Diabzen
type: channel
language: en
publication name: Diabzen
items: Weight Regain After Stopping GLP-1s Why obesity pharmacotherapy is long-term, disease-modifying treatment
items: ADA 2026 GLP-1 Pipeline: Retatrutide, CagriSema, Orforglipron The next wave of incretin therapies unveiled in New Orleans
items: GLP-1s and Multi-Organ Benefits: The Lancet 2026 Review Synthesising weight-loss-independent effects across ten organ systems
items: Tirzepatide Across the Cardiovascular Continuum From HFpEF to cardiorenal protection with a dual GLP-1/GIP agonist
items: FLOW Trial: Semaglutide and 24% Fewer Kidney Events The first dedicated GLP-1 kidney-outcomes trial in type 2 diabetes and CKD
items: SOUL Trial: Oral Semaglutide and MACE Reduction Cardiovascular protection from an oral GLP-1 in high-risk type 2 diabetes
items: GLP-1 Therapies Enter the CKM Guideline For the first time, GLP-1-based therapy is recommended to reduce cardiac events
items: Expanded 2026 ADA Guidance on SGLT2i in CKD Starting at eGFR ≥20 and combining with a nonsteroidal MRA
items: SGLT2 Inhibitor Safety Signals in FAERS Ketoacidosis and other adverse events across 154,476 spontaneous reports
items: SGLT2 Inhibitors in Elderly and Frail CKM Patients Consistent benefit across age and frailty, with no excess hypoglycaemia
items: SGLT2 Inhibitors: Cardiorenal Mechanisms How a glucose-lowering drug became a foundational heart and kidney therapy
items: Balancing Finerenone Efficacy Against Hyperkalemia Getting organ protection while keeping potassium safe
items: INFINITY: Long-Term Kidney and Heart Protection The largest pooled analysis of finerenone in chronic kidney disease
items: FIND-CKD: Finerenone in Non-Diabetic CKD Extending kidney and cardiovascular protection beyond diabetic kidney disease
items: Finerenone and Reduced Sudden Death Across CKM Stages A prespecified FINE-HEART analysis of 18,991 adults published in JACC
items: Finerenone Across the CKM Spectrum: FINE-HEART A participant-level pooled analysis of 18,991 adults with CKM conditions
items: Interdisciplinary Care and the CKM Coordinator Model A named point person to break down clinical silos and drive guideline-directed therapy
items: Screening Social Determinants of Health in CKM Food insecurity, housing instability and financial strain as core clinical variables
items: Routine Dual Kidney Assessment: eGFR + UACR Making albuminuria testing standard practice to catch CKM early
items: Why the 2013 Obesity Guideline Was Retired A paradigm shift from weight-as-number to weight-as-driver in a multi-organ syndrome
items: Top 10 Take-Home Messages of the 2026 CKM Guideline From staging and PREVENT risk to guideline-directed therapy across the spectrum
items: The Four-Stage CKM Staging System (0–4) Staging youths and adults to prevent progression and tailor therapy to risk
items: https://thediabzen.com/index.php/d/article/view/40
items: https://thediabzen.com/index.php/d/article/view/38
items: FIB-4 ≥1.3 is correlated with increased DKD risk in T2D, but SGLT2i therapy that lowers FIB-4 attenuates this
items: Evolutionary Role of GIP & GLP-1 Beyond Glycaemia Review: non-glycaemic role of GIP and GLP1 in current clinical practice
items: Underweight Status in Type 2 Diabetes Patients: Significantly Associated with Increased Risks of Cardiovascular Disease
items: Osteoarthritis and Type 2 Diabetes: From Metaflammation to Mechanism-Based Therapies
items: Cellular Senescence in the Cardio-Diabetes-Renal Continuum: Biology, Therapy, and Clinical Translation

Weight Regain After Stopping GLP-1s Why obesity pharmacotherapy is long-term, disease-modifying treatment
type: item
description: Abstract Background: As GLP‑1 and multiagonist therapies become widespread, clinicians need clear evidence on the consequences of discontinuation. This synthesis examines trial data and mechanisms behind weight regain after stopping incretin‑based obesity treatments. Methods and scope: We review extensions and randomized discontinuation trials (STEP‑1 extension, STEP‑4, SURMOUNT‑4) that explicitly compare continued therapy with placebo switch after initial weight loss, and summarise mechanistic explanations for relapse. Findings: Discontinuing GLP‑1 or dual/triple agonists reliably triggers clinically meaningful weight regain. In the STEP‑1 extension (n=327), mean weight change fell from −17.3% at week 68 to −5.6% at week 120 after stopping semaglutide—about two‑thirds of the weight lost was regained within a year. STEP‑4 (n=803) showed a 14.8 percentage‑point between‑arm difference driven by continued loss versus regain. SURMOUNT‑4 demonstrated an even larger effect: after open‑label tirzepatide (mean −20.9%), continued therapy achieved a further −5.5%, while placebo‑switch participants regained +14.0% over 52 weeks. Cardiometabolic improvements tracked weight: waist circumference, blood pressure, HbA1c, and lipids regressed with weight rebound. Mechanistically, appetite suppression wanes within weeks (roughly five half‑lives for semaglutide), while compensatory physiology—adaptive thermogenesis and counter‑regulatory hormonal changes (↑ghrelin, ↓leptin and PYY)—actively defends a higher adiposity set point. Conclusions: The reproducible rebound after stopping therapy underscores that GLP‑1 treatments are chronic, disease‑modifying interventions rather than short courses. Clinicians should counsel patients on the expected need for long‑term therapy, incorporate monitoring and safety planning, and consider cost/access implications—particularly in resource‑constrained settings where stopping therapy risks rapid health reversal.
subject: Articles
  topic: section
subject: Weight regain after discontinuation
  topic: keywords
subject: GLP‑1 receptor agonists
  topic: keywords
subject: Adaptive thermogenesis
  topic: keywords
subject: Chronic obesity therapy
  topic: keywords
subject: Cardiometabolic reversal
  topic: keywords
creator: Dr Ashutosh Mishra
rights: Copyright (c) 2026
date: 2026-07-07
publication date: 2026-07-07
starting page: 48
ending page: 49

ADA 2026 GLP-1 Pipeline: Retatrutide, CagriSema, Orforglipron The next wave of incretin therapies unveiled in New Orleans
type: item
description: Abstract Background: The ADA 2026 Scientific Sessions highlighted a rapid advance in incretin pharmacotherapy, with highly potent multiagonists and an emerging oral GLP‑1 candidate poised to alter treatment paradigms for obesity and cardiometabolic disease. Methods and scope: This newsletter summarises headline data presented at ADA 2026 for leading pipeline agents—retatrutide (GLP‑1/GIP/glucagon triple agonist), CagriSema (cagrilintide combined with semaglutide), and orforglipron (oral small‑molecule GLP‑1)—integrating trial outcomes, safety signals, and regulatory status. Findings: Retatrutide’s TRIUMPH‑1 trial reported mean body‑weight reductions of 28.3% at 80 weeks, with nearly half of high‑dose participants achieving ≥30% weight loss; TRANSCEND‑T2D‑1 showed A1C reductions up to 2.0% and weight loss up to 16.8% at 40 weeks. A modest excess of urinary tract infections among retatrutide recipients (≈7.5–8.8% vs 5.3% placebo) represents an early safety signal. CagriSema met primary glycaemic and secondary weight endpoints across REIMAGINE trials; regulatory review timelines point to potential approvals in 2026. Orforglipron (Foundayo) offers an oral, no‑food‑restriction GLP‑1 option that could improve uptake and adherence, though detailed efficacy data were not provided in the round‑up. These developments narrow the gap between pharmacotherapy and bariatric outcomes while diversifying delivery forms. Conclusions: The ADA 2026 pipeline signals a new era of potency and convenience in incretin therapy, with important implications for CKM practice. Enhanced efficacy must be balanced against emerging agent‑specific safety profiles and the necessity for robust post‑marketing surveillance.
subject: Articles
  topic: section
subject: Retatrutide
  topic: keywords
subject: CagriSema (cagrilintide‑semaglutide)
  topic: keywords
subject: Orforglipron (oral GLP‑1)
  topic: keywords
subject: Multiagonist efficacy
  topic: keywords
subject: Safety surveillance
  topic: keywords
creator: Dr Pallavi Mishra
rights: Copyright (c) 2026
date: 2026-07-07
publication date: 2026-07-07
starting page: 46
ending page: 47

