Clinical staging to guide management of metabolic disorders and their sequelae: a European Atherosclerosis Society consensus statement

Management of systemic metabolic disorder

Goal: The main aim of managing SMD is to prevent disease progression and protect organs. Treatment should be personalized, with lifestyle changes as the foundation.

Lifestyle changes
- Healthy diet: vegetables, whole grains, plant-based proteins, fish, low-fat dairy, and healthy oils; low in sugar, salt, and ultra-processed foods.
- Weight loss improves blood sugar, blood pressure, lipids, liver health, inflammation, and insulin sensitivity.
- Regular physical activity, including aerobic and resistance training, improves metabolism, prevents muscle and bone loss, and reduces sedentary time.
- Diet quality (Mediterranean or Nordic) matters as much as calorie reduction.

Metabolic surgery
- Recommended for severe obesity.
- Improves blood sugar, blood pressure, lipids, liver health, kidney function, and reduces risk of heart failure, heart attack, stroke, and mortality.
- Benefits go beyond weight loss, including better insulin sensitivity, anti-inflammatory effects, and improved lipid profiles.

Pharmacotherapy

Glucagon-like peptide-1 receptor agonists and dual and triple peptide agonists

GLP-1 and dual/triple agonists are drugs that go beyond treating diabetes and obesity—they protect multiple organs and improve outcomes in cardiovascular disease (ASCVD), heart failure with preserved ejection fraction (HFpEF), fatty liver disease (MASLD/MASH), and chronic kidney disease (CKD).

Key points:

Drugs: Semaglutide, liraglutide, dulaglutide, and tirzepatide (GLP-1 or GLP-1/GIP agonists) reduce blood sugar, promote weight loss, and have multi-organ benefits.
Cardiovascular benefits: Proven to reduce heart attacks, strokes, heart failure, and death—even in people without diabetes (SELECT trial).
Heart failure: Improve symptoms and exercise capacity in obese patients with HFpEF (STEP-HFpEF, SUMMIT trials).
Liver disease: Promote resolution of steatohepatitis (MASH), though fibrosis reversal is limited.
Kidney protection: Reduce CKD onset and progression, major kidney events, and cardiovascular death (FLOW, SOUL, SELECT trials).
Weight loss caution: Rapid weight loss may reduce muscle mass; strength training and sufficient protein are recommended to prevent functional decline.
Administration: Mainly subcutaneous; oral semaglutide and new non-peptide agonists are under development.

Bottom line: GLP-1 and related agonists are powerful multi-system therapies for SMD but should always be combined with lifestyle measures, including diet and exercise, to maximize benefits and protect muscle health.

Dosing schedules for the currently prescribed glucagon-like peptide-1 and glucagon-like peptide-1/glucose-dependent insulinotropic polypeptide receptor agonists

Dosing schedule for Type 2 diabetes (and obesity)^a
GLP-1 receptor agonist
Dulaglutide	0.75–4.5 mg once weekly
Exenatide	5–10 µg twice daily
Exenatide (extended-release)	2 mg once weekly
Liraglutide	0.6–1.8 mg once daily (3.0 mg/day for obesity)
Lixisenatide	10–20 µg once daily
Semaglutide subcutaneous	0.25–1.0 mg once weekly (2.4 mg/week for obesity)
Semaglutide tablet	3–14 mg once daily (50 mg/day for obesity)
Dual GLP-1/GIP receptor agonist
Tirzepatide	2.5–15 mg once weekly (same for obesity)

^aAll are administered subcutaneously, with the exception of semaglutide tablet. All drugs are initiated at the lowest dose, which is then increased over several weeks to attenuate possible gastrointestinal side effects.

