Diabetes Drug Dominos: How Your Genes Could Tip the Scales

A significant proportion of individuals diagnosed with Type 2 diabetes, exceeding one quarter, are currently undergoing treatment with GLP-1 receptor agonists. However, a recent investigation spearheaded by scientists at Stanford Medicine and their international colleagues suggests that these widely utilized antidiabetic medications may exhibit diminished efficacy in patients possessing particular genetic predispositions.

These specific genetic variations, present in approximately 10% of the global populace, contribute to a peculiar and not yet fully elucidated phenomenon. Researchers have termed this condition “GLP-1 resistance,” whereby the circulating levels of glucagon-like peptide-1 (GLP-1), a hormone pivotal in blood glucose regulation, are elevated yet demonstrate reduced biological impact.

The precise influence of these genetic variants on the weight-loss effects of drugs such as Ozempic and Wegovy remains uncertain. These medications are increasingly prescribed for the management of obesity, often necessitating higher dosages than those used for diabetes treatment.

The findings of this new study, published on March 29 in the journal *Genome Medicine*, were primarily centered on the intricate mechanisms of blood sugar regulation. This comprehensive, ten-year international undertaking encompassed a multifaceted approach, involving experimental studies in both human subjects and murine models, alongside rigorous analysis of data derived from diabetes drug clinical trials.

In some of the clinical trials, it became apparent that individuals carrying these specific genetic variants were less successful in achieving a reduction in their blood glucose levels after a six-month therapeutic regimen.”

Anna Gloyn, DPhil, Professor of Pediatrics and Genetics, and a Senior Author of the Study

At such a juncture, a clinician would typically reassess and modify the patient’s pharmacological intervention. Foreknowledge of an individual’s likelihood of responding positively could facilitate a more expedited initiation of appropriate therapeutic agents, thereby advancing the principles of precision medicine, as articulated by Dr. Gloyn.

The study’s other senior author is Markus Stoffel, MD, PhD, a distinguished professor specializing in metabolic diseases at the Institute of Molecular Health Sciences, ETH Zurich in Switzerland. Leading the research were Mahesh Umapathysivam, MBBS, DPhil, an endocrinologist and clinical researcher affiliated with the University of Adelaide in Australia and a former mentee of Dr. Gloyn, and Elisa Araldi, PhD, an associate professor of medicine and surgery at the University of Parma in Italy, who also trained under Dr. Stoffel.

“When I engage with patients in the diabetes clinic, I observe a considerable disparity in their responses to GLP-1-based therapies, and predicting these responses clinically proves challenging,” stated Dr. Umapathysivam. “This investigation represents a foundational step towards leveraging an individual’s genetic profile to enhance our decision-making processes in treatment selection.”

While this research constitutes the inaugural in-depth exploration of GLP-1 resistance, the underlying mechanistic pathways are yet to be definitively established by the investigators.

“That is the pivotal question,” Dr. Gloyn remarked. “We have systematically examined a comprehensive array of potential explanations for the emergence of GLP-1 resistance. Despite our thorough investigations, we have been unable to pinpoint the precise reason for this resistance.”

Puzzling Resistance Dynamics

The researchers concentrated their efforts on two specific genetic variants that compromise the functionality of an enzyme designated as PAM (peptidyl-glycine alpha-amidating monooxygenase). This enzyme possesses a unique capacity to activate a multitude of hormones within the body, including GLP-1.

“PAM is a truly remarkable enzyme, as it is the sole enzyme in our biological system capable of facilitating a chemical process known as amidation. This process enhances the biological half-life and potency of peptides that are active within the body,” explained Dr. Gloyn.

“Our hypothesis was that any impairment in this enzyme’s function would likely lead to a cascade of dysfunctions across various biological systems.”

Indeed, it was already known that PAM variants were more prevalent in individuals with diabetes. Dr. Gloyn’s prior research demonstrated that these variants interfere with insulin secretion from the pancreas. The research team therefore posited whether this genetic anomaly also exerted an influence on GLP-1, a gut hormone that plays a critical role in postprandial glucose homeostasis by stimulating insulin release, retarding gastric emptying, and suppressing appetite. GLP-1 receptor agonist medications function by emulating the action of this endogenous hormone.

The study involved recruiting adult participants, both with and without a specific PAM variant known as p.S539W. These individuals were administered a sugary beverage, and their blood glucose levels were meticulously monitored every five minutes for the subsequent four hours. (Participants without diabetes were chosen to mitigate the introduction of confounding variables associated with the disease.)

The research team initially anticipated that individuals carrying the PAM variant would exhibit reduced levels of circulating GLP-1, perhaps owing to diminished stability of the unamidated form. However, their observations diverged significantly from these expectations.

“Counterintuitively, we observed elevated levels of GLP-1 in their blood,” Dr. Gloyn stated. “This finding was diametrically opposed to our initial hypothesis.”

“Despite the presence of heightened circulating GLP-1 levels in individuals with the PAM variant, we found no indication of increased biological activity. Their blood glucose levels were not being reduced more rapidly. Consequently, a greater quantity of GLP-1 was required to elicit the same biological response, signifying their resistance to GLP-1’s effects.”

