Effect of GLP-1 receptor agonists on weight and cardiovascular outcomes: A review

In a meta-analysis comparing new-onset HF among normal-weight and overweight patients, being overweight increased the risk of developing HF by 33%.According to the Framingham Heart Study, each 1-unit increase in body mass index (BMI) is associated with a 5% increased HF risk in men and 7% in women, indicating a dose-dependent relationship.Statistics show that each 5 kg/mincrease in BMI increases the risk of hemorrhagic stroke and coronary heart disease by 10% and 15%, respectively. [] ⁷ [] ⁸ 2 [] ⁹

Another major concern with weight gain is its direct linear relationship with systolic and diastolic blood pressure (BP), which contributes to a significantly increased risk of primary hypertension.As a result, excess weight gain accounts for 78% of primary (essential) hypertension cases in men and 65% in women.Furthermore, a meta-analysis conducted by Zhu et alfound a strong correlation between the prevalence of myocardial infarction (MI) and obesity, as well as the importance of maintaining weight as a preventative measure. Abdominal obesity increases the risk of insulin resistance, a metabolic syndrome component that precedes the development of type 2 diabetes (T2D).Insulin resistance also increases the likelihood of other metabolic risk factors such as atherogenic dyslipidemia, hypertension, glucose intolerance, and a prothrombotic state, all of which are indirect risk factors for CVD.In essence, patients with abdominal obesity are more likely to develop T2D,which puts them at a higher risk of adverse CV events than normoglycemic subjects.The San Antonio Heart Study adds to this notion by demonstrating a 2- to 3-fold increase in mortality risk in subjects with diabetes or metabolic syndrome at baseline. [] ¹⁰ [] ¹¹ [] ¹² [] ¹³ [] ¹⁴ [] ¹⁵ [] ¹⁶ [] ¹⁷

The question of whether obesity's associated factors increase the risk of CVD or if obesity is the sole culprit is a source of ongoing debate. Some argue that epidemiological studies are skewed and that a phenotype known as "metabolically healthy obesity" exists, implying that the subset of obese people who do not have any other cardiometabolic abnormalities (such as hypertension, CVD, T2D, or hyperlipidemia) may not be at an increased risk of CVD or death. According to Mendelian randomization studies, the theory of "metabolically healthy obesity" has been debunked by demonstrating that the effect of obesity on CVD is causal.As a result, combating obesity is critical regardless of whether patients have CV risk factors or not, because significant weight loss may potentially reverse the hemodynamic changes that predispose to changes in cardiac performance and morphology. [] ¹⁸ [] ¹⁹

As an alternative, drugs were studied in 2 categories: those that could potentially increase metabolism or those that could suppress appetite. The first drugs to aid in weight loss, such as thyroid hormone, amphetamines (which also suppress appetite), and dinitrophenol, had short-lived success due to the CV effects of thyroid hormones, the potential for abuse with amphetamines, neuropathy, and cataracts with dinitrophenol. [] ²³

Unfortunately, the early appetite suppressants did not produce positive results either. In 1997, a widely used anti-obesity drug called fenfluramine, which was used in the combination drug fen-phen (fenfluramine and phentermine), was recalled in the United States after echocardiography revealed that 30% of patients had valvular heart disease.Sibutramine, a serotonin and epinephrine uptake inhibitor, was approved the same year for appetite suppression; however, it was discontinued in 2010 after a post-marketing study revealed statistical evidence of increased stroke and MIs in patients with preexisting CVD or diabetes.Lorcaserin was one of the most recent drugs to be removed from the market due to its questionable safety profile, which revealed an increased risk of cancer that far outweighed its appetite-suppressing benefit. [] ²⁴ [] ²⁵ [] ²⁶

Bariatric Surgery, which encompasses restrictive procedures (adjustable peri-gastric ring and sleeve gastrectomy) and malabsorptive procedures (gastric bypass and biliary pancreatic shunts), is a more effective and long-term solution for patients in need of excessive weight loss.However, these surgeries come with a long list of postoperative risks, including bleeding, herniation, anastomotic leak, and "dumping syndrome," to name a few.Furthermore, surgery is not considered the first line of treatment for everyone because it requires patients to meet the eligibility criteria, which include a BMI ≥40, the presence of one or more obesity-related comorbidities (heart disease, stroke, hypertension, and T2D), and the inability to maintain a healthy weight over time. [] ²⁷ [,] ^{28 29} [] ³⁰

