Synthetic agents in the context of metabolic/bariatric surgery: expanding the scope and impact of diabetes drug discovery

Abstract

Type 2 diabetes (T2D) – particularly with concurrent obesity (‘diabesity’) – is an intensifying global public-health problem. Medical needs and market opportunities in the T2D space have propelled discovery efforts aimed at inventing new synthetic T2D drugs differentiable by improved safety and efficacy and/or the ability to modulate emerging T2D targets. Particularly for moderately and severely obese individuals, weight-loss (bariatric) surgery offers an effective means of reducing obesity-driven T2D that is superior in many respects to medical T2D management. Yet, not all overweight or obese individuals with T2D qualify for bariatric surgery, and current healthcare resources are inadequate for applying surgical T2D control to more than a very small segment of qualified patients. Bariatric surgery is no guarantee of ‘curative’ T2D abrogation, significant rates of T2D non-remission or re-emergence having been observed in diabesity patients following bariatric procedures. Preoperative glucose control by oral hypoglycemic drugs reduces the chance of T2D recurrence post-surgery, and diabesity patients in whom glycemic indices have been improved by bariatric surgery may still require some level of T2D pharmacotherapy. Laboratory and clinical data indicate that synthetic T2D drugs can improve T2D-related outcomes following bariatric procedures, and current T2D drug-discovery efforts are being informed by the metabolic advantages associated with bariatric surgery. These circumstances intensify the need for and extend the impact of T2D drug discovery by demonstrating multiple levels of interplay between medical and surgical approaches to improve the health of individuals with diabesity and, perhaps, approach the overarching goal of decreasing long-term cardiovascular mortality.

Keywords::

• cardiovascular risk
• diabesity
• endocrine disease
• glycemic control
• insulin resistance
• metabolic syndrome
• obesity
• vascular disease

1. Background

In the November, 2013, issue of Expert Opinion on Drug Discovery, Safavi et al. [1] surveyed approved synthetic drugs and late-stage pipeline compounds as pharmacotherapeutics for type 2 diabetes (T2D). Concluding that ‘finding new targets and ... synthetic methods’ is the ‘main goal in T2D drug discovery,’ the authors mention in passing that weight-loss (bariatric) surgery ‘is a highly effective treatment for obesity-related T2D.’ This commentary aims to widen the aperture afforded by Safavi and colleagues by considering the proposition that the inability of bariatric surgery to eradicate the T2D pandemic expands the scope of and presents new opportunities for drug discovery in the T2D space.

2. Bariatric surgery can effectively address, but has not solved, the T2D problem

An intensifying worldwide epidemic, obesity contributes to the development of numerous disabling and lifespan-limiting maladies. One of these, T2D, is well recognized as obesity's principal metabolic comorbidity and one of the fastest-growing noncommunicable diseases, characterized by insulin resistance and insufficient pancreatic β-cell insulin production to maintain acceptable glucose control/euglycemia [2]. Poorly controlled T2D itself increases cardiovascular risk and invites micro- (neuropathy, retinopathy) and macrovascular (obstructive arteriopathy leading to stroke, myocardial infarction) complications, the latter jeopardizing survival [3]. The coordinate escalation in the global incidences of obesity and T2D serves as a signpost for the contemporary pandemic of T2D in the context of obesity (‘diabesity’) [4].

Durable weight loss has long remained both a primary medical recommendation and an elusive goal for most diabesity patients [5]. Traditional T2D medical management involving behavioral modification and individual drugs/drug combinations can elicit salutary effects (Figure 1), but with relatively poor long-term health benefit [6]. Intensive lifestyle intervention (medically supervised weight loss, increased physical activity), although effective in reducing the body weight of overweight or obese T2D patients, offered no clear evidence of cardiovascular benefit at a median follow-up of 9.6 years in the large, randomized, controlled ‘Look AHEAD’ study [7]. Other prospective studies indicate that only some 50% of patients with moderate-to-severe T2D ever attain successful, sustained glycemic control through drug treatment [8].

Figure 1. A pharmaco-surgical interactome for T2D management. The Venn diagram represents the principal patient populations/beneficial outcomes associated with medical T2D management with insulin and synthetic pharmacotherapeutics (left); surgical T2D management with metabolic/bariatric procedural intervention (right); and a synergistic combination of the two T2D management approaches (center). Treatment impact may vary with specific pharmacotherapeutic regimen and surgical procedure.

