The most important message is to treat CV-risk instead of glycemic control.

Lifestyle modification is recommended as the cornerstone for preventing and managing T2DM to improve glycemic control and more important CVD-risk reduction. In the Netherlands, reimbursement is available for the combined lifestyle intervention (GLI), and specifically for T2DM patients the lifestyle program ‘Keer Diabetes2 Om’. Lifestyle modification includes weight reduction, improving diet, increasing physical activity and exercise, as well as smoking cessation. Especially in those with T2DM and obesity, weight reduction is a central goal.

In addition, according to the ESC Guidelines, it is recommended to implement blood pressure control when office blood pressure is ≥ 140/90 mm Hg and aim for a systolic blood pressure of at least < 120 mm Hg at ‘very high’ CVD risk and no frailty. The Dutch Guidelines recommend a target systolic blood pressure of at least < 130 mm Hg for non-frail patients with a ‘very high’ CVD risk.

Moreover, lipid-lowering therapy is a priority for the reduction of CVD risk in patients with diabetes. The ESC Guidelines recommend to aim for an LDL at least < 2.6 mmol/l (< 3.0 mmol/l in the Dutch Guideline), but more specific at least < 1.8 mmol/l (< 2.6 mmol/l in the Dutch Guideline) when at ‘high’ risk for CVD, and < 1.4 mmol/l (< 1.8 mmol/l in the Dutch Guideline for non-frail patients) when having T2DM with already CVD. Statins are recommended as the primary LDL-C-lowering treatment based on the CVD risk profile and the LDL‑C (or non-HDL-C) target levels.

All patients with T2DM and atherosclerotic CVD should receive antithrombotic therapy. Often, a strategy combining antithrombotic therapy, anti-hypertensive drugs and lipid-lowering agents should be implemented (Figs. 2 and 3; [1, 2]) (All Class I indication with Level of evidence A).

Preferred CVD risk-lowering agents in T2DM

For patients with T2DM, the use of glucose-lowering agents with proven CVD risk reduction should be prioritised, followed by agents with proven CVD safety over those without demonstrated CVD risk reduction or proven CVD safety (Class I indication with Level of evidence C).

The 2023 ESC Guidelines categorise glucose-lowering agents into four groups:

1.

Glucose-lowering agents with proven risk reduction in randomised clinical trials: SGLT2 inhibitors (empagliflozin, canagliflozin, dapagliflozin, and sotagliflozin) and specific GLP‑1 receptor agonists (liraglutide, subcutaneous semaglutide, dulaglutide, and efpeglenatide);

2.

Glucose-lowering agents with suggested benefit in randomised clinical trials: metformin and pioglitazone;

3.

Glucose-lowering agents with proven safety in randomised clinical trials: DPP-4 inhibitors (saxaliptin, sitagliptin, alogliptin, and linagliptin), ertugliflozin, specific sulfonylureas (glimepiride and gliclazide), insulin glargine or insulin degludec, and other GLP‑1 receptor agonists (lixisenatide, exenatide, and oral semaglutide);

4.

Glucose-lowering agents without CVD safety evaluation: e.g., short-acting insulins and other sulfonylureas.

The prevailing Dutch General Practitioners (GP) guidelines Diabetes mellitus type 2 (NHG Guidelines-Diabetes Mellitus type 2) advise the use of glucose-lowering agents with proven CVD risk reduction in patients with T2DM at ‘very high’ CVD risk [7].

Thus, in order to reduce CVD risk in patients with T2DM with established CVD both GLP‑1 receptor agonists, and SGLT2 inhibitors are recommended, given their proven CVD risk reduction. In the prevailing iteration of the NHG Guidelines-Diabetes Mellitus type 2 an SGLT2 inhibitor is recommended as the first-line treatment, followed by metformine and GLP‑1 receptor agonists in patients at ‘very high’ CVD risk. A step-by-step scheme for prescription SGLT2 inhibitors and GLP‑1 receptor agonists in daily clinical practice is provided in Fig. 4 taking current Dutch reimbursement criteria into account. These agents can be prescribed on top of standard of care including GLI, and independent of glucose control, target HbA1c, or obesity. However, especially in case of HF, SGLT2i is strongly recommended. In case of obesity, treat with GLP‑1 receptor agonists if possible.

Fig. 4

A step by step scheme for prescription of SGLT2 inhibitors and GLP‑1 receptor agonists in patients with CVD and T2DM (irrespective of HF, CKD or obesity but taken current Dutch reimbursement-criteria into account) by cardiologists in clinical practice in the Netherlands

The prescription of glucose-lowering agents with suggested CVD risk reduction (i.e. metformin and pioglitazone) is still recommended for patients with T2DM without CV disease or already target organ damage. Glucose-lowering agents with only proven CVD safety, but without proven CVD risk reduction—such as specific sulfonylureas (i.e. glimepiride and gliclazide), or DPP-4 inhibitors (i.e. sitagliptin, alogliptin, linagliptin, and saxagliptin)—should ideally be replaced by SGLT2 inhibitors and GLP‑1 receptor agonists. However, in daily practice, reimbursement criteria must be taken into account.