As previously discussed, CVD is linked to diabetes; in fact, CVD is the leading cause of death in patients with diabetes mellitus, emphasizing the importance of antidiabetic pharmacotherapy that not only maintains CV neutrality but also reduces CV risk.Until recently, antidiabetic drugs were not required to demonstrate CV safety. However, following the safety concerns raised by rosiglitazone and its potential side effects such as an increased risk of death and MI,the Food and Drug Administration (FDA) mandated that innovative antidiabetic therapies for T2D be scrutinized by conducting safety trials to confirm their CV neutrality.This is critical because certain antidiabetic medications can worsen heart failure or increase the risk of potentially fatal lactic acidosis. [] ¹⁶ [] ³¹ [] ³² [] ³³

Subsequent resection experiments revealed the existence of an additional incretin, glucagon-like peptide (GLP), which was an unexpected processing fragment of the newly discovered proglucagon.It was then isolated from the gut and found to stimulate insulin and inhibit glucagon secretion.Unlike GIP, this peptide could maintain its effects in patients with T2D and was quickly recognized as having remarkable antidiabetic effects in clinical studies.One major limitation in the use of GLP-1 peptide was its extremely short half-life (1.5–5 minutes) due to rapid cleavage and degradation by the enzyme dipeptidyl peptidase-4 (DPP-4),so DPP-4 resistant GLP-1 RAs were developed for longer-lasting effects. [] ³⁶ [,] ^{37 38} [] ³⁹ [] ⁴⁰ [] ⁴¹

GLP-1 RAs were licensed for the treatment of T2DM due to their ability to lower A1C and achieve the hemoglobin A1c (HbA1c) goal of <7%. They also normalize fasting and prandial blood glucose levels.It is suggested that starting GLP-1 RA with insulin as an add-on therapy before or after 90 days resulted in more patients achieving blood sugar levels of <7% or 8%, and patients lowering their blood sugar levels by ≤%1 to 2% at 6 and 12 months.Unexpectedly, trials on diabetic patients revealed impressive weight loss,sparking researchers' interest in the potential use of GLP-1 RA drugs as weight loss therapy. [,] ^{42 43} [] ⁴⁴ [] ⁴⁵

To understand their mechanism, we must first understand the normal physiology of the incretin molecule's pathway, as well as the changes that GLP-1 RA undergoes during obesity. GLP-1 is produced by proglucagon cleavage in L-cells in the intestinal mucosa, α-cells in pancreatic islets, and neurons in the solitary tract nucleus.This hormone regulates energy homeostasis and feeding behavior by stimulating receptors on islet β-cells. It enhances insulin secretion, promotes β-cell proliferation, inhibits glucagon production, and increases resistance to apoptosis.In addition to its incretin effects, GLP-1 functions as a satiety signaling molecule, delaying gastric emptying and gastric acid secretion. [] ⁴⁶ [] ⁴⁷ [–] ^{48 50}