In contrast to medical management alone, multiple retrospective analyses and prospective clinical studies demonstrate that bariatric surgery is the most effective weight reduction treatment for both morbidly (i.e., severely) obese adults (body mass index [BMI] > 40 kg/m²) and moderately obese adults (BMI 35 – 40 kg/m²) with significant weight-related health problems [9-11]. Roux-en-Y gastric bypass (RYGB) accounts for 46.6% of the global number of bariatric procedures worldwide, followed in frequency by sleeve gastrectomy (SG) (27.8%), adjustable gastric banding (AGB) (17.8%) and biliopancreatic diversion (BPD) (2.2%) [12]. As detailed in recent authoritative overviews [9,13], RYGB is the prototypical restrictive-malabsorptive procedure designed to divert ingested nutrients from passage through the upper digestive tract. A restrictive procedure, SG markedly reduces gastric volume by laparoscopic removal of some 70 – 80% of the stomach. An easily reversible, minimally invasive restrictive procedure, AGB reduces the size of the stomach pouch by means of an inflatable band placed around the upper portion of the stomach such that satiety is induced by smaller amounts of food, whereas BPD is a restrictive-malabsorptive procedure whose risk profile has limited its application to the most severely obese. All four bariatric procedures not only elicit substantial and sustained weight loss in moderately or morbidly obese adults [9,10] but also reduce or ameliorate various obesity-associated comorbidities, including T2D, with positive impact on overall health, quality of life and survival [10,11,14-16]. RYGB is generally associated with better weight-reduction outcomes and diabetes control, and the superior T2D-related efficacy is thought to reflect, at least in part, bypass procedure-induced reprogramming of intestinal glucose metabolism (Figure 1) [9,10,17-19]. Notwithstanding post-surgical nutritional liabilities and effects on drug absorption, the outcome success and low procedural risk generally associated with bariatric surgery have engendered interest in its somewhat controversial application to non-obese (BMI < 30 kg/m²) and mildly obese (BMI 30 – 34.9 kg/m²) adults with T2D and to morbidly obese children and adolescents who have failed to achieve treatment targets with conservative weight-loss measures [11,20-22], the escalating rates of youth obesity and obesity-driven T2D being particularly alarming [23]. Indeed, accumulating evidence indicates that bariatric surgery in mildly obese subjects is associated with at least comparable, if not better, outcomes (including T2D remission rates) than in morbidly obese subjects for up to 6 years post surgery [11,24,25].

The acute negative caloric balance consequent to food restriction per se has been considered a likely contributor to improved glucose control within 7 – 14 days post surgery [26]. Although a meta-analysis suggests a proportional relationship between T2D resolution rates and the degree of weight loss after bariatric surgery [27], the mechanisms responsible for the acute therapeutic effects of bariatric surgery on glucose homeostasis, β-cell function and insulin sensitivity are not well understood and appear to be mostly weight-loss independent. Candidate weight-independent mechanisms not mimicked by current pharmacotherapy that may contribute to T2D resolution following bariatric surgery include altered nutrient flow and sensing within regions of the gastrointestinal tract and changes in the production of bile acids and gut hormones [26,28,29].

Mechanistic vagaries aside, bariatric surgery is successful in reducing the incidence of T2D in a significant proportion of diabesity patients. Depending upon such factors as procedure type, definition of remission, endpoint indices of glucose control, patient entry criteria, postoperative care regimen and study limitations (e.g., attrition rates), reductions in T2D-related indices of 6.0 – 95% at 1 – 2 years post surgery and 36% at 10 years post surgery have been reported [15,30,31]. Although circumscribed by a maximum of 2 years of follow-up and a rather limited number of subjects, six clinical trials have demonstrated through direct comparison the superior outcomes of bariatric surgery over conventional medical T2D management with respect to both weight loss and indices of glycemic control (Table 1) [32-37], a conclusion supported by a recent comparative overview [38] and cross-study meta-analysis [39]. These findings have led to recommendations by at least some sectors of the medical community and prominent diabetological associations that bariatric surgery be considered valid primary therapy for (obesity-driven) T2D and, as such, be incorporated into T2D treatment algorithms as ‘metabolic surgery’ [22,40,41]. Accordingly, the term ‘metabolic/bariatric surgery’ is used henceforth in this presentation.

