Type 2 Diabetes — Comorbidity-Stratified Medicine Selection
Based on: Type 2 Diabetes in Adults: Management (NG28) — NICE (last updated February 2026)
Reference: https://www.nice.org.uk/guidance/ng28
PURPOSE
Use this skill when initiating or intensifying glucose-lowering treatment in an adult with
type 2 diabetes. The NICE NG28 framework stratifies medicine choice by the person's
comorbidity profile rather than a single universal algorithm. This skill identifies the
correct comorbidity category, maps it to the guideline-recommended initial regimen, and
specifies when and how to add further medicines if glycaemic targets are not met.
STEP 1 — GATHER INFORMATION
Collect the following before selecting a medicine regimen:
Glycaemic status
- Current HbA1c (mmol/mol and %)
- Individualised HbA1c target already agreed (or needs agreeing — see NICE NG28 Section 1.5)
- Current glucose-lowering medicines (drug, dose, duration, tolerability)
- Duration since diagnosis
Comorbidity screen — ask and document each:
- Heart failure? (any ejection fraction)
- Established atherosclerotic cardiovascular disease (ASCVD)? (coronary artery disease, stroke, peripheral arterial disease)
- Early onset type 2 diabetes? (defined by NICE as diagnosis before age 40)
- Obesity? (BMI ≥30 kg/m², or ≥27.5 kg/m² in South Asian / Black African or Caribbean groups)
- Chronic kidney disease (CKD)? If yes: current eGFR (ml/min/1.73 m²)
- Frailty? (if suspected, confirm with validated frailty assessment before prescribing)
Safety parameters
- eGFR — essential for metformin and SGLT-2 inhibitor dosing and contraindications
- Risk factors for diabetic ketoacidosis (DKA): previous DKA, intercurrent illness, very low carbohydrate / ketogenic diet, dehydration
- Hypoglycaemia risk: driving / machinery, fall risk, impaired hypoglycaemia awareness
- Current use of DPP-4 inhibitor (incompatible with GLP-1 receptor agonists / tirzepatide)
- Pregnancy status or intent (separate guidance applies)
Patient factors
- Preference regarding injection vs oral route
- Adherence concerns or previous intolerances
- Weight trajectory and weight target
STEP 2 — RULE IN / RULE OUT
Confirm this skill applies:
- Adult with confirmed type 2 diabetes (if treatment response is atypical, revisit diagnosis per NICE NG17 on type 1 diabetes)
- Decision point is initiation or intensification of glucose-lowering medicine
Immediate escalation — do not use this skill as the primary action if:
- Hyperglycaemic emergency (DKA, hyperosmolar hyperglycaemic state) → emergency pathway
- HbA1c ≥75 mmol/mol (9.0%) on no treatment → consider combination basal insulin + oral agents from the outset (see Section 1.33.2)
- Intercurrent acute illness → sick day rules apply first (Section 1.10); defer medicine changes until stable
Contraindication checks before proceeding:
- Metformin is contraindicated if eGFR <30 ml/min/1.73 m²
- Most SGLT-2 inhibitors should not be initiated if eGFR <30 ml/min/1.73 m² (dapagliflozin and empagliflozin have specific lower thresholds — check SPC)
- GLP-1 receptor agonists / tirzepatide must NOT be combined with a DPP-4 inhibitor
- Pioglitazone is contraindicated in heart failure
Multiple comorbidities: If the person has more than one listed comorbidity (e.g. ASCVD and CKD), make a shared decision taking into account contraindications, relative benefits, and patient preference per Section 1.9.3.
STEP 3 — CLASSIFY OR STRATIFY
Identify the person's primary comorbidity profile from the six NICE categories. If multiple apply, see the note on multiple comorbidities in Step 2.