Obesity, according to documented evidence, may contribute to GLP-1 function impairment. In a study of 51 subjects with BMIs ranging from 20 to 61 kg/m, Muscelli et al discovered an inverse correlation between the incretin effect and BMI.The underlying pathophysiology for this reduced effect has not been definitively determined, but there are 2 plausible theories. The first is reduced GLP-1 secretion as a result of L-cells losing sensitivity to carbohydrates in obese people.Another reason for lower GLP-1 levels could be increased resistance to leptin, which is thought to regulate GLP-1 secretion.The second explanation for the decreased incretin effect in obese patients is a reduction in GLP-1's insulinotropic effectiveness. This hypothesis is supported by the Knop et al study, which found that a decrease in the incretin effect was not accompanied by a decrease in the secretion of these hormones.Even though the exact underlying cause of impairment is unknown, it is undeniable that obesity influences GLP-1, as evidence shows that weight loss, whether diet-inducedor following Roux-en-Y gastric bypass, can increase GLP-1 secretion.Finally, the impairment of GLP-1 and its effects on satiety explains why weight loss may appear impossible for obese people, trapping them in a never-ending cycle of overeating and weight gain that leads to additional incretin dysfunction. As a result, GLP-1 receptor analogs are required to aid in weight loss by pharmacologically reproducing appetite-suppressing effects such as delayed gastric emptyingand direct stimulation of satiety centers in the hindbrain and hypothalamus(Fig.). 2 [] ⁵¹ [] ⁵² [] ⁵³ [,] ^{54 55} [] ⁵⁶ [] ⁵⁷ [] ⁵⁸ [] ⁵⁹ 1

The discovery of GLP-1R on cardiomyocytes, endothelial cells, and the autonomic nervous system strongly suggests direct and indirect effects on the heart and vessels (Fig.).To begin, GLP-1 improves microvascular blood flow by increasing endothelial function and microvascular perfusion.Long-term studies of GLP-1 RA showed moderate BP reductions, which could be attributed to altered salt homeostasis, weight loss, sympathetic nervous system involvement, or serum atrial natriuretic peptide. 2 [–] ^{61 64} [–] ^{65 68} [] ⁶²

The meta-analysis concludes that GLP-1 RAs exenatide and liraglutide reduced systolic and diastolic BP by 1 to 5 mm Hg in T2DM patients compared to other antidiabetic drugs.Another CV marker affected by the GLP-1 peptide is heart rate, which is acutely increased in response to a suggested increase in sympathetic nervous system activity or direct sinoatrial node stimulation.Finally, GLP-1 RA improves lipid profiles by lowering postprandial triglyceride levels, apo B-48, apo C-III, remnant lipoprotein cholesterol, and remnant lipoprotein triglycerides.Overall, placebo-controlled clinical trials with GLP-1 RA revealed a consistent 0.2–0.3 mmol/L decrease in triglyceride concentrations.Semaglutide treatment has been shown to significantly reduce postprandial triglyceride, very low-density lipoprotein, and apoB-48 levels.These findings clearly indicate that the potential anti-atherosclerotic effects of GLP-1 RA correspond to a decrease in lipids. As previously stated, GLP-1 RAs are clearly recognized for reducing weight and HbA1c, which may have a positive impact on CV outcomes overall. [] ⁶⁹ [,,] ^{64 70 71} [] ⁷² [] ⁷³ [] ⁷⁴ [,] ^{75 76}

Exenatide (twice daily), liraglutide, lixisenatide (both once daily), oral semaglutide (once daily), and the once-weekly agents exenatide (Bydureon), albiglutide, semaglutide, and dulaglutide are among the GLP-1 RAs currently approved in the United States.These drugs were initially only used to treat T2D because they effectively reduced A1C and weight. The first GLP-1 RA drug to receive FDA approval and be officially classified as a weight loss medication was liraglutide. [–] ^{78 85} [] ⁸⁶

In 2014, this under the skin injection was approved as an adjunct to diet and exercise for adults with a BMI of ≥30 (obese) or ≥27 (overweight) and at least one weight-related condition (hypertension, T2D, dyslipidemia). The initial dosage of liraglutide is 0.6 mg daily, regardless of meals, and is increased weekly by 0.6 mg until the target dosage of 3 mg per day is met. Patients who can tolerate the 3 mg dosage can continue with treatment, while others are advised to discontinue, as are patients who are unable to lose 4% of their baseline body weight after 4 months of treatment or who do not show weight fluctuations after a year of medication. Patients may experience gastrointestinal (GI) side effects including nausea, diarrhea, constipation, and vomiting. Furthermore, approximately 1 in every 4 patients with T2D will experience symptomatic hypoglycemia at some point during the year.Nonetheless, liraglutide remains the superior weight loss agent when compared to orlistat (Xenical).The next drug to join liraglutide on the list of GLP-1 RA drugs used for chronic weight management was weekly semaglutide, 2.4 mg.This agent is also injected subcutaneously (SC), meets the same inclusion criteria as liraglutide, and has nearly identical side effects, with nausea being the most common.In comparison to liraglutide, semaglutide causes significantly more weight loss but may also cause more side effects.semaglutide is the only GLP-1 RA that provides the advantages of a highly effective GLP-1 RA in both injectable and oral formulations; however, oral semaglutide has yet to be approved as a weight loss medication. [] ⁸⁷ [] ⁸⁸ [] ⁸⁹ [] ⁹⁰ [] ⁹¹ [] ⁹²

