Key Facts

Type 2 diabetes management has been revolutionised by SGLT2 inhibitors and GLP-1 RAs, which offer benefits beyond glycaemic control. Treatment selection should consider cardiovascular risk, renal function, weight, and hypoglycaemia risk.

Epidemiology

• ~4 million people with diabetes in UK (~90% type 2)
• Diabetes: leading cause of CKD, blindness, and non-traumatic amputation in UK
• NHS spends 10% of budget on diabetes (£10 billion/year)

Drug Classes

• Biguanide: metformin — ↓ hepatic gluconeogenesis, ↑ insulin sensitivity
• SGLT2 inhibitors: block sodium-glucose co-transporter 2 in PCT → glycosuria
• GLP-1 RAs: incretin mimetics → stimulate glucose-dependent insulin, suppress glucagon, slow gastric emptying, promote satiety
• Sulfonylureas: stimulate pancreatic beta-cell insulin secretion (K-ATP channel blockade)
• DPP-4 inhibitors: prevent incretin degradation → enhance endogenous GLP-1/GIP
• Thiazolidinediones: PPARγ agonist → improve insulin sensitivity in adipose/muscle

Pathophysiology

• T2DM: progressive beta-cell dysfunction + insulin resistance → hyperglycaemia
• Glucotoxicity and lipotoxicity accelerate beta-cell decline
• Complications: microvascular (retinopathy, nephropathy, neuropathy) + macrovascular (MI, stroke, PAD)

Treatment Algorithm (NICE NG28)

1. Lifestyle + metformin: first-line
2. Dual therapy: metformin + one of: SGLT2i, GLP-1 RA, DPP-4i, sulfonylurea, pioglitazone
3. Triple therapy: metformin + two agents
4. Insulin ± other agents: if triple therapy insufficient

Side Effects by Drug

• Metformin: GI upset (start low, use MR formulation), B12 deficiency (long-term), lactic acidosis (rare — contraindicated eGFR <30)
• SGLT2i: genital candidiasis (~10%), UTI, euglycaemic DKA (rare — especially if unwell, fasting, surgery), Fournier's gangrene (very rare), volume depletion
• GLP-1 RA: nausea/vomiting (common initially), injection site reactions, pancreatitis (rare), gallstones
• Sulfonylureas: hypoglycaemia (most important — especially gliclazide, glibenclamide), weight gain
• DPP-4i: generally well-tolerated; nasopharyngitis; possible pancreatitis (rare)
• Pioglitazone: weight gain, fluid retention (worsens HF), fracture risk, bladder cancer association

Red Flags

• Euglycaemic DKA on SGLT2i: normal glucose + metabolic acidosis + ketonaemia → stop SGLT2i, treat as DKA
• Lactic acidosis on metformin: rare; usually in renal impairment or hypoxia → stop metformin, supportive care
• Severe hypoglycaemia on sulfonylurea: especially in elderly with CKD → may be prolonged; consider switch

Monitoring

• HbA1c: every 3–6 months until stable; then 6-monthly
• Target: 48 mmol/mol (6.5%) on metformin alone; 53 mmol/mol (7.0%) if on agents causing hypoglycaemia; individualise in elderly/frail
• U&Es: annually; more frequently if on SGLT2i, metformin, or renal impairment
• eGFR: determines metformin dosing, SGLT2i initiation
• LFTs: baseline and periodically on pioglitazone
• B12: periodically on long-term metformin (deficiency in ~5–10%)
• Lipids, BP, weight, foot check, retinal screening: annual diabetes review

Special Tests

• Urine ACR: annual — detect diabetic nephropathy early
• Ketone testing: blood ketones if unwell on SGLT2i (euglycaemic DKA screening)
• C-peptide: if diagnostic uncertainty (T1 vs T2 vs LADA)

Step 1: Lifestyle + Metformin

• Metformin 500 mg OD → 500 mg BD → 1 g BD: titrate over 4 weeks to minimise GI effects
• MR formulation if standard not tolerated
• Reduce dose if eGFR 30–45; stop if <30

Step 2: Add Second Agent

• With CVD or high CV risk: add SGLT2 inhibitor (empagliflozin 10 mg or dapagliflozin 10 mg)
• With heart failure: SGLT2 inhibitor (dapagliflozin — DAPA-HF)
• With CKD: SGLT2 inhibitor (dapagliflozin — DAPA-CKD); can initiate even if eGFR 20–25
• If weight management priority: GLP-1 RA (semaglutide 0.25 mg → 1 mg SC weekly)
• If cost/simplicity: sulfonylurea (gliclazide 40 mg → 160 mg BD) or DPP-4i (sitagliptin 100 mg OD)

Step 3: Triple Therapy

• Combine metformin + two agents from different classes
• Consider GLP-1 RA if BMI ≥35 and not yet tried

Step 4: Insulin

• Basal insulin (insulin glargine/detemir/degludec): start at 10 units ON, titrate to fasting glucose target
• Continue metformin and SGLT2i with insulin
• Stop sulfonylurea if starting insulin (hypoglycaemia risk)

Sick Day Rules

• Stop metformin, SGLT2i during acute illness, vomiting, diarrhoea, dehydration
• Resume when eating/drinking normally

Referral Criteria

• Diabetes specialist: insulin initiation, complex management, recurrent DKA, SGLT2i DKA
• Dietetics: lifestyle management, weight loss support
• Diabetes nurse: insulin education, dose titration

• Metformin: UKPDS — 32% reduction in diabetes-related endpoints
• Empagliflozin (EMPA-REG): 38% reduction in CV death in T2DM with CVD
• Dapagliflozin (DAPA-CKD): 39% reduction in renal composite endpoint (including non-diabetic CKD)
• Semaglutide (SUSTAIN-6): 26% reduction in MACE
• Liraglutide (LEADER): 13% reduction in MACE
• Intensive glycaemic control (UKPDS): reduces microvascular complications by ~25%
• Good glycaemic control + CV risk factor management: near-normal life expectancy achievable

Key Diabetes Trials

NICE NG28 Simplified Algorithm