Chronic Conditions: Management of Type 2 Diabetes

Introduction/Overview

Type 2 diabetes mellitus (T2DM) represents a chronic metabolic disorder characterized by insulin resistance and relative insulin deficiency. The prevalence of T2DM continues to rise worldwide, imposing significant burdens on patients, healthcare systems, and societies at large. Effective pharmacological management is essential for glycaemic control, prevention of microvascular and macrovascular complications, and improvement of overall quality of life. This chapter delivers a systematic review of antidiabetic pharmacotherapy, focusing on drug classification, mechanisms of action, pharmacokinetic profiles, therapeutic indications, safety profiles, drug interactions, and special considerations for distinct patient populations.

Learning Objectives

• Identify the major pharmacological classes utilized in the treatment of T2DM and their chemical characteristics.
• Elucidate the pharmacodynamic pathways and receptor interactions that underpin glycaemic control.
• Describe the absorption, distribution, metabolism, and excretion (ADME) parameters that influence dosing strategies.
• Recognise common and serious adverse effects, as well as contraindications and drug–drug interaction risks.
• Apply knowledge of special patient groups—including pregnancy, pediatrics, geriatrics, and renal/hepatic impairment—to optimise therapy.

Classification

Drug Classes and Categories

The pharmacotherapeutic arsenal for T2DM is stratified into several core classes, each targeting distinct pathophysiological mechanisms:

• Biguanides – Metformin is the prototype, acting primarily by reducing hepatic gluconeogenesis.
• Sulfonylureas – Glimepiride, glibenclamide, gliclazide, and glipizide; stimulate pancreatic β‑cell insulin release.
• Meglitinides – Repaglinide and nateglinide; rapid-acting insulin secretagogues.
• Thiazolidinediones (TZDs) – Pioglitazone and rosiglitazone; peroxisome proliferator‑activated receptor‑γ (PPAR‑γ) agonists.
• Dipeptidyl peptidase‑4 (DPP‑4) inhibitors – Sitagliptin, saxagliptin, linagliptin, and alogliptin; prolong incretin activity.
• Glucagon‑like peptide‑1 (GLP‑1) receptor agonists – Liraglutide, exenatide, dulaglutide, semaglutide; mimic endogenous GLP‑1.
• Small‑molecule sodium‑glucose cotransporter‑2 (SGLT2) inhibitors – Canagliflozin, dapagliflozin, empagliflozin, ertugliflozin; inhibit renal glucose reabsorption.
• Insulin analogues – Rapid‑acting (lispro, aspart), basal (glargine, detemir), and premixed formulations.

Chemical Classification

Pharmacologically, antidiabetic agents can be grouped by their core chemical scaffolds:

• Biguanide core (metformin).
• Thiophene and pyrimidine rings (sulfonylureas).
• Imidazoline moiety (meglitinides).
• Phenoxypropanoic acid derivatives (TZDs).
• Non‑peptide heterocyclic structures (DPP‑4 inhibitors).
• Peptide analogues of GLP‑1 (GLP‑1 receptor agonists).
• Phosphonate and bicyclic heterocycles (SGLT2 inhibitors).
• Linear or branched polypeptide chains (insulin analogues).

Mechanism of Action

Biguanides

Metformin’s primary pharmacodynamic effect is the inhibition of hepatic mitochondrial respiratory chain complex I, resulting in decreased ATP production and activation of AMP‑activated protein kinase (AMPK). AMPK activation suppresses gluconeogenic gene expression and enhances insulin‑mediated glucose uptake in peripheral tissues. The drug also modestly increases peripheral GLUT4 translocation, contributing to improved glucose disposal.

Sulfonylureas and Meglitinides

Both classes bind to the sulfonylurea receptor 1 (SUR1) subunit of the ATP‑sensitive potassium (K_ATP) channel on pancreatic β‑cell membranes. Binding leads to channel closure, membrane depolarisation, calcium influx, and subsequent insulin secretion. Sulfonylureas exhibit a longer binding affinity and duration of action, whereas meglitinides have rapid onset and short duration, allowing for post‑prandial glucose control.

Thiazolidinediones

TZDs function as selective PPAR‑γ agonists, modulating gene transcription involved in adipocyte differentiation, fatty acid storage, and insulin sensitivity. Activation of PPAR‑γ increases adiponectin secretion, reduces free fatty acid flux, and improves insulin receptor signalling in hepatic and peripheral tissues.

