12.2 NICE-Directed Type 2 Therapy & Microvascular Complications

3. Guideline-Directed Pharmacotherapy in Type 2 Diabetes (NICE NG28)

Contemporary NICE guidelines prioritize organ-specific cardiorenal protection over a purely glucose-centric stepped approach. Metformin remains standard initial monotherapy, but dual therapy with an SGLT2 inhibitor is mandated from the outset for individuals with established atherosclerotic cardiovascular disease (ASCVD), heart failure, or high cardiovascular risk.

Insulin Regimens & Initiation Rules

• Basal-Bolus (Multiple Daily Injections - MDI): Standard of care for Type 1 DM and advanced Type 2 DM. Consists of once- or twice-daily long-acting basal analogue (insulin glargine U100/U300, insulin degludec, or insulin detemir) plus rapid-acting prandial analogue (insulin aspart, lispro, or glulisine) administered immediately before meals.
• Biphasic Premixed Regimens: Fixed ratios of rapid/short-acting insulin with protaminated intermediate insulin (e.g., Novomix 30: 30% soluble aspart, 70% protaminated aspart). Administered twice daily before breakfast and evening meal. Best suited for patients with regular meal patterns requiring simpler injection schedules.
• Lipohypertrophy: Proliferation of subcutaneous adipocytes and fibrous tissue triggered by the lipogenic actions of insulin at repeated injection sites. Leads to delayed, erratic insulin absorption and unexplained glycaemic volatility. Prevented by systematic injection site rotation.

4. Chronic Microvascular Complications & Surveillance Targets

Glycaemic Control Targets (NICE NG28)

• Lifestyle or Single Agent (not associated with hypoglycaemia, e.g. Metformin): Target HbA1c $48\text{ mmol/mol}$ ($6.5%$).
• On Drug Associated with Hypoglycaemia (SU, Insulin) or Dual/Triple Therapy: Target HbA1c $53\text{ mmol/mol}$ ($7.0%$).
• Relaxed Individualized Targets ($58\text{–}64\text{ mmol/mol}$): Recommended for frail elderly patients, individuals with severe comorbidities, or those with impaired hypoglycaemia awareness.

Diabetic Retinopathy (DR)

Annual digital retinal screening with mydriatic photography evaluates fundal changes:

English National Screening Programme (ENSPDR) Grading:
- R0: No retinopathy
- R1 (Background): Microaneurysms, dot and blot haemorrhages, hard exudates → Routine 12-month recall
- R2 (Pre-proliferative): Venous beading, venous loops, intraretinal microvascular abnormalities (IRMA), multiple blot haemorrhages in all 4 quadrants, cotton wool spots (nerve fibre layer infarcts) → Urgent ophthalmology referral
- R3 (Proliferative): Neovascularisation of disc (NVD) or elsewhere (NVE), pre-retinal/vitreous haemorrhage, tractional retinal detachment → Immediate pan-retinal photocoagulation (PRP) ± anti-VEGF therapy
- Maculopathy (M0 = absent; M1 = present): Exudates or haemorrhages within 1 disc diameter of fovea, or unexplained reduction in visual acuity → Ophthalmology referral; focal laser / intravitreal anti-VEGF (aflibercept, ranibizumab)

Diabetic Nephropathy

• Screening: Annual measurement of urinary albumin-to-creatinine ratio (ACR) on early morning spot urine, combined with serum creatinine / eGFR.
• Diagnostic Thresholds:
  • Normal: $\text{ACR} < 3.0\text{ mg/mmol}$ ($< 30\text{ mg/g}$).
  • Microalbuminuria (Moderately Increased): $\text{ACR } 3.0\text{–}30.0\text{ mg/mmol}$. Requires confirmation on 2 out of 3 morning samples over 3–6 months to exclude transient causes (UTI, strenuous exercise, fever).
  • Macroalbuminuria (Severely Increased): $\text{ACR} > 30.0\text{ mg/mmol}$.
• Renoprotective Pharmacotherapy:
  • Type 1 DM: Initiate an ACE inhibitor (or ARB) if confirmed persistent $\text{ACR} \ge 3.0\text{ mg/mmol}$, irrespective of baseline blood pressure.
  • Type 2 DM: Initiate an ACE inhibitor (or ARB) if confirmed $\text{ACR} \ge 30.0\text{ mg/mmol}$, or if $\text{ACR } 3.0\text{–}30.0\text{ mg/mmol}$ in the presence of hypertension.
  • SGLT2 Inhibitors: Indicated to retard CKD progression in patients with $\text{eGFR } 20\text{–}60\text{ mL/min}$ or $\text{ACR} > 22.6\text{ mg/mmol}$ (DAPA-CKD, EMPA-KIDNEY trials).
  • Finerenone: Non-steroidal mineralocorticoid receptor antagonist shown in FIDELIO-DKD to reduce renal and cardiovascular outcomes in CKD associated with T2DM.
  • Blood Pressure Targets: $< 140/90\text{ mmHg}$ if $\text{ACR} < 3.0\text{ mg/mmol}$; tighter control to $< 130/80\text{ mmHg}$ if $\text{ACR} \ge 3.0\text{ mg/mmol}$.

Diabetic Neuropathy & The Diabetic Foot

• Distal Symmetric Sensorimotor Polyneuropathy: Chronic "glove and stocking" sensory loss. Earliest signs: loss of vibration perception (128 Hz tuning fork) and loss of protective sensation with 10g Semmes-Weinstein monofilament. Small-fibre neuropathy presents with burning night pain, allodynia, and dysaesthesias. Pharmacotherapy for painful neuropathy: first-line monotherapy with duloxetine, amitriptyline, gabapentin, or pregabalin.
• Autonomic Neuropathy:
  • Cardiovascular: Resting sinus tachycardia, fixed pulse rate, severe orthostatic postural hypotension (fall in systolic BP $\ge 20\text{ mmHg}$ without compensatory tachycardia; treated with midodrine, fludrocortisone).
  • Gastrointestinal: Gastroparesis diabeticorum (delayed gastric emptying causing early satiety, nausea, recurrent vomiting, and unpredictable erratic postprandial hypoglycaemia; treated with prokinetics like metoclopramide, erythromycin); diabetic diarrhoea (bacterial overgrowth or nocturnal autonomic hypermotility).
  • Genitourinary: Atonic neurogenic bladder (urinary retention, overflow incontinence); erectile dysfunction (first-line PDE5 inhibitors).
  • Sudomotor: Gustatory sweating (facial diaphoresis triggered by food ingestion) and foot anhidrosis.
• Diabetic Amyotrophy (Diabetic Lumbosacral Radiculoplexus Neuropathy): Acute, severe asymmetric proximal thigh pain followed by quadriceps muscle wasting and absent knee jerk reflex. Driven by immune-mediated microvasculitis.
• Cranial Mononeuropathy: Pupil-sparing diabetic third nerve palsy (ischaemia of the internal motor fibres sparing outer parasympathetic pupillomotor fibres; pupillary light reflex remains completely intact).
• Charcot Neuroarthropathy: Acute neuropathic osteoarthropathy triggered by autonomic hyperaemia and minor repetitive trauma. Presents as an acutely swollen, erythematous, warm foot (temperature difference $> 2^\circ\text{C}$ compared to contralateral foot) in a neuropathic limb, often mistaken for cellulitis or gout. Urgent management: non-weight-bearing immobilization in a total contact cast to prevent progressive articular collapse and irreversible "rocker-bottom" foot deformity.