Glipizide Mechanism of Action

Physiology and Mechanism of Action

The KATP channel plays a pivotal role in the regulation of insulin secretion as a function of glucose levels. In a state of low glucose, the KATP channel remains open, leading to the hyperpolarization of the beta cell membrane and, subsequently, a reduction in insulin secretion.

However, when glucose levels rise, glucose is absorbed into the beta cells of the pancreas, which undergoes metabolic processes to generate ATP. The increase in intracellular ATP leads to the closure of the KATP channel. This results in the depolarization of the cell membrane and triggers the influx of calcium ions through voltage-gated calcium channels. The escalation in intracellular calcium concentration then stimulates the exocytosis of insulin granules, releasing insulin into the bloodstream.

Sulfonylureas function by associating with and inhibiting the SUR1 subunit of the ATP-sensitive potassium (KATP) channels, a subunit that is predominantly expressed in pancreatic beta cells. The SUR1 subunit forms one of two constituent parts of the KATP channel, the other being the Kir6.2 subunit.

By inhibiting the ATP-sensitive potassium channel, sulfonylureas prevent it from opening and causing hyperpolarization of the cell membrane in response to decreasing glucose levels. This action maintains membrane depolarization and the influx of calcium ions, thus leading to an enhancement in insulin secretion.

Besides their inhibitory effect on the KATP channel, sulfonylureas can also boost insulin release by heightening the sensitivity of beta cells to glucose. This might activate intracellular signalling pathways that encourage insulin secretion or augment the expression of other proteins involved in insulin exocytosis.

It’s important to note that various sulfonylurea drugs exhibit differing binding affinities for the SUR1 subunit and durations of action. For instance, glyburide and glimepiride demonstrate a higher binding affinity for SUR1 and a prolonged duration of action compared to tolbutamide and glipizide, which exhibit lower binding affinities and briefer durations of action.

Practice Guide for Sulfonylureas

Glipizide undergoes hepatic metabolism, transforming into multiple inactive metabolites. This process allows its clearance and elimination half-life to remain consistent even in the presence of a reduced estimated glomerular filtration rate (GFR). Therefore, glipizide is often the preferred sulfonylurea for patients with compromised kidney function.

Glibenclamide and glyburide are excreted via both biliary and renal routes after undergoing liver metabolism. However, in patients whose estimated GFR is less than 60 mL/min, the administration of these drugs is not recommended due to potential risks.

Glimepiride undergoes hepatic transformation, producing two primary metabolites, one of which has a hypoglycemic effect. In chronic kidney disease (CKD), there is a potential for these metabolites to accumulate. Thus glimepiride use is not recommended for individuals with an estimated GFR of less than 60 mL/min. Interestingly, when compared to glyburide, glimepiride is associated with less frequent occurrences of hypoglycemia.

Finally, gliclazide is metabolized into inactive metabolites which are primarily (about 80%) eliminated through the kidneys. This drug is associated with a lower risk of hypoglycemia as compared to glibenclamide and glimepiride.

Sulfonylureas (pharmacokinetic profile)

Drug Name (Trade name)Dose RangeMaximum Daily DoseFrequencyOnset of ActionDuration of Action
Glimepiride (Amaryl)1–2 mg daily8 mgOnce or twice daily2 to 3 hours24 hours
Glipizide (Glucotrol)   Glipizide (Glucotrol XL)2.5–5 mg daily20 mgOnce daily1 to 3 hours12 to 24 hours
20 mg daily20 mgDaily6 to 12 hours12 to 24 hours
Glyburide (Glynase)1.25–5 mg daily20 mgOnce or twice daily2 to 4 hours≤24 hours
Glyburide, micronized (Glynase)0.75–3 mg daily12 mgOnce or twice daily2 to 4 hours≤24 hours

Sulfonylureas, widely used antidiabetic drugs, are known to increase the risk of hypoglycemia, particularly in elderly patients and those suffering from chronic kidney disease. Other notable side effects include weight gain and the potential for gradual exhaustion of pancreatic beta-cells.

In addition, sulfonylureas have raised cardiovascular safety concerns, warranting their cautious use, especially in patients with a history of cardiovascular disease. The landmark DIGAMI trial (Diabetes Mellitus, Insulin Glucose Infusion in Acute Myocardial Infarction) of the 1990s shed light on this issue. The trial involved type 2 diabetes patients who had experienced an acute myocardial infarction (AMI). It aimed to assess the impact of intensive glucose regulation using insulin therapy on these patients. Surprisingly, the group assigned to intensive insulin treatment did not show better cardiovascular outcomes than those under conventional treatment regimens. This finding was intriguing, considering that the SUR2 subtype of the KATP channel, which sulfonylureas inhibit, is present in cardiomyocytes, and its inhibition could potentially impair coronary vasodilation and predispose ischemic cardiomyocytes to arrhythmias.

Recent studies have sought to unravel the cardiovascular safety of sulfonylureas. A notable one is the CAROLINA (Cardiovascular Outcome Study of Linagliptin vs. Glimepiride in Patients with Type 2 Diabetes) trial, a randomized controlled trial designed to directly compare the cardiovascular safety and efficacy of linagliptin and glimepiride in patients with type 2 diabetes at high cardiovascular risk. The primary endpoint was cardiovascular death, non-fatal myocardial infarction, and stroke rates among all subjects. The trial demonstrated that both treatments had similar cardiovascular outcomes, suggesting that the cardiovascular safety of sulfonylureas might be comparable to other common diabetes medications.


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