Cardio · prevention-risk
Diabetes as cardiovascular disease: SGLT2 inhibitor and GLP-1 RA outcomes
Fellowship-level guide to cardiovascular protection in type 2 diabetes under the 2023 ESC diabetes guideline, the 2026 ESC heart failure guideline, the 2024 ESC chronic coronary syndromes and hypertension guidelines, ADA Standards of Care 2026, the 2026 AHA/ACC/ADA/ASN CKM guideline and the 2026 ACC/AHA dyslipidemia guideline: risk categories, severe target-organ damage and SCORE2-Diabetes; SGLT2 inhibitor and GLP-1 RA rows for ASCVD, no ASCVD, heart failure and CKD; pioglitazone, saxagliptin and the HF-neutral agents; lipid, blood pressure and aspirin rows in diabetes; and the cardiovascular outcome trials.
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Red flags
- ESC 2023: SGLT2 inhibitors and GLP-1 RAs with proven CV benefit are recommended in T2DM with ASCVD to reduce CV events, independent of baseline or target HbA1c and independent of concomitant glucose-lowering medication (each Class I, Level A)
- ESC 2023: pioglitazone (Class III, Level A) and saxagliptin (Class III, Level B) are not recommended for glucose-lowering treatment in patients at risk of HF (or with previous HF)
- ESC 2023: in T2DM without ASCVD or severe TOD, an SGLT2 inhibitor or GLP-1 RA at a SCORE2-Diabetes 10-year CVD risk ≥10% may be considered to reduce CV risk (Class IIb, Level C), a Task Force consensus
- ESC 2026 HF: an SGLT2 inhibitor (dapagliflozin or empagliflozin) is recommended in patients with symptomatic HF independent of LVEF to reduce the risk of HF hospitalisation or CV death (Class I, Level A)
- ADA 2026: SGLT2 inhibitors for cardiovascular and kidney events in type 1 diabetes are not currently recommended because of a significant increase in diabetic and euglycaemic ketoacidosis
This page is about one idea. In type 2 diabetes, some glucose-lowering drugs are chosen to reduce cardiovascular risk and the risk of kidney failure, independent of glucose control.[1]
- Risk scores in the general population: Cardiovascular risk prediction and when to treat: SCORE2, PREVENT and the Australian calculator.
- Antianginal and event-prevention therapy once coronary disease is established: Chronic coronary syndrome: antianginal therapy, event prevention and where revascularisation fits.
- Other comorbidities in heart failure, including CKD: HF comorbidities: iron deficiency, CKD, gout and cachexia.
- LDL-C goals and lipid drug choice: Dyslipidaemia: LDL-C targets, statin intensity, ezetimibe and PCSK9 inhibitors.
Why diabetes is managed as a cardiovascular disease
ESC 2023 starts from the numbers.[1] People with T2DM are at a two- to four-fold higher risk of developing CVD during their lifetime, including CAD, stroke, HF, AF and peripheral artery disease.[1] The overlap runs both ways: T2DM is common among patients with ASCVD, and ASCVD is common in patients with T2DM.[1] Many patients with CVD also have undiagnosed T2DM.[1]
ADA 2026 uses CVD as a broad term that includes ASCVD and heart failure.[2] ESC 2026 HF adds that patients with HF who have T2DM have a poorer prognosis than those who do not.[4]
Two reasons to prescribe a glucose-lowering drug
ESC 2023 separates the two intentions behind a glucose-lowering prescription.[1] One is to improve CV outcomes and safety; the other is to control glucose.[1] Its prescribing recommendations are split the same way.[1] Many decisions are independent of glucose management, so T2DM status can inform decisions on mitigating CV risk.[1]
Risk stratification in type 2 diabetes
The first question is whether the patient already has ASCVD or severe TOD.[1] ESC 2023 lists what to weigh: medical and family history, symptoms, examination, laboratory and other test results, and the presence of ASCVD or severe TOD.[1]
ESC 2023 Recommendation Table 2: Recommendations for assessing cardiovascular risk in patients with type 2 diabetes (all rows)
| ESC 2023 Recommendation Table 2 row | Class, Level |
|---|---|
| It is recommended to screen patients with diabetes for the presence of severe TOD. | I, A |
| It is recommended to assess medical history and the presence of symptoms suggestive of ASCVD in patients with diabetes. | I, B |
| In patients with T2DM without symptomatic ASCVD or severe TOD, it is recommended to estimate 10-year CVD risk via SCORE2-Diabetes (footnote: SCORE2-Diabetes refers to patients aged ≥40 years). | I, B |
What counts as severe target-organ damage
ESC 2023 defines severe TOD by kidney function, albuminuria and microvascular disease.[1]
- eGFR <45 mL/min/1.73 m² irrespective of albuminuria, or[1]
- eGFR 45–59 mL/min/1.73 m² and microalbuminuria (UACR 30–300 mg/g; stage A2), or[1]
- proteinuria (UACR >300 mg/g; stage A3), or[1]
- microvascular disease in at least three different sites, for example microalbuminuria (stage A2) plus retinopathy plus neuropathy.[1]
The four ESC 2023 risk categories
ESC 2023 Table 7: Cardiovascular risk categories in type 2 diabetes (all rows)
| Category | ESC 2023 criteria (patients with T2DM) |
|---|---|
| Very high CV risk | Clinically established ASCVD, or severe TOD, or 10-year CVD risk ≥20% using SCORE2-Diabetes |
| High CV risk | Not fulfilling the very high-risk criteria and a 10-year CVD risk 10% to <20% using SCORE2-Diabetes |
| Moderate CV risk | Not fulfilling the very high-risk criteria and a 10-year CVD risk 5% to <10% using SCORE2-Diabetes |
| Low CV risk | Not fulfilling the very high-risk criteria and a 10-year CVD risk <5% using SCORE2-Diabetes |
ESC 2023 Figure 3 adds a caution about the bands.[1] The thresholds suggested are not definitive; they are designed to prompt joint decision-making with patients about the intensity of treatment and additional interventions.[1] ESC 2023 also says the 10-year thresholds are for guidance only, and other patient characteristics may lead to decisions to treat or not treat irrespective of them.[1]
[1]SCORE2-Diabetes
SCORE2-Diabetes extends the regionally recalibrated European SCORE2 model to people with T2DM aged 40–69 years without ASCVD or severe TOD.[1] It estimates the individual 10-year risk of fatal and non-fatal CVD events (MI, stroke).[1] Its inputs combine conventional risk factors (age, smoking status, SBP, total and HDL-cholesterol) with diabetes-specific information such as age at diabetes diagnosis, HbA1c and eGFR.[1]
Model development extending the SCORE2 algorithms; external validation in 217 036 further individuals (38 602 CVD events)
Population: Individual-participant data from four large-scale datasets: 229 460 participants (43 706 CVD events) with type 2 diabetes and without previous CVD
Key finding
Good discrimination and improvement over SCORE2 (C-index change from 0.009 to 0.031)
The derivation paper gives an example of how the diabetes-specific inputs change the estimate.[10] In the moderate-risk region, a 60-year-old non-smoking man with T2DM, average conventional risk factors, HbA1c 50 mmol/mol, eGFR 90 mL/min/1.73 m² and diagnosis at 60 had an estimated 10-year CVD risk of 11%.[10] A similar man with HbA1c 70 mmol/mol, eGFR 60 mL/min/1.73 m² and diagnosis at 50 had an estimated risk of 17%; for a woman with the same characteristics, the risk was 8% and 13%, respectively.[10]
- Below 40 years: in T2DM without ASCVD and/or severe TOD, ESC 2023 says risk factors for ASCVD should be evaluated on an individual basis.[1]
- CAC and intima media thickness: ESC 2023 finds not enough robust evidence that either helps reclassify CV risk in people with T2DM.[1]
- BP decisions: ESC 2024 says SCORE2-Diabetes should be considered to estimate CVD risk among T2DM patients with elevated BP, particularly if they are <60 years of age (Class IIa, Level B).[6]
- ESC 2024 narrative: on average, patients with diabetes are at ≥10% 10-year risk for CVD.[6]
Other frameworks
How other guidelines place people with diabetes (selected entries)
| Framework | How diabetes is placed |
|---|---|
| ESC/EAS 2025 dyslipidaemia focused update Table 3, very high risk | DM with target organ damage (footnote: microalbuminuria, retinopathy, or neuropathy), or at least three major risk factors, or early onset of T1DM of long duration (>20 years) |
| ESC/EAS 2025 Table 3, high risk | Patients with DM without target organ damage (as defined in the footnote above), with DM duration ≥10 years or another additional risk factor |
| ESC/EAS 2025 Table 3, moderate risk | Young patients (T1DM <35 years; T2DM <50 years) with DM duration <10 years, without other risk factors |
| AHA/ACC/ADA/ASN CKM 2026, stage 2 | Metabolic risk factors (hypertriglyceridaemia, hypertension, metabolic syndrome or type 2 diabetes), moderate- to high-risk CKD, or both, in the absence of subclinical or clinical CVD |
| CKM 2026, stage 3 | Subclinical CVD with overlapping CKM risk factors, or the risk equivalents of very high-risk CKD or high 10-year predicted risk (≥20%) using the PREVENT equations |
| CKM 2026, stage 4 | Clinical CVD (coronary heart disease, HF, stroke, PAD or atrial fibrillation) overlapping with CKM risk factors |
| ACC/AHA 2026 dyslipidemia | Most adults 40 to 75 years of age with diabetes are at intermediate or high risk of a first ASCVD event |
| Australia 2023 | CVD risk assessment from 35 years in people with diabetes without known CVD; the Aus CVD Risk Calculator includes diabetes-specific risk markers |
The ESC/EAS 2025 Table 3 entries above are the diabetes lines of its cardiovascular risk categories; ESC 2023 Table 7 uses clinically established ASCVD, severe TOD and SCORE2-Diabetes bands instead.[8][1] State which framework you are using before you name a category.
