FIB-4 ≥1.3 is correlated with increased DKD risk in T2D, but SGLT2i therapy that lowers FIB-4 attenuates this
Abstract Non-alcoholic fatty liver disease (NAFLD) and diabetic kidney disease (DKD) frequently coexist in people with type 2 diabetes (T2D), reflecting shared pathophysiological mechanisms including insulin resistance, ectopic fat deposition, chronic inflammation, oxidative stress, and renin–angiotensin–aldosterone system activation. In this context, simple non-invasive biomarkers capable of capturing multi-organ risk are of increasing clinical value. The Fibrosis-4 index (FIB-4), originally developed to identify advanced hepatic fibrosis, has emerged as a systemic risk marker extending beyond the liver. Accumulating observational evidence demonstrates that a FIB-4 threshold of ≥1.3—commonly used to denote at-least-intermediate fibrosis risk—independently predicts incident DKD, proteinuria, and accelerated decline in estimated glomerular filtration rate, even in individuals with preserved baseline kidney function and after adjustment for conventional risk factors. These associations suggest that FIB-4 reflects an underlying systemic fibrotic and inflammatory milieu linking hepatic and renal vulnerability. In parallel, sodium–glucose cotransporter-2 inhibitors (SGLT2i) have transformed the management of T2D and chronic kidney disease, consistently reducing renal disease progression and heart failure events independent of glucose lowering. Emerging data indicate that SGLT2i may also improve hepatic steatosis and reduce non-invasive fibrosis indices, including FIB-4, raising the possibility that attenuation of liver-related fibrotic burden contributes to their renoprotective effects. Together, these findings support the concept of FIB-4 ≥1.3 as a “two-organ danger marker” identifying patients with heightened hepato-renal risk who may derive particular benefit from early, intensified organ-protective therapy centered on SGLT2 inhibition. While current evidence is largely observational, integrating FIB-4 into routine clinical assessment may refine risk stratification and advance a more unified cardio–renal–hepatic approach to care in T2D
Evolutionary Role of GIP & GLP-1 Beyond Glycaemia Review: non-glycaemic role of GIP and GLP1 in current clinical practice
Abstract Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) were initially identified as incretin hormones responsible for glucose-dependent insulin secretion after nutrient intake. While early therapeutic strategies focused primarily on glycaemic control in type 2 diabetes, a growing body of evidence now demonstrates that these hormones exert extensive non-glycaemic effects across multiple organ systems. Large cardiovascular outcome trials have consistently shown that long-acting GLP-1 receptor agonists reduce major adverse cardiovascular events by approximately 20–26%, with benefits that cannot be fully explained by modest reductions in HbA1c. Parallel data from renal outcome analyses and dedicated chronic kidney disease trials indicate that GLP-1 receptor agonists slow estimated glomerular filtration rate decline, reduce albuminuria, and delay progression to kidney failure through mechanisms largely independent of glucose lowering. Beyond the cardio-renal axis, GLP-1 signalling influences appetite regulation, body-weight reduction, adipose tissue quality, hepatic lipid metabolism, systemic inflammation, and central nervous system function. GIP, once considered primarily obesogenic, is now recognised as a context-dependent modulator of adipose tissue biology, lipid handling, and inflammation. Dual GIP/GLP-1 receptor co-agonism, exemplified by tirzepatide, integrates these complementary pathways, producing greater weight loss, improved lipid profiles, reduced hepatic steatosis, and enhanced cardiometabolic risk reduction compared with GLP-1 receptor agonism alone. Collectively, current evidence supports a paradigm shift in which GLP-1 and GIP are viewed as cardio-renal-metabolic and neuroendocrine hormones rather than solely incretins. Understanding and harnessing their non-glycaemic biology is central to contemporary strategies aimed at preventing cardiovascular disease, kidney failure, obesity-related complications, and potentially neurodegenerative disorders in people with diabetes and related metabolic diseases.
Underweight Status in Type 2 Diabetes Patients: Significantly Associated with Increased Risks of Cardiovascular Disease
Type 2 diabetes mellitus (T2D) is traditionally viewed through the lens of excess adiposity; however, accumulating evidence indicates that underweight status represents a distinct and under-recognized cardiometabolic risk phenotype. While the so-called obesity paradox suggests lower cardiovascular disease (CVD) risk among overweight individuals with T2D, large-scale cohort studies and meta-analyses now demonstrate a reverse J-shaped association between body mass index (BMI) and cardiovascular outcomes. Patients with T2D and a BMI <18.5 kg/m² exhibit the highest risks of major adverse cardiovascular events (MACE), with hazard ratios ranging from 1.6 to 2.8 compared with normal-weight or obese counterparts. This risk is particularly pronounced in younger individuals, women, non-smokers, and Asian populations, where underweight prevalence is disproportionately high. Mechanistically, underweight T2D is characterized by sarcopenia, malnutrition-inflammation-cachexia syndrome, ectopic fat deposition, persistent insulin resistance, metaflammation, oxidative endothelial injury, and adverse cardiac remodeling despite apparent leanness. Loss of skeletal muscle mass, myostatin overexpression, ubiquitin–proteasome activation, and mitochondrial dysfunction converge to accelerate frailty and atherosclerosis. Concurrent visceral, hepatic, and epicardial fat accumulation promotes lipotoxicity, myocardial fibrosis, heart failure with preserved ejection fraction, autonomic dysfunction, and arrhythmogenesis. Developmental and epigenetic programming from early-life undernutrition further amplifies cardiovascular vulnerability. Current diabetes and cardiovascular guidelines largely neglect underweight status, focusing predominantly on obesity-centric risk reduction. Emerging evidence supports a paradigm shift toward muscle-centric, frailty-inclusive cardiometabolic care incorporating routine nutritional assessment, sarcopenia screening, resistance training, targeted protein and micronutrient repletion, and judicious use of glucose-lowering therapies that favor ectopic fat redistribution rather than weight loss. Recognizing underweight T2D as a sentinel of heightened cardiovascular risk is essential to prevent premature morbidity and mortality in this vulnerable population.