DPP‑4 Inhibitors

DPP‑4 inhibitors prevent the enzymatic degradation of incretin hormones, primarily glucagon‑like peptide‑1 (GLP‑1) and glucose‑dependent insulinotropic polypeptide (GIP). Stabilisation of these peptides prolongs their action: GLP‑1 enhances glucose‑stimulated insulin secretion, suppresses glucagon release, delays gastric emptying, and promotes satiety; GIP similarly potentiates insulin release.

GLP‑1 Receptor Agonists

GLP‑1 receptor agonists bind to the GLP‑1 receptor on β‑cells and other tissues, mimicking the actions of endogenous GLP‑1. These agents increase insulin secretion in a glucose‑dependent manner, inhibit glucagon secretion during hyperglycaemia, slow gastric emptying, and reduce appetite, leading to weight loss. The peptide structure confers resistance to DPP‑4 degradation, extending half‑life.

SGLT2 Inhibitors

SGLT2 inhibitors selectively block the sodium‑glucose cotransporter‑2 in the proximal renal tubular epithelium, reducing glucose reabsorption and promoting glycosuria. The resulting urinary glucose loss lowers plasma glucose independent of insulin action. Additionally, modest reductions in blood pressure and weight are observed secondary to osmotic diuresis.

Insulin Analogues

Exogenous insulin mimics the endocrine function of endogenous insulin. Rapid‑acting analogues contain slight modifications at the B1, B3, or B29 positions, reducing hexamer formation and accelerating absorption. Basal analogues possess alterations in the amino acid sequence that promote monomeric stability and extended plasma half‑life. Pharmacological effects include activation of the insulin receptor tyrosine kinase, leading to intracellular signalling via IRS‑1, PI3K, and GLUT4 translocation.

Pharmacokinetics

Biguanides

Metformin is absorbed predominantly in the small intestine, with a bioavailability of approximately 50–60 %. Peak plasma concentrations (C_max) are reached within 1–2 h. Distribution is limited to extracellular fluid; the drug binds minimally to plasma proteins. Renal excretion is the primary elimination route, with a half‑life (t_1/2) of 4–8 h. Dose adjustments are required in acute kidney injury or chronic kidney disease (CKD) stages 4–5 to mitigate the risk of lactic acidosis.

Sulfonylureas

Glimepiride and gliclazide exhibit high oral bioavailability (>90 %) and extensive hepatic metabolism via CYP2C9 and CYP3A4, respectively. Their half‑lives range from 8 to 12 h. Metabolites contribute to pharmacologic activity in the case of gliclazide. Glibenclamide possesses a long half‑life (approximately 18 h) and a high lipophilicity, leading to a slow release and increased hypoglycaemia risk, especially in elderly patients.

Meglitinides

Repaglinide shows rapid absorption (t_max ≈ 1 h) and a short half‑life (≈ 1 h). The drug is largely metabolised by CYP3A4. Nateglinide has a slightly longer t_max (≈ 1.5 h) and a half‑life of 2–3 h. Both agents are cleared hepatically; renal excretion is minimal.

Thiazolidinediones

Pioglitazone has a bioavailability of ~40 %, is metabolised by CYP2C8 and CYP3A4, and exhibits a half‑life of 3–6 h, with active metabolites extending the pharmacologic effect. Rosiglitazone is mainly metabolised by CYP2C8 and has a shorter half‑life (~3 h). Both agents are highly protein‑bound (>95 %) and undergo hepatic clearance.

DPP‑4 Inhibitors

Sitagliptin demonstrates high oral bioavailability (>90 %) and is largely renally excreted unchanged; its half‑life is 12–14 h. Saxagliptin is metabolised by CYP3A4 to an active metabolite, with a combined half‑life of ~12 h. Linagliptin is predominantly excreted via the biliary route; its half‑life is ~12–18 h, independent of renal function. Alogliptin has a renal clearance mechanism and a half‑life of 12–14 h.

GLP‑1 Receptor Agonists

Exenatide (short‑acting) has a half‑life of 2–3 h, requiring twice‑daily dosing, whereas liraglutide’s half‑life (~13 h) permits once‑daily administration. Dulaglutide and semaglutide possess extended half‑lives (≈ 7–14 days) allowing weekly or monthly dosing. These peptides are predominantly cleared by proteolytic degradation and renal excretion; renal impairment influences dosing for some agents.