SGLT2 inhibitors and GLP-1 receptor agonists by population
The drug rows are organised by the patient in front of you: established ASCVD, no ASCVD, heart failure or CKD.[1] In each group, the HbA1c does not decide whether the drug is indicated.[1][4]
[1] [4]Type 2 diabetes with established ASCVD
ESC 2023 Recommendation Table 8: Recommendations for glucose-lowering treatment for patients with type 2 diabetes and atherosclerotic cardiovascular disease to reduce cardiovascular risk (all rows)
| Source group heading | ESC 2023 Recommendation Table 8 row | Class, Level |
|---|---|---|
| (no group heading) | It is recommended to prioritize the use of glucose-lowering agents with proven CV benefits followed by agents with proven CV safety over agents without proven CV benefit or proven CV safety. | I, C |
| Sodium–glucose co-transporter-2 inhibitors | SGLT2 inhibitors with proven CV benefit are recommended in patients with T2DM and ASCVD to reduce CV events, independent of baseline or target HbA1c and independent of concomitant glucose-lowering medication. | I, A |
| Glucagon-like peptide-1 receptor agonists | GLP-1 RAs with proven CV benefit are recommended in patients with T2DM and ASCVD to reduce CV events, independent of baseline or target HbA1c and independent of concomitant glucose-lowering medication. | I, A |
| Other glucose-lowering medications to reduce cardiovascular risk | If additional glucose control is needed, metformin should be considered in patients with T2DM and ASCVD. | IIa, C |
| Other glucose-lowering medications to reduce cardiovascular risk | If additional glucose control is needed, pioglitazone may be considered in patients with T2DM and ASCVD without HF. | IIb, B |
- Proven CV benefit, SGLT2 inhibitors (footnote c): empagliflozin, canagliflozin, dapagliflozin, sotagliflozin.[1]
- Proven CV benefit, GLP-1 RAs (footnote d): liraglutide, semaglutide s.c., dulaglutide, efpeglenatide.[1]
- Proven CV safety (footnote e): metformin, pioglitazone, DPP-4 inhibitor (sitagliptin, alogliptin, linagliptin), glimepiride, gliclazide, insulin glargine, insulin degludec, ertugliflozin, lixisenatide, exenatide (extended release), oral semaglutide.[1]
ESC 2023 Recommendation Table 22, first group: the SGLT2 inhibitor row for T2DM with multiple ASCVD risk factors or established ASCVD (selected row)
| Source group heading | ESC 2023 Recommendation Table 22 row | Class, Level |
|---|---|---|
| Recommendations for glucose-lowering medications to reduce heart failure hospitalization in patients with type 2 diabetes with or without existing heart failure | SGLT2 inhibitors (empagliflozin, canagliflozin, dapagliflozin, ertugliflozin, or sotagliflozin) are recommended in patients with T2DM with multiple ASCVD risk factors or established ASCVD to reduce the risk of HF hospitalization (footnote: sotagliflozin is a dual SGLT1/2 inhibitor). | I, A |
This ESC 2023 row names a different purpose from Recommendation Table 8 (HF hospitalisation rather than CV events), so a patient with T2DM and ASCVD meets both.[1] It also covers T2DM with multiple ASCVD risk factors and no ASCVD, which overlaps the next section's population.[1] The newer ESC 2026 HF Recommendation Table 1 row covers the same population (multiple ASCVD risk factors or established ASCVD), with the same Class I, Level A, to reduce the risk of HF and CV death.[4]
Why both classes, and why independent of metformin?[1] ESC 2023 reports that a meta-analysis of six SGLT2 inhibitor trials showed a reduction in MACE, most apparent in patients with established ASCVD.[1] It reports that a meta-analysis of seven GLP-1 RA trials (excluding ELIXA) gave a pooled estimate for GLP-1 RA vs. placebo 15% lower for the primary outcome (HR 0.85; 95% CI, 0.80–0.90).[1] On these aggregate results, ESC 2023 calls each class a preferred glucose-lowering therapy for T2DM with ASCVD, independent of glucose control considerations and of background metformin use.[1]
Not every drug in each class behaved the same way.[1] ESC 2023 notes that neither dapagliflozin nor ertugliflozin reduced MACE, but both reduced HF hospitalisation, with consistency across the class for HF benefits.[1] It also notes that five of the eight GLP-1 RAs tested demonstrated superior CV outcomes on the primary composite of CV death, MI and stroke compared with placebo.[1]
ESC 2023 reports that, in the seven-trial GLP-1 RA meta-analysis, the point estimate was lower in those with established ASCVD (HR 0.85) than in those without (HR 0.94), with P int = 0.068.[1] It reads this as suggesting but not conclusively proving that GLP-1 RAs may reduce risks more in those with established ASCVD.[1] It adds that, as absolute risks are greater in those with established CV disease, the absolute benefits are also expected to be greater.[1]
Other rows for diabetes with established atherosclerotic disease (selected rows)
| Guideline | Row | Class or grade |
|---|---|---|
| ESC 2024 CCS (Recommendation Table 19, CCS patients with type 2 diabetes) | SGLT2 inhibitors with proven CV benefit are recommended in patients with T2DM and CCS to reduce CV events, independent of baseline or target HbA1c and independent of concomitant glucose-lowering medication. | Class I, Level A |
| ESC 2024 CCS (Recommendation Table 19, CCS patients with type 2 diabetes) | GLP-1 receptor agonists with proven CV benefit are recommended in patients with T2DM and CCS to reduce CV events, independent of baseline or target HbA1c and independent of concomitant glucose-lowering medication. | Class I, Level A |
| ESC 2024 CCS (Recommendation Table 19, CCS patients without type 2 diabetes) | The GLP-1 receptor agonist semaglutide should be considered in overweight (BMI ≥27 kg/m²) or obese CCS patients without diabetes to reduce CV mortality, MI, or stroke. | Class IIa, Level B |
| ADA 2026 (10.40b) | In people with type 2 diabetes and established ASCVD or multiple ASCVD risk factors, or CKD, an SGLT2 inhibitor with demonstrated cardiovascular benefit is recommended to reduce the risk of cardiovascular events. | Grade A |
| ADA 2026 (10.40c) | In people with type 2 diabetes and established ASCVD or multiple risk factors for ASCVD, or CKD, a GLP-1 RA with demonstrated cardiovascular benefit is recommended to reduce the risk of cardiovascular events. | Grade A |
| AHA/ACC/ADA/ASN CKM 2026 (Recommendations for CKM Syndrome Stage 4 With T2D and ASCVD) | For adults with CKM syndrome stage 4 with T2D and ASCVD, the use of either an SGLT2i or a GLP-1-based therapy with proven cardiovascular benefit is recommended to reduce the risk of cardiovascular events and cardiovascular mortality. | COR 1, LOE A |