Malnutrition-inflammation-cachexia syndrome
Heart failure with preserved ejection fraction
Osteoarthritis and Type 2 Diabetes: From Metaflammation to Mechanism-Based Therapies
Osteoarthritis (OA) and type 2 diabetes (T2D) are increasingly recognised as biologically interconnected chronic diseases rather than coincidental comorbidities. Affecting over 500 million individuals globally, their coexistence accelerates disability, pain, healthcare utilisation, and socioeconomic burden. Emerging evidence reframes OA as a metabolic–inflammatory disorder, driven not solely by biomechanics but by metaflammation—a state of chronic, low-grade inflammation arising from adipose tissue dysfunction, insulin resistance, and hyperglycaemia. This comprehensive review synthesises epidemiological, molecular, genetic, and translational data linking OA and T2D through shared pathways involving adipokine dysregulation, AGE–RAGE signalling, oxidative stress, mitochondrial dysfunction, chondrocyte senescence, inflammasome activation, and subchondral bone remodelling. Bidirectional causality is highlighted: T2D increases OA risk and progression independent of BMI, while OA-related inflammation and inactivity elevate diabetes incidence. The article delineates a distinct “diabetic osteoarthritis phenotype”, characterised by accelerated cartilage loss, heightened pain, increased synovial COMP and AGEs, worse WOMAC scores, and higher arthroplasty rates. Genetic pleiotropy (DOT1L, GDF5, IL6R), epigenetic reprogramming, and SASP amplification further unify disease mechanisms. Importantly, the review advances mechanism-based therapeutic strategies, emphasising repurposed antidiabetic agents such as metformin, GLP-1 receptor agonists, and SGLT2 inhibitors, which modulate AMPK, NF-κB, senescence, and AGE burden beyond glycaemic control. Lifestyle intervention, weight loss, bariatric surgery, senolytics, RAGE and NLRP3 inhibitors, and biomarker-guided precision medicine are discussed as future-forward solutions. By integrating endocrinology and rheumatology, this work advocates a paradigm shift—from symptomatic palliation to metaflammation-targeted, precision-based care—with the potential to delay joint replacement, restore mobility, reduce disability-adjusted life years, and extend healthspan in ageing populations.
Cellular Senescence in the Cardio-Diabetes-Renal Continuum: Biology, Therapy, and Clinical Translation
Abstract Cellular senescence is increasingly recognised as a fundamental biological mechanism linking ageing to the interconnected progression of cardiovascular, metabolic, and renal diseases—the cardio-diabetes-renal (CDR) continuum. Senescent cells arise in response to telomere attrition, DNA damage, oncogenic and metabolic stress, and are characterised by stable cell-cycle arrest alongside sustained metabolic activity. Their accumulation drives tissue dysfunction through the senescence-associated secretory phenotype (SASP), a pro-inflammatory and pro-fibrotic secretome that remodels local and systemic microenvironments. Across metabolic tissues, vasculature, heart, and kidney, senescence contributes to insulin resistance, endothelial dysfunction, arterial stiffness, myocardial fibrosis, and progression of diabetic kidney disease. Distinct molecular pathways—primarily the p53–p21 and p16^INK4a^–Rb axes—govern senescence induction, while pronounced heterogeneity in senescent cell populations and temporal evolution of the SASP complicate therapeutic targeting. Experimental models demonstrate that clearance or modulation of senescent cells improves metabolic homeostasis, vascular function, cardiac performance, and renal outcomes, supporting a causal role in disease progression. These insights have catalysed the development of senolytic therapies, which selectively eliminate senescent cells, and senomorphic agents, which attenuate SASP signalling. Early-phase human studies using intermittent “hit-and-run” senolytic regimens have shown feasibility, biomarker reduction, and preliminary functional benefits in age-related and metabolic conditions, including diabetic kidney disease. However, translation into routine clinical practice requires biomarker-guided patient selection, careful safety monitoring, and integration with existing cardio-metabolic therapies. This review synthesises current understanding of senescence biology, molecular heterogeneity, and organ-specific roles across the CDR continuum, and critically evaluates emerging senescence-targeted therapies. By reframing cardio-metabolic disease as a manifestation of accelerated biological ageing, senescence-informed medicine offers a transformative paradigm aimed at preserving organ resilience, functional reserve, and health span.
Senescence-associated secretory phenotype (SASP)
Familial Hypercholesterolaemia in the Precision Medicine Era: Epidemiology, Genetics, Risk Stratification, and Therapeutic Innovations
Abstract Familial hypercholesterolaemia (FH) is one of the most common monogenic metabolic disorders, characterized by lifelong elevation of low-density lipoprotein cholesterol (LDL-C) and a markedly increased risk of premature atherosclerotic cardiovascular disease (ASCVD). Affecting approximately 1 in 250 individuals worldwide in its heterozygous form and far fewer in its homozygous form, FH remains profoundly underdiagnosed and undertreated despite the availability of effective therapies. Advances in genomic medicine, population screening strategies, and lipid-lowering therapeutics have fundamentally reshaped the diagnostic and therapeutic landscape of FH. This review synthesizes contemporary evidence on the epidemiology, genetic architecture, and natural history of FH, highlighting the role of next-generation sequencing, polygenic risk scores, and refined clinical criteria in improving diagnostic accuracy and enabling cascade and universal pediatric screening. Beyond LDL-C levels alone, modern risk stratification integrates imaging modalities, biomarkers such as lipoprotein(a), and genetic burden to individualize ASCVD risk and guide therapy intensity. Therapeutic innovation has expanded substantially, moving beyond statins and ezetimibe to include PCSK9 monoclonal antibodies, small-interfering RNA therapies such as inclisiran, ANGPTL3 inhibitors, and emerging oral and RNA-based agents. These therapies enable unprecedented LDL-C reductions, including in patients with homozygous FH or statin intolerance. Furthermore, gene-based approaches using antisense oligonucleotides and genome-editing technologies hold promise for durable or potentially curative interventions, although long-term safety, ethical, and equity considerations remain critical. Despite these advances, significant gaps persist in awareness, access, and implementation, particularly in low- and middle-income countries and among vulnerable populations. Closing these gaps through integrated public health strategies, equitable access to diagnostics and therapies, and precision-based care models is essential. In the precision medicine era, FH exemplifies how genomic insight and therapeutic innovation can transform a historically lethal inherited condition into a preventable and potentially curable disease.
