When Biology Advances, but Care Lags

Metabolic diseases, including type 2 diabetes (T2D), obesity, and metabolic syndrome, are a growing threat to global public health. More than 537 million adults currently live with T2D, and this number continues to rise, especially in developing countries where sedentary lifestyles and poor diets are driving the surge. These conditions impose a substantial economic burden on health systems worldwide, particularly in resource-limited areas.

These disorders disrupt energy metabolism and alter the mechanisms for generating, storing, and utilizing energy. T2D is characterized by insulin resistance and chronic hyperglycemia. Obesity exacerbates insulin resistance and triggers persistent low-grade inflammation, leading to compounded metabolic dysfunctions. Currently, 39% of adults are overweight, and 13% are classified as obese.

Metabolic syndromes include abdominal obesity, hypertension, dyslipidemia, and insulin resistance, together with a significantly increased risk for cardiovascular disease and T2D. This rising prevalence is driven by population aging and unhealthy lifestyles. Nonalcoholic fatty liver disease, also known as metabolic dysfunction-associated steatotic liver disease (MASLD), is a common complication of metabolic syndrome and is among the top causes of chronic liver disease globally.

Coexisting T2D, obesity, and metabolic syndrome sharply increase the risk for myocardial infarction, stroke, kidney failure, and neuropathy. This cluster leads to severe health consequences and increased costs, reinforcing the need for integrated preventive and therapeutic strategies.

Therapeutic Approaches

Current treatments for metabolic diseases, particularly T2D, include metformin; SGLT2 inhibitors such as empagliflozin, canagliflozin, and dapagliflozin; and GLP‑1 agonists, for example, liraglutide, semaglutide, and dulaglutide. Metformin remains the first-line therapy due to its proven efficacy, low cost, and tolerability. SGLT2 inhibitors lower blood glucose levels by increasing urinary glucose excretion and offer added benefits for weight and cardiovascular health but may increase the risk for urinary and genital infections. GLP‑1 agonists improve glycemic control and support weight loss and cardiovascular protection, although they often cause gastrointestinal side effects. Emerging therapies include dual GLP‑1/glucose-dependent insulinotropic polypeptide (GIP) agonists such as tirzepatide and triple agonists targeting GLP‑1, GIP, and glucagon, which aim to enhance efficacy, improve weight loss, and reduce dosing frequency to support better treatment adherence.

Research Highlights

Recent findings have reshaped the understanding and management of metabolic diseases by targeting the underlying biological mechanisms. Mitochondrial dysfunction in adipose tissue is a key contributor to insulin resistance in patients with T2D. Thus, enhancing mitochondrial biogenesis and function may offer an effective therapeutic strategy for treating these diseases. Disruption of circadian rhythms impairs energy metabolism and worsens obesity, T2D, and metabolic syndrome, supporting the use of chronotherapy by aligning meals, light exposure, and medication timing with the body’s natural rhythms. A 2024 report, “Heart Disease and Stroke Statistics,” provides comprehensive data on cardiovascular health and its link with metabolic diseases. This report underscores the importance of therapies that address both glucose regulation and subclinical vascular damage associated with metabolic conditions. A review in Frontiers in Medicine identified insulin resistance as a central factor in metabolic diseases and explored gut microbiome-based therapies for MASLD, including probiotics, prebiotics, targeted antibiotics, and fecal transplantation. Patient phenotype-based treatment was proposed to improve outcomes in T2D, aiming to tailor therapies based on individual metabolic profiles. Advances in imaging and biomarkers have been highlighted for the early detection of metabolic disorders, enabling timely intervention before the development of clinical symptoms.

Therapeutic Innovations

Gene therapy and gut-liver axis modulation improve insulin sensitivity and reduce liver fat in MASLD models, although safety and durability remain challenging. Dual and triple agonists targeting GLP‑1, GIP, and glucagon receptors improve glycemic control, weight loss, and cardiovascular health. These therapies may also alter gene expression through epigenetic mechanisms, thereby supporting personalized treatment approaches.

Early metabolic changes are linked to vascular damage, supporting early intervention in at-risk patients. mRNA therapies delivered via lipid nanoparticles improve glucose control with fewer side effects in diabetes models. Triple agonists show superior metabolic control, weight loss, and cardiovascular benefits, with better adherence and tolerability.

Future Challenges

Despite recent advances in the treatment of metabolic diseases, several barriers have hindered the widespread adoption of new therapies. A recent analysis highlighted the need for long-term clinical trials to validate therapies that target mitochondrial function in humans. Similarly, the implementation of personalized chronotherapy based on circadian rhythms remains technically and clinically challenging. In cardiovascular care, early vascular damage in young individuals at metabolic risk often goes undetected, delaying preventive intervention. Microbiome-based treatments for MASLD also face limitations due to individual variability and the lack of standardized protocols.

Environmental factors, such as diet and stress, can amplify gene expression linked to metabolic disorders, underscoring the need for multisectoral prevention strategies. Phenotypic classification of T2D could support personalized care, but its implementation requires resources and infrastructure that are not widely available. Advanced metabolic imaging and molecular diagnostics are still inaccessible with many limited resources, restricting early detection and personalized treatment. The long-term use of GLP-1 agonists may be limited by gastrointestinal side effects in some patients, highlighting the need for more precise therapeutic selection.

Triple GLP-1/GIP/glucagon agonists show strong potential but are costly and lack data in diverse populations, limiting global rollout. High costs, investment needs for gene and mRNA therapies, gaps in medical training, and public awareness are significant barriers. Addressing these challenges requires sustainable care models and innovative financing policies. Furthermore, the ongoing training of medical personnel and public education campaigns are key to ensuring effective prevention, early diagnosis, and equitable application of recent therapeutic advances.

Conclusions

Advances in the understanding of mitochondrial dysfunction, circadian rhythms, and the gut microbiome are transforming the management of metabolic diseases into clinical practice. Gene therapy and mRNA-based treatments show promise for T2D, obesity, and MASLD; however, further research is required to confirm their safety, effectiveness, and long-term outcomes.

Standard treatments, such as metformin, SGLT2 inhibitors, and GLP-1 agonists, remain widely used, whereas newer dual and triple agonists offer additional benefits for glycemic control, weight loss, and cardiovascular protection. Personalized medicine based on phenotypic and molecular data may improve treatment outcomes but faces logistical, technological, and economic barriers.

Limited access to advanced therapies in low- and middle-income countries highlights the global equity gap, which necessitates innovative public funding and sustainable care models. Strengthening diagnostic capacity, medical education, and public awareness are key to improving prevention, early diagnosis, and treatment.

A coordinated global effort involving healthcare professionals, policymakers, researchers, and communities is essential to ensure that new therapies lead to meaningful and equitable improvements in public health.

This story was translated and adapted from El Medico Interactivo.