ESC 2024 Recommendation Table 19 is given in full above: two rows for CCS with T2DM and one for CCS without diabetes.[5] Its footnotes list canagliflozin, dapagliflozin, empagliflozin and sotagliflozin, and dulaglutide, efpeglenatide, liraglutide and semaglutide.[5]
ADA 2026 reports that meta-analyses suggest GLP-1 RAs and SGLT2 inhibitors reduce atherosclerotic MACE to a comparable degree in T2DM with established ASCVD.[2] It adds that both classes also reduce HF hospitalisation and progression of kidney disease in people with established ASCVD, multiple ASCVD risk factors or albuminuric kidney disease.[2]
Type 2 diabetes without ASCVD or severe target-organ damage
In ESC 2023, the Recommendation Table 9 rows for T2DM without ASCVD or severe TOD are Class IIa or IIb.[1] ESC 2023 reports that the SGLT2 inhibitor meta-analysis showed no statistically significant MACE benefit in patients without ASCVD but with multiple risk factors, although the point estimate stayed favourable.[1]
ESC 2023 Recommendation Table 9: Recommendation for glucose-lowering treatment for patients with type 2 diabetes without atherosclerotic cardiovascular disease or severe target-organ damage to reduce cardiovascular risk (all rows)
| ESC 2023 Recommendation Table 9 row | Class, Level |
|---|---|
| In patients with T2DM without ASCVD or severe TOD at low or moderate risk, treatment with metformin should be considered to reduce CV risk. | IIa, C |
| In patients with T2DM without ASCVD or severe TOD at high or very high risk, treatment with metformin may be considered to reduce CV risk. | IIb, C |
| In patients with T2DM without ASCVD or severe TOD but with a calculated 10-year CVD risk ≥10% (using SCORE2-Diabetes), treatment with a SGLT2 inhibitor or GLP-1 RA may be considered to reduce CV risk. | IIb, C |
ESC 2023 explains the ≥10% row: it is a consensus within the Task Force, based on the assumption that some level of predicted CVD risk appears to be equivalent to severe TOD risk, acknowledging it is a Level C recommendation.[1]
Recommendation Table 9 is not the only ESC 2023 row for this population: if the patient has multiple ASCVD risk factors, the Recommendation Table 22 row above also applies.[1] It recommends SGLT2 inhibitors (empagliflozin, canagliflozin, dapagliflozin, ertugliflozin or sotagliflozin) to reduce the risk of HF hospitalisation (Class I, Level A).[1] Name the table and its purpose when you quote a class for a patient without ASCVD.
Other rows for diabetes without established ASCVD (selected rows)
| Guideline | Row | Class or grade |
|---|---|---|
| AHA/ACC/ADA/ASN CKM 2026 (Recommendations for T2D in CKM Syndrome Stage 2 to 3) | In adults with CKM syndrome stage 2 to 3 with T2D and increased risk for CVD (10-y PREVENT-CVD ≥7.5%), the treatment plan should include an SGLT2i or a GLP-1-based therapy with demonstrated benefit to reduce cardiovascular events and mortality. | COR 1, LOE A |
| CKM 2026 (same section) | In adults with CKM syndrome stage 2 to 3 with T2D and increased risk of CVD with A1C levels 0.5% to 1% above their individualized glycemic goal, metformin therapy can be effective when combined with cardioprotective antihyperglycemic therapies (GLP-1-based therapy or SGLT2i) to achieve glycemic targets. | COR 2a, LOE A |
| ADA 2026 (10.40b and 10.40c) | The SGLT2 inhibitor and GLP-1 RA rows include people with type 2 diabetes and multiple ASCVD risk factors. | Grade A |
For newly diagnosed T2DM without CVD or other major CV risk factors at low or moderate CV risk, ESC 2023 says factors other than CV and kidney risk may play a greater role in choosing the drug.[1] It names factors such as affordability, accessibility, side effects, weight benefits, tolerability and ease of use.[1]
Type 2 diabetes and heart failure
ESC 2026 HF says the diagnostic process and therapeutic approach to HF in T2DM are the same as without T2DM, with no evidence that diabetes alters the efficacy of foundational medical therapy.[4]
ESC 2026 HF rows on SGLT2 inhibitors and incretin therapy in established HF (selected rows)
| ESC 2026 HF row | Class, Level |
|---|---|
| An SGLT2-I (dapagliflozin or empagliflozin) is recommended in patients with symptomatic HF independent of LVEF to reduce the risk of HFH or CV death. (Recommendation Table 5) | I, A |
| In-hospital initiation of SGLT2-I is recommended in patients with DHF after initial stabilization to improve QoL and congestion symptoms and reduce the risk of HFH. (Recommendation Table 9) | I, B1 |
| Semaglutide or tirzepatide should be considered for patients with symptomatic HF, LVEF ≥45%, and BMI ≥30 kg/m², regardless of diabetes status, to reduce body weight, and improve exercise capacity and QoL. (Recommendation Table 18) | IIa, B1 |
ADA and CKM rows for type 2 diabetes with heart failure (selected rows)
| Guideline | Row | Class or grade |
|---|---|---|
| ADA 2026 (10.41a) | In people with type 2 diabetes and established heart failure with either preserved or reduced ejection fraction, an SGLT2 inhibitor (including SGLT1/2 inhibitor) with proven benefit in this population is recommended to reduce the risk of worsening heart failure and cardiovascular death. | Grade A |
| ADA 2026 (10.41b) | In people with type 2 diabetes and established heart failure with either preserved or reduced ejection fraction, an SGLT2 inhibitor with proven benefit in this population is recommended to improve quality of life. | Grade A |
| ADA 2026 (10.44d) | In adults with type 2 diabetes, obesity, and symptomatic HFpEF, the treatment plan should include a dual GIP/GLP-1 RA or a GLP-1 RA with demonstrated benefit for reduction in heart failure events. | Grade A (dual GIP/GLP-1 RA); grade B (GLP-1 RA) |
| CKM 2026 (Recommendations for CKM Syndrome Stage 4 With T2D and HF) | In patients with CKM syndrome stage 4 with T2D and HF, SGLT2i should be prioritized as the first-line cardioprotective glucose-lowering medications to reduce cardiovascular death and HF hospitalizations. | COR 1, LOE A |
| CKM 2026 (same section) | In patients with CKM syndrome stage 4 with T2D, HFpEF, and other CKM risk factors, the addition of GLP-1-based therapy with proven cardiovascular benefit to foundational SGLT2i therapy can be beneficial to improve HF symptomology and reduce CKM-related adverse outcomes. | COR 2a, LOE B-R |
- Other comorbidities in heart failure: HF comorbidities: iron deficiency, CKD, gout and cachexia.