Ultrasonics and AI-Assisted Ultrasound: Transforming Diabetic Nephropathy Diagnosis and Management
Abstract Diabetic nephropathy (DN) remains the leading cause of chronic kidney disease (CKD) and end-stage kidney disease (ESKD) worldwide, driven by the expanding global diabetes epidemic. Early and accurate diagnosis is critical for timely intervention and precision risk stratification, yet current diagnostic paradigms—reliant on albuminuria, estimated glomerular filtration rate (eGFR), and invasive renal biopsy—are limited by poor early sensitivity, lack of structural specificity, or procedural risk. In this context, ultrasonics—quantitative feature extraction from renal ultrasound imaging—combined with artificial intelligence (AI) has emerged as a transformative, non-invasive diagnostic approach. Ultrasonics enables high-dimensional characterization of renal structure, texture, morphology, and microvascular perfusion using grayscale ultrasound, Doppler imaging, and contrast-enhanced ultrasound (CEUS). Quantitative parameters such as peak enhancement, area under the curve, time to peak, mean transit time, and advanced textural features directly reflect underlying microangiopathy, interstitial fibrosis, and nephron loss characteristic of DN. When integrated with machine learning models—including random forests, ensemble classifiers, and deep learning frameworks—these features enable accurate differentiation between DN and non-diabetic renal disease, as well as reliable prediction of CKD progression. Recent validation studies report diagnostic accuracies exceeding 85–90%, with area under the receiver operating characteristic curve values comparable to, and in some settings rivaling, renal biopsy—without procedural risk or radiation exposure. Beyond diagnosis, AI-assisted ultrasonics supports longitudinal disease monitoring, therapy response assessment, and personalized treatment selection, aligning closely with emerging precision nephrology paradigms. Although challenges remain—particularly regarding standardization, interpretability, and large-scale multicentre validation—the rapid evolution of explainable AI, multi-omics integration, and health system interoperability positions ultrasonics as a future cornerstone of diabetic kidney disease management. Conclusion: Ultrasonics combined with AI represents a paradigm shift in the diagnosis and management of diabetic nephropathy, offering a scalable, safe, and precise alternative to traditional diagnostic strategies and holding promise to substantially reduce CKD progression and global renal disease burden.
Ultrasonics; Quantitative renal ultrasound
Very Low LDL-C Targets in Ischemic Stroke: Reframing Secondary Prevention in the PCSK9 Era
*]:pointer-events-auto scroll-mt-[calc(var(--header-height)+min(200px,max(70px,20svh)))]" dir="auto" tabindex="-1" data-turn-id="request-WEB:9a946f8a-5158-4f1b-a7da-40f581bb236b-8" data-testid="conversation-turn-18" data-scroll-anchor="true" data-turn="assistant"> Abstract Secondary prevention after ischemic stroke has entered a transformative phase with the advent of intensive lipid-lowering strategies in the PCSK9 inhibitor era. While earlier paradigms targeted LDL-cholesterol (LDL-C) levels below 70 mg/dL, substantial residual risk of recurrent stroke and major vascular events persisted. Accumulating evidence from randomized trials, meta-analyses, and real-world studies now supports a paradigm of very low LDL-C targets—often <40 mg/dL and, in selected high-risk patients, <25 mg/dL—as both achievable and safe. PCSK9 inhibitors, when added to high-intensity statins and ezetimibe, produce profound LDL-C reductions and significantly lower the risk of recurrent ischemic stroke without increasing hemorrhagic stroke or cognitive adverse events. Large outcome trials such as FOURIER and ODYSSEY OUTCOMES demonstrate a near-linear relationship between LDL-C lowering and cerebrovascular risk reduction, extending well below previously accepted thresholds. Mechanistic studies further show that aggressive LDL-C reduction promotes plaque regression, stabilizes vulnerable atheroma, reduces vascular inflammation, and improves endothelial function. Contemporary international guidelines now endorse lower LDL-C goals for secondary stroke prevention, particularly in patients with recurrent events, polyvascular disease, diabetes, or familial hypercholesterolemia. This review synthesizes the pathophysiological rationale, clinical trial evidence, safety data, and practical considerations supporting ultra-low LDL-C targets in ischemic stroke survivors. By reframing secondary prevention through the lens of the PCSK9 era, it underscores that “lower is better” for LDL-C, offering a powerful opportunity to reduce recurrent stroke, improve long-term vascular outcomes, and redefine standards of care in preventive neurology.
Mineralocorticoid Receptor (MR)-Mediated Urinary Potassium Secretion: Clinical Framework, Pathophysiology, and Diagnostic Pearls
*]:pointer-events-auto scroll-mt-[calc(var(--header-height)+min(200px,max(70px,20svh)))]" dir="auto" tabindex="-1" data-turn-id="9aacf718-e34e-4ae2-abfa-d47123c96a60" data-testid="conversation-turn-14" data-scroll-anchor="true" data-turn="assistant"> Abstract Mineralocorticoid receptor (MR)–mediated urinary potassium secretion is a central determinant of electrolyte balance, blood pressure regulation, and cardiovascular stability. Acting predominantly in the distal convoluted tubule, connecting tubule, and collecting duct, the MR integrates aldosterone signaling with epithelial sodium channel (ENaC), renal outer medullary potassium channel (ROMK), and Na⁺/K⁺-ATPase activity to coordinate sodium reabsorption and potassium excretion. Disruption of this finely regulated axis results in clinically significant disorders ranging from hypokalemia with resistant hypertension to hyperkalemia and salt-wasting syndromes. This chapter provides a comprehensive clinical and mechanistic framework for understanding MR-driven potassium handling. It synthesizes current knowledge of distal nephron physiology, aldosterone–MR signaling pathways, and the molecular regulation of ENaC and ROMK. Classical and non-classical causes of MR dysregulation—including primary and secondary hyperaldosteronism, apparent mineralocorticoid excess, Liddle syndrome, inherited salt-losing tubulopathies, drug-induced effects, and cortisol-mediated MR activation—are examined with emphasis on diagnostic differentiation. A structured diagnostic approach integrating blood pressure phenotype, acid–base status, plasma renin and aldosterone levels, urinary potassium indices, imaging, and genetic testing is outlined, highlighting key clinical “pearls” that enable accurate etiologic classification. Therapeutic implications are discussed, emphasizing mechanism-specific treatment strategies such as MR antagonism, ENaC blockade, correction of enzymatic defects, and targeted electrolyte replacement. By linking physiology, molecular pathophysiology, and bedside diagnostics, this review equips clinicians with practical tools to evaluate and manage MR-mediated potassium disorders. As advances in biomarker discovery, pharmacotherapy, and genetic diagnostics continue to evolve, a precision-medicine approach to mineralocorticoid-related electrolyte disorders is increasingly achievable, with the potential to significantly improve renal and cardiovascular outcomes.
