Mednotes

L12 Clinical Pharmacology Hypoglycaemics 2

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tagsclinicalpharmacology, lecture, diabetes, cardiorenal
aliasesL12 Clinical Pharmacology Hypoglycaemics 2

20 min read

Hypoglycaemics

Overview

This lecture covers two non-insulin drug classes for type 2 diabetes that act via distinct mechanisms but share cardiovascular and renal relevance: incretin modulators (GLP-1 receptor agonists such as dulaglutide, and DPP-IV inhibitors such as vildagliptin), and SGLT2 inhibitors (gliflozins, e.g. empagliflozin). The incretin section builds from the physiology of GLP-1/GIP release and breakdown, through the beta-cell signalling pathway, to the pharmacology, PKs and ADRs of dulaglutide and vildagliptin. The SGLT2 section builds from renal glucose handling physiology, through the rationale for selective SGLT2 (over SGLT1) inhibition, the tubuloglomerular feedback mechanism behind its renal protective effect, to empagliflozin’s dosing, ADRs (including euglycaemic DKA), and comparative cardiovascular/renal outcomes data across drug classes.

Incretin physiology and DPP-IV

The “incretin effect”: eating promotes release of incretin hormones, which stimulate insulin secretion and reduce glucagon. Insulin release is greater following oral glucose than IV glucose because of this incretin hormone effect.

Incretin hormones are secreted from the small/large intestine in response to glucose:

Both GLP-1 and GIP are rapidly metabolised by dipeptidyl-peptidase IV (DPP-IV), a cell surface peptidase; inactive metabolites are cleared renally (other mechanisms, including peripheral tissue extraction, may contribute).

In type 2 diabetes:

  • GLP-1 levels are reduced
  • Pancreatic beta-cell response to GIP and GLP-1 is impaired

This gives two therapeutic strategies:

  1. Activate GLP-1 signalling directly with an incretin mimetic (dulaglutide)
  2. Prevent endogenous GLP-1 breakdown by inhibiting DPP-IV (vildagliptin)

DPP-4 pathway: Food → small intestine releases GLP-1 → DPP-4 enzyme normally inactivates GLP-1 → DPP-4 inhibitors block this inactivation → preserved GLP-1 stimulates insulin secretion and suppresses glucagon secretion.

Slide flag

DPP-4 inhibitors and GLP-1 inhibitors are specifically not recommended in pregnancy.

Beta-cell intracellular signalling (dense diagram, adapted from Kahn et al. 2006):

  • Glucose enters the beta cell via a GLUT transporter → glucokinase converts it to glucose-6-phosphate → pyruvate → mitochondrial TCA cycle → increases ATP/ADP ratio.
  • Increased ATP/ADP closes the K+/ATP channel → membrane depolarisation opens voltage-gated Ca2+ channels → increased intracellular Ca2+ (with additional Ca2+ drawn from intracellular stores) → triggers insulin granule exocytosis.
  • Insulin/IGF-1 receptor → IRS-2 → Ras and PI(3)K/PKB(Akt) pathways → increased beta-cell proliferation and decreased beta-cell apoptosis.
  • Incretins act via the GLP-1 receptor → increase cAMP → activate PKA and EPAC2 → these promote K+/ATP channel closure and feed into the ATP/ADP and Ca2+ signalling above; incretins also contribute to beta-cell proliferation/reduced apoptosis via the same Ras/PI3K node.
  • β-adrenergic agonists → increase cAMP → promote insulin release (same cAMP/PKA/EPAC2 node as incretins).
  • α2-adrenergic agonists → inhibit the K+/ATP channel pathway → inhibit insulin release.
  • Muscarinic (M2) receptor stimulation (parasympathetic, via acetylcholine) → increases diacylglycerol → activates protein kinase C → contributes to the Ca2+/exocytosis pathway → promotes insulin release.
  • Fatty acyl-CoA (from NEFA) via the GPR40 receptor also feeds into the PKC/Ca2+/exocytosis pathway.