Table 1. Randomized controlled clinical trials comparing T2D response to conventional medical versus surgical treatment in obese individuals.

Treatment group	Analysis N (per group)	Follow-up (years)	T2D remission rates (respective percentages)	Ref.
Medical versus LAGB	30/30	2	13/73	[32]
Medical versus RYGB versus BPD	18/19/19	2	0/75/95	[33]
Medical versus RYGB versus SG	41/50/49	1	12/42/37	[34]
Medical versus RYGB versus SG	17/18/19	2	6.2/44.4/26.3	[35]
Medical versus RYGB	34/31	1	0/90	[36]
Medical versus RYGB	60/60	1	32/75	[37]

BPD: Biliopancreatic diversion; LAGB: Laparoscopic adjustable gastric banding; RYGB: Roux-en-Y gastric bypass; SG: Sleeve gastrectomy; T2D: Type 2 diabetes.

3. Multiple (surgery-related) niches for T2D synthetic drugs

Does the unique and impressive ability of metabolic/bariatric surgery to remit (obesity-driven) T2D marginalize medical treatment for diabesity such that the intensive, ongoing search for new T2D drugs/drug targets [1,6,42] risks – if not merits – de-emphasis? In the following paragraphs of this section, the author offers several considerations supporting an answer in the negative.

In Africa (Nigeria), Europe (UK), North America (USA) and Asia (Taiwan), the prevalence of T2D has been reported to be 7.1 – 20.4% in moderately obese and 13.8 – 44% in morbidly obese adults [43,44], patient populations considered eligible for metabolic/bariatric surgery by current clinical, regulatory and specialist-association guidelines [9-11,22]. Thus, most individuals who undergo bariatric surgery do not have T2D [45]. These statistics substantiate conclusion that the overarching therapeutic goal of metabolic/bariatric surgery remains weight reduction and not glycemic control such that T2D population-based treatment continues to be centered around synthetic drugs (with or without insulin). Nonetheless, in moderately or morbidly obese, nondiabetic subjects, metabolic/bariatric surgery does exert a strong T2D prevention effect, reducing the risk of developing T2D at 2 (by 75 – 96%), 10 (by 75 – 84%) and 15 (by 78%) years post surgery [46].

Notwithstanding the fact that obesity is an independent pro-inflammatory risk factor for T2D [2], obesity and T2D do not co-occur only in the moderately and morbidly obese. Some 3 – 4% of normal-weight (BMI < 25 kg/m²), 3 – 4% overweight (BMI 25 – 30 kg/m²), and 10 – 12% mildly obese individuals in the USA have T2D and would be considered ineligible for metabolic/bariatric surgery by current guidelines, but could qualify as candidates for synthetic anti-T2D drugs [10,22,43].

Metabolic/bariatric surgery is by no means a ‘magic-bullet cure’ for either obesity or T2D in the sense that the signs and symptoms of these diseases inevitably remit post procedure without risk of re-emergence. Results from both meta-analyses and randomized trials show 1- and 2-year T2D remission rates in morbidly obese subjects from 57% after the less invasive AGB procedure to 80% after the more invasive RYGB, that is, metabolic/bariatric surgery proved unable to resolve T2D in some 20% to over 40% of diabesity patients within 1 – 2 years post procedure [30,32-34,47]. At 3 years after RYGB, T2D re-emerged or worsened in 24% of diabesity patients [48] and in 35% at 5 years post surgery [49]. Other studies report that recurrence of T2D after initial surgical remission was evident in 19% within a 5 – 9-year follow-up range across various procedures [15] and 31.4% within 7 – 9 years after RYGB [50]. Among morbidly obese patients with remission of diabetes at 2 years after metabolic/bariatric surgery involving RYGB, AGB and other procedures, T2D was reported to have reoccurred in 50% by 10 years' follow-up [30,46]. Re-emergence of T2D after metabolic/bariatric surgery has been potentially associated with several preoperative factors, including poor glycemic control, severity of β-cell dysfunction, T2D duration and insulin use as well as a host of postoperative factors, such as maladaptive eating leading to weight regain, time after surgery and definition of clinical T2D remission [51,52]. Even significant, surgically-induced weight loss need not be accompanied by any signs of improved glycemic control whatsoever [53]. These clinical data substantiate the existence of a substantial number of diabesity patients who had undergone metabolic/bariatric surgery, yet would still be candidates for medical treatment with synthetic drugs to keep T2D in-check and help maintain glucose homeostasis due to lack of post-surgical T2D resolution.