GLP-1s and Multi-Organ Benefits: The Lancet 2026 Review Synthesising weight-loss-independent effects across ten organ systems
type: item
description: Abstract Background: Recent large trials and meta-analyses suggest incretin‑based and multiagonist obesity medications deliver organ‑level benefits that cannot be fully explained by weight loss alone. This review synthesises randomised trial, meta‑analytic, and mechanistic evidence for multisystem effects of GLP‑1 receptor agonists and related agents. Methods and scope: Savas et al. critically appraise evidence for phentermine‑topiramate, naltrexone‑bupropion, and a range of GLP‑1–based therapies (liraglutide, semaglutide, tirzepatide, survodutide, mazdutide, retatrutide, cagrilintide‑semaglutide, amycretin), focusing on outcomes in ten organ systems: glycaemic control/type 2 diabetes, MASLD, chronic kidney disease, heart failure, cardiovascular disease, obstructive sleep apnoea, PCOS, osteoarthritis, skeletal muscle, depression, and neurodegenerative disorders. Findings: Aggregated trial data, including a meta‑analysis of 11 trials (n≈85,373), demonstrate GLP‑1 RAs reduce composite kidney events (HR 0.82), MACE (HR 0.87), and all‑cause mortality (HR 0.88). Clinical benefits extend into non‑diabetic populations; high‑dose semaglutide lowered MACE in SELECT despite participants lacking diabetes. Mechanistic evidence implicates pleiotropic effects—anti‑inflammatory actions, direct renal and myocardial signalling, and neurohormonal modulation—contributing to outcomes independent of the magnitude of weight loss. Conclusions: The evidence supports reframing GLP‑1 and multiagonist therapies as multi‑organ disease‑modifying agents. Recognition of weight‑loss‑independent effects strengthens the rationale for broader therapeutic use and underpins guideline shifts integrating cardiometabolic and renal care.
subject: Articles
  topic: section
subject: GLP‑1 receptor agonists
  topic: keywords
subject: Weight‑loss‑independent effects
  topic: keywords
subject: Cardiorenal protection
  topic: keywords
subject: Multisystem benefits
  topic: keywords
subject: Multiagonist therapies
  topic: keywords
creator: Dr Ashutosh Mishra
rights: Copyright (c) 2026
date: 2026-07-07
publication date: 2026-07-07
starting page: 44
ending page: 45

Tirzepatide Across the Cardiovascular Continuum From HFpEF to cardiorenal protection with a dual GLP-1/GIP agonist
type: item
description: Abstract Tirzepatide, a dual GLP-1/GIP receptor agonist, is emerging as a disease-modifying therapy across the cardiovascular continuum, particularly in obesity-related HFpEF and broader cardiovascular-kidney-metabolic (CKM) disease. In the SUMMIT trial, 731 patients with obesity and HFpEF were randomized to tirzepatide or placebo; over a median follow-up of about two years, tirzepatide reduced cardiovascular death or worsening heart-failure events by 38% and improved symptoms, exercise capacity, and health status. The treatment also produced substantial weight loss, lowered inflammatory burden, and showed favorable reverse-remodeling signals, including reduced left-ventricular mass and paracardiac adipose tissue. SURPASS-CVOT further confirmed cardiovascular safety compared with dulaglutide and demonstrated a reduction in all-cause mortality. Together, these findings position tirzepatide as more than a glucose- or weight-lowering therapy: it addresses obesity, heart-failure symptoms, and hard cardiovascular outcomes. The 2026 CKM guideline reflects this evolution by incorporating GLP-1-based therapies, including dual agonists, for patients with obesity or other CKM risk factors, especially when HFpEF is present.
subject: Articles
  topic: section
subject: Tirzepatide
  topic: keywords
subject: HFpEF
  topic: keywords
subject: Obesity-related HF
  topic: keywords
subject: Cardiovascular outcomes
  topic: keywords
subject: Reverse remodeling
  topic: keywords
creator: Dr Ashutosh Mishra
rights: Copyright (c) 2026
date: 2026-07-07
publication date: 2026-07-07
starting page: 42
ending page: 43

FLOW Trial: Semaglutide and 24% Fewer Kidney Events The first dedicated GLP-1 kidney-outcomes trial in type 2 diabetes and CKD
type: item
description: Abstract FLOW (NCT03819153) was the first dedicated kidney‑outcomes trial of a GLP‑1 receptor agonist, randomising 3,533 adults with type 2 diabetes and chronic kidney disease to once‑weekly semaglutide 1.0 mg or placebo with a median follow‑up of 3.4 years; the trial was stopped early for efficacy.1 The primary composite kidney outcome occurred in 331 patients on semaglutide versus 410 on placebo, a 24% relative risk reduction (HR 0.76; 95% CI 0.66–0.88; P=0.0003). Semaglutide also significantly attenuated eGFR decline, slowing the mean annual slope by 1.16 mL/min/1.73 m² (P<0.001), reflecting tangible preservation of filtration over time. Concurrent cardiovascular benefits included an 18% reduction in MACE (HR 0.82) and a 20% reduction in all‑cause mortality (HR 0.80), with cardiovascular‑cause death reduced (HR 0.71). Serious adverse events were fewer with semaglutide than placebo (49.6% vs 53.8%), supporting a favourable benefit‑risk profile. A 2026 subgroup analysis confirmed consistent kidney and mortality effects across patients with and without ASCVD and heart failure, and the trial yielded low numbers needed to treat (eg, 13–22 across subgroups) over three years. As the first GLP‑1 trial powered for renal endpoints, FLOW advances semaglutide from secondary signal to proven renoprotective therapy, justifying guideline recommendations to consider GLP‑1 agents for persistent albuminuria alongside RAS blockade and SGLT2 inhibition. FLOW’s early stop for efficacy underscores the robustness and clinical importance of the kidney benefit
subject: Articles
  topic: section
subject: FLOW trial
  topic: keywords
subject: Semaglutide
  topic: keywords
subject: Major‑kidney events
  topic: keywords
subject: eGFR slope preservation
  topic: keywords
subject: MACE and mortality
  topic: keywords
subject: Low NNTs
  topic: keywords
creator: Dr Ashutosh Mishra
rights: Copyright (c) 2026
date: 2026-07-07
publication date: 2026-07-07
starting page: 40
ending page: 41

SOUL Trial: Oral Semaglutide and MACE Reduction Cardiovascular protection from an oral GLP-1 in high-risk type 2 diabetes
type: item
description: Abstract The SOUL trial evaluated whether oral semaglutide reduces major adverse cardiovascular events in high‑risk patients with type 2 diabetes and established atherosclerotic cardiovascular disease, chronic kidney disease, or both. In this randomized, double‑blind trial of 9,650 participants (4,825 per arm) followed for a median of 49.5 months, oral semaglutide produced a statistically significant 14% reduction in the primary three‑point MACE composite (all‑cause death, nonfatal myocardial infarction, or nonfatal stroke) compared with placebo (12.0% vs 13.8%; HR 0.86; 95% CI 0.77–0.96; P=0.006). Secondary analyses demonstrated a pronounced effect on myocardial infarction (≈26% reduction) and a 22% reduction in a heart‑failure composite among those with baseline heart failure, a benefit concentrated in HFpEF (HR 0.59) rather than HFrEF (HR 0.98). The trial’s design intentionally mirrors the CKM population, enhancing generalisability to patients with overlapping cardiometabolic and renal disease. The oral route offers important pragmatic advantages—improved acceptability for people who avoid injections and reduced logistical barriers to access—without new safety concerns identified in the primary report. Collectively, SOUL demonstrates that the cardiovascular protection attributable to GLP‑1 receptor agonism extends to an oral formulation, supporting inclusion of oral semaglutide as a therapeutic option for cardiovascular risk reduction in high‑risk type 2 diabetes.
subject: Articles
  topic: section
subject: Oral semaglutide
  topic: keywords
subject: MACE reduction
  topic: keywords
subject: Myocardial infarction
  topic: keywords
subject: Heart failure phenotype
  topic: keywords
subject: CKM population
  topic: keywords
creator: Dr Ashutosh Mishra
rights: Copyright (c) 2026
date: 2026-07-07
publication date: 2026-07-07
starting page: 38
ending page: 39

