CVD in diabetes: new treatments DL Flashcards
(15 cards)
Explain the link between increased plasma glucose, oxidative stress and the increased risk of CVD in T2D
Hyperglycaemia is a hallmark of T2D, primarily due to insulin resistance and/or impaired insulin secretion.
Chronic high glucose levels lead to:
○ Increased production of reactive oxygen species (ROS) → causes oxidative stress.
○ Oxidative stress contributes to:
§ Endothelial dysfunction (damaged blood vessel lining).
§ Hyper-reactive platelets, increasing clotting risk.
§ Altered serum albumin-metal-lipid interactions, affecting coagulation and inflammation.
§ Dyslipidaemia (e.g., increased LDL, decreased HDL).
§ Elevated levels of pro-coagulant factors and microparticles.
These changes promote:
○ Atherosclerosis, thrombosis, cardiac dysfunction, and blood pressure dysregulation.
Ultimately leading to macrovascular (e.g., coronary artery disease, stroke) and microvascular (e.g., retinopathy, nephropathy) complications.
What are the key sources of increased ROS in hyperglycaemia
NADPH oxidases (NOX)
○ NOX1, NOX2, and NOX5 generate superoxide (O₂⁻).
○ NOX4 produces hydrogen peroxide (H₂O₂).
○ These are activated by hyperglycemia and inflammation.
mitochondrial ROS
○ High intracellular glucose increases mitochondrial respiration, producing excess superoxide.
Glucose autoxidation
○ Glucose reacts non-enzymatically with molecular oxygen, especially in the presence of transition metals (e.g., Fe²⁺ or Cu²⁺), generating superoxide, H₂O₂, and hydroxyl radicals (*OH).
○ This process directly increases oxidative stress and supports advanced glycation end-product (AGE) formation, further damaging endothelial cells and amplifying ROS production.
What is the link of “uncoupled eNOS” and endothelial/vascular dysfunction giving detail of how they act under normal conditions, in oxidative stress and what ROS can combine to
Under normal conditions:
○ Shear stress and acetylcholine (ACh) raise intracellular Ca²⁺, activating calmodulin (CaM) and PKA, which phosphorylates eNOS at Ser1177.
○ eNOS, with cofactors (BH₄, FMN, FAD, NADPH) and substrates (L-arginine and O₂), produces nitric oxide (NO) and L-citrulline.
○ NO induces vasodilation by activating sGC and increasing cGMP in smooth muscle cells.
In oxidative stress:
○ ROS (from NOX, mitochondria, and glucose autoxidation) react with NO to form peroxynitrite (ONOO⁻).
○ ONOO⁻ oxidizes BH₄ to BH₂, reducing eNOS cofactor availability and causing eNOS uncoupling.
○ Uncoupled eNOS produces superoxide instead of NO, further contributing to ROS and vascular dysfunction.
○ ONOO⁻ also oxidizes the zinc-thiolate (ZnS₄) core of eNOS, destabilizing the enzyme and reinforcing the vicious cycle of oxidative stress and endothelial injury.
Overall consequence:
ROS from glucose autoxidation, NOX enzymes, and mitochondria combine to:
○ Deplete NO,
○ Damage endothelial cells,
○ Promote endothelial-to-mesenchymal transition (EndMT),
○ Contribute to atherosclerosis, hypertension, and vascular complications in T2D.
Hpw do the kidneys play a role in homeostasis
○ Gluconeogenesis
○ Glucose utilisation
○ Glucose reabsorption from the filtrate in the proximal tubule
What is the mechanism of glucose reabsorption
Two main families of glucose transporters:
○ SGLTs (Sodium-Glucose Co-Transporters): Active, sodium-coupled transport on the apical (luminal) membrane.
○ GLUTs (Glucose Transporters): Facilitate passive glucose transport across the basolateral membrane into the blood.
~90% of filtered glucose is reabsorbed by SGLT2 in segment 1 of the proximal convoluted tubule (PCT).
The remaining ~10% is reabsorbed by SGLT1 in segment 2 of the PCT and segment 3 of the proximal straight tubule (PST).
Once inside the epithelial cell, glucose exits into the bloodstream via GLUT2 (in early PCT) and GLUT1 (in later segments).
What are the alterations in glucose homeostasis in T2D
In type 2 diabetes, SGLT2 and SGLT1 are often upregulated, increasing renal glucose reabsorption and contributing to persistent hyperglycaemia.
This maladaptive response worsens glycaemic control by preventing glucose excretion in urine, even when blood glucose levels are high.
What is the mechanism of SGLT2i
○ SGLT2 inhibitors (e.g., dapagliflozin, empagliflozin) are a class of antidiabetic drugs that block SGLT2 in the proximal tubule.
○ This prevents glucose reabsorption, promotes glycosuria (glucose loss in urine), and lowers blood glucose levels independently of insulin.