The resolution of T2D after metabolic/bariatric surgery is more likely to occur in diabesity patients whose T2D had been controlled by oral hypoglycemic medications, and poor preoperative glycemic control and insulin use are associated with increased chance of T2D recurrence after surgically improved glucose control [15,51,52]. These results suggest an important role for synthetic drugs in a positive post-surgical prognosis by limiting the degree of preoperative glucose dysregulation.

Although variable among studies, criteria for complete (surgical) remission of T2D generally include both evidence of normal glycemic control and discontinuation of all diabetes medications [9,16,52,54]. Yet, diabesity patients who show acute surgical improvement in glycemic indices may need to remain on some (usually, reduced) level of T2D pharmacotherapy for months to over 1 year post surgery, depending upon the surgical procedure employed [9,55,56]. Indeed, caution has been sounded regarding inappropriate cessation of T2D medications post surgery [57].

Healthcare and surgical resources are considered inadequate for applying metabolic/bariatric surgery as a primary treatment modality for obesity, let alone obesity-related comorbidities such as T2D. Metabolic/bariatric surgery is capable of treating a very limited percentage of obese individuals who qualify for the procedure, especially given the projected surges in global diabesity incidence [10,12]. As a specific example, in the USA, metabolic/bariatric surgery is utilized for < 1% of currently eligible patients, thereby excluding some 99% of qualified individuals [58]. Thus, metabolic/bariatric surgery alone cannot be relied upon to manage the diabesity epidemic, whereas the applicability of synthetic T2D drugs is intrinsically much more inclusive across the overall T2D patient population.

4. New avenues for pharmaco-surgical T2D treatment synergies

Among the advantageous humoral responses to RYGB favoring glycemic control, the exaggerated postprandial glucagon-like peptide-1 (GLP-1) secretion observed acutely and up to 10 years post procedure has been considered of paramount importance, perhaps reflecting GLP-1's abilities to promote pancreatic β-cell regeneration and help ensure euglycemia by increasing insulin biosynthesis and secretion after meal ingestion [59,60]. In diet-induced obese rats, Habegger et al. recently reported that a GLP-1 receptor agonist enhances the surgically induced decreases in body weight and adiposity after AGB, whereas pharmacological attenuation of orexigenic drive through the endocannabinoid biosignaling system with a cannabinoid receptor-1 antagonist/inverse agonist (rimonabant) did not improve experimental AGB outcome [61]. These laboratory results suggest that GLP-1 receptor agonists might find new clinical utility as the pharmaceutical component of a pharmaco-surgical approach for optimizing AGB (Figure 1). In this manner, AGB might attain the levels of weight reduction and metabolic improvement associated with the more invasive RYGB, although procedure-related complications have led to a decline in the use of AGB [12], and currently available GLP-1-based therapies have been associated with potential risks of pancreatitis and pancreatic cancer [62]. Extrapolation of any such preclinical efficacy studies to the clinic must also be tempered by our incomplete understanding of the factors that impact upon T2D diabetes resolution after AGB or RYGB [26-29]. Nonetheless, experimental findings of this type do suggest practical avenues of synergy between pharmacotherapy and metabolic/bariatric surgery potentially applicable to humans.

A recent clinical study has demonstrated that obese (BMI ≥ 35 kg/m²) patients with insulin-treated T2D who were managed after RYGB surgery with a personalized titration schedule for the insulin analog glargine and the synthetic anti-hyperglycemic agent metformin reported no symptomatic hypoglycemia and achieved complete T2D remission at 1-year follow-up with a rate several-fold greater (i.e., 50 vs 6.1%) than a matched cohort whose postoperative care did not include a protocol-driven drug treatment [63]. Although this result needs confirmation in a large-scale, randomized, controlled clinical trial, the data suggest that even the T2D-related benefits of RYGB, the most efficacious metabolic/bariatric-surgery approach [9,13,18], might be enhanced with pharmacological glycemic management (Figure 1).