Complement Physiology and Tubular Epithelial Cells: Central Paradigms in Diabetic Kidney Disease
Abstract Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease and end-stage renal failure worldwide, yet its pathophysiology extends far beyond the traditional glomerulocentric model. Emerging evidence over the past decade has established tubular epithelial cells and dysregulated complement activation as central, early, and active drivers of renal injury in diabetes. Chronic hyperglycemia, advanced glycation end products, oxidative stress, and protein overload converge on the tubular compartment, transforming proximal tubular epithelial cells into metabolic sensors and immune effectors that amplify inflammation, fibrosis, and nephron loss. The complement system, a critical arm of innate immunity, becomes maladaptively activated in diabetes through altered regulation, enhanced local synthesis, and increased exposure to filtered complement proteins. Sub-lytic membrane attack complex formation and persistent C3a–C5a signaling induce mitochondrial dysfunction, inflammatory cytokine release, and profibrotic pathways within tubular cells. These processes promote apoptosis, ferroptosis, pyroptosis, cellular senescence, and ultimately tubulointerstitial fibrosis—the strongest histological predictor of renal outcome in DKD. This chapter synthesizes current understanding of complement biology, tubular epithelial cell physiology, and their pathogenic crosstalk in diabetic kidneys. It highlights translational advances in urinary biomarkers reflecting real-time tubulointerstitial injury and reviews emerging therapeutic strategies targeting complement activation, senescence, ferroptosis, autophagy, and mitochondrial dysfunction, alongside established renoprotective agents. By reframing DKD as a disease driven by the tubule–complement axis, this paradigm offers new opportunities for earlier diagnosis, precision therapy, and meaningful slowing of renal decline in diabetes.
Triple Threat-Triple Benefit: The Rise of GLP1-GCG-FGF21 Tritagonists in Tomorrow’s Metabolic Medicine
Abstract The global burden of metabolic disease—encompassing type 2 diabetes, obesity, severe hypertriglyceridemia, metabolic dysfunction–associated steatotic liver disease (MASLD), and premature atherosclerotic cardiovascular disease—continues to rise at an alarming pace, particularly in India and South Asia. These disorders rarely exist in isolation; rather, they represent interlinked manifestations of disturbed metabolic signalling, for which traditional mono-targeted therapies have delivered only incremental benefit. Although GLP-1 receptor agonists have transformed glycaemic and weight management, significant therapeutic gaps persist in patients with mixed dyslipidaemia, advanced MASLD, and overlapping diabetes–obesity phenotypes. GLP-1–glucagon–FGF21 tritagonists represent a new paradigm designed to address this complexity through simultaneous, synergistic activation of three key metabolic axes. By integrating GLP-1–mediated glycaemic control and appetite suppression, glucagon-driven energy expenditure and lipid oxidation, and FGF21-induced hepatic fat clearance and insulin sensitization, tritagonists aim to reproduce the breadth of metabolic benefits previously achievable only with bariatric surgery—within a once-weekly injectable therapy. Among emerging agents, the Fc-fusion tritagonist DR10624 has demonstrated unprecedented efficacy in Phase 2 trials, with profound reductions in fasting triglycerides, marked reversal of hepatic steatosis, meaningful improvements in glycaemic control, and clinically relevant weight loss, all within an acceptable safety profile. Importantly, these benefits appear preserved in Indian and South Asian populations, where metabolic disease presents earlier, progresses more aggressively, and clusters across multiple pathways. This chapter reviews the scientific rationale, mechanistic integration, and clinical evidence supporting GLP-1–glucagon–FGF21 tritagonists, with particular emphasis on their relevance to the Indian cardio-metabolic landscape. Tritagonist therapy heralds a shift from sequential, siloed treatment to integrated disease modification, offering a promising foundation for the next era of comprehensive, patient-centred metabolic care.
The Double-Dare of Cholesterol: Why Indian Patients Need Both LDL and ApoB to Outwit Heart & Kidney Risk
Abstract India faces a disproportionate burden of premature cardiovascular disease (CVD) and chronic kidney disease (CKD), driven by a distinct dyslipidaemic profile known as “South Asian dyslipidaemia.” This phenotype—characterized by elevated triglycerides, low high-density lipoprotein cholesterol, and a predominance of small, dense low-density lipoprotein (LDL) particles—frequently results in discordance between LDL cholesterol (LDL-C) and apolipoprotein B (ApoB). Reliance on LDL-C alone may therefore underestimate true atherogenic risk in Indian patients.
