Only ten years ago the phrase "start with metformin" sounded like a law. ADA 2026 puts it differently. Recommendation 9.5: the choice of glucose-lowering agents in adults with T2DM is a shared decision. It takes into account sufficient efficacy for individual goals; effects on the heart, kidney, weight and other comorbidities; risk of hypoglycaemia; cost and access; adverse reactions; and the person's preferences (level E). Recommendation 9.6: consider combination therapy right from the start, to shorten the path to the individual goal (level A).
This does not abolish metformin. ADA 2026 Table 9.2 gives it high glucose-lowering efficacy, a neutral or slightly weight-reducing profile, and no hypoglycaemia as a class. The contraindication the course states as a number: eGFR <30 mL/min/1.73 m². KDIGO 2022 recommends metformin in T2DM, CKD and eGFR ≥30 (Recommendation 4.1.1, 1B) and reduces the dose at eGFR <45. The ADA/KDIGO 2022 consensus: at eGFR 30–44 the dose is reduced to 1000 mg/day; in some people with eGFR 45–59 and a high risk of lactic acidosis, likewise. MoH RK 2022 protocol: metformin is the priority starting drug if tolerated and in the absence of contraindications; it is contraindicated at GFR ≤30, hepatic failure, hypoxic states, alcoholism and any acidosis; it is withheld for two days before and after radiocontrast procedures.
What shifted "always metformin". Classes appeared whose RCTs showed reductions not only in HbA1c percentage points but in hospitalisations and death — in specific populations. ADA 2026 therefore draws the algorithm in Fig. 9.4 in two columns: on the left, organ protection (ASCVD, HF, CKD, metabolic dysfunction-associated steatohepatitis (MASH, formerly non-alcoholic steatohepatitis, NASH)); on the right, glycaemia and weight. MASH is the inflammatory-fibrotic form of metabolic fatty liver disease; ADA 2026 (9.12–9.13a) uses it as a separate axis for choosing the glycaemic class, not as a morphological "lipomatosis".
The first-line map by comorbidity (ADA 2026, §9):
- Established ASCVD or high risk of it — a GLP-1 receptor agonist and/or an SGLT2 inhibitor with proven cardiovascular benefit is included in the plan, regardless of HbA1c (9.7, level A).
- Heart failure (reduced or preserved ejection fraction, EF) — an SGLT2 inhibitor regardless of HbA1c (9.8, level A).
- Symptomatic HFpEF plus obesity — a dual GIP/GLP-1 agonist with proven benefit on symptoms and HF events (9.9a, level A); a GLP-1 agonist with benefit on symptoms (9.9b).
- CKD with eGFR 20–60 and/or albuminuria — an SGLT2 inhibitor or a GLP-1 agonist with proven benefit in this population, regardless of HbA1c (9.10, level A). The glycaemic effect of SGLT2 inhibitors weakens at eGFR <45; organ protection does not.
- Advanced CKD with eGFR <30 — for glycaemia a GLP-1 agonist is preferred because of the lower risk of hypoglycaemia and for the reduction of cardiovascular events (9.11, level B); on dialysis, GLP-1 therapy that does not depend on renal clearance can be started or continued (level C).
In its text on management, the MoH RK 2022 protocol is already close in spirit: with ASCVD — a GLP-1 RA or SGLT2i; with CKD — an SGLT2i or GLP-1 RA; with CHF — an SGLT2i; metformin remains the priority for starting. The divergence lies in the GFR details for SGLT2i (next lesson) and in the fact that ADA 2026 no longer requires "metformin first, then an add-on" if the comorbidity itself points to an organ-protective class.
Insulin at the start. Recommendation 9.20: consider insulin regardless of background therapy and disease duration with symptoms of hyperglycaemia or very high values — HbA1c >10% (>86 mmol/mol) or glucose ≥300 mg/dL (≥16.7 mmol/L) (level E). If there is no severe hyperglycaemia and no crisis, GLP-1 therapy is preferred to insulin as a start or add-on (9.21, level A). The MoH RK 2022 protocol does not make the presence of an acute coronary syndrome (ACS) an automatic reason to switch everyone to insulin.
The conclusion. The first line is the answer to the question "which event do we want to prevent in this person", not to the question "which drug is cheaper in table 9 of the protocol". Metformin often remains in the regimen. It has stopped being the only correct first move.