5. Expert opinion

Despite metabolic/bariatric surgery's unique ability to effect long-term T2D remission in some – but not all – diabesity patients, surgical T2D management is unlikely to become a population-based therapeutic modality with the degrees of practicality, applicability and versatility already attained by T2D synthetic drugs. Consequently, known and emerging T2D synthetic agents will be required not only to manage those diabetics disqualified from metabolic/bariatric surgery, but also to control T2D in post-surgery diabesity patients with residual or re-emergent T2D who have not achieved an acceptable level of metabolic homeostasis following surgery. This line of thinking argues for the potential of active glycemic management with synthetic T2D drugs to become an integral component of more personalized post-surgical glucose control.

As complex disease states, obesity and T2D are promoted and sustained by several directionally variable, interacting information pathways inherently resistant to interventional perturbation of a single process/molecular component and subject to influence by multiple (epi)genetic and environmental factors [64]. This systems-biology perspective may help explain why the obesity and T2D therapeutic spaces are replete with drug failures, market withdrawals and adverse-event cautions, despite the fact that most pharmacotherapeutics for these indications have been developed as agents directed to apparently pathologically important, mechanism-based disease targets [6,65]. As applied to T2D patients in the contexts of moderate and severe obesity, both known and emerging T2D drugs may themselves shed much-needed, therapeutically relevant light on the molecular dialog underpinning diabesity so as to facilitate identification of etiological drivers whose pharmaco-surgical modulation would have a more comprehensive salutary effect on T2D in the obesity setting than current best-care approaches. Such insight might also remove some of the mechanistic mystery surrounding the responses of glycemic status to metabolic/bariatric surgery [66].

Although historic and more recent data suggest that some synthetic T2D drugs can have beneficial effects on cardiovascular risk factors and increase life expectancy in obese individuals with cardiovascular disease and T2D [67], robust demonstrations from large-scale prospective clinical trials of a decisive effect of metabolic/bariatric surgery on long-term cardiovascular outcomes in moderately or morbidly obese individuals with T2D have been elusive [6,11,30,68]. Utilization of synthetic T2D drugs in conjunction with metabolic/bariatric surgery may make it possible to realize decisively at least one of two prominent ‘holy grails’ that would enhance surgical outcomes: i) increase post-surgical T2D remission rates with pharmacotherapeutics efficacious in improving β-cell function prior to surgery, since T2D non-remission/recurrence has been correlated with the starting degree of β-cell dysfunction [69,70]; and/or ii) militate cardiovascular risk sufficiently to decrease long-term mortality and improve overall survival of individuals with diabesity, occlusive macrovascular disease leading to myocardial infarction or ischemic stroke constituting the leading underlying cause of T2D-related deaths [3].

While these scenarios at present belong more to the realm of possibility than prescription, connectivity between medical and surgical approaches to T2D treatment has already spurred active drug-discovery efforts that attempt to modulate pharmacologically novel T2D-related molecular mechanisms so as to mimic specific beneficial effects of metabolic/bariatric surgery (Figure 1). For example, observed increases in bile flow and plasma bile acids associated with the immediate post-RYGB period and believed to stimulate β-cell function by potentiating incretin-hormone (i.e., GLP-1) signaling via activation of the G-protein-coupled bile acid receptor (TGR5) have prompted discovery campaigns to design proprietary, orally active TGR5 agonists as antidiabetic agents [71,72]. Likewise, the critical role of the high-affinity sodium-glucose cotransporter (SGLT-1) in both glucose transport by the proximal intestine and consequent nutrient-sensing information pathways, the SGLT-1 overexpression observed in experimental and clinical T2D, and the reduced glucose-transport capacity of the proximal intestine following RYGB have led to the development of novel SGLT-1 inhibitors with preclinical antidiabetic efficacy [73-75]. Such findings suggest that increased cross-talk between bariatric surgeons and T2D drug-discovery practitioners will not only augment our understanding of the mechanistic basis of surgical T2D remission, but will also generate as-yet unanticipated avenues for novel synthetic T2D drugs in managing and optimizing glycemic control and overall cardiometabolic status in the pre- and post-surgical diabesity patient.

Declaration of interest

The author declares no conflict of interest and has received no payment in the preparation of this manuscript.

Notes