The following outlines treatment options for patients with indicators of high risk or established atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease (CKD), or heart failure (HF).
In patients with predominantly atherosclerotic cardiovascular disease
If a patient has documented ASCVD or indicators of high ASCVD risk, treatment with GLP-1 receptor agonists (GLP-1RA) with proven cardiovascular benefit or SGLT-2 inhibitors (SGLT-2i) with documented cardiovascular benefit should be preferred, provided that eGFR is adequate. High risk is defined as age >55 and two or more additional risk factors.
If HbA1c remains above the individually agreed target on monotherapy, a combination therapy of GLP-1RA and SGLT-2i is recommended. If targets are still not achieved, it is not recommended to immediately switch to insulin therapy. Instead, barriers to achieving the target should be identified. A refresher training should be considered, as well as continuous glucose monitoring (CGM) to detect therapeutic gaps. Importantly, social determinants of health should also be taken into account. Insulin therapy is therefore considered the last resort if goals cannot be achieved with other measures.
In patients with heart failure
In patients with heart failure with reduced ejection fraction (HFrEF) or preserved ejection fraction (HFpEF), treatment with an SGLT-2 inhibitor is recommended.
In patients with chronic kidney disease
In patients with CKD with an eGFR < 60 ml/min per 1.73 m² body surface area or albuminuria, initial treatment should be with the maximum tolerated dose of an ACE inhibitor or an angiotensin receptor blocker. For patients with type 2 diabetes and CKD, additional therapy with an SGLT-2 inhibitor is recommended. If there are contraindications, intolerance, or insufficient glomerular filtration rate, treatment with a GLP-1RA may be considered. If HbA1c targets are not achieved, combination therapy with both SGLT-2i and GLP-1RA can be used.
Modified after: https://diabetesjournals.org/care/article/48/Supplement_1/S181/157569/9-Pharmacologic-Approaches-to-Glycemic-Treatment
ACEi, angiotensin-converting enzyme inhibitor; ACR, albumin-to-creatinine ratio; ARB, angiotensin receptor blocker; ASCVD, atherosclerotic cardiovascular disease; CGM, continuous glucose monitoring; CKD, chronic kidney disease; CV, cardiovascular; CVD, cardiovascular disease; CVOT, cardiovascular outcomes trial; DPP-4i, dipeptidyl peptidase 4 inhibitor; DSMES, diabetes self-management education and support; eGFR, estimated glomerular filtration rate; GLP-1 RA, glucagon-like peptide 1 receptor agonist; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; HHF, hospitalization for heart failure; MACE, major adverse cardiovascular events; MASH, metabolic dysfunction–associated steatohepatitis; MASLD, metabolic dysfunction–associated steatotic liver disease; MI, myocardial infarction; SDOH, social determinants of health; SGLT2i, sodium–glucose cotransporter 2 inhibitor; T2D, type 2 diabetes
To understand the mechanism of action of GLP-1 receptor agonists (GLP-1RA), knowledge of the incretin effect is essential.
What are incretins and how do they work?
It has long been known that blood glucose levels are regulated by gut hormones: the incretins GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic peptide). After a meal, GLP-1 and GIP are released in the intestinal mucosa. The incretins activate the autonomic nervous system in the intestinal mucosa. From there, the signal is transmitted via a brain region, the hypothalamus, to the target organs.
The target organs are the alpha and beta cells in the pancreas, the liver, and the stomach. Depending on the current blood glucose level, incretins exert the following effects:
How do incretins affect blood glucose?
Incretins are responsible for 60–70% of total insulin secretion after meals (incretin effect). As a result of their action, blood glucose levels decrease. The effects of incretins are limited by the enzyme dipeptidyl peptidase-4 (DPP-4), which breaks down GIP and GLP-1 within minutes.
GLP-1 is a peptide consisting of 30 amino acids (peptide = organic compound made up of amino acids).
The incretin effect is reduced in people with type 2 diabetes, which makes postprandial blood glucose regulation more difficult:
In type 2 diabetes
GLP-1 receptor agonists (GLP-1RAs, substances that act on the GLP-1 receptor in the same way as GLP-1) are small peptides. Since peptides are digested in the stomach, they must be injected into the subcutaneous fat tissue, like insulin. For one preparation, a formulation was developed that allows oral administration (oral semaglutide, Rybelsus®).
In these GLP-1RAs, the amino acids at the binding site of the enzyme DPP-4 were modified so that the peptides can no longer be cleaved. In addition, the amino acid sequence was altered to prolong the duration of action. GLP-1RAs are classified into short-acting and long-acting agents.
Short-acting, daily administration:
Long-acting, weekly administration:
Fixed combinations with insulin in one pen:
Depending on baseline blood glucose, GLP-1RAs can reduce HbA1c by about 1–2%. They also promote weight loss, with patients losing about 2.5 kg on average. With dietary changes, greater weight loss can be achieved. Thus, GLP-1RAs are especially suitable for patients with significant obesity.
Main side effect: Nausea, which usually decreases over time. In some patients, however, it is severe enough to require discontinuation of therapy. With Bydureon®, injection site reactions (redness, itching) may occur.