Adrenergic balance

α-adrenergic stimulation inhibits insulin release; β-adrenergic stimulation promotes it. Muscarinic (M2) stimulation also promotes insulin release.

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The beta-cell signalling diagram is dense with many labelled steps (a–j); all visible labels are transcribed above, but some individual connecting arrows/lettered steps are not further specified beyond the pathway shown.

GLP-1’s systemic effects (secretion stimulated by food intake):

  • Brain: promotes satiety, reduces appetite
  • Pancreas α-cells: ↓ postprandial glucagon secretion
  • Liver: ↓ postprandial glucagon reduces hepatic glucose output
  • Pancreas β-cells: enhances glucose-dependent insulin secretion
  • Stomach: delays/regulates gastric emptying, which reduces peak sugar intake and thereby decreases beta-cell workload/insulin demand

GLP-1 receptor agonists — Dulaglutide

  • A recombinant synthetic analogue of exendin-4 (a potent GLP-1 agonist isolated from the salivary gland venom of the Gila Monster), resistant to degradation by endogenous DPP-IV.
  • Delivery: once-weekly subcutaneous, microsphere-coupled formulation (t½ 5 days); start with a low dose and build up slowly.
  • Structure: two GLP-1 peptide chains (NH2 termini) linked via linker peptides to an IgG4-Fc domain (COOH termini).

Mechanism of action (can be combined with SC insulin, with insulin dose adjustment):

  1. Binds GLP-1 receptors on β-cells → increases insulin secretion and reduces glucagon secretion at α-cells.
  2. Reduces gastric emptying, promoting satiety.
  3. Little effect on fasting glucose but boosts insulin release in post-prandial conditions.
  4. No impact on hepatic insulin-induced glycogen storage.

Use and effects:

  • Used ± insulin and in combination with other hypoglycaemic agents.
  • Promotes weight loss.
  • Reduces HbA1c (7 mmol/mol).
  • Established value as an adjunct in patients with cardiovascular disease/risk factors.
  • GLP-1 receptor agonists have glucose-lowering effects independent of their insulinotropic action — namely glucagon suppression and delayed gastric emptying (Andersen et al., 2018).

Pharmacokinetics:

  • Peak plasma concentration at 48 hours.
  • Predominantly eliminated by protein catabolism into amino acids.
  • Not affected by renal impairment (apart from ESRD requiring dialysis) or hepatic impairment.

Cardiac benefits of GLP-1/GLP-1 receptor agonists (Ussher & Drucker 2014): GLP-1 acts on the pancreas (↑insulin, ↓glucagon), intestine (↓circulating TAGs), kidney (↑natriuresis, blood volume changes), hypothalamus/brainstem (↓appetite, ↓body weight, ↑sympathetic activity), immune cells (↓inflammation) and adipose tissue (altered adipokines) — all converging on myocardial metabolism:

  • Healthy heart: ↑glucose utilisation, ↓fatty acid utilisation, ↑coronary flow, ↑heart rate
  • Ischaemic heart: ↑glucose utilisation, ↓fatty acid utilisation, ↓infarct size, ↑coronary flow, ↑LV ejection fraction, ↑myocardial salvage index
  • Failing heart: ↑glucose utilisation, ↑coronary flow, ↑LV ejection fraction, ↑myocardial oxygen consumption

Guideline position

Following demonstration of CV safety and proven CV benefit, GLP-1 receptor agonists are now recommended as first-line therapy in combination with metformin and SGLT2 inhibitors in people with T2DM who have atherosclerotic cardiovascular disease or CKD.

Dulaglutide ADRs and interactions:

  • GI: nausea, vomiting (rarely unpleasant sulphur burps), diarrhoea — commonly.
  • Acute pancreatitis (1 in 100); nasopharyngitis; needle site reactions.
  • Contraindicated in pancreatitis and in severe renal or hepatic impairment.
  • Do not use to treat DKA.
  • Interacts with insulin secretagogues and insulin — mild-to-moderate hypoglycaemia particularly with sulphonylureas (30%).
  • Delayed gastric emptying can affect concurrent oral medications.