Fighting Against the Odds: Reducing Cardiovascular Mortality in CKD
Abstract Background: Chronic kidney disease (CKD) is a powerful and independent amplifier of cardiovascular morbidity and mortality. Across all stages of CKD, the risk of cardiovascular death far exceeds the likelihood of progression to end-stage kidney disease, driven by a convergence of traditional risk factors and CKD-specific mechanisms such as chronic inflammation, vascular calcification, oxidative stress, anemia, sympathetic overactivity, and disordered mineral metabolism. Objective: To provide a practical, evidence-based overview of contemporary strategies aimed at reducing cardiovascular mortality in CKD, with a focus on lipid modulation, blood pressure optimization, proteinuria reduction, antithrombotic therapy, and emerging cardiometabolic agents. Methods: This narrative review synthesizes evidence from landmark randomized controlled trials, meta-analyses, and international guidelines to evaluate the efficacy and safety of established and novel pharmacologic interventions in CKD populations, including nondialysis and dialysis patients. Results: Statins remain foundational for cardiovascular risk reduction in early to moderate CKD, while combination therapy with ezetimibe and the introduction of PCSK9 inhibitors address residual atherogenic risk, including elevated lipoprotein(a). High-dose, purified eicosapentaenoic acid has demonstrated promising reductions in cardiovascular events in dialysis patients, redefining the role of omega-3 therapy in this population. Blood pressure management centered on renin–angiotensin system blockade, calcium channel blockers, and vasodilatory beta-blockers improves central aortic pressure and mitigates sympathetic overdrive. Proteinuria reduction through ACE inhibitors, ARBs, mineralocorticoid receptor antagonists, and SGLT2 inhibitors slows CKD progression while conferring cardiovascular protection. Antiplatelet and anticoagulant therapies reduce ischemic events but require individualized risk–benefit assessment due to heightened bleeding risk, particularly in advanced CKD and dialysis. Conclusion: Reducing cardiovascular mortality in CKD requires early, aggressive, and individualized intervention targeting dyslipidemia, hypertension, proteinuria, and thrombosis within the context of CKD-specific pathophysiology. Integration of novel lipid-lowering agents, SGLT2 inhibitors, refined antihypertensive strategies, and emerging evidence-based therapies enables a shift from reactive to proactive cardiovascular risk mitigation. Personalized, multidisciplinary care across the cardio–renal interface offers a tangible opportunity to defy the historically poor cardiovascular outcomes associated with chronic kidney disease.
Beta-Blockers Across the Cardio-Diabetes-Renal Axis: An Engaging, Comprehensive Guide
Abstract Beta-blockers remain a cornerstone of cardiovascular therapeutics, yet their role has evolved significantly within the interconnected cardio–diabetes–renal axis. Once considered a homogeneous drug class, beta-blockers are now recognized as pharmacologically diverse agents with distinct receptor selectivity, vasodilatory properties, central nervous system penetration, and metabolic effects. These differences are particularly relevant in patients with diabetes mellitus and chronic kidney disease (CKD), where sympathetic overactivity, endothelial dysfunction, and metabolic derangements drive adverse cardiovascular and renal outcomes. Objective: To comprehensively review the mechanisms, clinical evidence, metabolic and renal implications, and contemporary guideline positioning of beta-blockers across the cardio-diabetes-renal spectrum, with emphasis on individualized therapy. Methods: This narrative review synthesizes data from randomized controlled trials, meta-analyses, observational studies, and international guidelines. The pharmacodynamic heterogeneity of beta-blockers—including cardioselectivity, vasodilatory and nitric oxide–mediated effects, and central sympatholytic actions—is examined in relation to blood pressure control, central aortic hemodynamics, metabolic outcomes, renal protection, and cardiovascular morbidity and mortality. Results: Traditional non-vasodilating beta-blockers demonstrate inferior central aortic pressure reduction and less favorable metabolic profiles compared with renin–angiotensin system inhibitors and calcium channel blockers, limiting their role as first-line agents in uncomplicated hypertension. In contrast, newer vasodilatory beta-blockers such as carvedilol and nebivolol improve arterial compliance, reduce central blood pressure, and exhibit metabolic neutrality or benefit, particularly in patients with diabetes. In CKD, beta-blockers attenuate sympathetic overactivity, contributing to blood pressure control, cardiovascular protection, and potential slowing of renal disease progression when used alongside renin–angiotensin system blockade. Beta-blockers remain indispensable in heart failure with reduced ejection fraction, post–myocardial infarction patients with systolic dysfunction, arrhythmias, pregnancy-related hypertension, and conditions characterized by heightened sympathetic tone. Conclusion: Beta-blockers have transitioned from broadly applied antihypertensive agents to precision tools within modern cardio-diabetes-renal medicine. Optimal outcomes depend on agent selection tailored to molecular characteristics, comorbid conditions, and patient phenotype. Vasodilatory and cardioselective beta-blockers offer expanded utility by combining hemodynamic efficacy with improved metabolic and vascular profiles. Integrated use with renin–angiotensin system inhibitors, calcium channel blockers, and emerging cardiometabolic therapies represents contemporary best practice. Personalized beta-blocker therapy is central to optimizing cardiovascular, metabolic, and renal outcomes across this complex clinical spectrum.
Comprehensive Review: Oral Antidiabetic Agents and Adjunctive Drugs in Diabetes and Peripheral Artery Disease (PAD)
Diabetes mellitus (DM) and peripheral artery disease (PAD) frequently coexist, synergistically amplifying the risk of cardiovascular morbidity, critical limb ischemia, amputations, and mortality. Hyperglycaemia-driven endothelial dysfunction, accelerated atherosclerosis, neuropathy, and microvascular disease underpin the aggressive course of PAD in patients with diabetes, necessitating integrated therapeutic strategies beyond glucose control alone.
Battle of the Incretins: Do Tirzepatide and Semaglutide Change the Cardiovascular Game in Diabetes and Obesity?
Abstract The management of type 2 diabetes and obesity has undergone a fundamental transformation with the advent of incretin-based therapies, particularly semaglutide and tirzepatide. These agents extend beyond glucose lowering to deliver substantial weight reduction and cardiovascular risk modification, redefining treatment paradigms in cardiometabolic disease. Given that cardiovascular disease remains the leading cause of morbidity and mortality in individuals with diabetes and obesity, understanding the comparative cardiovascular effects of these therapies has become a clinical priority. Semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, has demonstrated consistent reductions in major adverse cardiovascular events (MACE) in randomized cardiovascular outcome trials such as SUSTAIN-6. Tirzepatide, a novel dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor agonist, has shown superior glycaemic control and weight loss compared with GLP-1 receptor agonists and has demonstrated cardiovascular safety and promising efficacy in the SURPASS-CVOT program. However, direct head-to-head cardiovascular outcome trials comparing tirzepatide and semaglutide remain unavailable. This narrative review synthesizes evidence from landmark randomized trials, real-world data analyses, and trial-emulation studies that approximate comparative cardiovascular effectiveness in routine clinical practice. Emerging real-world evidence suggests that both agents significantly reduce cardiovascular events compared with older glucose-lowering therapies, with semaglutide showing consistent MACE reduction and tirzepatide demonstrating comparable cardiovascular outcomes alongside superior metabolic benefits. Subgroup analyses reveal nuanced differences, with semaglutide potentially favoring patients with established cardiovascular disease, while tirzepatide may offer advantages in populations prioritizing profound weight loss and glycaemic improvement. Mechanistic insights highlight that while tirzepatide’s dual incretin agonism enhances metabolic outcomes, this does not yet translate into unequivocal cardiovascular superiority over selective GLP-1 receptor activation. Clinical decision-making should therefore prioritize individualized therapy based on cardiovascular risk, obesity severity, metabolic goals, tolerability, and patient preference. In conclusion, semaglutide and tirzepatide represent powerful, complementary tools in contemporary diabetes and obesity management. Rather than a definitive “winner,” the evolving evidence supports a personalized, cardiometabolic approach that integrates both agents to optimize cardiovascular and metabolic outcomes while awaiting further direct comparative trials.
