Classify oral antidiabetic drugs with their mechanisms. Describe metformin and the choice of agent in different situations.

Classification of Oral Antidiabetic Drugs

Metformin — the First-line Drug

• First-line in type 2 diabetes in every major guideline, unless contraindicated — effective, cheap, weight-neutral, does not cause hypoglycaemia, and has the longest safety record
• Adverse effects — gastrointestinal upset (nausea, diarrhoea, metallic taste) in up to a third, reduced by starting low, taking it with food and using the extended-release form; vitamin B12 malabsorption with long-term use, which should be checked periodically, particularly where neuropathy is present
• Lactic acidosis — rare but with high mortality; occurs when metformin accumulates in renal impairment, or with hypoxia, sepsis, cardiac failure or alcohol
• Contraindicated if eGFR is below 30; the dose is reduced between 30 and 45. It must be withheld before iodinated contrast and during any acute illness with dehydration, and restarted only when renal function is confirmed stable
• Other uses — polycystic ovary syndrome (restores ovulation and reduces insulin resistance), and prevention of progression from prediabetes

Choosing Between Agents

Adverse Effects of the Newer Classes

• SGLT2 inhibitors — genital mycotic infection (common, and a frequent reason for stopping), urinary infection, volume depletion and hypotension, and euglycaemic diabetic ketoacidosis, which is easily missed because the glucose is not high; rarely Fournier gangrene. They should be withheld during acute illness, fasting and surgery
• GLP-1 agonists — nausea and vomiting (dose-limiting but usually settling), pancreatitis, gallstones; contraindicated with a family history of medullary thyroid carcinoma or men 2
• Pioglitazone — fluid retention and worsening of heart failure (contraindicated), weight gain, fractures in women, macular oedema, and a debated association with bladder cancer
• DPP-4 inhibitors — generally well tolerated; arthralgia, pancreatitis, bullous pemphigoid; saxagliptin was associated with heart failure admission
• Acarbose — flatulence, bloating and diarrhoea, from undigested carbohydrate reaching the colon

Diabetic Ketoacidosis — Outline of Drug Management

• Fluid first — the deficit is typically several litres; normal saline, guided by the clinical state; fluid alone lowers glucose substantially
• Insulin by fixed-rate intravenous infusion of regular insulin (about 0.1 units/kg/h) — this suppresses ketogenesis, which is the actual purpose; lowering glucose is secondary
• Potassium — total body potassium is markedly depleted even though the initial level may be high; insulin drives potassium into cells, so replacement begins as soon as the level falls into the normal range, and insulin is withheld if potassium is below about 3.3 mmol/L
• Glucose is added when the blood glucose falls to about 14 mmol/L, so that the insulin infusion can continue to clear the ketones without causing hypoglycaemia — the ketones, not the glucose, define resolution
• Bicarbonate is not routinely given; it worsens intracellular acidosis and hypokalaemia, and the acidosis corrects as ketogenesis stops
• Treat the precipitating cause — infection, myocardial infarction, or most often omitted insulin
• Continue the basal insulin throughout and overlap subcutaneous insulin with the infusion before stopping it, or ketoacidosis recurs

Applied Aspects

• Lifestyle change remains the foundation — diet, weight loss and exercise; no drug substitutes for it, and in early disease it can achieve remission
• Individualise the HbA1c target — tighter in the young and newly diagnosed, looser in the elderly, those with a long duration, cardiovascular disease or hypoglycaemia unawareness, where tight control causes harm
• Withhold metformin before contrast and during acute illness, and make sure the patient knows to do so — "sick day rules" apply to oral agents as well as to insulin
• Screen for complications regardless of control — annual retinal examination, foot examination, urine albumin and renal function; these detect the disease that actually disables
• Diabetes in India presents younger, at lower body mass index, and with more central adiposity than in Western populations, and coronary disease is commoner and earlier; treatment thresholds and cardiovascular risk assessment must reflect that
• Cost drives real prescribing — metformin and sulphonylureas remain the mainstay for most Indian patients, and the newer agents, whatever their trial data, are unaffordable for many; generic availability is changing this
• Blood pressure and lipid control matter more for survival than glucose control; a statin and an ACE inhibitor prevent more events than tightening HbA1c by a further percentage point
• Ask about fasting — religious fasts are common and doses of sulphonylureas and insulin must be adjusted in advance rather than after an admission with hypoglycaemia
• Type 2 diabetes is progressive, and needing more drugs over time is the natural history rather than a failure by the patient — framing it that way preserves the relationship and the adherence
• Withhold SGLT2 inhibitors during fasting, acute illness and before surgery, because of euglycaemic ketoacidosis, and warn the patient about genital hygiene and infection
• Avoid pioglitazone in heart failure and in anyone with a fracture risk, and stop it if oedema or weight gain develops
• Substantial weight loss can put type 2 diabetes into remission in the first few years after diagnosis, which is worth telling every newly diagnosed patient rather than starting with a prescription alone
• Acarbose-treated hypoglycaemia must be corrected with glucose, not sucrose, since the enzyme that would split table sugar is blocked — a point that must be explained to the patient and the family
• GLP-1 agonists delay gastric emptying, which affects the absorption of other drugs and matters before anaesthesia, where a prolonged fast is now advised
• Check renal function before and periodically during treatment with any agent, since several are contraindicated or need dose reduction as it declines