Oral DPP-IV inhibitors — Vildagliptin

Administration: oral, 50 mg once–twice daily, with or without food.

Uses:

  • Monotherapy or in combination with metformin in T2DM.
  • Option for patients with resistant HbA1c elevation.
  • Adjunct to diet and exercise.
  • Can be continued if insulin is initiated; can be used as add-on to basal insulin (± metformin).
  • Discontinue if a GLP-1 receptor agonist is initiated.
  • No value in patients with type 1 diabetes.

Efficacy: monotherapy reduces HbA1c by 6–9 mmol/mol; with metformin, by 7–12 mmol/mol.

Mechanism of action: DPP-IV inhibition by vildagliptin prolongs the activity of endogenous incretin hormones (GLP-1 and GIP) →

  • ↑ insulin secretion response to glucose
  • ↓ glucagon secretion
    → improved post-prandial glycaemic control. Vildagliptin is generally well tolerated and weight neutral, and increases sensitivity to insulin and levels of endogenous insulin.

Pharmacokinetics:

  • Orally well absorbed.
  • Mostly cleared unchanged in urine (~85%).
  • Dose adjustment needed in renal impairment (CrCl <50 mL/min).
  • Avoid in severe heart failure and in raised LFT indices.

ADRs: respiratory tract infection, nasopharyngitis (cold symptoms), headache; angioedema, back pain and diarrhoea reported.

SGLT transporters and renal/GI glucose handling

Most hypoglycaemics fail to reduce adverse cardiovascular outcomes in diabetes and carry side effects — hypoglycaemia, weight gain, fluid retention, and increased risk of congestive heart failure.

The sodium-glucose cotransporter (SGLT) family has two major isoforms of pharmacological interest, SGLT2 and SGLT1:

  • SGLT1 — distribution: small intestine, heart, trachea, kidney, brain. Function: co-transports Na+ with glucose and galactose across the brush border of the intestine, the proximal tubule (S3 segment), and cardiomyocytes.
  • SGLT2 — distribution: kidney, heart (uncertain in man). Function: co-transports Na+ and glucose in the S1 segment of the proximal tubule.
  • SGLT3 — small intestine, uterus, lungs, thyroid, testis; transports sodium only (not glucose).
  • SGLT4 — small intestine, kidney, liver, stomach, lung; transports glucose and mannose.
  • SGLT5 — kidney; function unknown.
  • SGLT6 — spinal cord, kidney, brain, small intestine; transports myo-inositol and glucose.

Historical context — phlorizin: a competitive SGLT1/SGLT2 inhibitor that competes with D-glucose for the carrier, reducing renal glucose reuptake; studied as a T2DM treatment but oral dosing was ineffective (mostly converted to phloretin by intestinal hydrolytic enzymes, giving poor bioavailability). Large oral doses needed to achieve significant renal SGLT2 inhibition also significantly inhibited SGLT1 in the gut, causing diarrhoea, and blocked glucose uptake into the brain (including glucose-sensitive neurons). This is why selective SGLT2 inhibition is more appealing than dual inhibition.

Why inhibiting GI tract SGLT1 is a bad idea:

  • Dietary glucose (~60–80 g/day) enters the intestinal epithelial cell via SGLT1 (co-transporting 2 Na+ with glucose; leptin inhibits SGLT1; an SGLT1 inhibitor would block this uptake); glucose exits basolaterally via GLUT2, with Na+/K+-ATPase maintaining the Na+ gradient.
  • In the proximal intestinal L cell, glucose uptake via SGLT1 triggers acute GLP-1 release.
  • Unabsorbed glucose reaching the microbiome produces short-chain fatty acids that act via FFAR2/3 on the distal intestinal L cell, triggering sustained GLP-1 release.
  • Net point: inhibiting SGLT1 blocks intestinal glucose uptake and the GLP-1 release that normally follows it — the rationale for avoiding SGLT1 inhibition.

