Lecture 9

What is the incretin effect?

The incretin effect is the greater insulin release that occurs after oral glucose compared with an equivalent intravenous glucose load, because eating stimulates intestinal incretin hormones (GLP-1 and GIP), which increase glucose-dependent insulin secretion and reduce glucagon release.

Which intestinal cells release GLP-1 and GIP?

K-cells in the small intestine release glucose-dependent insulinotropic peptide (GIP), while L-cells in the large intestine release glucagon-like peptide-1 (GLP-1). Both hormones are released in response to food intake.

How are GLP-1 and GIP normally broken down?

Both GLP-1 and GIP are rapidly metabolised by the cell-surface peptidase DPP-IV into inactive metabolites, which are cleared mainly through the kidneys and potentially by extraction in peripheral tissues.

How do GLP-1 and GIP responses change in Type 2 diabetes?

In diabetes, GLP-1 levels are reduced and pancreatic beta-cell responses to both GLP-1 and GIP are impaired.

What are the two main therapeutic strategies for increasing incretin activity in Type 2 diabetes?

1. GLP-1 receptor agonists, such as dulaglutide, directly activate GLP-1 receptors and supplement GLP-1 activity.

2. DPP-IV inhibitors, such as vildagliptin, prevent the breakdown of endogenous GLP-1 and GIP, prolonging their activity.

What are the effects of GLP-1 on the brain and pancreas?

GLP-1 promotes satiety and reduces appetite in the brain; enhances glucose-dependent insulin secretion from pancreatic beta cells; and reduces postprandial glucagon secretion from alpha cells, thereby reducing hepatic glucose output.

What are the effects of GLP-1 on the gut?

GLP-1 delays gastric emptying, slowing the delivery of glucose into the bloodstream, and reduces food intake and fat absorption in the gut.

How does GLP-1 reduce the demand placed on pancreatic beta cells after a meal?

GLP-1 enhances glucose-dependent insulin secretion but also delays gastric emptying, spreading glucose absorption over a longer period. This reduces the size of the post-meal glucose spike and helps avoid a large, sudden demand for insulin secretion.

What is dulaglutide?

Dulaglutide is a recombinant GLP-1 receptor agonist and analogue of exendin-4, a potent GLP-1 agonist originally isolated from Gila monster salivary gland venom.

Why does dulaglutide have a prolonged duration of action?

It resists degradation by endogenous DPP-IV and uses a microsphere-coupled, slow-release formulation, allowing once-weekly administration with a half-life of approximately five days.

How does dulaglutide lower blood glucose?

Dulaglutide binds GLP-1 receptors on pancreatic beta cells to increase glucose-dependent insulin secretion and reduces glucagon secretion from alpha cells. It also delays gastric emptying, promoting satiety and slowing glucose entry into the bloodstream. Its effects are strongest for postprandial glucose rather than fasting glucose, and it has no direct effect on hepatic insulin-induced glycogen storage.

How is dulaglutide administered, and how can its dose be managed alongside insulin?

Dulaglutide is administered subcutaneously once weekly. Treatment begins at a low dose and is increased gradually. It can be used with or without insulin and alongside other glucose-lowering drugs, but the insulin dose may need to be reduced because dulaglutide also lowers blood glucose.

What are the main therapeutic benefits of dulaglutide?

Dulaglutide promotes weight loss and reduces HbA1c by approximately 7 mmol/mol. It can be used alone or with other glucose-lowering treatments, including insulin, and has established value as an adjunct in patients with cardiovascular disease or cardiovascular risk factors. Its glucose-lowering effects include reduced glucagon secretion and delayed gastric emptying, in addition to increased insulin secretion.

What are the pharmacokinetic characteristics of dulaglutide?

Dulaglutide reaches peak plasma concentration within approximately 48 hours and is predominantly eliminated through protein catabolism into amino acids.

What cardiovascular benefits are associated with GLP-1 and GLP-1 receptor agonists?

Their effects across the pancreas, intestine, kidney, brain and immune cells influence myocardial metabolism and can increase glucose utilisation, reduce afterload, reduce infarct size, reduce heart rate, increase cardiac output and decrease myocardial oxygen consumption.

When are GLP-1 receptor agonists recommended for patients with Type 2 diabetes and cardiovascular or kidney disease?

Following evidence of cardiovascular safety and benefit, GLP-1 receptor agonists are recommended alongside metformin and SGLT2 inhibitors for people with Type 2 diabetes who have atherosclerotic cardiovascular disease or chronic kidney disease.

What are the main adverse effects of dulaglutide?

Common adverse effects include nausea, vomiting and diarrhoea. Other reported effects include acute pancreatitis, nasopharyngitis and injection-site reactions.

What are the interactions and contraindications of dulaglutide?