| Profile | Defining Feature |
|---|
| No relevant comorbidity | T2DM without heart failure, ASCVD, early onset, obesity, CKD, or frailty |
| Heart failure | Any ejection fraction |
| Atherosclerotic cardiovascular disease (ASCVD) | Established coronary artery disease, prior stroke/TIA, or peripheral arterial disease |
| Early onset T2DM | Diagnosis before age 40 |
| Obesity | BMI ≥30 kg/m² (≥27.5 kg/m² in some ethnic groups) |
| Chronic kidney disease | CKD regardless of cause — eGFR subgroup is critical (see Step 4) |
| Frailty | Confirmed by validated frailty assessment |
STEP 4 — DECIDE
INITIAL MEDICINE REGIMEN (first prescription)
| Profile | First-Line Offer | If Metformin Contraindicated / Not Tolerated |
|---|
| No relevant comorbidity | Modified-release metformin + SGLT-2 inhibitor | SGLT-2 inhibitor monotherapy |
| Heart failure | Modified-release metformin + SGLT-2 inhibitor | SGLT-2 inhibitor monotherapy |
| ASCVD | Modified-release metformin + SGLT-2 inhibitor + subcutaneous semaglutide (Ozempic) up to 1 mg/week | SGLT-2 inhibitor + subcutaneous semaglutide up to 1 mg/week |
| Early onset T2DM | Modified-release metformin + SGLT-2 inhibitor; consider adding GLP-1 receptor agonist OR tirzepatide | SGLT-2 inhibitor; consider adding GLP-1 receptor agonist or tirzepatide |
| Obesity | Modified-release metformin + SGLT-2 inhibitor | SGLT-2 inhibitor monotherapy |
| CKD — eGFR >30 | Modified-release metformin + SGLT-2 inhibitor | SGLT-2 inhibitor monotherapy |
| CKD — eGFR 20–30 | Dapagliflozin or empagliflozin + DPP-4 inhibitor | DPP-4 inhibitor monotherapy |
| CKD — eGFR <20 | DPP-4 inhibitor (consider) | Pioglitazone or insulin-based treatment |
| Frailty | Modified-release metformin; SGLT-2 inhibitor only if frailty does not place person at risk of volume depletion or hypotension | If frailty permits: SGLT-2 inhibitor. If not: DPP-4 inhibitor |
Stepwise introduction: Start metformin first, titrate to maximum tolerated dose, then add SGLT-2 inhibitor; if GLP-1 receptor agonist or tirzepatide is part of the plan, add after SGLT-2 inhibitor is at maximum tolerated dose.
FURTHER MEDICINES (HbA1c not at target on initial regimen)
Trigger: HbA1c rises to ≥58 mmol/mol (7.5%) on current treatment — reinforce lifestyle advice, confirm adherence, then intensify medicines.
| Profile | Next Step | If That Is Contraindicated / Not Tolerated / Not Effective |
|---|
| No relevant comorbidity | Add DPP-4 inhibitor | Sulfonylurea OR pioglitazone OR insulin |
| Heart failure | Add DPP-4 inhibitor | Sulfonylurea OR insulin (note: pioglitazone is contraindicated in heart failure) |
| ASCVD (new diagnosis after initial Rx) | Add subcutaneous semaglutide up to 1 mg/week | Then: sulfonylurea OR pioglitazone OR insulin |
| ASCVD (already on semaglutide, needs more) | Add sulfonylurea OR pioglitazone OR insulin | — |
| Early onset (not on GLP-1/tirzepatide) | Consider GLP-1 receptor agonist or tirzepatide; if not suitable: DPP-4 inhibitor | Sulfonylurea OR pioglitazone OR insulin |
| Early onset (already on GLP-1/tirzepatide) | Sulfonylurea OR pioglitazone OR insulin | — |
| Obesity (not on GLP-1/tirzepatide, ≥3 months initial Rx) | Consider GLP-1 receptor agonist or tirzepatide; if not suitable: DPP-4 inhibitor | Sulfonylurea OR pioglitazone OR insulin |
| Obesity (already on GLP-1/tirzepatide) | Sulfonylurea OR pioglitazone OR insulin | — |
| CKD | Consider DPP-4 inhibitor; if already on one: pioglitazone OR sulfonylurea (only if eGFR >30) OR insulin | — |
| Frailty | Consider DPP-4 inhibitor; if not suitable: pioglitazone OR sulfonylurea OR insulin | Warn: sulfonylurea and insulin increase hypoglycaemia and fall risk |
INSULIN-BASED TREATMENT (when indicated across any profile)
- Offer basal insulin (once or twice daily) as initial insulin therapy
- If HbA1c ≥75 mmol/mol (9.0%), consider combining basal + short/rapid-acting insulin from the outset
- Continue metformin on starting insulin; stop other medicines used solely for glycaemia
- Continue SGLT-2 inhibitors if retained for cardiovascular or renal benefit — reassess DKA risk
- Provide structured education: injection technique, self-monitoring, dose titration, hypoglycaemia management, DVLA requirements
STEP 5 — CLINICAL GUARDRAILS
Common Mistakes
- Giving the same regimen to everyone: The NICE 2026 update specifically differentiates initial medicines by comorbidity — a single universal algorithm no longer applies. The most common error is starting metformin alone as the first-line treatment across all profiles.
