Key Facts

T2DM is a major public health crisis with significant cardiovascular, renal, and microvascular complications. Modern management emphasises individualised therapy, cardiovascular risk reduction, and early use of drugs with proven cardiorenal benefits (SGLT2i, GLP-1 RA).

Epidemiology

~4.3 million in UK (~3.4 million diagnosed + ~1 million undiagnosed). Prevalence ~6-7% of adult population. Increasing — linked to obesity epidemic. Higher prevalence in South Asian (2-4× risk), African-Caribbean, and deprived populations. Increasingly diagnosed in younger adults and adolescents.

Aetiology

Multifactorial: genetic susceptibility + environmental/lifestyle factors. >400 genetic loci identified. Strongest modifiable risk factor: obesity (especially central/visceral). Other: physical inactivity, high-calorie diet, South Asian/African-Caribbean ethnicity, advancing age, PCOS, prior GDM.

Pathophysiology

Two core defects: peripheral insulin resistance (skeletal muscle, liver, adipose tissue) + progressive beta cell dysfunction (failure to compensate → relative insulin deficiency). Also: increased hepatic glucose output, impaired incretin effect, increased lipolysis, increased renal glucose reabsorption, CNS appetite dysregulation (collectively: 'ominous octet' — DeFronzo). Beta cell mass declines ~50% by time of diagnosis. Progressive nature means most patients eventually require combination therapy and many require insulin.

Typical Presentation

• Often asymptomatic — diagnosed on screening (NHS Health Check, routine bloods)
• Polyuria, polydipsia, nocturia: osmotic diuresis (if significantly hyperglycaemic)
• Fatigue, blurred vision
• Recurrent infections: UTIs, thrush (candidiasis), skin infections
• Slow wound healing
• Acanthosis nigricans: velvety hyperpigmentation in skin folds (axillae, neck) — marker of insulin resistance

Complications at Diagnosis (~25%)

• Up to 25% of T2DM patients have complications at diagnosis (delayed diagnosis)
• Retinopathy, neuropathy, nephropathy, cardiovascular disease

Red Flags

• Young, lean patient with diabetes → consider T1DM, LADA, MODY
• DKA in apparent T2DM → may be T1DM or ketosis-prone T2DM
• HHS (hyperosmolar hyperglycaemic state) → emergency (see HHS)

Diagnosis (NICE NG28)

• HbA1c ≥48 mmol/mol (6.5%): on 2 occasions if asymptomatic; single measurement if symptomatic
• Fasting glucose ≥7.0 mmol/L or random ≥11.1 mmol/L (with symptoms)
• OGTT: 2-hour glucose ≥11.1 mmol/L (not routinely needed for T2DM diagnosis; used in GDM)

Baseline Assessment

• HbA1c: baseline and every 3-6 months
• Renal: eGFR, urine ACR (microalbuminuria screening)
• Lipid profile: total cholesterol, HDL, LDL, triglycerides
• LFTs: baseline (NAFLD very common)
• BP: target <140/90 (or <130/80 if renal/eye/cerebrovascular disease — NICE NG136)
• BMI, waist circumference

Complication Screening (Annual)

• Retinal screening: from diagnosis (unlike T1DM which is from age 12)
• Foot: annual assessment (monofilament, pulses)
• Renal: ACR + eGFR annually
• Cardiovascular risk assessment: QRISK3

Lifestyle (Foundation — Throughout)

• Weight loss: target 5-10% body weight; very-low-calorie diets may achieve remission (DiRECT trial — 46% remission at 1 year with intensive weight management)
• Diet: Mediterranean style, reduced refined carbohydrates, portion control
• Exercise: ≥150 min/week moderate intensity
• Smoking cessation
• Structured education: DESMOND (Diabetes Education and Self-Management for Ongoing and Newly Diagnosed)

Pharmacological (NICE NG28 — Stepwise)

Step 1: Metformin 500mg OD → 500mg-1g BD → max 1g BD (2g/day)

• Mechanism: reduces hepatic glucose output, improves insulin sensitivity
• Benefits: weight neutral/loss, cardiovascular benefit (UKPDS), no hypoglycaemia
• Side effects: GI (nausea, diarrhoea — use modified-release if not tolerated), B12 deficiency, lactic acidosis (rare — avoid in severe renal/hepatic impairment)
• Contraindicated: eGFR <30

Step 2 (if HbA1c above target on metformin):

• Add one of: SGLT2 inhibitor (preferred if CVD, HF, or CKD), GLP-1 RA (preferred if BMI ≥35 or weight management priority), DPP-4 inhibitor, pioglitazone, sulfonylurea

Key Drug Classes:

• SGLT2 inhibitors (empagliflozin 10-25mg OD, dapagliflozin 10mg OD, canagliflozin 100-300mg OD): block renal glucose reabsorption; weight loss, BP reduction, CV benefit (EMPA-REG OUTCOME), renal protection (CREDENCE, DAPA-CKD); risk: UTI, genital thrush, DKA (rare — euglycaemic), Fournier gangrene (very rare)
• GLP-1 receptor agonists (semaglutide 0.25-1mg SC weekly or oral 14mg OD, liraglutide 0.6-1.8mg SC OD, dulaglutide 0.75-4.5mg SC weekly): incretin mimetics; significant weight loss (5-15%), CV benefit (LEADER, SUSTAIN-6, REWIND); SE: nausea, vomiting; contraindicated in pancreatitis history/medullary thyroid cancer
• DPP-4 inhibitors (sitagliptin 100mg OD, linagliptin 5mg OD): weight neutral, well-tolerated; moderate efficacy
• Sulfonylureas (gliclazide 40-320mg/day): rapid efficacy; risk of hypoglycaemia and weight gain
• Pioglitazone 15-45mg OD: insulin sensitiser; weight gain, fluid retention; avoid in HF; bladder cancer concern (debated)

Step 3 (triple therapy or insulin):

• Triple oral/injectable combination
• Insulin: when oral agents insufficient; usually basal insulin (glargine, degludec) added to metformin + other agents

Cardiovascular Risk Management

• Statin: atorvastatin 20mg OD for primary prevention (QRISK ≥10%); 80mg for secondary prevention
• BP: target <140/90 (NICE NG136); ACEi/ARB first-line; ramipril 1.25-10mg OD
• Antiplatelet: only for established CVD (not primary prevention)

Bariatric Surgery

• Consider if BMI ≥35 with recent-onset T2DM (or ≥30 if South Asian); significant evidence for diabetes remission (>60% at 5 years for gastric bypass)

Referral Criteria

• Specialist diabetes team: insulin initiation, complex management
• Diabetic foot team: any foot ulceration
• Bariatric surgery: BMI ≥35 (or ≥30 in high-risk ethnic groups) with T2DM

T2DM is progressive; most patients require treatment intensification over time. UKPDS: tight glycaemic control reduces microvascular complications by ~25%. Cardiovascular disease is the leading cause of death (~60-70%). SGLT2i and GLP-1 RA have demonstrated cardiovascular and renal benefits beyond glucose lowering. DiRECT trial: ~46% of patients achieved diabetes remission at 1 year with intensive weight management. Life expectancy reduced by ~6-8 years on average. Early diagnosis and aggressive multifactorial risk management (glucose, BP, lipids) improves outcomes.

NICE NG28 Treatment Ladder (Simplified)

Key T2DM Cardiovascular/Renal Trials