Mild to moderate hypoglycaemia is more likely when combined with sulphonylureas or insulin. Delayed gastric emptying can delay absorption of oral medicines. Dulaglutide is contraindicated in pancreatitis, severe renal or hepatic impairment, and diabetic ketoacidosis.

What is tirzepatide?

Tirzepatide is a once-weekly dual GIP and GLP-1 receptor agonist. Activating both pathways may produce greater metabolic effects than targeting either alone. It is more potent at the GIP receptor than the GLP-1 receptor and has biased GLP-1 receptor signalling, favouring cAMP generation over beta-arrestin recruitment, with weaker receptor internalisation than GLP-1 alone.

What are the clinical uses and reported weight-loss effects of tirzepatide?

Tirzepatide has been trialled at 5–15 mg subcutaneously once weekly in adults with obesity or Type 2 diabetes and received regulatory approval in May 2022. It is also being studied for non-alcoholic steatohepatitis (NASH) and heart failure with preserved ejection fraction (HFpEF). In SURMOUNT-1, 15 mg weekly produced up to 22.5% weight loss over 72 weeks in adults with obesity.

What is vildagliptin, and how does it improve glucose control?

Vildagliptin is an oral DPP-IV inhibitor that prevents the breakdown of endogenous GLP-1 and GIP, prolonging their activity. This increases glucose-dependent insulin secretion and decreases glucagon secretion, improving postprandial glucose control. It is generally well tolerated and weight neutral.

How is vildagliptin used in Type 2 diabetes?

Vildagliptin is taken orally at 50 mg once or twice daily, with or without food, usually alongside metformin. It can be used as monotherapy or in combination with metformin, as an add-on for elevated HbA1c, alongside diet and exercise, and can be continued after insulin is initiated.

When should vildagliptin be discontinued?

Vildagliptin should be discontinued if a GLP-1 receptor agonist is started because the treatments act on overlapping pathways.

How much does vildagliptin reduce HbA1c, and which patients are unlikely to benefit?

DPP-IV inhibitors reduce HbA1c by approximately 6–9 mmol/mol as monotherapy and 7–12 mmol/mol when combined with metformin. They may be added to basal insulin, with or without metformin, but have no value in Type 1 diabetes because there is little or no endogenous insulin response left to enhance.

What are the pharmacokinetic properties of vildagliptin?

Vildagliptin is well absorbed orally and approximately 85% is cleared unchanged in urine. Dose adjustment is needed in renal impairment when creatinine clearance is below 50 mL/min. It should be avoided in severe heart failure and in patients with elevated liver function tests.

What are the adverse effects of vildagliptin?

Adverse effects include respiratory tract infections, nasopharyngitis and headache; angioedema, back pain and diarrhoea have also been reported.

Why is oral phlorizin a poor diabetes treatment?

Phlorizin competitively inhibits both SGLT1 and SGLT2, reducing renal glucose reabsorption. However, oral phlorizin is poorly bioavailable because intestinal enzymes convert much of it into phloretin.

Why is selective SGLT2 inhibition preferred over phlorizin-style inhibition?

Large doses of phlorizin are needed for renal SGLT2 inhibition, but these doses also inhibit intestinal SGLT1, causing diarrhoea, and phlorizin can interfere with glucose uptake in the brain. Selective SGLT2 inhibition is therefore a more attractive strategy.

Where is SGLT1 found, and what does it transport?

SGLT1 is found in the small intestine, heart, trachea, kidney and brain, and co-transports sodium with glucose or galactose. It contributes to glucose absorption across the intestinal brush border, reabsorption in the proximal renal tubule and transport in cardiomyocytes.

Where is SGLT2 found, and what does it transport?

SGLT2 is found predominantly in the kidney and co-transports sodium and glucose in the S1 segment of the proximal tubule. Other SGLT-family transporters occur in tissues including the intestine, kidney, liver, stomach, lung, spinal cord and brain.

Why is selective SGLT2 inhibition preferred over intestinal SGLT1 inhibition?

Intestinal SGLT1 absorbs dietary glucose into epithelial cells, after which glucose exits into the interstitium through GLUT2. Blocking SGLT1 interferes with normal glucose absorption and can also reduce GLP-1 release from intestinal L-cells, because GLP-1 release is linked to glucose entry through SGLT1. Selectively inhibiting SGLT2 avoids disrupting these beneficial intestinal functions.

How is filtered glucose normally reabsorbed in the kidney?

In the proximal tubule, SGLT2 in the S1 segment reabsorbs approximately 90% of filtered glucose, while SGLT1 in the S2 and S3 segments reabsorbs most of the remainder. Selectively blocking SGLT2 therefore prevents reabsorption of most filtered glucose and associated sodium, increasing urinary glucose excretion.

Why is SGLT2 considered a viable therapeutic target for Type 2 diabetes?