GLP-1 Therapies Enter the CKM Guideline For the first time, GLP-1-based therapy is recommended to reduce cardiac events
type: item
description: Abstract The 2026 CKM guideline integrates glucagon‑like peptide‑1 (GLP‑1)–based therapies into the armamentarium for cardiovascular and kidney risk reduction, recommending their use for select adults with obesity and/or type 2 diabetes who carry cardiovascular risk factors. This represents a paradigm shift that recognises GLP‑1 agents not only for glycaemic control and weight loss but as therapies capable of reducing major adverse cardiovascular events in appropriate populations. The guideline endorses a comorbidity‑guided approach—permitting SGLT2 inhibitors, GLP‑1–based therapy, or both—tailored to prevailing conditions such as chronic kidney disease with albuminuria, atherosclerotic cardiovascular disease, heart failure phenotypes, obesity, hyperglycaemia, or metabolic‑associated steatotic liver disease. For albuminuric CKD, the document recommends adding a nonsteroidal mineralocorticoid receptor antagonist or a GLP‑1 agent to background renin–angiotensin system inhibition and SGLT2 therapy when albuminuria persists. In HFpEF, GLP‑1 therapy is advised for patients with obesity or other CKM risk features. Mechanistic evidence points to GLP‑1 effects on visceral fat reduction, anti‑inflammatory signalling, and metabolic improvements that plausibly mediate cardiovascular protection. By positioning GLP‑1 agents alongside SGLT2 inhibitors and nonsteroidal MRAs, the guideline supports integrated, multi‑organ treatment strategies that align metabolic, renal, and cardiovascular goals. Clinicians should select GLP‑1 therapy based on individual risk profiles, therapeutic aims (weight reduction, glycaemia, ASCVD risk), and tolerability, embedding these agents into a holistic CKM care plan.
subject: Articles
  topic: section
subject: GLP‑1–based therapy
  topic: keywords
subject: Comorbidity‑guided selection
  topic: keywords
subject: Albuminuric CKD
  topic: keywords
subject: HFpEF
  topic: keywords
subject: Multi‑organ effects
  topic: keywords
subject: Guideline integration
  topic: keywords
creator: Dr Pallavi Mishra
rights: Copyright (c) 2026
date: 2026-07-07
publication date: 2026-07-07
starting page: 36
ending page: 37

Expanded 2026 ADA Guidance on SGLT2i in CKD Starting at eGFR ≥20 and combining with a nonsteroidal MRA
type: item
description: Abstract The 2026 ADA Standards of Care sharpen and liberalize recommendations for SGLT2 inhibitor use in chronic kidney disease associated with type 2 diabetes. Key updates permit initiation of SGLT2 inhibitors at an eGFR threshold of ≥20 mL/min/1.73 m² and endorse continuation even if eGFR subsequently falls below that level, recognizing preserved cardiorenal benefits throughout advanced CKD. For adults with type 2 diabetes, UACR ≥100 mg/g, and eGFR 30–90 mL/min/1.73 m² on maximal renin–angiotensin system blockade, clinicians may consider simultaneous initiation of an SGLT2 inhibitor and the nonsteroidal mineralocorticoid receptor antagonist finerenone rather than sequential escalation. This recommendation is driven by quantitative evidence from the CONFIDENCE study, in which the combined regimen produced an approximate 52% reduction in albuminuria—roughly 30% greater than either agent alone—providing a mechanistic surrogate for long‑term renal benefit. The KDIGO 2026 draft and CKM guideline converge on similar thresholds and combination strategies, supporting a unified clinical approach. Practical considerations include baseline and serial monitoring of eGFR and potassium, vigilance for hyperkalaemia when adding MRAs, and patient counselling about adverse effects. While individualized judgment remains essential—especially in frail or polypharmacy patients—the updated guidance favors early, aggressive, evidence‑based renoprotective combination therapy to slow progression in albuminuric CKD.
subject: Articles
  topic: section
subject: SGLT2 inhibitors
  topic: keywords
subject: Finerenone (nonsteroidal MRA)
  topic: keywords
subject: Albuminuria (UACR ≥100 mg/g)
  topic: keywords
subject: eGFR threshold ≥20
  topic: keywords
subject: CONFIDENCE study
  topic: keywords
subject: Guideline convergence
  topic: keywords
creator: Dr Pallavi Mishra
rights: Copyright (c) 2026
date: 2026-07-07
publication date: 2026-07-07
starting page: 34
ending page: 35

SGLT2 Inhibitor Safety Signals in FAERS Ketoacidosis and other adverse events across 154,476 spontaneous reports
type: item
description: Abstract A June 2026 FAERS extract of 154,476 reports highlights real‑world safety signals for SGLT2 inhibitors (2013–early 2026). Serious outcomes were frequently reported (66.1% serious; 8.6% fatal), reflecting reporting bias toward severe events. Diabetic ketoacidosis was the dominant signal: 15,288 ketoacidosis reports including 3,108 euglycaemic DKA cases—an important clinical hazard because normal glucose can mask the diagnosis. Other notable signals included volume depletion/AKI (9,162), genital mycotic infections (5,385), lower‑limb amputation (4,819), and rare Fournier’s gangrene (630). Prior disproportionality analyses show markedly higher acidosis reporting versus DPP‑4 inhibitors, reinforcing vigilance. FAERS counts are not incidence estimates, so findings should guide risk‑mitigation rather than abandonment of therapy. Clinically, implement structured patient education, sick‑day rules, perioperative holds, and low threshold for ketone testing in unwell patients on SGLT2 inhibitors.
subject: Articles
  topic: section
subject: FAERS dataset
  topic: keywords
subject: SGLT2 inhibitors
  topic: keywords
subject: Ketoacidosis/DKA
  topic: keywords
subject: Euglycaemic DKA
  topic: keywords
subject: Volume depletion/AKI
  topic: keywords
subject: Genital mycotic infection
  topic: keywords
subject: Lower‑limb amputation
  topic: keywords
subject: Fournier’s gangrene
  topic: keywords
subject: Reporting bias
  topic: keywords
creator: Dr Ashutosh Mishra
rights: Copyright (c) 2026
date: 2026-07-07
publication date: 2026-07-07
starting page: 32
ending page: 33

SGLT2 Inhibitors in Elderly and Frail CKM Patients Consistent benefit across age and frailty, with no excess hypoglycaemia
type: item
description: Abstract Recent evidence shows SGLT2 inhibitors provide consistent cardiorenal benefits in older and frail patients without excess hypoglycaemia, supporting broader use in CKM populations. A 2026 J Clin Med review found reduced all-cause mortality (RR 0.88), cardiovascular death, heart‑failure hospitalisation (RR 0.72), and MACE (RR 0.87) among adults ≥65 years, with similar or larger absolute benefits in those ≥75. Heart‑failure hospitalisation reductions of 28–34% persisted with advancing age, and frailty did not attenuate efficacy across major trials (DAPA‑HF, DELIVER, EMPEROR‑Preserved, CANVAS/CREDENCE). Safety signals were reassuring: no increased hypoglycaemia, lower albuminuria (RR 0.71), and reduced acute kidney injury (RR 0.70). Practical considerations include monitoring volume status, diuretic adjustment, and attention to nutrition and muscle mass because trials (e.g., EMPA‑ELDERLY) showed modest weight and non‑significant lean‑mass reductions. Older age and frailty should generally prompt initiation rather than withholding of SGLT2 therapy, with individualized clinical judgment for underrepresented very old or nursing‑home populations.
subject: Articles
  topic: section
subject: SGLT2 inhibitors
  topic: keywords
subject: Older adults
  topic: keywords
subject: Frailty
  topic: keywords
subject: Hypoglycaemia risk
  topic: keywords
subject: Heart‑failure hospitalization
  topic: keywords
subject: Albuminuria
  topic: keywords
subject: Acute kidney injury
  topic: keywords
subject: Body composition
  topic: keywords
creator: Dr Ashutosh Mishra
rights: Copyright (c) 2026
date: 2026-07-07
publication date: 2026-07-07
starting page: 28
ending page: 29