Renal handling of glucose (non-diabetic):

  • Glomerular filtration: (180 L/day) × (1000 mg/L) = 180 g/day glucose filtered.

  • 90% reabsorbed via SGLT2 in the S1 segment of the proximal convoluted tubule; the remaining <10% reabsorbed via SGLT1 in the S3 segment (PST).

  • Apical SGLT2 (or SGLT1) co-transports Na+/glucose from lumen into the epithelial cell; basolateral GLUT2 (or GLUT1) exports glucose to the peritubular capillary; Na+/K+-ATPase maintains the Na+ gradient using ATP.
  • Result: minimal glucose excretion normally — the kidney is a major site of glucose clearance.

SGLT2 in diabetes:

  • Pharmacological reasoning for targeting SGLT2 comes partly from familial renal glucosuria (a benign autosomal genetic disorder from SGLT2 gene mutations).
  • SGLT2 (and GLUT2) transporter levels are upregulated in Type 2 DM compared with healthy controls (both P<0.05), giving increased renal glucose reabsorption in T2DM.

Renal threshold for glucose (RTG): the lowest plasma glucose concentration at which appreciable urinary glucose excretion occurs.

  • Healthy RTG ≈ 10 mmol/L.
  • Type 2 DM RTG ≈ 13.8 mmol/L — i.e. the threshold for glucosuria is higher in T2DM than in healthy individuals, meaning more glucose is reabsorbed before it spills into urine.

SGLT2 inhibition — mechanism and renal/cardiac protection

SGLT2/NHE3 link in the early proximal tubule: SGLT2 is functionally interlinked with NHE3 — the Na+ gradient SGLT2 establishes drives both bicarbonate reabsorption and Na+/K+-ATPase activity. SGLT2 inhibition therefore indirectly reduces bicarbonate reabsorption and Na+/K+-ATPase activity, and also reduces water reuptake (diuresis), in addition to reducing glucose and Na+ reabsorption.

Gliflozins (empagliflozin, dapagliflozin, canagliflozin, etc.) selectively inhibit SGLT2:

  • Increase urinary glucose excretion and reduce plasma glucose (reducing glucotoxicity risk).
  • Produce increased glucosuria (greater than in untreated T2DM).
  • Complementary action to other antidiabetic agents including insulin; useful even in refractory T2DM.
  • Potential for weight loss; low risk of hypoglycaemia; short-term diuresis and BP drop.
  • Greatly reduce the renal threshold for glycosuria even in T2DM: with empagliflozin, RTG ≈ 4.8 mmol/L, much lower than both untreated T2DM (~13.8 mmol/L) and healthy (~10 mmol/L) thresholds.

Tubuloglomerular feedback (TGF) mechanism of renal protection:

  • Untreated diabetic nephron: increased NaCl and glucose filtration/reabsorption via SGLT2 → decreased distal NaCl delivery to the macula densa → reduced feedback signal → afferent arteriole vasodilation → high glomerular pressure (P_GC).
  • With SGLT2 inhibition: reduced proximal tubule NaCl/glucose reabsorption → increased distal NaCl delivery to the macula densa → increased feedback signal (adenosine generated from ATP cleavage, activating the A1 receptor) → afferent arteriole vasoconstriction (reversing the vasodilation) → normalised glomerular pressure.
  • Net effect: SGLT2 inhibition lowers GFR back toward normal via TGF, believed to be protective against glomerular hyperfiltration injury in diabetes.

The "initial eGFR dip" is protective, not harmful

Both RAAS inhibitors and SGLT2 inhibitors reduce intraglomerular pressure (via efferent arteriolar vasodilation and afferent arteriolar vasoconstriction respectively), preserving kidney function over time. Creatinine/cystatin-C commonly rise (an initial eGFR dip) on starting these drugs — this is expected and reflects protection, not harm. Comparative trajectories to end-stage kidney disease (ESKD): untreated declines at −12 mL/min/year (ESKD by ~year 4–5); RAAS-inhibitor-only declines at −4.6 mL/min/year (ESKD by ~year 10); combined SGLT2 inhibitor + RAAS inhibitor declines slowest at −1.85 mL/min/year (ESKD by ~year 25) — combination therapy delays ESKD by roughly 15 years versus RAAS inhibitor alone.