Type 2 diabetes and chronic kidney disease
ESC 2023 Recommendation Table 24: Recommendations for patients with chronic kidney disease and diabetes (selected rows)
| ESC 2023 Recommendation Table 24 row | Class, Level |
|---|---|
| A SGLT2 inhibitor (canagliflozin, empagliflozin, or dapagliflozin) is recommended in patients with T2DM and CKD with an eGFR ≥20 mL/min/1.73 m² to reduce the risk of CVD and kidney failure. | I, A |
| Finerenone is recommended in addition to an ACE-I or ARB in patients with T2DM and eGFR >60 mL/min/1.73 m² with a UACR ≥30 mg/mmol (≥300 mg/g), or eGFR 25–60 mL/min/1.73 m² and UACR ≥3 mg/mmol (≥30 mg/g) to reduce CV events and kidney failure. | I, A |
| A GLP-1 RA is recommended at eGFR >15 mL/min/1.73 m² to achieve adequate glycaemic control, due to low risk of hypoglycaemia and beneficial effects on weight, CV risk, and albuminuria. | I, A |
| Low-dose ASA (75–100 mg o.d.) is recommended in patients with CKD and ASCVD. | I, A |
ESC 2026 HF: Recommendations for prevention of heart failure, CKD rows (selected rows)
| ESC 2026 HF Recommendation Table 1 row | Class, Level |
|---|---|
| An SGLT2-I is recommended in patients with T2DM and CKD to reduce the risk of HF or CV death. | I, A |
| Finerenone is recommended in patients with T2DM and CKD to reduce the risk of HF. | I, A |
In these two ESC 2026 HF rows, CKD is defined by the entry criteria of the trials: DAPA-CKD, EMPA-KIDNEY and CREDENCE for the SGLT2 inhibitor row, and FIDELIO-DKD and FIGARO-DKD for finerenone.[4] ESC 2026 HF calls the evidence that both SGLT2 inhibitors and finerenone lower HF risk in T2DM and CKD strong.[4] The 2026 ESC guideline on cardiovascular disease and chronic kidney disease is not held as text for this topic, so its rows are not given here.
ADA and CKM rows for type 2 diabetes with CKD (selected rows)
| Guideline | Row | Class or grade |
|---|---|---|
| ADA 2026 (10.42) | For individuals with type 2 diabetes and CKD with albuminuria treated with maximum tolerated doses of ACE inhibitor or ARB, recommend treatment with a nonsteroidal MRA with demonstrated benefit to improve cardiovascular outcomes and reduce the risk of CKD progression. | Grade A |
| ADA 2026 (10.44f) | In individuals with type 2 diabetes and CKD, recommend treatment with a nonsteroidal MRA with demonstrated benefit to reduce the risk of hospitalization for heart failure. | Grade A |
| CKM 2026 (Recommendations for Management of CKD in CKM Syndrome Stage 2 to 3) | In adults with CKM syndrome stage 2 to 3 who have CKD, T2D, and UACR ≥30 mg/g despite ACEi/ARB and SGLT2i as tolerated, with eGFR ≥25 mL/min/1.73 m², the addition of a nonsteroidal MRA with proven kidney and cardiovascular benefit is recommended to reduce the risks of losing kidney function and kidney failure, and to lower the risk of CVD. | COR 1, LOE A |
| CKM 2026 (same section) | In adults with CKM syndrome stage 2 to 3 who have CKD, T2D, and UACR ≥100 mg/g despite ACEi/ARB and SGLT2i as tolerated, treatment with GLP-1-based therapy with proven kidney and cardiovascular benefit is recommended to reduce the risks of losing kidney function and kidney failure, and to lower the risk of CVD. | COR 1, LOE B-R |
Combining the two classes
Combination SGLT2 inhibitor plus GLP-1-based therapy (selected rows)
| Guideline | Row | Class or grade |
|---|---|---|
| ADA 2026 (10.40d) | In people with type 2 diabetes and established ASCVD or multiple risk factors for ASCVD, combined therapy with an SGLT2 inhibitor with demonstrated cardiovascular benefit and a GLP-1 RA with demonstrated cardiovascular benefit may be considered for additive reduction of the risk of adverse cardiovascular and kidney events. | Grade B |
| CKM 2026 (stage 4 with T2D and ASCVD) | For adults with CKM syndrome stage 4 with T2D and ASCVD, the use of a combination of SGLT2i and a GLP-1-based therapy can be beneficial to improve cardiovascular outcomes. | COR 2a, LOE C-LD |
| CKM 2026 (stage 2 to 3 with T2D) | In adults with CKM syndrome stage 2 to 3 with T2D and increased risk for CVD or multiple CKM risk factors, or both, combination therapy with a GLP-1-based therapy with proven benefit and an SGLT2i may be considered for reducing the risk of cardiovascular events beyond that conferred by a single agent. | COR 2b, LOE B-NR |
ADA 2026 frames the rationale as emerging data suggesting an additive cardiovascular and kidney outcomes benefit that is largely independent of glycaemic management.[2]
The 2026 ADA/EASD consensus report on the management of type 2 diabetes is a consensus statement, not a guideline, and gives no class or grade in its abstract.[24] Its abstract says: "earlier combination use of SGLT2 inhibitors and GLP-1-based therapies should be considered in people with concomitant cardiovascular disease, chronic kidney disease, and heart failure".[24] It also says: "earlier use, potentially from diagnosis, of sodium-glucose cotransporter 2 (SGLT2) inhibitors and/or glucagon-like peptide 1 (GLP-1)-based therapies to offer organ protection and improve long-term outcomes in type 2 diabetes is advocated".[24]
Drug-specific heart failure rows
Some glucose-lowering drugs are neutral for HF hospitalisation; two raise it.[1] ESC 2023 Recommendation Table 22 groups them by that effect.[1]
ESC 2023 Recommendation Table 22: Recommendations for glucose-lowering medications in patients with type 2 diabetes with and without heart failure (selected rows)
| Source group heading | ESC 2023 row | Class, Level |
|---|---|---|
| Recommendations for additional glucose-lowering agents with safety demonstrated for heart failure hospitalization in patients with type 2 diabetes if additional glucose control is needed | GLP-1 RAs (lixisenatide, liraglutide, semaglutide, exenatide ER, dulaglutide, efpeglenatide) have a neutral effect on the risk of HF hospitalization, and should be considered for glucose-lowering treatment in patients with T2DM at risk of or with HF. | IIa, A |
| Same group | DPP-4 inhibitors (sitagliptin and linagliptin) have a neutral effect on the risk of HF hospitalization, and should be considered for glucose-lowering treatment in patients with T2DM at risk of or with HF. | IIa, A |
| Same group | Basal insulins (glargine and degludec) have a neutral effect on the risk of HF hospitalization and should be considered for glucose-lowering treatment in patients with T2DM at risk of or with HF. | IIa, B |
| Same group | Metformin should be considered for glucose-lowering treatment in patients with T2DM and HF (footnote: chronic and stable HF). | IIa, B |
| Recommendations for glucose-lowering medications with an increased risk of heart failure hospitalization in patients with type 2 diabetes | Pioglitazone is associated with an increased risk of incident HF in patients with diabetes and is not recommended for glucose-lowering treatment in patients at risk of HF (or with previous HF). | III, A |
| Same group | The DPP-4 inhibitor saxagliptin is associated with an increased risk of HF hospitalization in patients with diabetes and is not recommended for glucose-lowering treatment in patients at risk of HF (or with previous HF). | III, B |
| Recommendations for special consideration | It is recommended to switch glucose-lowering treatment from agents without proven CV benefit or proven safety to agents with proven CV benefit. | I, C |