SGLT2 Inhibitors: Cardiorenal Mechanisms How a glucose-lowering drug became a foundational heart and kidney therapy
type: item
description: Abstract Sodium–glucose cotransporter 2 (SGLT2) inhibitors, originally developed for glucose lowering, have become foundational therapies for heart failure (HF) and chronic kidney disease (CKD). Renal effects center on restoration of tubuloglomerular feedback: increased distal sodium delivery causes afferent arteriolar vasoconstriction, lowers intraglomerular pressure and produces an early, modest eGFR “dip” that stabilizes and signals long-term nephroprotection rather than injury. Cardiorenal benefits arise from complementary hemodynamic and metabolic pathways, including natriuresis and osmotic diuresis (reducing plasma volume, blood pressure, and ventricular filling pressures), improved myocardial energetics (ketone utilization), anti-inflammatory and anti-fibrotic signalling, reduced uric acid and oxidative stress. These mechanisms operate largely independently of glucose lowering and explain efficacy in patients without diabetes. Large outcome trials show consistent reductions in HF hospitalization and cardiovascular death (relative risk reductions ~18–26%) and in CKD progression or cardiorenal death (~28–39%). SGLT2 inhibitors also lower acute kidney injury risk and slow chronic kidney disease progression across glycemic status. Clinicians should counsel patients about the expected initial eGFR dip and avoid premature discontinuation. Contemporary guidelines now recommend SGLT2 inhibitors as core cardioprotective and kidney-protective therapy, including first-line use in HFmrEF and HFpEF.
subject: Articles
  topic: section
subject: SGLT2 inhibitors
  topic: keywords
subject: Tubuloglomerular feedback
  topic: keywords
subject: eGFR dip
  topic: keywords
subject: Natriuresis/osmotic diuresis
  topic: keywords
subject: Myocardial energetics
  topic: keywords
subject: Anti-inflammatory/anti-fibrotic signalling
  topic: keywords
subject: Heart failure outcomes
  topic: keywords
subject: CKD progression
  topic: keywords
creator: Dr Ashutosh Mishra
rights: Copyright (c) 2026
date: 2026-07-11
publication date: 2026-07-11
starting page: 28
ending page: 29

SGLT2 Inhibitors: Cardiorenal Mechanisms How a glucose-lowering drug became a foundational heart and kidney therapy
type: item
description: *:first-child]:mt-0 [&_>*:last-child]:mb-0" data-renderer="lm"> Abstract Background: SGLT2 inhibitors have shifted from antidiabetic drugs to core therapies for cardiovascular and kidney protection. Their clinical value is best understood through their hemodynamic, metabolic, and anti-inflammatory mechanisms, which act largely independent of glucose lowering. Mechanisms: In the kidney, SGLT2 inhibition increases sodium delivery to the macula densa, restoring tubuloglomerular feedback and producing afferent arteriolar vasoconstriction, lower intraglomerular pressure, and less hyperfiltration injury. The early, modest eGFR dip seen after treatment initiation reflects this hemodynamic effect and should generally be interpreted as expected rather than harmful. In the heart and circulation, natriuresis and osmotic diuresis reduce plasma volume, blood pressure, and ventricular filling pressures. Additional proposed pathways include improved myocardial energetics, reduced inflammation and fibrosis, and lower uric acid and oxidative stress. Clinical outcomes: These mechanisms align with trial evidence showing reductions in heart-failure hospitalization and cardiovascular death, along with slower CKD progression and lower acute kidney injury risk. Benefits are seen across patients with and without type 2 diabetes, confirming that the class acts through broader organ-protective pathways rather than glycaemic control alone. Implications: For clinicians, the key counseling point is that the initial eGFR dip is usually a marker of reduced intraglomerular pressure, not kidney injury. The 2026 CKM guideline reflects this evidence by positioning SGLT2 inhibitors as foundational guideline-directed therapy for cardiorenal disease and first-line treatment in HFmrEF and HFpEF. div]:!block [&>div]:w-full [&>div]:!min-w-0 px-sm pt-xs pb-sm max-h-[300px] [contain:layout]" data-radix-scroll-area-viewport=""> Results for "NEWSLETTER 13 Balancing Finerenone Efficacy Against Hyperkalemia Gett…
subject: Articles
  topic: section
subject: SGLT2 inhibitors
  topic: keywords
subject: Cardiorenal protection
  topic: keywords
subject: Tubuloglomerular feedback
  topic: keywords
subject: eGFR dip
  topic: keywords
subject: Heart failure
  topic: keywords
subject: CKM guideline
  topic: keywords
creator: Dr Ashutosh Mishra
rights: Copyright (c) 2026
date: 2026-07-07
publication date: 2026-07-07
starting page: 28
ending page: 29

Balancing Finerenone Efficacy Against Hyperkalemia Getting organ protection while keeping potassium safe
type: item
description: Abstract Background: Finerenone provides kidney and cardiovascular protection in chronic kidney disease, but hyperkalaemia remains its principal safety concern. This newsletter summarizes the benefit–risk balance and the monitoring steps that allow safe use across the CKM spectrum.thelancet+2 Methods and safety framework: Evidence from the pooled CKD analysis and the INFINITY programme shows that hyperkalaemia is more frequent with finerenone than placebo, although serious events requiring hospitalisation are uncommon. Trial dosing begins at 10–20 mg once daily and is titrated to 20–40 mg by eGFR, with potassium measured before initiation, after dose changes, and periodically during treatment.pubmed.ncbi.nlm.nih+3 Results: The pooled 14,574-patient analysis confirmed a real hyperkalaemia signal, but routine monitoring and protocol-based dose adjustments limited severe consequences. INFINITY supported a favourable safety profile across diverse CKD populations, reinforcing that the drug can be used broadly when monitoring is in place. Benefits of finerenone were maintained with or without SGLT2-inhibitor co-therapy, and SGLT2 inhibitors may help preserve GFR and reduce hyperkalaemia risk, making them useful partners in patients already on RAAS blockade
subject: Articles
  topic: section
subject: Finerenone
  topic: keywords
subject: Hyperkalaemia
  topic: keywords
subject: Potassium monitoring
  topic: keywords
subject: CKM syndrome
  topic: keywords
subject: SGLT2 inhibitors
  topic: keywords
subject: Cardiorenal protection
  topic: keywords
creator: Dr. Ashutosh Mishra
rights: Copyright (c) 2026
date: 2026-07-07
publication date: 2026-07-07
starting page: 26
ending page: 27