- Missing ASCVD at initiation: Patients with established coronary artery disease, prior stroke, or peripheral arterial disease qualify for triple therapy from the outset (metformin + SGLT-2 + semaglutide). Failing to identify ASCVD leads to undertreatment.
- Combining GLP-1 receptor agonist / tirzepatide with a DPP-4 inhibitor: These should never be prescribed together — the guideline explicitly prohibits this combination (Section 1.24.6).
- Continuing SGLT-2 inhibitors in frail patients at risk of falls: Volume depletion and hypotension are real risks in frail older adults. Frailty assessment should precede prescribing, not follow it.
- Not reassessing SGLT-2 inhibitor suitability as eGFR declines: An SGLT-2 inhibitor that was appropriate at eGFR 45 may be contraindicated when eGFR falls below 30. Monitor and review at each visit.
- Stopping SGLT-2 inhibitors when glycaemic target is reached: The guideline states they should be continued for cardiovascular and renal protection even if glycaemic contribution is minimal (Section 1.24.2).
- Prescribing pioglitazone in heart failure: Pioglitazone is contraindicated in heart failure due to fluid retention risk — it appears in further medicine options for several profiles but must be excluded for the heart failure group.
Mimics and Diagnostic Traps
- Latent autoimmune diabetes in adults (LADA): Can present identically to type 2 diabetes in adults aged 30–50. Consider if: rapid deterioration on oral agents, low BMI, personal or family history of autoimmune disease, unexplained DKA. Check GAD antibodies and C-peptide.
- Monogenic diabetes (MODY): Consider in young adults with a strong family history and mild, stable hyperglycaemia — particularly if their treatment response to oral agents is unusually good or poor. Genetic testing changes management significantly.
- Steroid-induced hyperglycaemia: Requires a separate management approach — capillary blood glucose monitoring is indicated, and glucose patterns differ (predominantly postprandial). Do not apply standard T2DM targets.
What NOT To Do
- Do NOT prescribe GLP-1 receptor agonist / tirzepatide + DPP-4 inhibitor together — no additive benefit and guideline-prohibited
- Do NOT start a ketogenic or very low carbohydrate diet without suspending the SGLT-2 inhibitor — euglycaemic DKA risk (Section 1.21.3)
- Do NOT initiate SGLT-2 inhibitors in an unwell, dehydrated, or perioperative patient — DKA risk
- Do NOT use sulfonylureas as initial therapy in patients who drive or operate machinery without discussing hypoglycaemia risk and DVLA implications
- Do NOT apply adult targets to pregnancy — refer to NICE guideline on diabetes in pregnancy
Special Populations
- Older adults / frailty: Consider deprescribing — the smallest effective number of medicines at the lowest effective dose is the explicit NICE recommendation for frail patients. Relax HbA1c targets on a case-by-case basis.
- CKD: Dose adjustments are required across all drug classes — refer to the SPC for each product. Avoid nephrotoxic combinations. Involve pharmacy or nephrology for complex regimens.
- Ethnicity: Obesity thresholds differ — BMI ≥27.5 kg/m² triggers the obesity profile for South Asian, Black African, and Black Caribbean patients.
- Early onset T2DM (diagnosis <40 years): This group typically has a more aggressive disease course, greater insulin resistance, and is more likely to need triple therapy early. GLP-1 receptor agonists and tirzepatide are specifically considered from initiation.
- Pregnancy / childbearing potential: GLP-1 receptor agonists and tirzepatide require specific counselling. SGLT-2 inhibitors are contraindicated in pregnancy. Metformin may be continued in pregnancy under specialist guidance. Refer to NICE NG3 on diabetes in pregnancy.
- Reproductive health: When discussing GLP-1 receptor agonists and tirzepatide with women, trans men, and non-binary people of childbearing potential, follow MHRA guidance on these agents and pregnancy risk (Section 1.9.4).
SOURCE
National Institute for Health and Care Excellence. Type 2 Diabetes in Adults: Management (NG28). London: NICE; 2015, last updated February 2026.
Available from: https://www.nice.org.uk/guidance/ng28