The first group of Recommendation Table 22 also has rows for T2DM and HFrEF and for T2DM and LVEF >40% (HFmrEF and HFpEF).[1] They are omitted here because, for symptomatic HF, this page gives the newer ESC 2026 HF row (SGLT2 inhibitor independent of LVEF, to reduce the risk of HF hospitalisation or CV death) above.[4] The first-group row recommending SGLT2 inhibitors (empagliflozin, canagliflozin, dapagliflozin, ertugliflozin or sotagliflozin) in T2DM with multiple ASCVD risk factors or established ASCVD to reduce the risk of HF hospitalisation (Class I, Level A) is given under type 2 diabetes with established ASCVD.[1]
[1] [4]Pioglitazone: allowed in ASCVD, not in heart failure
Pioglitazone is the drug that trips candidates. ESC 2023 says that, if additional glucose control is needed, it may be considered in T2DM and ASCVD without HF (Class IIb, Level B).[1] The same guideline says it is not recommended for glucose-lowering in patients at risk of HF or with previous HF (Class III, Level A).[1]
ESC 2023 reports that thiazolidinediones increase the risk of HF, at an estimated 0.4% annualised absolute increase with pioglitazone.[1] It says HF with thiazolidinediones appears to be attributable to expanded plasma volume, with no evidence of myocardial toxicity.[1] CKM 2026 agrees that pioglitazone may lower ASCVD risk but is associated with increased risk of HF.[3] ADA 2026 says thiazolidinediones should be avoided in people with heart failure.[2]
Saxagliptin and the other DPP-4 inhibitors
ESC 2023 reports that saxagliptin significantly increased the risk of HF hospitalisation and is not recommended in patients with diabetes with or at increased risk of HF.[1] Alogliptin showed a non-significant trend towards more HF hospitalisation, while sitagliptin and linagliptin had a neutral effect.[1] ADA 2026 adds that DPP-4 inhibitor outcome trials have not shown cardiovascular benefit relative to placebo.[2]
ESC 2026 HF states that saxagliptin and thiazolidinediones have been associated with an approximately 30% increased risk of HF hospitalisation and, thus, are contraindicated in patients with HF.[4] That is a narrative statement (no class or level given); the formal ESC rows remain the ESC 2023 rows, which do not recommend either drug for glucose-lowering in patients at risk of HF (or with previous HF) (Class III).[4][1]
Metformin, insulin and sulphonylureas in heart failure
- Metformin: ESC 2023 says it is suggested to be safe at all stages of HF with preserved or stable, moderately reduced kidney function (eGFR >30 mL/min/1.73 m²); ESC 2026 HF says it is not recommended at eGFR <30 mL/min/1.73 m² or with hepatic impairment because of the risk of lactic acidosis.[1][4]
- Metformin, ADA 2026 (10.45, grade B): in type 2 diabetes with stable HF, metformin may be continued for glucose lowering if eGFR remains >30 mL/min/1.73 m², but should be avoided in unstable or hospitalised individuals with HF.[2]
- Insulin: ESC 2023 reports that in T2DM and advanced HF, insulin use is independently associated with a significantly worse prognosis; ESC 2026 HF says patients should be monitored for worsening HF after starting insulin.[1][4]
- Sulphonylureas: ESC 2023 calls the HF data inconsistent; ESC 2026 HF says no consistent data are available in HF.[1][4]
- GLP-1 RA with DPP-4 inhibitor: ESC 2023 Figure 16 notes GLP-1 RAs are preferred in ASCVD and if weight reduction is needed, and are not to be combined with DPP-4 inhibitors.[1]
Lipids in diabetes
The full lipid ladder is in Dyslipidaemia: LDL-C targets, statin intensity, ezetimibe and PCSK9 inhibitors; this section gives the diabetes rows. ESC 2023 Recommendation Table 11 sets LDL-C targets by the ESC 2023 risk category.[1]
ESC 2023 Recommendation Table 11: Recommendations for the management of dyslipidaemia in patients with diabetes (selected rows)
| Source group heading | ESC 2023 row | Class, Level |
|---|---|---|
| Lipid targets | In patients with T2DM at moderate CV risk, an LDL-C target of <2.6 mmol/L (<100 mg/dL) is recommended. | I, A |
| Lipid targets | In patients with T2DM at high CV risk, an LDL-C target of <1.8 mmol/L (<70 mg/dL) and LDL-C reduction of at least 50% is recommended. | I, A |
| Lipid targets | In patients with T2DM at very high CV risk, an LDL-C target of <1.4 mmol/L (<55 mg/dL) and LDL-C reduction of at least 50% is recommended. | I, B |
| Lipid-lowering treatment | Statins are recommended as the first-choice LDL-C-lowering treatment in patients with diabetes and above-target LDL-C levels. | I, A |
| Lipid-lowering treatment | If the target LDL-C is not reached with statins, combination therapy with ezetimibe is recommended. | I, B |
ACC/AHA 2026 Recommendations for Adults With Diabetes Without Established ASCVD (selected rows)
| ACC/AHA 2026 row (Section 4.2.5, Diabetes in Adults Without Established ASCVD) | COR, LOE |
|---|---|
| In adults 40 to 75 years of age with diabetes and without clinical ASCVD, moderate-intensity statin therapy is indicated to achieve a ≥30% to 49% reduction in LDL-C and a goal of LDL-C <100 mg/dL (2.6 mmol/L) and non-HDL-C <130 mg/dL (3.4 mmol/L) to reduce ASCVD risk. | 1, A |
| In adults with diabetes who have statin-attributed side effects, initiation of ezetimibe and/or bempedoic acid or a PCSK9 mAb is recommended to lower LDL-C and reduce ASCVD risk. | 1, B-R |
| In adults 40 to 75 years of age with diabetes who have multiple ASCVD risk factors, it is reasonable to prescribe high-intensity statin therapy to achieve a ≥50% reduction in LDL-C and a goal of LDL-C <70 mg/dL (1.8 mmol/L) and non-HDL-C <100 mg/dL (2.6 mmol/L) to reduce ASCVD risk. | 2a, B-R |
| In adults with diabetes and 10-year ASCVD risk of ≥10% by the PREVENT-ASCVD equations, it may be reasonable to add ezetimibe or a PCSK9 mAb to maximally tolerated statin therapy to achieve an LDL-C goal of <70 mg/dL (1.8 mmol/L) and non-HDL-C <100 mg/dL (2.6 mmol/L) to reduce ASCVD risk. | 2b, C-LD |
| In adults >75 years of age with diabetes and an estimated life expectancy of at least 2.5 years, it may be reasonable to initiate moderate-intensity statin therapy after a clinician–patient discussion of potential benefits and risks to reduce ASCVD risk. | 2b, C-LD |
| In adults 20 to 39 years of age with diabetes of long duration (≥10 years of type 2 diabetes, ≥20 years of type 1 diabetes), albuminuria (≥30 μg of albumin/mg creatinine), estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m², retinopathy, neuropathy, or ankle-brachial index <0.9, it may be reasonable to initiate moderate-intensity statin therapy to reduce ASCVD risk. | 2b, C-LD |
- ADA 2026 (10.18, grade A): for people with diabetes aged 40–75 years without ASCVD, use moderate-intensity statin therapy in addition to lifestyle therapy.[2]
- ADA 2026 (10.20, grade A): for people with diabetes aged 40–75 years at higher cardiovascular risk, including those with one or more additional ASCVD risk factors, high-intensity statin therapy is recommended to reduce LDL cholesterol by ≥50% of baseline and to obtain an LDL cholesterol goal of <70 mg/dL (<1.8 mmol/L).[2]