INFINITY: Long-Term Kidney and Heart Protection The largest pooled analysis of finerenone in chronic kidney disease
type: item
description: Abstract Background: Chronic kidney disease (CKD) drives substantial global morbidity and mortality. INFINITY, the largest pooled analysis of finerenone in CKD, combined participant‑level data from FIDELIO‑DKD, FIGARO‑DKD, and FIND‑CKD to quantify long‑term kidney and cardiovascular benefits. Methods and population: The pooled dataset included more than 14,500 participants with a median follow‑up of approximately three years. Outcomes evaluated included a composite kidney endpoint (kidney failure or sustained large eGFR decline), kidney failure alone, a composite cardiovascular endpoint (heart‑failure hospitalization or cardiovascular death), all‑cause mortality, and need for dialysis or transplantation. Subgroup analyses assessed consistency across diabetic status, CKD aetiology, baseline eGFR, albuminuria, and SGLT2‑inhibitor use. Results: Finerenone reduced the risk of the composite kidney outcome by 24% and kidney failure alone by 15% compared with placebo. Cardiovascular protection included a 20% lower risk of heart‑failure hospitalization or cardiovascular death, along with reductions in all‑cause mortality and the need for dialysis or transplantation. Importantly, benefits were consistent across diabetic and non‑diabetic CKD and across baseline kidney function, albuminuria strata, and concurrent SGLT2‑inhibitor therapy. Conclusions and implications: INFINITY provides robust, generalisable evidence that finerenone confers simultaneous kidney and heart protection in a broad CKD population. These findings support the 2026 guideline endorsement of nonsteroidal MRAs as add‑on therapy for persistent albuminuria and offer clinicians and health systems data to inform treatment selection and resource planning—especially in regions with high CKD prevalence. Would you like this formatted with Harvard in‑text citations or condensed to a single‑paragraph news blurb?
subject: Articles
  topic: section
subject: INFINITY pooled analysis
  topic: keywords
subject: Finerenone
  topic: keywords
subject: Chronic kidney disease
  topic: keywords
subject: Cardiorenal protection
  topic: keywords
subject: Albuminuria
  topic: keywords
creator: dr ashutosh mishra
rights: Copyright (c) 2026
date: 2026-07-10
publication date: 2026-07-10
starting page: 24
ending page: 25

FIND-CKD: Finerenone in Non-Diabetic CKD Extending kidney and cardiovascular protection beyond diabetic kidney disease
type: item
description: Abstract Background: Evidence for finerenone has primarily come from trials in diabetic kidney disease; FIND‑CKD aimed to evaluate its efficacy and safety in non‑diabetic CKD and was incorporated into an individual participant‑data meta‑analysis published in The Lancet. Methods and population: The pooled analysis combined FIND‑CKD with FIDELIO‑DKD and FIGARO‑DKD, yielding 14,574 participants (mean age 63.7 years; 30.7% female), mean eGFR 56.4 mL/min/1.73 m², and median UACR 567.4 mg/g. Follow‑up encompassed contemporary care including RAS blockade and SGLT2‑inhibitor use. Primary outcomes included a composite kidney endpoint (kidney failure or sustained ≥57% eGFR decline) and a composite cardiovascular endpoint (heart‑failure hospitalization or cardiovascular death). Results: Finerenone reduced the composite kidney outcome by 24% (HR 0.76, 95% CI 0.68–0.86) and the composite cardiovascular outcome by 20% (HR 0.80, 95% CI 0.70–0.91). Heart‑failure hospitalization (HR 0.78) and all‑cause mortality (HR 0.88) were also favorably impacted. Crucially, kidney benefit was consistent regardless of glycaemic status, CKD aetiology, baseline eGFR, degree of albuminuria, and concurrent SGLT2‑inhibitor therapy. Conclusions and implications: FIND‑CKD extends finerenone’s demonstrable kidney and cardiovascular benefits to non‑diabetic, albuminuric CKD, supporting use when residual albuminuria persists despite RAS and SGLT2 blockade and potassium monitoring is available. These results expand the therapeutic toolkit for a previously underserved CKD population and align with guideline recommendations positioning nonsteroidal MRAs as add‑on organ‑protective therapy.
subject: Articles
  topic: section
subject: Finerenone
  topic: keywords
subject: FIND‑CKD
  topic: keywords
subject: Non‑diabetic CKD
  topic: keywords
subject: Albuminuria
  topic: keywords
subject: Cardiorenal protection
  topic: keywords
subject: Nonsteroidal MRA
  topic: keywords
creator: Dr Ashutosh Mishra
rights: Copyright (c) 2026
date: 2026-07-07
publication date: 2026-07-07
starting page: 22
ending page: 23

Finerenone and Reduced Sudden Death Across CKM Stages A prespecified FINE-HEART analysis of 18,991 adults published in JACC
type: item
description: Abstract Background: Sudden death is a major and often underappreciated component of cardiovascular mortality among patients with overlapping cardiovascular, kidney, and metabolic (CKM) disease. A prespecified FINE‑HEART analysis evaluated the association between finerenone and sudden death across CKM stages in 18,991 adults. Methods and population: Participant‑level data were pooled and analyzed over a median follow‑up of 2.9 years. Sudden death events and potential predictors were assessed across CKM Stages 2–4. Finerenone dosing mirrored trial protocols, initiated at 10–20 mg once daily and titrated according to eGFR. Results: Sudden death occurred in 418 participants (2.2%) and comprised 47% of cardiovascular deaths. Finerenone reduced sudden‑death risk by 19% compared with placebo (P = .034), with a number needed to treat of 216 to prevent one sudden death. Risk rose markedly with disease stage: Stage 4 patients had a 2.7‑fold higher sudden‑death risk than those in Stages 2–3 (P < .001). Independent predictors included older age, prior heart failure, atrial fibrillation, prior myocardial infarction, higher urinary albumin‑to‑creatinine ratio, lower systolic blood pressure, and reduced kidney function (all P < .05). Conclusions and implications: The analysis demonstrates that a substantial portion of cardiovascular mortality in CKM is sudden and potentially preventable. Stage‑dependent risk stratification using routinely collected clinical variables can identify patients who may derive the greatest absolute benefit from finerenone. These findings reinforce finerenone’s role in guideline‑directed therapy for patients with combined cardiorenal risk and support prioritizing Stage 4 patients for intensive monitoring and treatment.
subject: Articles
  topic: section
subject: Finerenone
  topic: keywords
subject: Sudden death
  topic: keywords
subject: CKM stages
  topic: keywords
subject: FINE‑HEART analysis
  topic: keywords
subject: Arrhythmic mortality
  topic: keywords
subject: Risk stratification
  topic: keywords
creator: Dr Ashutosh Mishra
rights: Copyright (c) 2026
date: 2026-07-07
publication date: 2026-07-07
starting page: 20
ending page: 21

Finerenone Across the CKM Spectrum: FINE-HEART A participant-level pooled analysis of 18,991 adults with CKM conditions
type: item
description: Abstract Background: Finerenone, a nonsteroidal mineralocorticoid receptor antagonist, has demonstrated kidney and cardiovascular benefits in individual trials of patients with diabetic kidney disease and heart failure. FINE‑HEART pooled participant‑level data from FIDELIO‑DKD, FIGARO‑DKD, and FINEARTS‑HF to evaluate finerenone’s effects across the full CKM spectrum. Methods and population: The analysis combined 18,991 adults with CKM conditions followed for a median of 2.9 years. Participants were staged using an adapted CKM framework to permit stage‑specific inference. Prespecified outcomes included all‑cause mortality, all‑cause hospitalization, heart‑failure hospitalization, a composite kidney outcome, and new‑onset atrial fibrillation. A cancer‑history subanalysis examined safety and efficacy among participants with prior malignancy (n=1,389). Results: Finerenone treatment was associated with reductions in all‑cause mortality, all‑cause and heart‑failure hospitalizations, the composite kidney endpoint, and incidence of new‑onset atrial fibrillation. The magnitude of benefit was observable across CKM stages, enabling clinicians to interpret effect sizes by disease severity. In participants with a history of cancer, finerenone showed consistent efficacy and no signal for increased cancer incidence or cancer‑related mortality. Conclusions: FINE‑HEART offers robust, participant‑level evidence that finerenone delivers multiorgan protection across the CKM spectrum, supporting its guideline role as add‑on therapy for persistent albuminuria and combined cardiorenal risk. The pooled design increases power to detect less frequent but clinically relevant outcomes and reduces uncertainty for real‑world prescribing, including among patients with prior malignancy.
subject: Articles
  topic: section
subject: Finerenone
  topic: keywords
subject: FINE‑HEART pooled analysis
  topic: keywords
subject: CKM syndrome
  topic: keywords
subject: Nonsteroidal mineralocorticoid receptor antagonist
  topic: keywords
subject: Cardiorenal outcomes
  topic: keywords
subject: Atrial fibrillation
  topic: keywords
creator: Dr Pallavi Mishra
rights: Copyright (c) 2026
date: 2026-07-07
publication date: 2026-07-07
starting page: 18
ending page: 19