SGLT2 Inhibitors

Canagliflozin exhibits an oral bioavailability of ~70 %, with a half‑life of 13–14 h. Dapagliflozin has a half‑life of 12–13 h and is metabolised by CYP3A4. Empagliflozin’s half‑life is 12–13 h, metabolised via UGT1A9. All agents are eliminated via the kidneys and gut; dose adjustments are recommended in moderate to severe CKD.

Insulin Analogues

Insulin absorption is site‑dependent; rapid‑acting analogues achieve peak action within 30–60 min, whereas basal analogues peak at 4–7 h. Half‑lives range from 5–7 h for basal analogues to 2–4 h for rapid‑acting formulations. Insulin is degraded by proteases and cleared via hepatic and renal mechanisms; renal impairment can prolong action, necessitating dose adjustments.

Therapeutic Uses/Clinical Applications

Approved Indications

All classes listed above are authorised for the management of T2DM, either as monotherapy or in combination with other antidiabetic agents. Insulin analogues are indicated for both type 1 and type 2 diabetes, particularly when glycaemic targets are not achieved with oral medications. Combination therapy is frequently employed to target multiple pathogenic processes.

Off‑Label Uses

• GLP‑1 receptor agonists are occasionally prescribed for obesity management, given their anorectic effects.
• SGLT2 inhibitors have shown cardiovascular benefits in patients with heart failure and chronic kidney disease, leading to off‑label use in these contexts.
• Metformin is sometimes utilised in non‑diabetic metabolic conditions such as polycystic ovary syndrome (PCOS) to improve insulin sensitivity.
• Insulin analogues are occasionally employed in severe hyperglycaemia acutely, irrespective of diabetes type.

Adverse Effects

Common Side Effects

Metformin may cause gastrointestinal discomfort, including nausea, vomiting, and diarrhoea; these symptoms often resolve with dose titration. Sulfonylureas and meglitinides are associated with hypoglycaemia, especially when combined with insulin or in renal dysfunction. TZDs can induce oedema, weight gain, and fluid retention. GLP‑1 receptor agonists frequently provoke nausea, vomiting, and diarrhoea due to delayed gastric emptying. SGLT2 inhibitors may lead to genital mycotic infections, urinary tract infections, and mild dehydration. Insulin therapy is linked to local injection site reactions and hypoglycaemia; insulin analogues may also cause weight gain.

Serious or Rare Adverse Reactions

Lactic acidosis, although rare, is a potentially fatal complication associated with metformin, particularly in patients with renal impairment or hepatic dysfunction. Sulfonylureas carry a risk of severe, prolonged hypoglycaemia, especially in advanced age or with renal insufficiency. TZDs have been implicated in heart failure exacerbation and, in the case of rosiglitazone, increased cardiovascular event rates (data remain contested). DPP‑4 inhibitors are associated with rare cases of pancreatitis and hypersensitivity reactions. GLP‑1 agonists have been linked to transient increases in pancreatitis risk and, in pre‑clinical studies, thyroid C‑cell hyperplasia. SGLT2 inhibitors carry a risk of euglycaemic diabetic ketoacidosis and haemorrhagic strokes in some populations. Insulin therapy can precipitate severe hypoglycaemia, and long‑term use is associated with an increased risk of certain cancers, though evidence remains inconclusive.

Black Box Warnings

Metformin carries a boxed warning for lactic acidosis; patients with significant renal impairment, liver disease, or hypoxia should receive cautionary monitoring. SGLT2 inhibitors have boxed warnings for euglycaemic ketoacidosis and the potential for increased risk of lower‑extremity amputations with canagliflozin. GLP‑1 receptor agonists possess a warning regarding pancreatitis and potential thyroid C‑cell tumour risk based on rodent studies.

Drug Interactions

Major Drug–Drug Interactions

Metformin’s absorption can be reduced by cimetidine and proton pump inhibitors. Sulfonylureas are potentiated by cimetidine, chlorpromazine, and thioridazine, increasing hypoglycaemia risk. Meglitinides may interact with CYP3A4 inhibitors such as ketoconazole, leading to elevated plasma levels. TZDs are contraindicated with strong CYP2C8 inhibitors (e.g., gemfibrozil). DPP‑4 inhibitors interact with CYP3A4 inhibitors and inducers; linagliptin is largely unaffected by hepatic enzymes. GLP‑1 receptor agonists may exhibit reduced absorption when co‑administered with gastric motility inhibitors. SGLT2 inhibitors’ glycosuric effect is diminished by diuretics and ACE inhibitors. Insulin’s hypoglycaemic effect is compounded by alcohol consumption and β‑blockers.