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Empagliflozin — dosing, PKs and ADRs

Dosing and PKs:

  • 10 mg up to 25 mg PO once daily (not affected by food).
  • Oral bioavailability ~90%; peak plasma time 1.5 hours; t½ 13 hours.
  • Primary metabolism: glucuronidation by UDP-glucuronosyltransferases; active product and metabolites cleared in urine and faeces.
  • Enters the renal proximal tubule lumen via glomerular filtration and tubular secretion.
  • No dosage adjustment required for hepatic impairment; assess renal function.
  • Advise adequate fluid intake to reduce hypotension risk, particularly if used with a diuretic.
  • In renal impairment, the diuretic effect causes temporary volume contraction and drops GFR; can only be initiated if GFR >20 mL/min/1.73m².

ADRs:

  • UTIs (7.6–9.3%), associated with high glucose excretion (though DM itself also raises UTI risk) and poor hygiene.
  • Female and male genital polymicrobial/mycotic infections relatively common, including Fournier’s gangrene.
  • Ketoacidosis is a major risk with SGLT2 inhibition (1.5–5 fold increase); SGLT2-inhibitor-induced euglycaemic ketoacidosis is harder to identify than standard DKA.
  • Prescribe carefully considering the patient’s medical/drug history.

Mechanism of euglycaemic DKA (eDKA): SGLT2 inhibitors can promote euglycaemic ketoacidosis through simultaneous volume depletion and lowered plasma insulin.

  1. SGLT2 inhibitor → glycosuria → ↓ plasma glucose and ↓ volume.
  2. ↓ volume → brain → ↑ catecholamines/↑ glucocorticoids.
  3. Combined with ↓ plasma insulin/↑ plasma glucagon → ↑ lipolysis → ↑ free fatty acids.
  4. Liver: ↑ ketogenesis, ↑ acetyl-CoA, ↑ gluconeogenesis → ketoacidosis.
  • The mechanism by which SGLT2 inhibition raises circulating glucagon remains unclear [slide does not elaborate].
  • Risk factors: diet/starvation, surgery, pregnancy.

Value in DM and heart failure:

  • Lowering the RTG provides an insulin-independent mechanism for correcting hyperglycaemia.
  • Not approved for type 1 diabetes.
  • HbA1c reduced by 4.2–5.6 mmol/mol (0.6–0.8%).
  • Lowering systemic glucose load reduces glucotoxicity (particularly cardiovascular), improves β-cell function and reverses insulin resistance.
  • Decreased plasma glucose shifts cardiac metabolism toward fat utilisation (energetically more efficient).
  • Reduced Na+ load to the heart is beneficial even in non-diabetic heart failure.
  • Volume depletion/BP drop is valuable in heart failure.

Comparative effects across hypoglycaemic drug classes on the myocardium

Effects of different diabetic drug classes on myocardial function (Honka et al. 2021), plus a bariatric surgery/calorie restriction comparator, all feeding into the heart:

  • SGLT2 inhibitors: SGLT2 not expressed in the heart itself (linked to NHE3); increase FA, ketone and BCAA oxidation, providing extra fuel for the energy-starved heart; ↑ myocardial ATP content.
  • Biguanides (metformin): organic cation transporter not expressed in the heart; possible LVH regression secondary to effects on BP, weight loss and adiposity; possible reduced incidence of macrovascular events in diabetic patients.
  • GLP-1 receptor agonists: GLP-1 receptor is expressed in the heart; no effect on cardiac substrate utilisation rates in humans with reduced ejection fraction; protection from ischaemia-reperfusion injury.
  • TZDs (pioglitazone): PPAR-γ expressed in cardiomyocytes; improves insulin-stimulated myocardial glucose uptake; lowers plasma FFA and decreases cardiac steatosis; corrects multiple metabolic defects of insulin resistance syndrome.
  • Bariatric surgery/calorie restriction: ↓ insulin resistance, ↓ plasma FFA, possibly ↓ cardiac steatosis and ↑ myocardial glucose oxidation.