Major Adverse Cardiovascular Events (MACE)
Hypertriglyceridemia: From Biochemical Aberration to Cardiometabolic Syndrome - Emerging Pathophysiology, Clinical Challenges, and Novel Therapeutics
Abstract Hypertriglyceridemia has long been regarded as a secondary lipid abnormality, overshadowed by low-density lipoprotein cholesterol in cardiovascular risk assessment. However, accumulating evidence has firmly established elevated triglycerides (TGs) as an independent and clinically significant driver of cardiometabolic disease. Mild to moderate hypertriglyceridemia is strongly associated with insulin resistance, atherogenic dyslipidaemia, and residual atherosclerotic cardiovascular disease (ASCVD) risk, particularly in individuals with diabetes, obesity, and metabolic syndrome. Severe hypertriglyceridemia, conversely, represents a medical emergency, markedly increasing the risk of acute pancreatitis and multisystem complications. The global escalation of obesity and type 2 diabetes has fueled a parallel rise in hypertriglyceridemia, with South Asian populations demonstrating a disproportionate burden due to genetic susceptibility combined with rapid lifestyle transitions. Pathophysiologically, hypertriglyceridemia arises from dysregulated production and impaired clearance of triglyceride-rich lipoproteins, driven by insulin resistance, hepatic overproduction of very-low-density lipoproteins, and inhibition of lipoprotein lipase activity by apolipoproteins and angiopoietin-like proteins. These mechanisms contribute to endothelial dysfunction, inflammation, and accelerated atherosclerosis, while extreme elevations precipitate pancreatic injury through free fatty acid–mediated cytotoxicity. This narrative review synthesizes contemporary evidence on the epidemiology, molecular mechanisms, clinical implications, and diagnostic framework of hypertriglyceridemia, emphasizing its role as a cardiometabolic syndrome rather than a mere biochemical abnormality. It further examines current management strategies, spanning lifestyle modification and conventional pharmacotherapy to emerging targeted agents such as apoC-III inhibitors, ANGPTL3 antagonists, and novel triple agonists, including DR10624. These therapies herald a new era of precision medicine with the potential to reduce triglyceride levels while addressing broader metabolic risk. In conclusion, hypertriglyceridemia represents a critical, modifiable contributor to both chronic cardiovascular disease and acute pancreatitis. Recognition of its complex biology and integration of evolving therapeutic approaches are essential to reducing residual cardiovascular risk and improving long-term cardiometabolic outcomes in high-risk populations.
Heart Failure Mortality in High-Income Nations: Diabetes, Disparities, and Unmet Challenges in the Modern Era
Heart Failure Mortality in High-Income Nations: Diabetes, Disparities, and Unmet Challenges in the Modern Era Heart failure (HF) has grown into a major public health challenge, defying many of the improvements seen in other cardiovascular diseases, particularly in high-income countries. Over the past twenty years, there has been a dramatic shift in mortality patterns: while deaths from coronary heart disease (CHD) and stroke have steadily declined due to advances in acute care, public health interventions, and aggressive risk factor management, heart failure deaths have stagnated or even increased in many developed regions. This “HF mortality plateau” indicates not only clinical complexity and limitations in existing therapies, but also exposes persistent health system vulnerabilities and rising comorbidity burdens, particularly driven by diabetes, obesity, and aging populations.​ The growing prevalence and severity of HF are compounded by demographic transitions. The world's population is aging, and metabolic diseases like obesity and diabetes continue to accelerate globally. In high-income countries, where the expectation is for the greatest clinical resources and preventive capabilities, HF now accounts for an outsized share of cardiovascular mortality. Between 2025 and 2050, for instance, crude cardiovascular mortality is projected to rise sharply, and though age-standardized rates may show minor declines, the absolute number of deaths from HF will likely remain unchanged or increase due to the expanding base of at-risk elderly and chronically ill patients.​ Diabetes, in particular, has emerged as a critical amplifier of heart failure risk and mortality. Epidemiological studies show that individuals living with diabetes have up to double the risk of HF death compared to the general population, and this excess has not improved over recent decades, despite declines in other cardiovascular risks. This stagnation is not due to lack of medical innovation; rather, it reflects complex interactions between chronic metabolic damage, healthcare inequities, socioeconomic gradients, and underutilization or inaccessibility of lifesaving therapies.​ Moreover, changing epidemiological contexts—such as the transition from HFrEF to the more refractory HFpEF phenotype, and the additional complexity brought on by COVID-19 disruptions—underscore the urgency for renewed analysis and multifactorial strategies. The imperative is clear: contemporary heart failure must be recognized as both a consequence and a barometer of changing population health, clinical practice, and health system adaptability. This chapter aims to dissect the epidemiology, drivers, disparities, and mechanisms behind the HF mortality plateau and to present actionable recommendations on clinical, research, and public health fronts, with special attention to diabetic populations who remain at greatest risk. Epidemiological Overview Global and Regional Mortality Trends Recent analyses of cardiovascular mortality covering nearly three million deaths across multiple Western nations illuminate striking patterns. Standardized five-year intervals from 2000 forward show CHD and overall cardiovascular (CV) mortality fell by 11–32%, and stroke death rates also decreased, albeit with international variation. In contrast, HF mortality either plateaued or increased, with pronounced rises in regions such as Ontario, Canada, and only marginal improvements elsewhere. In the U.S., HF was a contributing cause in 425,147 deaths, accounting for roughly 45% of CV deaths as of 2022. Data from the past decade indicate not only that HF mortality is stable or rising, but that this trend is especially intractable among diabetic populations.