Guideline recommendation:
In patients with established atherosclerotic cardiovascular disease or indicators of high risk for ASCVD, treatment with GLP-1RAs should be initiated in addition to metformin. Patients older than 55 with stenoses in coronary arteries, carotid arteries, or leg arteries are considered at increased risk.
Only GLP-1RAs with proven cardiovascular benefit should be used.
At the American Diabetes Association (ADA) 2016 Congress in New Orleans, the first cardiovascular outcomes trial of the GLP-1 analogue liraglutide (Victoza®) was presented. The U.S. Food and Drug Administration (FDA) requires such studies to ensure that these medications do not increase the risk of heart attack, stroke, or death from any cause. Diabetes drugs are developed to lower blood glucose. Lowering blood glucose may also reduce the risk of cardiovascular events or death. Therefore, these drugs are always tested in double-blind, placebo-controlled trials (neither doctor nor patient knows whether placebo or drug is administered). Both groups receive standard therapy with other diabetes medications and insulin. Glycemic control must be equivalent between groups so that any potential cardiovascular risk is not masked by improved blood glucose control. Since blood glucose reduction must be comparable in both groups, no positive effect can be expected, and the trials are primarily designed to demonstrate non-inferiority regarding cardiovascular risk. Groups must also be comparable in all other risk factors, including age, weight, blood pressure control, statin therapy, antiplatelet agents, etc.
The study was conducted internationally, enrolling more than 4,600 patients per group. Despite more frequent insulin use, the placebo group did not achieve the same level of glycemic control as the liraglutide group. After an average follow-up of 36 months, HbA1c remained 0.4% lower in the liraglutide group compared to placebo. Systolic blood pressure was reduced by 1.2 mmHg, and patients on liraglutide lost 2.3 kg. Liraglutide had no effect on LDL or HDL cholesterol.
The primary endpoint was a composite of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. Surprisingly, liraglutide reduced the risk of this composite endpoint by 13%. All-cause mortality was also reduced by 15%. Patients on liraglutide experienced fewer eye complications and slower progression of diabetic kidney disease.
Thus, after empagliflozin, another antidiabetic agent became available that not only lowers blood glucose, weight, and blood pressure but also significantly reduces the risk of death (ADA 2016, New Orleans).
Subsequently, similar trials have been conducted for the GLP-1RAs dulaglutide and semaglutide. Weekly administration is very popular among patients and is easy to manage. The study results show particularly for semaglutide a markedly greater effect on HbA1c reduction, weight loss, cardiovascular death, myocardial infarction, and stroke.
GIP and GLP-1 receptor agonists
Tirzepatide (Mounjaro®), a dual GIP and GLP-1 receptor agonist, is an analogue of GIP. GIP is a gastrointestinal hormone released similarly to GLP-1. Tirzepatide acts on both GLP-1 and GIP receptors. It lowers blood glucose more strongly and, above all, promotes greater weight loss. Like GLP-1RAs, it is administered once weekly by subcutaneous injection. Obese patients (BMI > 30) lost 15% of their baseline weight after 72 weeks with the 5 mg dose and 20% with the 10 mg dose. Side effects are similar to those of other GLP-1RAs. Tirzepatide is contraindicated in patients with a family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2 (MEN2).
In addition to GLP-1RAs, SGLT-2 inhibitors can also be used in patients with established atherosclerotic cardiovascular disease or indicators of high ASCVD risk.
Substance / Class | Studies / Results | Effects | Side Effects | Special Features / Indication |
Liraglutide (Victoza®) | ADA 2016 (≈4,600 pts per group, 36 months) • HbA1c ↓ 0.4% vs. placebo • Weight ↓ 2.3 kg • Blood pressure ↓ 1.2 mmHg • CV endpoint (MI, stroke, CV death) ↓ 13% • All-cause mortality ↓ 15% • Fewer eye and kidney complications | • Reduction of HbA1c, weight, blood pressure • Reduction of cardiovascular events | • Nausea (usually subsides) | • GLP-1RA with proven cardiovascular benefit • Recommended for ASCVD or high CV risk |
Dulaglutide (Trulicity®) | Cardiovascular outcome trials available • Effective HbA1c and weight reduction • Weekly injection, highly accepted | • HbA1c reduction • Weight loss • CV protection | • Nausea, GI complaints | • Long-acting GLP-1RA (weekly dosing) |
Semaglutide (Ozempic®, Wegovy®, Rybelsus® oral) | Multiple large trials • Greater HbA1c and weight reduction than other GLP-1RAs • Reduction in CV death, MI, stroke | • Strong HbA1c reduction • Significant weight loss • CV protection | • Nausea, GI complaints | • Only GLP-1RA available in oral form (Rybelsus®) |
Tirzepatide (Mounjaro®) – GIP + GLP-1RA | SURPASS trials • Marked HbA1c reduction • Weight loss 15% (5 mg) to 20% (10 mg) after 72 weeks in patients with BMI >30 | • Very strong HbA1c reduction • Profound weight loss | • GI side effects similar to GLP-1RAs | • Dual agonist (GLP-1 + GIP) • Weekly subcutaneous injection • Contraindicated in medullary thyroid carcinoma / MEN2 |