- ADA 2026 (10.27, grade B): for people with diabetes and ASCVD, high-intensity statin therapy is recommended to obtain an LDL cholesterol reduction of ≥50% from baseline and a goal of <55 mg/dL (<1.4 mmol/L), adding ezetimibe or a PCSK9 inhibitor with proven benefit if this goal is not achieved on maximum tolerated statin therapy.[2]
- ACC/AHA 2026 Table 17 (diabetes-specific risk enhancers): long duration (≥10 years for type 2, ≥20 years for type 1 diabetes), albuminuria ≥30 μg of albumin/mg creatinine, eGFR <60 mL/min/1.73 m², retinopathy, neuropathy and ABI <0.9.[7]
Blood pressure in diabetes
ESC 2024 Recommendation Table 25: Recommendations for managing hypertension in patients with diabetes (selected rows)
| ESC 2024 hypertension row | Class, Level |
|---|---|
| In most adults with elevated BP and diabetes, after a maximum of 3 months of lifestyle intervention, BP lowering with pharmacological treatment is recommended for those with confirmed office BP ≥130/80 mmHg to reduce CVD risk. | I, A |
| In persons with diabetes who are receiving BP-lowering drugs, it is recommended to target systolic BP to 120–129 mmHg, if tolerated. | I, A |
- ESC 2026 HF (Recommendation Table 1): strict BP control (systolic target <130 mmHg) is recommended in patients with hypertension or stage B HF to reduce the risk of HF (Class I, Level A).[4]
- ADA 2026 (10.4, grade A): if it can be safely attained, the on-treatment BP goal is <130/80 mmHg; a systolic goal <120 mmHg should be encouraged in individuals with high cardiovascular or kidney risk.[2]
- ADA 2026 (10.6, grade A): with confirmed office BP ≥130/80 mmHg, pharmacologic therapy should be initiated and titrated to the individualised goal.[2]
- ADA 2026 (10.8, grade A): treatment should include drug classes demonstrated to reduce cardiovascular events in diabetes; ACE inhibitors or ARBs are recommended first-line therapy for hypertension in diabetes and albuminuria or coronary artery disease.[2]
- ADA 2026 (10.43, grade A): in diabetes aged ≥55 years with established ASCVD or multiple ASCVD risk factors, ACE inhibitor or ARB therapy is recommended to reduce the risk of cardiovascular events.[2]
Aspirin and antithrombotic therapy in diabetes
For primary prevention, the ESC 2023 and ADA 2026 rows both say "may be considered".[1][2] ESC 2023 says that in adults with T2DM without a history of symptomatic ASCVD or revascularisation, aspirin (75–100 mg once daily) may be considered to prevent the first severe vascular event, in the absence of clear contraindications (Class IIb, Level A).[1] Its footnote defines those contraindications as high bleeding risk due to gastrointestinal haemorrhage or peptic ulcer within 6 months, active hepatic disease, or aspirin allergy.[1]
ESC 2023 reports the ASCEND trial as the largest adequately powered, placebo-controlled RCT of low-dose aspirin in T1DM or T2DM without evident CVD (n = 15 480).[1] Over 7.4 years, aspirin reduced serious vascular events (8.5% vs. 9.6%; RR 0.88; NNT 91).[1] BARC type 3–5 bleeding occurred in 4.1% vs. 3.2% of patients in the aspirin and placebo arms (RR 1.29; number needed to harm 111).[1]
-
ADA 2026 (10.36, grade A): aspirin (75–162 mg/day) may be considered for primary prevention in those with diabetes at increased cardiovascular risk, after a comprehensive discussion of the benefits versus the comparable increased risk of bleeding.[2]
-
ADA 2026 (10.33, grade A): use aspirin (75–162 mg/day) as secondary prevention in those with diabetes and a history of ASCVD.[2]
-
ESC 2023 (Recommendation Table 24, Class I, Level A): low-dose aspirin (75–100 mg once daily) is recommended in patients with CKD and ASCVD.[1]
-
ESC 2023 narrative: patients with diabetes and documented significant CAD or prior revascularisation are at very high CV risk, and low-dose aspirin (75–100 mg once daily) is recommended, although ad hoc RCTs are lacking.[1]
-
ADA 2026 (10.35, grade A): aspirin 81 mg daily plus rivaroxaban 2.5 mg twice daily should be considered for stable coronary and/or peripheral artery disease with low bleeding risk to prevent major adverse limb and cardiovascular events.[2]
-
Once coronary disease is established: Chronic coronary syndrome: antianginal therapy, event prevention and where revascularisation fits.
The cardiovascular outcome trials
The cards below give each trial's population, design and primary result as reported in its abstract.[11][15][21] Read the population first: it decides whom the result applies to.
SGLT2 inhibitors
Randomised to empagliflozin 10 mg or 25 mg or placebo once daily; primary outcome CV death, nonfatal MI or nonfatal stroke
Population: Type 2 diabetes at high cardiovascular risk; 7020 patients treated, median observation 3.1 years
Key finding
Primary outcome 10.5% in the pooled empagliflozin group vs. 12.1% with placebo (HR 0.86; 95.02% CI 0.74 to 0.99; P=0.04 for superiority); lower CV death (38% relative risk reduction) and HF hospitalisation (35% relative risk reduction)
Randomised to canagliflozin or placebo; primary outcome CV death, nonfatal MI or nonfatal stroke
Population: 10,142 participants with type 2 diabetes and high cardiovascular risk in two trials; 65.6% had a history of cardiovascular disease; mean follow-up 188.2 weeks
Key finding
Primary outcome 26.9 vs. 31.5 per 1000 patient-years (HR 0.86; 95% CI 0.75 to 0.97); increased risk of amputation (HR 1.97), primarily at the level of the toe or metatarsal
Randomised to dapagliflozin or placebo
Population: 17,160 patients with type 2 diabetes who had or were at risk for ASCVD, including 10,186 without ASCVD; median follow-up 4.2 years
Key finding
MACE not lower (8.8% vs. 9.4%; HR 0.93; 95% CI 0.84 to 1.03); CV death or HF hospitalisation lower (4.9% vs. 5.8%; HR 0.83), reflecting fewer HF hospitalisations (HR 0.73)
Multicentre, double-blind; ertugliflozin 5 mg or 15 mg or placebo once daily; with the two dose groups pooled, noninferiority to placebo for MACE
Population: 8246 patients with type 2 diabetes and ASCVD; mean follow-up 3.5 years
Key finding
MACE 11.9% in both groups (HR 0.97; 95.6% CI 0.85 to 1.11; P<0.001 for noninferiority)
GLP-1 receptor agonists and tirzepatide
Double-blind; liraglutide or placebo; primary outcome CV death, nonfatal MI or nonfatal stroke
Population: 9340 patients with type 2 diabetes and high cardiovascular risk; median follow-up 3.8 years
Key finding
Primary outcome 13.0% vs. 14.9% (HR 0.87; 95% CI 0.78 to 0.97; P=0.01 for superiority)
Once-weekly semaglutide (0.5 mg or 1.0 mg) or placebo for 104 weeks
Population: 3297 patients with type 2 diabetes on standard care; 83.0% had established CVD, CKD or both
Key finding
Primary outcome 6.6% vs. 8.9% (HR 0.74; 95% CI 0.58 to 0.95; P<0.001 for noninferiority); retinopathy complications significantly higher (HR 1.76)
Multicentre, randomised, double-blind, placebo-controlled; weekly dulaglutide 1.5 mg or placebo
Population: 9901 men and women aged at least 50 years with type 2 diabetes and either a previous cardiovascular event or cardiovascular risk factors; median follow-up 5.4 years
Key finding
Primary outcome 12.0% vs. 13.4% (HR 0.88; 95% CI 0.79-0.99; p=0.026)
Randomised, placebo-controlled, 344 sites in 28 countries; weekly subcutaneous efpeglenatide 4 or 6 mg or placebo
Population: Type 2 diabetes with either a history of cardiovascular disease or current kidney disease (eGFR 25.0 to 59.9 mL/min/1.73 m²) plus at least one other cardiovascular risk factor; median follow-up 1.81 years