What are the extra glycaemic effects of SGLT2i
blood pressure reduction
osmotic diuresis and volume reduction
anti-inflammatory effects
improved vascular function and reduced oxidatve stress
potential SGLT1 inhibition
What is the theory that can explain the extraglycaemic effect of reduced BP in SGLT2i
○ Observed effect: Modest reduction (~3–5 mmHg systolic).
○ Mechanism: Likely due to osmotic diuresis and natriuresis (sodium loss) caused by SGLT2 inhibition → leads to reduced plasma volume and arterial stiffness.
○ While beneficial, BP lowering alone is unlikely to fully explain the observed cardiorenal protection.
What is the theory that can explain the extraglycaemic effect of osmotic diuresis and volume reduction in SGLT2i
○ Mechanism: SGLT2 inhibition increases urinary glucose and sodium excretion, leading to increased urine output (osmotic diuresis) and reduced preload and afterload.
○ This may alleviate heart failure symptoms, especially in HFpEF and HFrEF.
○ Evidence: Seen in trials like DAPA-HF and EMPEROR-Reduced, which showed improved heart failure outcomes independent of HbA1c.
What is the theory that can explain the extraglycaemic effect of anti-inflammatory effects in SGLT2i
Mechanism 1: Glucose restriction in immune cells
§ Macrophages rely on glycolysis; reduced glucose availability may dampen their inflammatory activity.
Mechanism 2: Inhibition of the NLRP3 inflammasome
§ NLRP3 promotes IL-1β and IL-18 production, contributing to chronic inflammation in metabolic and cardiovascular diseases.
§ SGLT2 inhibitors have been shown to suppress NLRP3 activation, though the exact mechanism remains unclear.
§ One proposed pathway: SGLT2 inhibitors increase β-hydroxybutyrate (BHB), a ketone body known to inhibit NLRP3. This suggests an indirect anti-inflammatory effect.
What is the theory that can explain the extraglycaemic effect of improved vascular function and reduced oxidative stress in SGLT2i
Mechanism:
§ Reduced hyperglycemia and glucotoxicity → less ROS production and endothelial dysfunction.
§ May also enhance NO bioavailability, improving vascular tone.
Evidence: Studies report improved arterial stiffness and vascular reactivity following SGLT2 inhibitor therapy.
What is the theory that can explain the extraglycaemic effect of potential SGLT1 inhibition in SGLT2i
○ Some SGLT2 inhibitors (e.g., canagliflozin at high doses) may partially inhibit SGLT1, which is expressed in the intestine and heart.
○ This could affect glucose absorption and possibly cardiac metabolism, though the clinical significance remains under investigation.
What is the mechanism of action and CV effects of the GLP-1 receptor agonist Semaglutide
Mechanism of Action:
§ Semaglutide mimics glucagon-like peptide-1 (GLP-1), an incretin hormone released from L cells in the small intestine postprandially.
§ Binds to the GLP-1 receptor on pancreatic β-cells, leading to:
□ Glucose-dependent insulin secretion
□ Suppression of glucagon release
□ Slowed gastric emptying, promoting satiety
□ Reduction in appetite and food intake
Metabolic Effects:
§ Lowers fasting and postprandial plasma glucose
§ Promotes weight loss
§ Improves lipid profiles and blood pressure
CV Risk Reduction:
§ In the SUSTAIN-6 trial, semaglutide significantly reduced major adverse cardiovascular events (MACE)(CV death, nonfatal MI, nonfatal stroke).
§ Benefits likely mediated by weight loss, glycemic control, blood pressure reduction, and anti-inflammatory/anti-atherogenic effects.
What is the mechanism of action and CV effects of the GIP receptor agonist tirzepatide
Mechanism of Action:
§ Tirzepatide is a dual incretin receptor agonist, targeting:
□ GLP-1 receptor (as above)
□ GIP receptor, which is expressed in pancreatic β-cells, adipose tissue, and the CNS.
§ GIP is secreted by K cells in the duodenum and jejunum in response to nutrient ingestion.
§ GIP potentiates insulin secretion, may improve β-cell function, and enhances lipid storage in metabolically active brown adipose tissue.
Signaling Bias:
§ Tirzepatide is a biased agonist at the GLP-1 receptor: favors cAMP production over β-arrestin recruitment.
§ This leads to less receptor internalization and desensitization, potentially prolonging therapeutic effects.
Metabolic Effects:
§ More potent glucose lowering and weight loss than GLP-1 RAs alone
§ Reduces plasma triglycerides and improves insulin sensitivity
CV Risk Reduction:
§ The SURPASS CVOT trial is ongoing, but SURPASS-4 showed favorable CV safety and risk marker improvement.
§ Mechanisms likely include:
□ Profound weight loss
□ Better glycemic and lipid control
□ Improved vascular and metabolic health