Lastly, dulaglutide, liraglutide, and injectable semaglutide have been approved to reduce major adverse cardiovascular events (MACE) in adults with T2D who have established CVD or multiple CV risk factors.In contrast, none of the GIP RA drugs have been approved by the FDA, but tirzepatide, a dual-GIP and GLP-1 RA, is thought to have undiscovered potential. It is currently in phase 3 development for managing blood glucose in adults with T2D, chronic weight management, and heart failure with preserved ejection fraction (HFpEF). [–] ^{93 95} [] ⁹⁶

One such trial was the Researching Cardiovascular Events with a Weekly Incretin in Diabetes trial which investigated dulaglutide's effect on MACE in individuals with T2D.In this study, 9901 patients with an HbA1c >7% and proven CVD or CV risk factors, were randomized to weekly dulaglutide 1.5 mg or placebo. The primary composite outcome was the first occurrence of CV death, nonfatal MI, or nonfatal stroke. During a median follow-up of 5·4 years, the primary endpoint occurred in 12% of participants in the dulaglutide group compared with 13.4% in the placebo group, which was significant ( = .026). The analysis of secondary CV outcomes showed that nonfatal stroke was also significantly lower in the dulaglutide group compared with placebo (2.7% vs 3.5%, = .017), however, dulaglutide did not show any effects on all-cause mortality ( = .067). [] ¹¹⁵ P P P

The first trial which evaluated lixisenatide, published in 2016, was the Evaluation of Lixisenatide in Acute Coronary Syndrome trial which included 6068 patients with T2DM who had sustained an acute coronary event within 180 days before randomization.They were assigned to either lixisenatide or placebo for a median of 25 months. The primary endpoint was the first occurrence of one of the following: death from CV causes, nonfatal stroke, nonfatal MI, or hospitalization for unstable angina. Results showed an insignificant effect of lixisenatide compared with placebo on the occurrence of the primary composite outcome (13.4% vs 13.2% in the placebo group, < .001 for noninferiority, p ¼ 0.81 for superiority) proving noninferiority of lixisenatide, but not superiority. [] ¹¹⁶ P

In 2018, the trial on albiglutide and CV outcomes in patients with T2DM and CV disease (Heart Attack Reduction with Medications Organized as New Therapies Outcomes) was performed on 9463 participants who were followed for a median duration of 1.6 years; all patients had a preexisting coronary, cerebrovascular, or peripheral artery disease.In patients receiving standard care, addition of once-weekly albiglutide reduced the risk of the primary composite outcome (3-point MACE) by 22%, compared with the addition of placebo. These results indicated that albiglutide was superior to placebo ( < .0001 for noninferiority; = .0006 for superiority). [] ¹¹⁷ P P

To summarize, GLP-1 RAs are particularly effective for individuals with T2D requiring enhanced glycemic control and especially beneficial for overweight or obese patients, as they help promote weight loss.Approved for weight management, GLP-1 RAs, such as liraglutide and semaglutide, are recommended for individuals with a BMI of 30 kg/m² or greater or 27 kg/m² with related comorbidities like hypertension.They are also preferred for type 2 diabetic patients with established CVD or those at high risk, given the significant reductions in MACE seen in trials like LEADER and Semaglutide in Subjects with Type 2 Diabetes.Liraglutide also has reno-protective properties, making it suitable for patients with mild to moderate chronic kidney disease, although caution is necessary in advanced cases due to dehydration risks.Patient should be thoroughly screened for a history of pancreatitis or medullary thyroid carcinoma, due to GLP-1 RAs potential exacerbation of these diseases.When considering patient preferences, those seeking weight loss or wanting to avoid hypoglycemia risks associated with insulin or sulfonylureas are suitable candidates. [] ¹¹⁸ [] ¹¹⁹ [,] ^{97 110} [] ¹²⁰ [] ¹²¹ [] ¹²²