Interdisciplinary Care and the CKM Coordinator Model A named point person to break down clinical silos and drive guideline-directed therapy
type: item
description: Abstract Background: Cardiovascular, kidney, and metabolic (CKM) conditions frequently coexist, producing overlapping morbidity that fragments care across specialties and settings. The 2026 CKM guideline responds by elevating team-based, interdisciplinary management and recommending a named CKM coordination point person to integrate care. Intervention: The CKM coordinator model designates a single accountable clinician—often a nurse navigator, pharmacist, or care manager—who links patients, primary care, specialists (cardiology, nephrology, endocrinology), social services, and community health workers. Core tasks include arranging follow-up, reconciling and titrating guideline-directed medical therapy (GDMT), monitoring adherence and adverse effects, facilitating lifestyle interventions, and addressing social determinants that impede care. Outcomes and benefits: Centralizing responsibility reduces therapeutic inertia and loss to follow-up, increases delivery of organ-protective therapies, and streamlines multidisciplinary decision-making. Coordinated workflows and shared care pathways improve efficiency and patient experience while enabling measurement of process and outcome metrics important to administrators. Implementation considerations: Effective deployment requires role definition, training, electronic communication pathways, pharmacist involvement for medication review, and metrics for GDMT uptake and clinical outcomes. Challenges include resourcing, cross-disciplinary culture change, and interoperable records. Conclusion: The CKM coordinator model offers a practical, scalable strategy to translate guideline recommendations into measurable improvements for patients with complex, multisystem cardiometabolic disease.
subject: Articles
  topic: section
subject: CKM coordinator
  topic: keywords
subject: Interdisciplinary care
  topic: keywords
subject: Guideline-directed medical therapy
  topic: keywords
subject: Care coordination
  topic: keywords
subject: Therapeutic inertia
  topic: keywords
subject: Multiorgan disease
  topic: keywords
creator: Dr Ashutosh Mishra
rights: Copyright (c) 2026
date: 2026-07-07
publication date: 2026-07-07
starting page: 16
ending page: 17

Screening Social Determinants of Health in CKM Food insecurity, housing instability and financial strain as core clinical variables
type: item
description: Abstract The 2026 cardiovascular–kidney–metabolic (CKM) guideline reframes social context as a core clinical pillar rather than background “risk,” elevating routine screening of social determinants of health (SDOH) to the same encounter as estimated glomerular filtration rate and urine albumin-to-creatinine ratio assessment. The document highlights food insecurity, housing instability and financial strain as priority SDOH, each independently associated with incident CKM syndrome, accelerated progression and adverse outcomes once disease is established. In addition, intimate partner violence is explicitly named, and the guideline calls for systematic engagement of social workers, community health workers and other allied professionals as integral members of CKM care teams. Biological and epidemiologic rationale is grounded in the recognition that obesity and related metabolic disturbances arise from intertwined social, behavioural and biological drivers, in a context where overweight and obesity affect most of the U.S. adult population. Within this paradigm, identifying patients who cannot reliably access food, housing or medications is described as practice-changing information that should reshape treatment planning as directly as any laboratory value, shifting emphasis from prescriptions alone to activation of social and community-based referral pathways. The newsletter summarised here argues that documenting food insecurity, housing instability and financial strain functions as a measurable clinical variable that predicts medication access, visit adherence and capacity for sustained lifestyle change, thereby informing prognostic assessment as robustly as many traditional biomarkers. Integration of pharmacists and other allied professionals extends the impact of SDOH screening through medication affordability counselling, adherence support and triage to appropriate services, particularly in resource-constrained settings. Routine SDOH documentation at the point of C…
subject: Articles
  topic: section
subject: Cardiovascular–kidney–metabolic syndrome
  topic: keywords
subject: Social determinants of health
  topic: keywords
subject: Food insecurity
  topic: keywords
subject: Housing instability
  topic: keywords
subject: Financial strain
  topic: keywords
subject: Intimate partner violence
  topic: keywords
subject: Multidisciplinary care\
  topic: keywords
subject: Medication adherence
  topic: keywords
subject: Population health
  topic: keywords
subject: American Heart Association guideline
  topic: keywords
creator: Dr Ashutosh Mishra
rights: Copyright (c) 2026
date: 2026-07-07
publication date: 2026-07-07
starting page: 14
ending page: 15

Routine Dual Kidney Assessment: eGFR + UACR Making albuminuria testing standard practice to catch CKM early
type: item
description: Abstract Background: Up to 90% of people with chronic kidney disease (CKD) are unaware of their diagnosis because reliance on serum creatinine/eGFR alone misses early albuminuric disease. The 2026 CKM Guideline recommends routine dual kidney assessment (eGFR + UACR) to improve detection and guide organ‑protective therapy. Objective: To summarise evidence supporting combined eGFR and UACR testing, describe how dual assessment informs staging and treatment decisions, and provide practical implementation strategies for primary care and health systems. Methods: We review the complementary roles of eGFR (filtration capacity) and UACR (glomerular leak/endothelial injury), summarise outcome data linking albuminuria to cardiovascular and kidney risk, and outline the guideline‑aligned therapeutic sequence for CKD with type 2 diabetes or albuminuria: RAS inhibitors and SGLT2 inhibitors as first‑line, with addition of nonsteroidal mineralocorticoid receptor antagonists or GLP‑1‑based therapies when albuminuria persists. We highlight KDIGO and trial evidence supporting early intervention. Results/Conclusions: Routine dual assessment increases early CKD detection, closes a large diagnostic gap, and directly enables timely initiation of evidence‑based, kidney‑ and cardioprotective therapies. Health systems can operationalise this recommendation with automatic UACR reflex orders for diabetic and hypertensive panels and by tracking UACR completion as a quality metric—an inexpensive, high‑yield step toward earlier staging and improved outcomes.
subject: Articles
  topic: section
subject: eGFR
  topic: keywords
subject: UACR
  topic: keywords
subject: dual kidney assessment
  topic: keywords
subject: albuminuria screening
  topic: keywords
subject: CKD detection
  topic: keywords
subject: SGLT2 inhibitors
  topic: keywords
subject: RAS inhibitors
  topic: keywords
subject: nonsteroidal MRA
  topic: keywords
subject: GLP‑1 therapy
  topic: keywords
subject: CKM guideline
  topic: keywords
subject: quality improvement
  topic: keywords
creator: Dr Ashutosh Mishra
rights: Copyright (c) 2026
date: 2026-07-07
publication date: 2026-07-07
starting page: 11
ending page: 12