Glucose-lowering agents without proven CVD safety evaluation should be reserved for situations when other aforementioned options are exhausted. Moreover, treatment strategies should be tailored to avoid hypoglycemias (Fig. 3; [1]).

In patients with HF—irrespective of ejection fraction—it is recommended that all patients with T2DM be treated with an SGLT2 inhibitor in addition to standard care, to reduce HF hospitalisation and CVD death (Class I indication with Level of evidence A). Pioglitazone and saxagliptin are not recommended in patients with T2DM with HF or at increased risk for HF.

Patients with T2DM and CKD should receive a statin, as well as treatment with angiotensin-converting enzyme inhibitors (ACEi) or angiotensin-II receptor blockers (ARB), and appropriate blood pressure control (ESC-target ≤ 120 mm Hg and Dutch-target at least < 130 mm Hg for non-frail patients). To reduce the risk of both CVD and kidney failure, these patients should be treated with an SGLT2 inhibitor (empagliflozin or dapagliflozin), provided the eGFR ≥ 20 mL/min/1.73 m2 at the time of SGLT2 inhibitor prescription. The non-steroidal mineralocorticoid receptor antagonist finerenone is recommended in addition to an ACEi or ARB when:

an eGFR ≥ 60 mL/min/1.73 m2 with a UACR ≥ 30 mg/mmol, or

an eGFR 25–60 mL/min/1.73 m2 and UACR ≥ 3 mg/mmol (All Class I indication with Level of evidence A) (Fig. 5; [1]).

Fig. 5

Pharmacological management to reduce cardiovascular or kidney failure risk in patients with type 2 diabetes and chronic kidney disease. ACE‑I angiotensin-converting enzyme inhibitor, ARB angiotensin-II receptor blocker, BP blood pressure, CKD chronic kidney disease, CV cardiovascular, CVD cardiovascular disease, DPP‑4 dipeptidyl peptidase‑4, eGFR estimated glomerular filtration rate, GLP‑1 RA glucagon-like peptide‑1 receptor agonist, RAS renin–angiotensin system, SGLT2 sodium–glucose co-transporter‑2, T2DM type 2 diabetes mellitus, UACR urinary albumin-to-creatinine ratio. aA statin-based regimen reduces CV risk in CKD while ACE‑I or ARBs reduce kidney failure risk; SGLT2 inhibitors, BP control, and finerenone reduce both CV risk and kidney failure risk. SGLT2 inhibitors, RAS inhibitors, and finerenone are particularly effective at reducing risk of kidney failure when albuminuria is present (e.g. UACR ≥ 3 mg/mmol (30 mg/g); stage A2 and A3). bCanagliflozin, empagliflozin, or dapagliflozin. With permission from Oxford University Press

In addition, personalised HbA1c targets are recommended, when possible with a tight target (< 53 mmol/mol) to prevent microvascular complications. HbA1c targets should be adjusted based on the balance between frailty, life expectancy, anticipated benefit, risk of hypoglycemias, and treatment side-effects.

In general, early detection of T2DM and implementation of glucose-lowering treatment with generic (and thereby affordable) agents such as metformin, antihypertensives, and statins has been shown to lower CVD risk in patients with T2DM without manifest CVD.

Finally, management of CVD in patients with T2DM benefits from a multidisciplinary approach (intensive collaboration between all healthcare-professionals involved, especially taken into account the healthcare-professionals who are responsible for the diabetes-care at the GPs) to implement evidence-based personalised strategies to reduce the burden of disease and to improve prognosis.

Infobox 2

Recommendations for personalised treatment strategies in patients with CVD and T2DM in the Netherlands

Evidence-based recommendations for personalised treatment in T2DM includes:

Improve lifestyle.

Implement blood pressure control when office blood pressure is ≥ 140/90 mm Hg aiming for a target of < 120 mm Hg (the Dutch Guideline recommends at least < 130 mm Hg for non-frail patients).

Prescribe statins or other lipid-lowering drugs based on the CVD risk profile and recommended lipid targets for non-HDL (both LDL and TGs).

Prioritise the use of glucose-lowering medications with proven CVD risk reduction benefits, followed by agents with proven CV safety, over agents without proven CV benefit or proven CV safety. Especially in case of HF, SGLT2i is mandatory. In case of obesity, treat with GLP‑1 receptor agonists if possible.Treat patients with CVD and T2DM with a statin, an ACEi or ARB, appropriate blood pressure control (≤ 120/80 mm Hg), and antitrombotic therapy.

Treat patients with T2DM and HF—irrespective of ejection fraction—with an SGLT2 inhibitor.

Treat patients with T2DM and CKD with an SGLT2 inhibitor, a statin, an ACEi or ARB, possibly finerenone, and appropriate blood pressure control.

Use personalised HbA1c targets, with a possible tighter target (< 53 mmol/mol) to prevent microvascular complications.