Clinical practice points:

  • SGLT2 inhibitors are available in combination formulations with metformin, sulphonylureas, GLP-1 agonists, DPP-IV inhibitors, sacubitril/valsartan, etc.
  • Individually, SGLT2 inhibitors reduced mortality and HF hospital admission more than GLP-1 receptor agonists (Palmer S, Lancet).
  • GLP-1 receptor agonists reduced non-fatal stroke more than SGLT2 inhibitors.
  • Alone or in combination, SGLT2 inhibitor administration to non-diabetic HFrEF patients significantly improves LV volumes, LV mass, LV systolic function, functional capacity and quality of life (DAPA-HF & EMPEROR trials).

Self-test

  1. Define the “incretin effect” and explain why oral glucose produces more insulin release than IV glucose.
  2. Name the two main incretin hormones, their cell of origin, and the enzyme responsible for their rapid breakdown.
  3. Describe the two therapeutic strategies available for boosting incretin action in T2DM, with an example drug for each.
  4. Outline, in order, how activation of the beta-cell GLP-1 receptor leads to insulin granule exocytosis.
  5. Contrast the effect of α-adrenergic versus β-adrenergic and muscarinic (M2) stimulation on insulin release.
  6. List the systemic effects of GLP-1 across at least four organs/tissues.
  7. Describe dulaglutide’s mechanism of action and explain why it is resistant to degradation despite being a GLP-1 analogue.
  8. Explain why GLP-1 receptor agonists lower glucose even independent of their insulinotropic effect.
  9. A patient with T2DM and known atherosclerotic cardiovascular disease is being started on treatment. According to the guidance in this lecture, which drug classes should be used first-line in combination, and why?
  10. List the significant ADRs and contraindications of dulaglutide.
  11. Describe vildagliptin’s mechanism of action and state its effect on HbA1c as monotherapy versus with metformin.
  12. Distinguish the renal handling requirements of vildagliptin from those of dulaglutide.
  13. List the SGLT transporter isoforms and, for SGLT1 and SGLT2, state their tissue distribution and function.
  14. Explain why phlorizin failed as a clinical treatment for T2DM despite being an effective SGLT inhibitor in principle.
  15. Explain why inhibiting SGLT1 in the gastrointestinal tract is undesirable, referencing GLP-1 release.
  16. Define the renal threshold for glucose (RTG) and state how it differs between healthy individuals, untreated T2DM, and T2DM treated with empagliflozin.
  17. Describe the mechanism by which SGLT2 inhibition restores tubuloglomerular feedback and explain why this is renoprotective.
  18. Explain why an initial dip in eGFR after starting an SGLT2 inhibitor or RAAS inhibitor should be interpreted as reassuring rather than concerning.
  19. Describe the mechanism by which SGLT2 inhibitors can cause euglycaemic diabetic ketoacidosis, and list the risk factors that predispose to it.
  20. List the significant ADRs of empagliflozin.
  21. A non-diabetic patient with heart failure with reduced ejection fraction is prescribed an SGLT2 inhibitor. Using the mechanisms covered in this lecture, explain how this drug could benefit them despite them not having diabetes.
  22. Compare the outcome benefits of SGLT2 inhibitors versus GLP-1 receptor agonists on hospitalisation for heart failure versus non-fatal stroke.
  23. Integrative: a patient with T2DM has both cardiovascular disease and early diabetic kidney disease. Explain, drawing on both the incretin and SGLT2 sections, why a combination of a GLP-1 receptor agonist and an SGLT2 inhibitor might be favoured over either alone.

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