Why the 2013 Obesity Guideline Was Retired A paradigm shift from weight-as-number to weight-as-driver in a multi-organ syndrome
type: item
description: Abstract Background: The 2013 obesity guideline focused largely on weight as a numeric target. Emerging evidence and the 2026 Cardiovascular–Kidney–Metabolic (CKM) Guideline have shifted the paradigm, positioning excess adiposity—particularly abdominal/visceral fat—as a causal driver of multi‑organ disease. Objective: To summarise reasons for retiring the 2013 document and to outline the CKM Guideline’s integrated, organ‑protective approach to assessing and treating adiposity within CKM syndrome. Methods: We review epidemiologic associations linking incremental increases in BMI and central adiposity to heart failure, coronary events, stroke, and kidney disease, and summarise guideline recommendations to combine BMI with waist circumference, reframe weight as a driver rather than an endpoint, offer lifestyle interventions with adjunctive obesity pharmacotherapy, and refer selected patients for metabolic/bariatric surgery. We also describe guidance on non‑stigmatizing communication strategies. Results/Conclusions: The 2026 CKM Guideline replaces the 2013 weight‑centric approach because treating adiposity as a modifiable driver better aligns prevention and treatment with downstream cardiovascular and renal benefits. Routine measurement of waist circumference, earlier use of effective pharmacotherapies, and appropriate surgical referral create opportunities to reduce CKM incidence and progression. The guideline’s patient‑centred messaging aims to reduce stigma and improve engagement, supporting broader implementation of multisystem treatments that deliver benefits beyond weight loss
subject: Articles
  topic: section
subject: obesity guideline retirement
  topic: keywords
subject: adiposity as driver
  topic: keywords
subject: waist circumference
  topic: keywords
subject: BMI
  topic: keywords
subject: metabolic surgery
  topic: keywords
subject: obesity pharmacotherapy
  topic: keywords
subject: CKM syndrome
  topic: keywords
subject: cardiovascular risk
  topic: keywords
subject: kidney disease
  topic: keywords
subject: patient‑centred communication
  topic: keywords
creator: Dr Ashutosh Mishra
rights: Copyright (c) 2026
date: 2026-07-07
publication date: 2026-07-07
starting page: 10
ending page: 11

Top 10 Take-Home Messages of the 2026 CKM Guideline From staging and PREVENT risk to guideline-directed therapy across the spectrum
type: item
description: Abstract Background: The 2026 Cardiovascular–Kidney–Metabolic (CKM) Guideline introduces an integrated approach to prevent, detect, evaluate, and manage overlapping cardiometabolic, renal, and metabolic conditions. Its companion "Top Things to Know" distils the guideline into ten clinically actionable messages. Objective: To summarise the guideline’s top 10 messages and map them onto a pragmatic clinical workflow—stage, predict, assess, coordinate, and treat—facilitating rapid translation into practice. Methods: We synthesise the companion guidance, emphasising CKM staging for youths and adults, application of PREVENT equations for 10‑ and 30‑year risk estimation in Stages 0–3, systematic assessment of metabolic and kidney parameters (including eGFR and UACR), targeted screening for pre‑heart failure, MASLD, and OSA, routine evaluation of social determinants of health, and the role of an interdisciplinary CKM coordination point person. We summarise pharmacotherapy recommendations: cardioprotective antihyperglycaemic agents (SGLT2 inhibitors, GLP‑1 receptor agonists), renin–angiotensin system inhibitors plus SGLT2 inhibitors as first‑line for CKD with albuminuria, and addition of nonsteroidal MRAs or GLP‑1 therapy when albuminuria persists. Guidance for ASCVD and heart‑failure phenotypes is also outlined. Results/Conclusions: The ten messages function as an implementation blueprint that supports creation of order sets, dashboards, and quality metrics. They enable clinicians and health systems to operationalise evidence‑based, organ‑protective care across CKM stages and comorbidities, thereby closing implementation gaps and improving patient outcomes.
subject: Articles
  topic: section
subject: CKM guideline
  topic: keywords
subject: cardiovascular–kidney–metabolic syndrome
  topic: keywords
subject: PREVENT risk
  topic: keywords
subject: CKD staging
  topic: keywords
subject: SGLT2 inhibitors
  topic: keywords
subject: GLP‑1 receptor agonists
  topic: keywords
subject: nonsteroidal MRA
  topic: keywords
subject: obesity pharmacotherapy
  topic: keywords
subject: interdisciplinary care
  topic: keywords
subject: implementation
  topic: keywords
subject: ASCVD
  topic: keywords
subject: heart failure
  topic: keywords
creator: Dr Ashutosh Mishra
rights: Copyright (c) 2026
date: 2026-07-07
publication date: 2026-07-07
starting page: 6
ending page: 7

The Four-Stage CKM Staging System (0–4) Staging youths and adults to prevent progression and tailor therapy to risk
type: item
description: *:first-child]:mt-0 [&_>*:last-child]:mb-0" data-renderer="lm"> Abstract The 2026 cardiovascular–kidney–metabolic (CKM) guideline formalizes a four-stage staging system designed to support earlier prevention and individualized treatment in both youths and adults. Stage 0 represents absence of CKM risk factors, Stage 1 includes overweight or obesity and/or prediabetes without other metabolic, kidney, or cardiovascular disease, Stage 2 includes one or more metabolic risk factors or established kidney disease without clinical cardiovascular disease, Stage 3 captures asymptomatic cardiovascular disease or very-high-risk CKD or elevated predicted cardiovascular risk, and Stage 4 includes established cardiovascular disease with concurrent CKM risk factors. The staging framework is intended to prevent progression, reduce cardiovascular and kidney complications, and encourage regression through lifestyle intervention and weight loss. By linking treatment decisions to absolute risk and disease stage, the system provides a practical clinical tool for prevention, therapy selection, and population management.
subject: Articles
  topic: section
subject: CKM syndrome
  topic: keywords
subject: staging system
  topic: keywords
subject: cardiovascular disease
  topic: keywords
subject: chronic kidney disease
  topic: keywords
subject: obesity
  topic: keywords
subject: prediabetes
  topic: keywords
subject: metabolic risk factors
  topic: keywords
subject: PREVENT equations
  topic: keywords
subject: risk stratification
  topic: keywords
subject: youth prevention
  topic: keywords
subject: lifestyle intervention
  topic: keywords
subject: regression
  topic: keywords
creator: Dr Pallavi Mishra
rights: Copyright (c) 2026
date: 2026-07-07
publication date: 2026-07-07
starting page: 4
ending page: 5

https://thediabzen.com/index.php/d/article/view/40
type: item
title: Stratifying Cardiovascular–Kidney–Metabolic Syndrome by Metabolic Dysfunction-Associated Steatotic Liver Disease: A Pathophysiology-Anchored, India-Contextualised Framework for Node-Directed Pharmacotherapy
description: Abstract The same drug can protect the heart, the kidney and the liver at once—not by coincidence, but because these organs share a small set of molecular failure points. Cardiovascular–kidney–metabolic (CKM) syndrome, formalised by the American Heart Association in 20231,2 and codified in the first-ever 2026 AHA/ACC/ADA/ASN multisociety guideline3, describes the progression from dysfunctional adiposity through cardiorenal and metabolic injury. Its staging construct, however, incorporates the liver only implicitly, despite metabolic dysfunction-associated steatotic liver disease (MASLD)4 being both a near-universal companion of CKM and an independent, pharmacologically actionable amplifier of its trajectory. This review advances a pathophysiology-anchored framework positioning MASLD as the hepatic node of CKM and liver fibrosis stage as a quantitative modifier that reclassifies cardiorenal-metabolic risk. We first deconstruct the shared molecular nodes linking liver, heart, kidney and adipose tissue—adipose lipotoxicity, hepatic de novo lipogenesis and the thyroid/ATP-citrate lyase axis, stellate-cell fibrosis, NLRP3-inflammasome inflammation, the mineralocorticoid–fibrotic axis, the cardiorenal hemodynamic–tubular axis, and the gut–liver axis. We then map the contemporary pharmacopoeia—incretin and multi-agonists, sodium–glucose cotransporter-2 (SGLT2) inhibitors, pioglitazone, the thyroid hormone receptor-β agonist resmetirom, fibroblast growth factor 21 (FGF21) analogues, the nonsteroidal mineralocorticoid antagonist finerenone, bempedoic acid, low-dose colchicine, and microbiome-directed strategies—onto these nodes rather than onto organ silos; two agents (resmetirom36 and semaglutide24) now carry regulatory approval for steatohepatitis with fibrosis. Because the epidemiology, phenotype, genetics, diet and drug-access realities of South Asia materially alter how the framework applies, we integrate an India-specific analysis throughout59,62. Synthesising the evid…
subject: Articles
  topic: section
subject: cardiovascular–kidney–metabolic syndrome
  topic: keywords
subject: MASLD
  topic: keywords
subject: MASH
  topic: keywords
subject: liver fibrosis
  topic: keywords
subject: resmetirom
  topic: keywords
subject: GLP-1 receptor agonist
  topic: keywords
subject: finerenone
  topic: keywords
subject: saroglitazar
  topic: keywords
subject: lean NAFLD
  topic: keywords
creator: Ashutosh Mishra, MBBS, MD (General Medicine)¹
rights: Copyright (c) 2026
date: 2026-07-07
publication date: 2026-07-07
starting page: 1
ending page: 23

