ObjectiveExcessive alcohol consumption is a leading cause of global morbidity and mortality. However, knowledge of the biological factors that influence ad libitum alcohol intake may be incomplete. Two large studies recently linked variants in the KLB locus with levels of alcohol intake in humans. KLB encodes β-klotho, co-receptor for the liver-derived hormone fibroblast growth factor 21 (FGF21). In mice, FGF21 reduces alcohol intake, and human Fgf21 variants are enriched among heavy drinkers. Thus, the liver may limit alcohol consumption by secreting FGF21. However, whether full-length, active plasma FGF21 (FGF21 (1–181)) levels in humans increase acutely or sub-chronically in response to alcohol ingestion is uncertain.MethodsWe recruited 10 healthy, fasted male subjects to receive an oral water or alcohol bolus with concurrent blood sampling for FGF21 (1–181) measurement in plasma. In addition, we measured circulating FGF21 (1–181) levels, liver stiffness, triglyceride, and other metabolic parameters in three healthy Danish men before and after consuming an average of 22.6 beers/person/day (4.4 g/kg/day of ethanol) for three days during Oktoberfest 2017 in Munich, Germany. We further correlated fasting FGF21 (1–181) levels in 49 healthy, non-alcoholic subjects of mixed sex with self-reports of alcohol-related behaviors, emotional responses, and problems. Finally, we characterized the effect of recombinant human FGF21 injection on ad libitum alcohol intake in mice.ResultsWe show that alcohol ingestion (25.3 g or ∼2.5 standard drinks) acutely increases plasma levels of FGF21 (1–181) 3.4-fold in fasting humans. We also find that binge drinking for three days at Oktoberfest is associated with a 2.1-fold increase in baseline FGF21 (1–181) levels, in contrast to minor deteriorations in metabolic and hepatic biomarkers. However, basal FGF21 (1–181) levels were not correlated with differences in alcohol-related behaviors, emotional responses, or problems in our non-alcoholic subjects. Finally, we show that once-daily injection of recombinant human FGF21 reduces ad libitum alcohol intake by 21% in mice.ConclusionsFGF21 (1–181) is markedly increased in circulation by both acute and sub-chronic alcohol intake in humans, and reduces alcohol intake in mice. These observations are consistent with a role for FGF21 as an endocrine inhibitor of alcohol appetite in humans.

Cardiovascular (CV) disease is the leading cause of death and morbidity in patients with type 2 diabetes. Five CV risk factors (blood pressure, resting heart rate, body weight, cholesterol levels and blood glucose) are monitored routinely as safety and efficacy endpoints in randomized clinical trials for diabetes therapies. To determine if different glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) had varying effects on these CV risk factors, we reviewed 16 head‐to‐head trials directly comparing GLP‐1RAs that included at least one of the five factors. Few trials reported statistical differences between GLP‐1RAs in terms of systolic blood pressure (SBP), body weight and total cholesterol. Liraglutide increased heart rate vs its comparators in three separate trials. All GLP‐1RAs reduced glycated haemoglobin (HbA1c), but exenatide twice daily and lixisenatide had statistically smaller effects compared with other GLP‐1RAs. These descriptive data indicate that individual GLP‐1RAs affect CV risk factors differently, potentially because of their individual pharmacokinetics and/or size. Short‐acting GLP‐1RAs appeared to result in smaller changes in SBP and total cholesterol compared with continuous‐acting treatments, while large GLP‐1RAs had a reduced effect on body weight compared with small GLP‐1RAs. For glycaemic control, short‐acting GLP‐1RAs had a greater impact on postprandial glucose levels vs continuous‐acting GLP‐1RAs, but for fasting plasma glucose levels and HbA1c, continuous‐acting treatments had the greater effect. No differentiating trends were obvious in heart rate data. These diverse actions of GLP‐1RAs on CV risk factors should aid individualized patient treatment.