Key finding
MACE 7.0% vs. 9.2% (HR 0.73; 95% CI 0.58 to 0.92; P = 0.007 for superiority)
Double-blind, placebo-controlled, event-driven superiority trial; once-daily oral semaglutide (maximal dose 14 mg) or placebo
Population: 9650 participants aged 50 years or older with type 2 diabetes (HbA1c 6.5 to 10.0%) and known ASCVD, CKD or both; median follow-up 49.5 months
Key finding
MACE 12.0% vs. 13.8% (HR 0.86; 95% CI 0.77 to 0.96; P = 0.006); confirmatory secondary outcomes did not differ significantly
Active-comparator-controlled, double-blind noninferiority trial; weekly tirzepatide (up to 15 mg) vs. dulaglutide (1.5 mg)
Population: Type 2 diabetes and ASCVD; 6586 patients assigned tirzepatide and 6579 dulaglutide in the modified intention-to-treat population
Key finding
Primary end point (CV death, MI or stroke) 12.2% vs. 13.1% (HR 0.92; 95.3% CI 0.83 to 1.01; P = 0.003 for noninferiority; P = 0.09 for superiority)
Two newer trial results matter here.[19][20][2][1] ESC 2023 listed oral semaglutide among agents with proven CV safety.[1] SOUL (2025; double-blind, placebo-controlled; 9650 participants aged 50 years or older with type 2 diabetes, HbA1c 6.5 to 10.0%, and known ASCVD, CKD or both; median follow-up 49.5 months) then reported a lower MACE risk with oral semaglutide against placebo.[19] ADA 2026 describes tirzepatide outcome trials as ongoing; SURPASS-CVOT (N Engl J Med 2025; active-comparator-controlled, double-blind; type 2 diabetes and ASCVD) reports tirzepatide noninferior to dulaglutide for CV death, MI or stroke.[2][20]
Kidney outcome trial
Randomised to subcutaneous semaglutide 1.0 mg weekly or placebo; primary outcome major kidney disease events, including death from kidney-related or cardiovascular causes
Population: 3533 patients with type 2 diabetes and CKD; median follow-up 3.4 years after early cessation at a prespecified interim analysis
Key finding
Primary outcome 24% lower (HR 0.76; 95% CI 0.66 to 0.88); death from cardiovascular causes HR 0.71 (95% CI 0.56 to 0.89)
The heart failure safety signals
Randomised to saxagliptin or placebo
Population: 16,492 patients with type 2 diabetes who had a history of, or were at risk for, cardiovascular events; median follow-up 2.1 years
Key finding
Primary end point 7.3% vs. 7.2% by 2-year Kaplan-Meier estimates (HR 1.00; 95% CI 0.89 to 1.12); hospitalisation for HF 3.5% vs. 2.8% (HR 1.27; 95% CI 1.07 to 1.51)
Prospective randomised controlled trial; pioglitazone or placebo added to existing therapy
Population: 5238 patients with type 2 diabetes and evidence of macrovascular disease; average observation 34.5 months
Key finding
Primary composite not significantly reduced (HR 0.90, 95% CI 0.80-1.02, p=0.095); main secondary endpoint of all-cause mortality, non-fatal MI and stroke reduced (0.84, 0.72-0.98, p=0.027); more HF admissions with pioglitazone (6% vs. 4%)
Safety and special situations
- Genital and urinary infections: ESC 2026 HF, in its section on diabetes, says SGLT2 inhibitors are generally well tolerated but may cause urinary infections and genital fungal infections, with a prevalence of up to 6.9% in women and 4.8% in men.[4]
- Ketoacidosis: in DECLARE-TIMI 58 (17,160 patients with type 2 diabetes who had or were at risk for ASCVD, dapagliflozin vs placebo, median 4.2 years), diabetic ketoacidosis was more common with dapagliflozin than placebo (0.3% vs. 0.1%); ADA 2026 (10.46, grade E) says to educate individuals with diabetes at risk of DKA who are treated with SGLT inhibition on the risks and signs of ketoacidosis and methods of risk mitigation management, provide them with appropriate tools for ketone measurement (serum β-hydroxybutyrate) and discourage a ketogenic eating pattern.[13][2]
- Euglycaemic ketoacidosis: ADA 2026 notes the infrequent but serious risk of diabetic ketoacidosis with SGLT inhibition, including the atypical presentation of euglycaemic ketoacidosis.[2]
- Type 1 diabetes: ADA 2026 says SGLT2 inhibitors for cardiovascular and kidney events in type 1 diabetes are being investigated and are not currently recommended, because of a significant increase in diabetic and euglycaemic ketoacidosis.[2]
- Pregnancy: ESC 2026 HF says ACE-Is, ARBs, ARNIs, MRAs, ivabradine and SGLT2 inhibitors are not recommended during pregnancy due to the risk of foetotoxicity or teratogenicity (Class III, Level C).[4]
- Amputation: the CANVAS Program (10,142 participants with type 2 diabetes and high cardiovascular risk, canagliflozin vs placebo, mean follow-up 188.2 weeks) reported an increased risk of amputation with canagliflozin (6.3 vs. 3.4 per 1000 patient-years; HR 1.97), primarily at the level of the toe or metatarsal.[12]
- Retinopathy: SUSTAIN-6 (3297 patients with type 2 diabetes on standard care, once-weekly semaglutide vs placebo for 104 weeks) reported significantly more retinopathy complications with semaglutide (HR 1.76).[16]
- Older adults: ACC/AHA 2026 says that above 75 years with diabetes and an estimated life expectancy of at least 2.5 years, it may be reasonable to start moderate-intensity statin therapy after a clinician–patient discussion (COR 2b, LOE C-LD).[7]
Screening the asymptomatic patient
- ADA 2026 (10.37a, grade A): in asymptomatic individuals, routine screening for coronary artery disease is not recommended, as it does not improve outcomes as long as ASCVD risk factors are treated.[2]
- ADA 2026 (10.38a, grade B): adults with diabetes are at increased risk of stage B or stage C HF; consider screening by measuring a natriuretic peptide (BNP or NT-proBNP) to facilitate prevention of stage C HF.[2]
- ADA 2026 (10.44c): in type 2 diabetes with asymptomatic (stage B) HF or with high risk of or established CVD, an SGLT inhibitor with proven HF prevention benefit (grade A) or a GLP-1 RA with HF prevention benefit (grade B) is recommended to reduce the risk of hospitalisation for HF.[2]
Evidence, guidelines and regional differences
Europe (ESC)
2023 diabetes; 2024 CCS; 2026 HF
- T2DM and ASCVD: an SGLT2 inhibitor with proven CV benefit and, in a separate row, a GLP-1 RA with proven CV benefit are recommended to reduce CV events, independent of baseline or target HbA1c and of concomitant glucose-lowering medication, each Class I, Level A (ESC 2023; ESC 2024 for T2DM and CCS)
- T2DM without ASCVD or severe TOD, SCORE2-Diabetes 10-year CVD risk ≥10%: an SGLT2 inhibitor or GLP-1 RA may be considered to reduce CV risk, Class IIb, Level C (ESC 2023)
- T2DM at risk of HF (multiple ASCVD risk factors or established ASCVD): an SGLT2 inhibitor is recommended to reduce the risk of HF and CV death, Class I, Level A (ESC 2026 HF); ESC 2023 Recommendation Table 22 recommends SGLT2 inhibitors (empagliflozin, canagliflozin, dapagliflozin, ertugliflozin or sotagliflozin) in the same population to reduce the risk of HF hospitalisation, Class I, Level A
United States (ADA and AHA/ACC)
ADA 2026; CKM 2026
- T2D with established ASCVD, multiple ASCVD risk factors or CKD: an SGLT2 inhibitor (10.40b) and a GLP-1 RA (10.40c), each with demonstrated cardiovascular benefit, are each recommended to reduce the risk of cardiovascular events, grade A (ADA 2026)
- Adults with CKM stage 2 to 3 with T2D and 10-year PREVENT-CVD ≥7.5%: the treatment plan should include an SGLT2i or GLP-1-based therapy with demonstrated benefit to reduce cardiovascular events and mortality, COR 1, LOE A (CKM 2026)