​ Disparities by Diabetes Status Diabetes substantially magnifies the risk of HF death. Epidemiological studies consistently demonstrate that DM is associated with a twofold or greater incidence of HF, with an even higher risk for cardiovascular-related death among those suffering both conditions. For example, the Framingham study found that people with DM are 2.4–5 times more likely to develop HF. More than one-quarter of HF patients exhibit concurrent DM, with registries showing rates up to 40%, depending upon population demographics. Mortality rate ratios remain stubbornly elevated for diabetics—with crude rates for HF as a contributing cause at 61.2 per million in recent U.S. data. Notably, while death rates from stroke and heart attack in diabetics have improved, those for HF have not.​ Demographic and Geographic Gaps Disparities in HF mortality extend by gender (higher rates in females), race (highest in White individuals; fastest recent rises in Asian and Pacific Islander groups), urban-rural status, and socioeconomic gradients. Mortality post-2010 increased most rapidly among males and some minority groups, reflecting changing patterns of healthcare access and disease management.​ Drivers of Persistent Heart Failure Mortality Epidemiological Shifts and the Survival Paradox With advances in acute cardiovascular interventions—such as stenting, thrombolysis, and modern antihypertensives—more people are surviving heart attacks and strokes. However, this often leaves a large cohort of people living longer with residual cardiac damage, prone to chronic HF. Instead of dying acutely, individuals enter protracted courses of heart failure, shifting the makeup of cardiovascular mortality toward this end-stage diagnosis.​ Diabetes, Obesity, and the "Comorbidities Tsunami" Global diabetes prevalence has doubled in the past 15 years, reaching 463 million cases by 2019 and projected to balloon further. This, alongside parallel rises in obesity and hypertension, produces a comorbid burden uniquely hazardous for HF outcomes. DM contributes to HF by promoting myocardial fibrosis, microvascular dysfunction, glycotoxic damage, and renal impairment. Hospitalizations, arrhythmias, and pump failures are more frequent in diabetic patients. Moreover, the aging, obese population increasingly develops HFpEF (heart failure with preserved ejection fraction), a phenotype resistant to many traditional interventions.​ Mixed Progress in Heart Failure Therapy Modern drugs—ACE inhibitors, beta-blockers, ARNIs, MRAs, and SGLT2 inhibitors—have slashed mortality for HFrEF (reduced ejection fraction) but not HFpEF (preserved ejection fraction), which accounts for more than 50% of contemporary HF cases and especially affects older, diabetic, hypertensive women. HFpEF lacks proven mortality-reducing therapies. Moreover, high costs, insurance gaps, and prescriber inertia mean that even the best medicines are underutilized.​ Health System and Socioeconomic Barriers Systemic disadvantage persists for lower-income, racial minority, and rural patients: later diagnoses, poorer care continuity, and limited access to guideline-based therapies mean higher rates of avoidable death. Hospital-based, episodic models dominate over community-based, chronic management, with insufficient transition-of-care and follow-up programs.​ COVID-19 Effects The pandemic further aggravated HF risks, delaying routine care, exacerbating viral-related cardiac injury, and straining health resources worldwide.​ Underutilization of Novel Therapies Even where innovation is available, proven agents (SGLT2i, ARNI, MRAs, device therapy) are given to only a minority of eligible patients, hindered by cost, prescription inertia, insurance policies, and disparities in health system infrastructure.​ Mechanistic Considerations Pathophysiology: Why Diabetes Amplifies HF Mortality The interplay between DM and HF is complex, synergistic, and bidirectional. Chronic hyperglycemia induces myocardial fibrosis, impairs microvasculature, and causes autonomic imbalance, contributing to diastolic dysfunction, arrhythmias, and increased pump failure. In addition, insulin resistance and elevated insulin levels constrict compensatory cardiac mechanisms, triggering inflammatory cascades and worsening renal-cardiac interactions ("cardiorenal syndrome"). Patients with DM and HF show rapid disease progression and diminished response to standard HF therapies.​ HF Phenotypes: HFrEF vs. HFpEF While HFrEF (systolic dysfunction) benefits from multiple pharmacologic and device-based interventions, HFpEF (diastolic dysfunction) is growing fastest, particularly in high-risk groups—older women, diabetics, hypertensives, and obese individuals. The absence of proven life-prolonging therapies for HFpEF is now a major contributor to the persistence of HF mortality.​ Multinational Data and Trend Analysis CHD and Stroke: Areas of Success Public health investments, statin use, expanded antihypertensives, and acute reperfusion therapies have driven steady improvements in MI and stroke mortality for two decades. This success proves that coordinated, systems-level approaches can produce transformative population-wide change.​ Heart Failure: Mortality Plateau and Data Challenges In contrast, both prevalence and deaths from HF continue to climb, especially as populations age and the pool of survivors from acute cardiac events enters chronic failure. Death certificate data may understate the HF burden, yet hospitalization-based metrics confirm continued high rates of admissions and deaths—especially among diabetics.​ Diabetes—The Unchanging Multiplier Despite better glycemic management, diabetics continue to face a doubled risk of HF and HF mortality, with little improvement over the past decade. This lack of progress versus CHD marks a major therapeutic and research gap.​ Clinical Practice and Research Gaps Prevention Early, intensive management of risk factors—glycemia, blood pressure, obesity, and lifestyle—is fundamental. Community-based and multidisciplinary models outperform episodic hospital-based care, and need expansion globally.​ HFpEF: New Frontiers Significant research investment must address HFpEF, now the dominant heart failure phenotype. SGLT2 inhibitors show promise, but other strategies—precision medicine, anti-fibrotic agents, and biomarkers—are urgently needed.​ Chronic Disease Management and Equity Integrated, multidisciplinary heart failure clinics optimizing transition-of-care, remote monitoring, and social support show improved outcomes but require resource investment. Digital health and self-management can extend reach, but disparities in access must be addressed.​ Treatment Access and Affordability Universal, affordable access to all proven HF therapies and devices is imperative. This will require government procurement, insurance reform, and training programs for providers.