Confirmation Efforts Underway

The unexpected nature of these findings prompted Dr. Gloyn’s team to dedicate several subsequent years to rigorous confirmation of their results.

“The inexplicable nature of this observation necessitated that we explore every possible avenue to ascertain the robustness and reproducibility of our findings,” she elaborated.

In collaboration with researchers in Zurich, they investigated murine models with a genetically engineered absence of the PAM gene. These animal models also exhibited hallmarks of GLP-1 resistance, characterized by elevated GLP-1 concentrations that failed to adequately regulate blood glucose levels.

A key function of GLP-1, and by extension, drugs that mimic its action, is the deceleration of gastric emptying, a process that contributes to both glucose homeostasis and weight management. The researchers ascertained that mice lacking the PAM gene displayed accelerated gastric emptying. Crucially, treatment of these mice with a GLP-1 receptor agonist did not result in a normalization of their gastric emptying rate.

Furthermore, they noted a diminished response to GLP-1 within the pancreas and intestinal tissues of these mice, indicative of GLP-1 resistance. Importantly, no alterations were observed in the expression levels of GLP-1 receptors in these specific tissues.

In partnership with researchers based in Copenhagen, it was demonstrated that a defect in PAM does not compromise the capacity of GLP-1 receptors to bind with GLP-1, nor does it affect the downstream signaling cascade initiated by the hormone’s interaction with its receptor. This collective evidence suggests that the phenomenon of GLP-1 resistance arises at a point subsequent to receptor binding and activation.

Therapeutic Implications of Varied Responses

To ascertain whether GLP-1 resistance translated into tangible therapeutic differences, the researchers conducted an examination of data from several clinical trials involving GLP-1 receptor agonists in individuals with diabetes. A meta-analysis encompassing three trials, with a cumulative total of 1,119 participants, revealed that individuals carrying PAM variants exhibited a less pronounced response to these medications and a reduced capacity to lower their HbA1c levels, a key indicator of long-term glycemic control. Specifically, approximately 25% of non-carriers achieved the recommended HbA1c target after six months of treatment, in contrast to 11.5% of participants with the p.S539W variant and 18.5% of those with the p.D563G variant.

Notably, participants bearing these variants did not display differential responses to other commonly prescribed antidiabetic agents, including sulfonylureas, metformin, and DPP-4 inhibitors.

“A particularly striking observation was the absence of any discernible impact of these variants on treatment response to other classes of diabetes medications,” Dr. Gloyn commented. “It is unequivocally clear that this resistance is specific to pharmacological agents that operate through the GLP-1 receptor pathway.”

In two additional clinical trials, funded by pharmaceutical entities and excluded from the primary meta-analysis due to methodological disparities, similar drug responses were observed between carriers and non-carriers of the PAM variants. According to Dr. Gloyn, these particular trials involved longer-acting GLP-1 receptor agonists, which might possess the capacity to mitigate GLP-1 resistance.

Unraveling a Complex Biological Enigma

Dr. Gloyn’s team initially identified the phenomenon of GLP-1 resistance nearly a decade ago, predating the considerable surge in interest surrounding GLP-1 receptor agonists as agents for weight management. Only two of the clinical trials analyzed in the present study provided weight-related data, which indicated no significant difference in weight reduction between individuals with and without PAM variants. However, Dr. Gloyn cautioned that this dataset is too limited to permit definitive conclusions.

A substantial volume of clinical trial data detailing the influence of genetic factors on various responses to GLP-1 receptor agonists, including weight loss, is likely available. Nevertheless, accessing such data has historically presented considerable challenges.

“It is a common practice for pharmaceutical corporations to compile genetic data pertaining to their trial participants,” she noted. “For contemporary GLP-1 medications, it would be highly beneficial to investigate whether specific genetic variants, such as those identified within the PAM gene, are instrumental in explaining the suboptimal responses observed in certain patient cohorts.”

At present, the precise molecular mechanisms underpinning GLP-1 resistance remain elusive, though it is presumed to be a multifaceted and complex interplay of biological factors, as suggested by Dr. Gloyn. She draws an analogy to insulin resistance, a condition that, despite decades of research since its discovery, is still not entirely understood. Nevertheless, scientific advancements have yielded effective strategies for managing insulin resistance.

“We have developed an entire class of medications known as insulin sensitizers. Consequently, it is plausible that we could develop analogous therapeutic agents that enhance sensitivity to GLP-1s, or alternatively, devise novel formulations of GLP-1, such as extended-release versions, that effectively circumvent the challenges posed by GLP-1 resistance,” she proposed.

Collaborating researchers from the University of Oxford, University of Dundee, University of Copenhagen, University of British Columbia, Churchill Hospital, Newcastle University, University of Bath, and the University of Exeter also made significant contributions to this research endeavor.

Financial support for this study was provided by Wellcome, the Medical Research Council, the European Union Horizon 2020 Programme, the National Institutes of Health (grants U01-DK105535, U01-DK085545, and UM-1DK126185), the National Institute for Health Research Oxford Biomedical Research Centre, the Canadian Institutes of Health Research, the Novo Nordisk Foundation, Boehringer Ingelheim, and Diabetes Australia.