- T2D with established ASCVD or multiple ASCVD risk factors: combined therapy with an SGLT2 inhibitor and a GLP-1 RA, each with demonstrated cardiovascular benefit, may be considered for additive reduction of the risk of adverse cardiovascular and kidney events, grade B (ADA 2026, 10.40d); in adults with CKM stage 4 with T2D and ASCVD, a combination of an SGLT2i and a GLP-1-based therapy can be beneficial to improve cardiovascular outcomes, COR 2a, LOE C-LD (CKM 2026)
Australia
2023 CVD risk guideline
- CVD risk assessment in people with diabetes without known CVD from 35 years, using the Aus CVD Risk Calculator (5-year risk; high ≥10%)
- BP-lowering and lipid-modifying drugs should be prescribed for high risk and considered for intermediate risk, unless contraindicated or clinically inappropriate
Guidelines checked for this topic
- ESC: 2023 diabetes guideline, 2026 heart failure guideline, 2024 chronic coronary syndromes guideline, 2024 hypertension guideline and the 2025 ESC/EAS dyslipidaemia focused update.[1][4][5][6][8]
- United States: ADA Standards of Care in Diabetes 2026 (Section 10), the 2026 AHA/ACC/ADA/ASN CKM guideline and the 2026 ACC/AHA dyslipidemia guideline.[2][3][7]
- Australia: 2023 guideline for assessing and managing CVD risk (Med J Aust summary abstract).[9]
- Consensus documents checked (not guidelines; PubMed abstracts only): the 2026 ADA/EASD consensus report on the management of type 2 diabetes, quoted under combining the two classes, and the 2026 EJHF expert consensus statement on pharmacological strategies to prevent HF across the cardiovascular-kidney-metabolic spectrum, which changes no row on this page.[24][25]
- Trials: the outcome trials above, from their PubMed abstracts.[11][19][20]
The 2023 ESC diabetes guideline is the newest ESC diabetes guideline among the guidelines checked for this topic (census 2026-10-09). Where a newer ESC guideline covers the same decision, such as ESC 2026 HF for heart failure or ESC 2024 for blood pressure targets, the newer row is given. The 2026 ESC guideline on cardiovascular disease and chronic kidney disease is not held as text for this topic and is not used. No Australian or New Zealand diabetes-specific cardiovascular guideline was held as text for this topic; the Australian content comes from the 2023 CVD risk guideline summary.[9]
Pitfalls
Exam pearls
- ESC 2023 proven CV benefit: SGLT2 inhibitors empagliflozin, canagliflozin, dapagliflozin, sotagliflozin; GLP-1 RAs liraglutide, semaglutide s.c., dulaglutide, efpeglenatide.[1]
- ESC 2023 severe TOD: eGFR <45; eGFR 45–59 with UACR 30–300 mg/g; UACR >300 mg/g; or microvascular disease in at least three sites.[1]
- ESC 2023 categories by SCORE2-Diabetes: very high ≥20%, high 10% to <20%, moderate 5% to <10%, low <5%.[1]
- ESC 2026 HF Recommendation Table 1, T2DM: an SGLT2 inhibitor is recommended at risk of HF (multiple ASCVD risk factors or established ASCVD) to reduce the risk of HF and CV death (I A), and with CKD to reduce the risk of HF or CV death (I A); finerenone is recommended with CKD to reduce the risk of HF (I A); a GLP-1 RA should be considered with at least one other additional CV risk factor to reduce the risk of HF or CV death (IIa A).[4]
- In those two CKD rows, CKD is defined by trial entry criteria that differ by row: footnote c gives the entry criteria of DAPA-CKD, EMPA-KIDNEY and CREDENCE for the SGLT2 inhibitor, and footnote d those of FIDELIO-DKD and FIGARO-DKD for finerenone.[4]
- ESC 2023 Recommendation Table 22, if additional glucose control is needed: the listed GLP-1 RAs (lixisenatide, liraglutide, semaglutide, exenatide ER, dulaglutide, efpeglenatide) and sitagliptin and linagliptin (each IIa A), and basal insulins glargine and degludec (IIa B), have a neutral effect on the risk of HF hospitalisation and should be considered for glucose-lowering treatment in T2DM at risk of or with HF; metformin should be considered for glucose-lowering treatment in T2DM and chronic and stable HF (IIa B).[1]
- EMPA-REG OUTCOME (7020 patients with type 2 diabetes at high cardiovascular risk treated, empagliflozin vs placebo, median 3.1 years): primary composite of CV death, nonfatal MI or nonfatal stroke, HR 0.86 for the pooled empagliflozin group.[11]
- LEADER (double-blind; 9340 patients with type 2 diabetes and high cardiovascular risk, liraglutide vs placebo, median 3.8 years): primary outcome HR 0.87.[15]
- SUSTAIN-6 (3297 patients with type 2 diabetes on standard care, once-weekly semaglutide vs placebo for 104 weeks): primary outcome HR 0.74, P<0.001 for noninferiority.[16]
- DECLARE-TIMI 58 (17,160 patients with type 2 diabetes who had or were at risk for ASCVD, dapagliflozin vs placebo, median 4.2 years): MACE not lower (HR 0.93; P=0.17), but CV death or HF hospitalisation lower (HR 0.83).[13]
- SAVOR-TIMI 53 (16,492 patients with type 2 diabetes who had a history of, or were at risk for, cardiovascular events, saxagliptin vs placebo, median 2.1 years): HF hospitalisation HR 1.27.[21]
References25ShowHide
- [1]Marx N, et al. 2023 ESC Guidelines for the management of cardiovascular disease in patients with diabetes. Eur Heart J, 2023.PMID 37622663
- [2]American Diabetes Association Professional Practice Committee for Diabetes*, et al. 10. Cardiovascular Disease and Risk Management: Standards of Care in Diabetes-2026. Diabetes Care, 2026.PMID 41358899
- [3]Ndumele CE, et al. 2026 AHA/ACC/ADA/ASN Guideline for the Prevention, Detection, Evaluation, and Management of Cardiovascular-Kidney-Metabolic Syndrome: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol, 2026.PMID 42265997
- [4]Køber L, et al. 2026 ESC Guidelines for the management of heart failure. Eur Heart J, 2026.PMID 42661420
- [5]Vrints C, et al. 2024 ESC Guidelines for the management of chronic coronary syndromes. Eur Heart J, 2024.PMID 39210710
- [6]McEvoy JW, et al. 2024 ESC Guidelines for the management of elevated blood pressure and hypertension. Eur Heart J, 2024.PMID 39210715
- [7]Blumenthal RS, et al. 2026 ACC/AHA/AACVPR/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Dyslipidemia: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol, 2026.PMID 41824590
- [8]Mach F, et al. 2025 Focused Update of the 2019 ESC/EAS Guidelines for the management of dyslipidaemias. Eur Heart J, 2025.PMID 40878289
- [9]Nelson MR, et al. 2023 Australian guideline for assessing and managing cardiovascular disease risk. Med J Aust, 2024.PMID 38623719
- [10]SCORE2-Diabetes Working Group and the ESC Cardiovascular Risk Collaboration, et al. SCORE2-Diabetes: 10-year cardiovascular risk estimation in type 2 diabetes in Europe. Eur Heart J, 2023.PMID 37247330
- [11]Zinman B, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med, 2015.PMID 26378978
- [12]Neal B, et al. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med, 2017.PMID 28605608
- [13]Wiviott SD, et al. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med, 2019.PMID 30415602
- [14]Cannon CP, et al. Cardiovascular Outcomes with Ertugliflozin in Type 2 Diabetes. N Engl J Med, 2020.PMID 32966714
- [15]Marso SP, et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med, 2016.PMID 27295427
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