Contraindications

Metformin is contraindicated in patients with severe renal insufficiency (eGFR <30 mL/min/1.73 m²), acute or chronic hepatic failure, severe dehydration, or conditions predisposing to hypoxia. Sulfonylureas and meglitinides are contraindicated in type 1 diabetes and in patients with sulfonylurea hypersensitivity. TZDs are contraindicated in patients with decompensated heart failure or uncontrolled oedema. DPP‑4 inhibitors are contraindicated in patients with a history of hypersensitivity to the drug. GLP‑1 receptor agonists are contraindicated in patients with a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2. SGLT2 inhibitors are contraindicated in patients with type 1 diabetes, severe renal impairment, or a history of recurrent genital infections. Insulin is contraindicated in patients with known hypersensitivity to the formulation.

Special Considerations

Pregnancy/Lactation

Metformin is classified as pregnancy category B and is generally considered safe during pregnancy; however, evidence regarding long‑term neonatal outcomes is limited. Sulfonylureas and meglitinides are category B but may cross the placenta; undue hypoglycaemia may occur in the fetus. TZDs are category D, with teratogenic effects observed in animal studies; they should be avoided. DPP‑4 inhibitors and GLP‑1 receptor agonists lack robust safety data in pregnancy and are usually discontinued. SGLT2 inhibitors are contraindicated in pregnancy due to potential foetal harm. Insulin is the preferred agent during pregnancy and lactation, as it does not cross the placenta and is not excreted in breast milk in significant amounts.

Pediatric Considerations

Insulin remains the mainstay of treatment in children with type 2 diabetes. Metformin has limited pediatric data but is widely used off‑label for adolescents with T2DM. DPP‑4 inhibitors and GLP‑1 receptor agonists have emerging evidence in 10–18 year‑olds; dosing adjustments are often required. SGLT2 inhibitors are not approved for use in the pediatric population due to insufficient safety data. Sulfonylureas and meglitinides are rarely used in children because of hypoglycaemia risk and limited evidence.

Geriatric Considerations

Elderly patients exhibit altered pharmacokinetics due to decreased renal clearance and increased body fat. Metformin dosing should be initiated at low doses with careful titration. Sulfonylureas, particularly glibenclamide, carry a heightened risk of hypoglycaemia; newer agents (glimepiride, gliclazide) or incretin‑based therapies may be preferable. TZDs induce fluid retention, worsening heart failure risk; caution is warranted. GLP‑1 receptor agonists and SGLT2 inhibitors are generally well tolerated, but renal dysfunction may necessitate dose adjustment. Insulin therapy requires meticulous monitoring for hypoglycaemia and falls risk.

Renal/Hepatic Impairment

Metformin is contraindicated in severe renal dysfunction; dose reduction is advised in mild to moderate CKD. Sulfonylureas should be avoided or dose‑reduced in advanced CKD. TZDs may accumulate in hepatic impairment; close monitoring of liver enzymes is advised. DPP‑4 inhibitors vary in renal handling: linagliptin is suitable for all CKD stages; sitagliptin, saxagliptin, and alogliptin require dose adjustment. GLP‑1 receptor agonists are generally safe in CKD, but dose adjustments are needed for some agents (e.g., exenatide). SGLT2 inhibitors are contraindicated in eGFR <45 mL/min/1.73 m²; dose adjustments are necessary for moderate CKD. Insulin clearance is impaired in renal failure; dose reductions and more frequent glucose monitoring are essential.

Summary/Key Points

• Type 2 diabetes management relies on a diverse pharmacologic portfolio, each class targeting distinct pathophysiological mechanisms.
• Understanding pharmacodynamics and pharmacokinetics is crucial for individualising therapy, particularly in special populations.
• Common adverse effects such as hypoglycaemia, gastrointestinal upset, and fluid retention require proactive mitigation strategies.
• Drug–drug interactions and contraindications necessitate thorough medication reconciliation and patient education.
• Special considerations—including pregnancy, pediatrics, geriatrics, and renal/hepatic impairment—must guide therapeutic decisions to optimise safety and efficacy.

Clinical pearls: Initiate therapy with metformin as first‑line unless contraindicated; consider incretin‑based therapies for weight management; monitor renal function closely when prescribing SGLT2 inhibitors; employ insulin with careful titration to avoid hypoglycaemia in elderly or renal‑impaired patients. Continuous patient education and multidisciplinary collaboration remain cornerstones of successful long‑term diabetes care.

References

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