Familial renal glucosuria, a benign autosomal genetic disorder caused by mutations in SGLT2-related genes, causes glucose excretion in urine without other major ill effects, supporting the viability of SGLT2 inhibition. In Type 2 diabetes, SGLT2 levels become upregulated, increasing renal glucose reabsorption; GLUT2 levels on the other side of tubular cells also increase, allowing more reabsorbed glucose to return to the bloodstream.

What is the renal threshold for glucose excretion (RTg)?

The RTg is the lowest plasma glucose concentration at which appreciable glucose excretion occurs in urine. Below this threshold, almost all filtered glucose is reabsorbed; above it, reabsorptive capacity is exceeded and glucose spills into urine.

How does the RTg differ in Type 2 diabetes?

The lecture gives a threshold of around 10 mmol/L in healthy people and approximately 11.6 mmol/L or higher in Type 2 diabetes, where increased SGLT2 activity allows more glucose to be reabsorbed before glucosuria occurs.

How does SGLT2 inhibition affect sodium, bicarbonate and water reabsorption in the proximal tubule?

SGLT2 is functionally linked to the sodium-hydrogen exchanger NHE3, helping provide the sodium gradient that supports bicarbonate reabsorption and Na+/K+ ATPase activity. Inhibiting SGLT2 reduces glucose and sodium reabsorption and indirectly reduces bicarbonate reabsorption and water reuptake, producing a diuretic effect.

What are gliflozins, and how do they lower blood glucose?

Gliflozins, including empagliflozin, dapagliflozin and canagliflozin, selectively inhibit SGLT2. This increases urinary glucose excretion, lowers plasma glucose and reduces glucotoxicity (the damaging effects of chronically elevated glucose on tissues). Their action is complementary to other antidiabetic drugs, including insulin, and can be useful in treatment-resistant Type 2 diabetes. They may promote weight loss, produce diuresis and have a low risk of hypoglycaemia when used alone.

How do SGLT2 inhibitors change the renal glucose threshold in Type 2 diabetes?

SGLT2 inhibitors greatly reduce the renal threshold for glucose excretion, potentially lowering it below that of healthy individuals. As a result, more glucose is excreted in urine at a given plasma glucose concentration, even though people with Type 2 diabetes normally have an elevated threshold.

What are the pharmacokinetic characteristics of empagliflozin?

Empagliflozin has approximately 90% oral bioavailability, reaches peak plasma concentration in about 1.5 hours and has a half-life of around 13 hours. It is primarily metabolised through glucuronidation by UDP-glucuronosyltransferases. The drug and its metabolites are eliminated in urine and faeces, and empagliflozin reaches the proximal tubule lumen through glomerular filtration and tubular secretion via transporters such as OATs.

How can renal impairment affect empagliflozin treatment?

Empagliflozin’s diuretic effect can contract plasma volume and reduce glomerular filtration rate (GFR), particularly in renal impairment. The lecture notes state it is contraindicated when estimated GFR is consistently below approximately 30–45 mL/min/1.73 m².

What are the main adverse effects of empagliflozin?

Urinary tract infections occur in approximately 7.6–9.3% of patients and are associated with increased urinary glucose, although diabetes itself also raises UTI risk. Genital fungal infections in both women and men are also relatively common because glucose-rich urine promotes fungal growth. Diabetic ketoacidosis is a major risk associated with SGLT2 inhibition.

How does empagliflozin lower glucose independently of insulin?

Empagliflozin lowers the renal threshold for glucose excretion, increasing urinary glucose loss independently of insulin signalling.

What are the benefits of empagliflozin in diabetes?

It reduces HbA1c by approximately 4.2–5.6 mmol/mol (0.6–0.8%), reduces glucotoxicity, may improve beta-cell function and insulin resistance, and shifts cardiac metabolism toward fat utilisation as systemic glucose availability falls. It is not approved for Type 1 diabetes.

Why can empagliflozin benefit people with heart failure, including those without diabetes?

Empagliflozin reduces sodium delivery to the heart and produces volume depletion and lower blood pressure through diuresis, which can benefit heart failure independently of glucose lowering. The lecture notes that SGLT2 inhibitors can improve left ventricular volumes, mass, systolic function, functional capacity and quality of life in non-diabetic patients with HFrEF, as shown in the DAPA-HF and EMPEROR trials.

How do the cardiovascular benefits of SGLT2 inhibitors compare with those of GLP-1 receptor agonists?

The lecture notes that SGLT2 inhibitors have shown greater reductions in mortality and hospital admission for heart failure than GLP-1 receptor agonists, whereas GLP-1 receptor agonists have shown greater reductions in non-fatal stroke. SGLT2 inhibitors are available in combination formulations with metformin, sulphonylureas, GLP-1 agonists, DPP-IV inhibitors, sacubitril/valsartan and other agent