https://thediabzen.com/index.php/d/article/view/38
type: item
title: Stratifying Cardiovascular–Kidney–Metabolic Syndrome by Metabolic Dysfunction-Associated Steatotic Liver Disease: A Pathophysiology-Anchored, India-Contextualized Framework for Node-Directed Pharmacotherapy
description: Abstract The same drug can protect the heart, the kidney and the liver at once—not by coincidence, but because these organs share a small set of molecular failure points. Cardiovascular–kidney–metabolic (CKM) syndrome, formalized by the American Heart Association in 20231,2 and codified in the first-ever 2026 AHA/ACC/ADA/ASN multisociety guideline3, describes the progression from dysfunctional adiposity through cardiorenal and metabolic injury. Its staging construct, however, incorporates the liver only implicitly, despite metabolic dysfunction-associated steatotic liver disease (MASLD)4 being both a near-universal companion of CKM and an independent, pharmacologically actionable amplifier of its trajectory. This review advances a pathophysiology-anchored framework positioning MASLD as the hepatic node of CKM and liver fibrosis stage as a quantitative modifier that reclassifies cardiorenal-metabolic risk. We first deconstruct the shared molecular nodes linking liver, heart, kidney and adipose tissue—adipose lipotoxicity, hepatic de novo lipogenesis and the thyroid/ATP-citrate lyase axis, stellate-cell fibrosis, NLRP3-inflammasome inflammation, the mineralocorticoid–fibrotic axis, the cardiorenal hemodynamic–tubular axis, and the gut–liver axis. We then map the contemporary pharmacopoeia—incretin and multi-agonists, sodium–glucose cotransporter-2 (SGLT2) inhibitors, pioglitazone, the thyroid hormone receptor-β agonist resmetirom, fibroblast growth factor 21 (FGF21) analogues, the nonsteroidal mineralocorticoid antagonist finerenone, bempedoic acid, low-dose colchicine, and microbiome-directed strategies—onto these nodes rather than onto organ silos; two agents (resmetirom36 and semaglutide24) now carry regulatory approval for steatohepatitis with fibrosis. Because the epidemiology, phenotype, genetics, diet and drug-access realities of South Asia materially alter how the framework applies, we integrate an India-specific analysis throughout59,62. Synthesising the evid…
subject: Articles
  topic: section
subject: cardiovascular–kidney–metabolic syndrome
  topic: keywords
subject: MASLD
  topic: keywords
subject: MASH
  topic: keywords
subject: liver fibrosis
  topic: keywords
subject: resmetirom
  topic: keywords
subject: GLP-1 receptor agonist
  topic: keywords
subject: FGF21
  topic: keywords
subject: finerenone
  topic: keywords
subject: SGLT2 inhibitor
  topic: keywords
subject: India
  topic: keywords
subject: lean NAFLD
  topic: keywords
subject: saroglitazar
  topic: keywords
creator: Ashutosh Mishra, MBBS, MD (General Medicine)
rights: Copyright (c) 2026
date: 2026-07-07
publication date: 2026-07-07
starting page: 1
ending page: 23

FIB-4 ≥1.3 is correlated with increased DKD risk in T2D, but SGLT2i therapy that lowers FIB-4 attenuates this
type: item
description: 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 an…
subject: Articles
  topic: section
subject: FIB-4 index
  topic: keywords
subject: Type 2 diabetes mellitus
  topic: keywords
subject: Diabetic kidney disease
  topic: keywords
subject: Chronic kidney disease
  topic: keywords
subject: Non-alcoholic fatty liver disease
  topic: keywords
subject: Liver fibrosis
  topic: keywords
subject: SGLT2 inhibitors
  topic: keywords
subject: Hepato-renal axis
  topic: keywords
subject: Risk stratification
  topic: keywords
subject: Cardio–renal–hepatic medicine
  topic: keywords
creator: Dr Sayed Yasmeen
rights: Copyright (c) 2025
date: 2025-12-15
publication date: 2025-12-15
starting page: 120
ending page: 127

Evolutionary Role of GIP & GLP-1 Beyond Glycaemia Review: non-glycaemic role of GIP and GLP1 in current clinical practice
type: item
description: 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 potenti…
subject: Articles
  topic: section
subject: GLP-1
  topic: keywords
subject: GIP
  topic: keywords
subject: Incretin hormones
  topic: keywords
subject: Non-glycaemic effects
  topic: keywords
subject: Cardiovascular outcomes
  topic: keywords
subject: Renal protection
  topic: keywords
subject: Adipose tissue biology
  topic: keywords
subject: Ectopic fat
  topic: keywords
subject: Inflammation
  topic: keywords
subject: Dual GIP/GLP-1 receptor agonists
  topic: keywords
subject: Tirzepatide
  topic: keywords
subject: Cardio-renal-metabolic medicine
  topic: keywords
creator: Dr Ashutosh Mishra
rights: Copyright (c) 2025
date: 2025-12-15
publication date: 2025-12-15
starting page: 111
ending page: 119

Underweight Status in Type 2 Diabetes Patients: Significantly Associated with Increased Risks of Cardiovascular Disease
type: item
description: 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 micronut…
subject: Articles
  topic: section
subject: Type 2 diabetes mellitus
  topic: keywords
subject: Underweight
  topic: keywords
subject: Cardiovascular disease
  topic: keywords
subject: Sarcopenia; Frailty
  topic: keywords
subject: Malnutrition-inflammation-cachexia syndrome
  topic: keywords
subject: Ectopic fat
  topic: keywords
subject: Metaflammation
  topic: keywords
subject: Insulin resistance;
  topic: keywords
subject: Heart failure with preserved ejection fraction
  topic: keywords
subject: Asian populations
  topic: keywords
subject: Muscle-centric cardiometabolic care
  topic: keywords
creator: Dr Pallavi Mishra
rights: Copyright (c) 2026
date: 2026-01-22
publication date: 2026-01-22
starting page: 104
ending page: 111

Osteoarthritis and Type 2 Diabetes: From Metaflammation to Mechanism-Based Therapies
type: item
description: 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…
subject: Articles
  topic: section
subject: Osteoarthritis
  topic: keywords
subject: Type 2 Diabetes
  topic: keywords
subject: Metaflammation
  topic: keywords
subject: AGE–RAGE axis
  topic: keywords
subject: Chondrocyte senescence
  topic: keywords
subject: Adipokines
  topic: keywords
subject: Insulin resistance
  topic: keywords
subject: Subchondral bone;
  topic: keywords
subject: GLP-1 receptor agonists
  topic: keywords
subject: Metformin
  topic: keywords
subject: Precision medicine
  topic: keywords
creator: Dr Ashutosh Mishra
rights: Copyright (c) 2025
date: 2025-12-15
publication date: 2025-12-15
starting page: 96
ending page: 102

Cellular Senescence in the Cardio-Diabetes-Renal Continuum: Biology, Therapy, and Clinical Translation
type: item
description: 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 …
subject: Articles
  topic: section
subject: Cellular senescence
  topic: keywords
subject: Senescence-associated secretory phenotype (SASP)
  topic: keywords
subject: Cardio-diabetes-renal continuum
  topic: keywords
subject: Diabetic kidney disease
  topic: keywords
subject: Cardiovascular ageing
  topic: keywords
subject: Metabolic disease
  topic: keywords
subject: Senolytics
  topic: keywords
subject: Senomorphics
  topic: keywords
subject: Precision medicine
  topic: keywords
subject: Biological ageing
  topic: keywords
creator: Dr. Ashutosh Mishra
rights: Copyright (c) 2025
date: 2025-12-01
publication date: 2025-12-01
starting page: 91
ending page: 96