Sodium–glucose co-transporter 2 inhibitors

SGLT2 inhibitors are drugs that control blood sugar and also protect the heart and kidneys.
Key points:

Reduce hospitalizations and cardiovascular deaths in people with heart failure, with or without diabetes.
Most evidence comes from dapagliflozin, empagliflozin, and sotagliflozin.
Early use is recommended, even for hospitalized heart failure patients once stabilized.
Protect against kidney disease progression and reduce heart failure events in people with CKD, with or without diabetes.
Sotagliflozin also lowers the risk of heart attacks and strokes in high-risk individuals.
Can be used in CKD patients with eGFR as low as 20, regardless of diabetes.

Bottom line: SGLT2 inhibitors are effective for blood sugar, heart, and kidney protection and should be started early in at-risk patients.

Other anti-hyperglycaemic drugs

Other drugs for Type 2 diabetes include metformin, sulfonylureas, meglitinides, acarbose, thiazolidinediones (pioglitazone), and DPP-4 inhibitors.

Key points:

Metformin and pioglitazone improve insulin sensitivity and may help protect blood vessels.
All except pioglitazone can be combined with insulin.
Only GLP-1 receptor agonists and SGLT2 inhibitors have proven heart and kidney benefits.
Other drugs are cardiovascularly safe based on long-term trials.

Lipid-lowering medications

The main goal of lipid-lowering therapy is to reduce LDL-cholesterol, but residual risk can remain in people with atherogenic dyslipidaemia due to high triglyceride-rich lipoproteins (TRLs). Guidelines recommend also targeting non–HDL-cholesterol and apoB.

Key points:

High-intensity statins are first-line; combination therapy may include ezetimibe, bempedoic acid, or PCSK9 inhibitors (e.g., alirocumab, evolocumab, inclisiran).
Metformin with statins may further lower LDL and PCSK9 levels. Statins slightly increase diabetes risk but greatly reduce cardiovascular events.
Fibrates lower triglycerides but don’t clearly reduce cardiovascular risk; high-dose icosapent ethyl is effective in statin-treated patients with high triglycerides.
New therapies for severe hypertriglyceridaemia target apoCIII and ANGPTL3; they lower triglycerides but cardiovascular benefits are still being studied.
Severe hypertriglyceridaemia requires triglyceride-lowering to prevent pancreatitis (e.g., fenofibrate, omega-3).
Lipoprotein(a) is an independent cardiovascular risk factor and should be considered in treatment planning.