Additionally, regular monitoring plays a crucial role in maximizing treatment efficacy. HbA1c evaluations conducted every 3 to 6 months are critical for assessing glycemic control, with anticipated decreases of 0.5% to 1.5%.Consistent weight monitoring is also crucial, as patients may experience a 5% to 10% reduction in body weight during the initial year.For individuals with compromised kidney function, it is advisable to monitor serum creatinine and eGFR to avoid acute kidney injury.Healthcare professionals should also be vigilant for common digestive side effects, including nausea, vomiting, and diarrhea, which can be addressed through gradual dose increases.Although GLP-1 RAs have a low hypoglycemia risk, it is crucial to educate patients about symptom recognition, particularly if they are using other glucose-lowering medications.To ensure patient safety, it is essential to monitor for indications of pancreatitis and thyroid function, especially in those with a family history of thyroid cancer. [] ¹²³ [] ¹²⁴ [] ¹²⁵ [] ¹²⁶ [] ¹²⁷ [] ¹²⁸

While GLP-1 RAs offer numerous advantages, their effective implementation in clinical settings faces several obstacles. The high cost of these medications, coupled with limited insurance coverage, can impede patients' ability to maintain long-term treatment.Moreover, the need for injection may deter individuals who are averse to needles, although oral semaglutide presents a non-injectable option with specific usage instructions.It is important for patients to be educated on the medication and to have realistic expectations about treatment outcomes, including the timeframe for improvements in blood sugar levels and weight reduction.For elderly patients, it is crucial to weigh the risks associated with multiple medications and potential drug interactions, as GI side effects could increase the risk of dehydration. [] ¹²⁹ [] ¹³⁰ [] ¹³¹ [] ¹³²

Concurrent with the obesity epidemic, the prevalence of nonalcoholic fatty liver disease (NAFLD) has risen dramatically, becoming the most prevalent liver disorder in Western nations.At present, no FDA-approved medications exist for NAFLD treatment, with the primary recommendation being lifestyle modifications aimed at weight reduction, which is often challenging to achieve and sustain.Consequently, innovative therapeutic advancements like GLP-1 RAs are crucial. These drugs not only facilitate weight loss but also contribute to reducing liver inflammation and fibrosis.For instance, liraglutide has shown promise in enhancing nonalcoholic steatohepatitis histology and decelerating fibrosis progression in the "Liraglutide Efficacy and Action in Diabetes" (LEAD) study, while semaglutide has also exhibited potential in NAFLD treatment.Despite these encouraging results, many GLP-1 RAs still require thorough investigation for NAFLD treatment, necessitating additional clinical trials to confirm their effectiveness. [] ¹³³ [] ¹³⁴ [] ¹³⁵ [,] ^{136 137} [] ¹³⁵

Another promising area of investigation is the potential neuroprotective effects of GLP-1 RAs in conditions such as Alzheimer disease. Preliminary studies indicate that GLP-1 RAs may mitigate neuroinflammation, enhance brain insulin sensitivity, and safeguard against cognitive decline.Further investigation into CV and renal benefits is underway, particularly concerning heart failure and chronic kidney disease, with ongoing research assessing whether these benefits extend to nondiabetic populations.Personalized medicine approaches are gaining traction, with research focusing on identifying biomarkers and genetic profiles to predict patient response to GLP-1 RAs, potentially improving treatment outcomes. [] ¹³⁸ [] ¹³⁹ [] ¹⁴⁰

The future of GLP-1 RAs is promising, with expanding indications and ongoing trials that could transform the management of metabolic, liver, neurodegenerative, and CVDs.Addressing challenges related to safety, cost, and access will be crucial to maximizing their potential in clinical practice. [–] ^{133 138}