​ Research Recommendations Stress must be placed on large-scale, phenotype-stratified studies, robust registry development, data harmonization, and translational insight sharing.​ Socioeconomic and Public Health Perspectives Social Determinants Social determinants—income, race, education, geography—powerfully shape HF risk, management, and survival. Addressing these factors through tailored interventions and community-based support reduces HF disparities and overall cardiovascular burdens.​ System Reform and Education Patient empowerment, workforce training, and re-engineered care pathways underpin all sustainable improvements. Telehealth, remote monitoring, expanded medication access, and resilient networks are necessary for both current care and future contingencies, as highlighted during the COVID-19 pandemic. Conclusion: The enduring challenge of heart failure mortality—especially within the context of diabetes, obesity, and aging—demands a paradigm shift in both medical and public health approaches. Contemporary data show that high-income countries, despite sophisticated health infrastructures, are struggling to make substantive progress against HF death rates. Improvements in acute coronary syndrome and stroke mortality have not extended to HF, which now claims the lives of ever-more patients with complex chronic profiles and substantial comorbidity burdens.​ Key mechanisms underlie this persistent threat. The increasing prevalence of diabetes and obesity synergistically accelerates both the onset and progression of HF, contributing to myocardial fibrosis, inflammatory cascades, and cardiac-renal dysfunction. Meanwhile, population aging ensures a growing pool of vulnerable individuals who, after surviving initial cardiovascular insults, face long-term declines in cardiac reserve. Healthcare systems face challenges of continuity: hospital-based, episodic care models are poorly suited for the chronic nature of heart failure, resulting in frequent readmissions, suboptimal long-term management, and unequal access to advanced therapies.​ Systemic disparities—whether by income, geography, gender, race, or education—further magnify the burden, particularly among diabetic patients. Despite the availability of life-extending therapeutics, their underutilization—due to cost, complexity, physician familiarity, and insurance gaps—constitutes a major lost opportunity. The COVID-19 pandemic has exacerbated these weaknesses, emphasizing the importance of resilient care pathways, digital health solutions, and universal access to essential medicines and devices. Moving forward, resolving the HF mortality plateau calls for multi-level action. Prevention must be prioritized by enhancing early risk factor control, integrating community-based chronic disease management, and erasing gaps in care that disproportionately affect the marginalized. For HFpEF and diabetic HF—now the dominant forms—intensive research, precision medicine, and innovative drug/device development are essential. In practice, broadening the reach of proven therapies and optimizing health system design for chronic care, transitions, and self-management will be pivotal. Ultimately, heart failure serves as both a sentinel and a challenge in modern cardiovascular and metabolic health. Its resistance to declining mortality spotlights wider issues of equity, healthcare delivery, and the limits of current knowledge. Nevertheless, with collective commitment from societies, clinicians, researchers, and policymakers, the next decade offers the potential not only for turning the tide against HF mortality but also for setting new standards in chronic disease management. This shift will require sustained investment, intelligent policy reform, and relentless innovation—ensuring that the benefits of modern medicine extend to every patient, particularly those with diabetes who remain most vulnerable to the consequences of heart failure.​ References: Lippi, G. et al. (2020) ‘Global epidemiology and future trends of heart failure’, AMJ, 22 Mar.​ Goh, RSJ. et al. (2024) ‘The burden of cardiovascular disease in Asia from 2025 to 2050’, PMC, 9 July.​ Harikrishnan, S. et al. (2025) ‘One-year mortality and re-admission rate by disease’, Nature.​ WHO (2025) ‘Cardiovascular diseases (CVDs)’, World Health Organization.​ The Lancet (2025) ‘Time trends in mortality from heart failure and atherosclerotic CVD by diabetes status’, The Lancet, 7 Nov.​ World Heart Federation (2025) ‘World Heart Report 2025’.​ Shahzad, M. et al. (2025) ‘Trends and disparities in heart failure mortality with and without diabetes’, Nature.​ Explorationpub.com (2025) ‘A comprehensive review on diabetes mellitus and heart failure’.
Rebuilding the Barrier: How GLP-1-Engineered Probiotics Transform the Management of Fibre-Deficient Colitis
*:first-child]:mt-0"> Abstract Fiber-deficient diets drive gut dysbiosis, erode the colonic mucus barrier, and exacerbate ulcerative colitis through disrupted short-chain fatty acid (SCFA) production and impaired GLP-1 signaling from L-cells. This review elucidates the fiber deficiency–microbiota–colitis axis, where SCFA shortage via GPR43 weakens tight junctions (ZO-1, occludin), unleashes NF-κB/MAPK-mediated inflammation, and amplifies neutrophil chemokines like CXCL2, priming severe dextran sulfate sodium (DSS)-induced phenotypes observed clinically.​ Beyond glucose regulation, GLP-1 exerts potent gut-protective effects by restoring barrier integrity, suppressing proinflammatory cytokines (TNF-α, IL-1β, IL-6), and modulating microbiota toward anti-inflammatory taxa. Synthetic biology addresses this via engineered probiotics (E. coli Nissle 1917 or Lactobacillus chassis) that colonize the colon and secrete GLP-1 peptides in situ, bypassing dietary fiber needs for sustained local delivery with minimal systemic exposure.​ Preclinical models demonstrate these probiotics normalize colon architecture, reduce myeloperoxidase/neutrophil infiltration, inhibit AKT/NF-κB pathways, and reverse fiber-deprived dysbiosis, weight loss, and bleeding—effects mirrored by GLP-1 agonists. Multiplexed strains incorporating IL-10, trefoil factors, or antioxidants enable synergistic therapy for heterogeneous colitis.​ Translation requires GMP production, genetic stability validation, phased trials against 5-ASA/biologics, and monitoring via fecal calprotectin/endoscopy in relapsing patients with poor fiber adherence. Future "sense-and-respond" biosensors promise precision, preventive deployment in at-risk cohorts, heralding microbiome-centric paradigms that harmonize diet, microbes, and immunity for transformative IBD management. Engineered probiotics,​
ulcerative colitis, gut barrier integrity,