Emerging therapies for hypertriglyceridaemia

Drug	Dose	Mechanism of action	Comments
Volanesorsen	Subcutaneous injection of 300 mg once a week	ASO inhibiting apoCIII mRNA production	A randomized, placebo-controlled trial in 15 adults with Type 2 diabetes (HbA1c >7.5%) and hypertriglyceridaemia [2.26–5.65 mmol/L (200–500 mg/dL)]; volanesorsen reduced triglyceride levels by 69% after 91 days.²⁷⁸ Volanesorsen has been approved in EU and UK to treat familial chylomicronaemia syndrome, and it has been shown to reduce the risk of acute pancreatitis²⁷⁹
Olezarsen	Subcutaneous injection of 50 or 80 mg every 4 weeks	GalNAc-conjugated ASO inhibiting apoCIII mRNA production	Bridge-TIMI 73a, a randomized, placebo-controlled Phase 2b trial in 154 adults either with moderate hypertriglyceridaemia [1.69–5.63 mmol/L (150–499 mg/dL)] and elevated cardiovascular risk or with severe hypertriglyceridaemia [≥5.65 mmol/L (500 mg/dL)]; olezarsen reduced triglyceride levels by 53% at the highest dose and reduced the risk of acute pancreatitis²⁸⁰
Plozasiran	Subcutaneous injection of 10, 25, or 50 mg on Day 1 and at Week 12 (follow-up through Week 48)	siRNA inhibiting apoCIII mRNA production	SHASTA-2, a placebo-controlled, double-blind, dose-ranging, Phase 2b randomized trial in 229 adults with severe hypertriglyceridaemia [5.65–45.2 mmol/L (500–4000 mg/dL)]; plozasiran reduced triglyceride levels by 57% at the highest dose.²⁸¹ A Phase 2b, double-blind, randomized, placebo-controlled trial in 353 adults with mixed hyperlipidaemia triglycerides 1.69–5.63 mmol/L (150–499 mg/dL) and either LDL-cholesterol ≥1.8 mmol/L (70 mg/dL) or non–HDL-cholesterol ≥2.6 mmol/L (100 mg/dL)]; plozasiran reduced triglyceride levels by 62% at the highest dose²⁸²
Evinacumab	Intravenous injection of 15 mg/kg every 4 weeks	Monoclonal antibody targeting circulating ANGPTL3 protein	A randomized, placebo-controlled Phase 2 trial; evinacumab reduced triglyceride levels by 62% and 82% after 12 weeks in patients with multi-factorial chylomicronaemia syndrome (MCS) with heterozygous loss-of-function LPL pathway mutations [n = 15; triglycerides 11.3–26.0 mmol/L (1000–2300 mg/dL)] and MCS without LPL pathway mutations [n = 19, triglycerides 13.5–29.3 mmol/L (1200–2600 mg/dL)], respectively²⁸³
Zodasiran	Subcutaneous injection of 50, 100, or 200 mg on Day 1 and Week 12 (follow-up through Week 36)	siRNA inhibiting ANGPTL3 mRNA production	ARCHES-2, a placebo-controlled, dose-ranging Phase 2b trial in 204 adults with mixed hyperlipidaemia [triglycerides 1.69–5.63 mmol/L (150–499 mg/dL) and either LDL-cholesterol ≥1.8 mmol/L (70 mg/dL) or non–HDL-cholesterol ≥2.6 mmol/L (100 mg/dL)]; zodasiran reduced triglyceride levels by 74% after 24 weeks at the highest dose²⁸⁴

ASO, anti-sense oligonucleotide. See the full publication for all references.

Anti-hypertensive medications

Anti-hypertensive treatment should follow international guidelines. Most recommend a target of <130/80 mmHg if tolerated, though some (like ESH) suggest <140/90 mmHg.
Key points:

First-line drugs: thiazide diuretics, calcium channel blockers, ACE inhibitors, or ARBs.
Combination therapy is recommended if BP is >140/90 mmHg or more than 20/10 mmHg above target.
High-risk groups (ASCVD, CKD) may need stricter targets; CKD patients may aim for <120/70 mmHg if safe.
Special indications: ACE inhibitors or ARBs for albuminuria or heart failure; mineralocorticoid receptor antagonists for resistant hypertension; beta-blockers for HFrEF; alpha-1 blockers for men with prostate issues.
Renal denervation is an option for resistant hypertension despite using three or more drugs.

Anti-inflammatory drugs

Statins lower LDL-cholesterol and reduce systemic inflammation (hsCRP), but many patients still have residual inflammatory risk linked to higher rates of heart events and death.
Key points:

Lifestyle changes (exercise, diet) are basic anti-inflammatory measures.
Low-dose colchicine (0.5 mg daily) is now recommended in selected high-risk patients for secondary prevention when risk factors are not fully controlled.
Colchicine is not routinely used immediately after a heart attack.
Other therapies like IL-6 inhibitors are being studied; PCSK9 inhibitors mainly reduce plaque lipids, not hsCRP.
hsCRP >2 mg/L on statins may indicate residual risk and the need for anti-inflammatory therapy.

Pharmacotherapy for metabolic dysfunction–associated steatotic liver disease

Resmetirom is the first FDA-approved drug specifically for MASLD. It can reduce liver fibrosis, resolve MASH, and lower LDL-cholesterol, triglycerides, and lipoprotein(a). Clinical outcome data are still limited, and it is not yet approved in Europe.
Pegozafermin (an FGF21 analogue) is in development for severe hypertriglyceridaemia and MASLD, showing promise in improving fibrosis in MASH patients.