑38% ↓±
Ezetimibe18% ↓2% ↑5% ↓±
Vitorin®†† (ezetamibe + simvastatin)45–60% ↓6–10% ↑23–31% ↓±
Anacetrapib‡‡16–40% ↓44–139% ↑Not statedNot stated

An extensive search of both the EMEA and FDA websites for guidelines on the efficacy/safety criteria necessary for the registration of new dyslipidaemic agents revealed no guidance on the subject. However, it is probably safe to assume that two Phase III pivotal studies of the design employed [92] with both placebo and active comparator arms, patient numbers in excess of 1000 and a 1-year treatment duration would be the minimum required for registration of any new drug in this therapeutic indication.

For comparison, the effects of the antiobesity drugs sibutramine, orlistat and rimonabant are also shown in Table 5. Orlistat has been reported to produce moderate improvements in plasma lipid profiles in obese patients with hypercholesterolaemia [93–95] or Metabolic Syndrome [96]. Orlistat is the only antiobesity drug to have been shown to reduce LDL-cholesterol. In addition to its beneficial effects on plasma lipid profiles, orlistat also decreased bodyweight by 1–6 kg in these subjects. In the only double-blind, randomized, placebo-controlled study that has been performed with sibutramine in obese patients with dyslipidaemia, it decreased plasma triglycerides by 17% and increased HDL-cholesterol by 6% at week 24 [97]. It also decreased bodyweight by 4.3 kg. In the RIO-Lipids trial, rimonabant decreased plasma triglycerides by 12%, increased HDL-cholesterol by 8% and decreased bodyweight by 5.4 kg at 1 year [86]. It is evident that although antiobesity drugs have some beneficial effects on plasma lipid profiles and bodyweight in obese patients with dyslipidaemia, their actions are modest compared with those of existing agents. Moreover, rimonabant and sibutramine do not lower plasma LDL-cholesterol (the primary action of the statins), and no outcome trial data are available to demonstrate a reduction in cardiovascular morbidity and mortality with long-term antiobesity drug treatment. Contrasted against this is a wealth of positive outcome data for the statins, e.g. WOSCOPS [98], AFCAPS/TexCaps [99], the simvastatin 4S study [100, 101], the pravastatin PPP [102] and LIPID [103] trials. On this basis, there is no compelling case to support the approval of antiobesity drugs specifically for the treatment of any type of dyslipidaemia.

Conclusions

There is undeniably an enormous unmet clinical need for new drugs that are safe and more efficacious than existing agents to treat the escalating global problem of obesity and its cardio-metabolic consequences. In this quest, the pharmaceutical industry is pursuing many divergent central and peripheral drug targets. The recent tribulations of rimonabant have severely dampened enthusiasm for obesity as a therapeutic indication for new drug development. However, the perception that the regulatory bar for the approval of antiobesity drug candidates is higher is probably not justified. With respect to the regulatory challenges for developing antiobesity drugs for other metabolic disorders, Type 2 diabetes is now believed by the industry and FDA to be the most appropriate alternative therapeutic indication. Metabolic Syndrome is not accepted by either FDA or EMEA as a discrete disease entity, and therefore it is not a viable option for the development of antiobesity drug candidates. Whilst there is some benefit of the antiobesity drugs in the treatment of obesity with dyslipidaemia (that is reflected in the product labelling), the moderate beneficial effects of antiobesity agents in comparison with current treatments for dyslipidaemia indicate that it is not a viable alternative drug development strategy for drugs that act predominantly by reducing bodyweight.

In future, the regulatory environment for antiobesity drugs and the spectrum of indications for which they will be approved and marketed would change dramatically if positive data were to emerge from either the SCOUT or CRESCENDO outcome trials.

Competing interests

None declared.

Ancillary