In what can only be considered fantastic news for doctors everywhere, a new international study has confirmed that genetically predicted higher plasma caffeine levels are associated with a lower BMI and a reduced risk of type 2 diabetes.
The results, published 15 March 2023 in The BMJ, also showed that people who carried genetic variants associated with slower caffeine metabolism drank less coffee on average, yet had higher levels of caffeine in their blood than people who metabolised it quickly to reach or retain the levels required for its stimulant effects.
Significantly, caffeine dependent weight loss was demonstrated to drive nearly half (43%) of the drug’s effect on reducing the risk of type 2 diabetes, and the genetic variants associated with higher plasma caffeine concentrations were not related to an increased risk of adiposity, type 2 diabetes, or major cardiovascular diseases.
The study also found that the genetic variants were not associated with the risk of atrial fibrillation, a common cardiac arrhythmia.
The researchers (from Sweden’s Karolinska Institute and Uppsala University, the University of Bristol, London’s School of Hygiene and Tropical Medicine, London Imperial College, and Denmark’s Chief Scientific Advisor’s Office) explained that while caffeine’s thermogenic effects are known to cause weight loss, it had been unclear whether long-term exposure to higher plasma caffeine concentrations could impact these conditions, due to the observational nature of the previous studies.
“An average cup of coffee contains around 70–150 mg of caffeine… and while previously published research has indicated that drinking 3-5 daily cups of coffee was associated with a lower risk of type 2 diabetes and cardiovascular disease… such studies could not reliably infer causality because coffee consumption is associated with other factors, potentially resulting in confounded associations,” the authors said.
“Furthermore, the specific effect of caffeine on the risk of cardiometabolic diseases might be difficult to disentangle from the other compounds included in caffeinated drinks and foods.”
To establish a causal relationship the team looked at the role of two common genetic variants of the CYP1A2 and AHR genes, single nucleotide polymorphisms (SNPs) associated with the speed of caffeine metabolism in the body, in nearly 10,000 people of European ancestry, who were active participants in six longitudinal, genome-wide association studies.
Estimates of the associations of the caffeine SNPs were obtained for BMI and body composition from the GIANT consortium and the Medical Research Council’s Integrative Epidemiology Unit, with the corresponding genetic data for type 2 diabetes and cardiovascular disease subtypes obtained from several consortiums.
The researchers employed a two-sample mendelian randomisation design and to improve causal inference, selected genetic variants that were reliably and strongly associated with the exposure as unbiased proxy indicators.
Results showed that genetically predicted higher plasma caffeine concentrations were associated with a lower risk of type 2 diabetes per SD increase in plasma caffeine.
“Genetically predicted higher plasma concentrations of caffeine were associated (beta −0.08 SD) with lower BMI, where 1 standard deviation (SD) equals about 4.8kg/m2 for every SD increase in plasma caffeine, and whole-body fat mass (beta −0.06 SD), where 1 SD equals about 9.5kg,” the authors explained.
“[However, higher plasma concentrations had a nonsignificant association with fat-free mass, (beta −0.01 SD (−0.02 to −0.00), where 1 SD equals about 11.5kg.
“We also conducted a phenome-wide association analysis and found that only a few of the associated phenotypes (coffee and tea consumption and renal biomarkers) had a stronger association with the specific outcome phenotypes under study than plasma caffeine concentration did, despite the much larger sample sizes of these studies (about 7to 80 times larger than in the plasma caffeine study).”
This finding implied that the associated phenotypes were probably downstream consequences of higher plasma caffeine, rather than biasing pleiotropic effects.
“Our mendelian randomisation finding suggests that caffeine might, at least in part, explain the inverse association between coffee consumption and risk of type 2 diabetes,” the authors concluded.
“Caffeine is known to boost metabolism, increase fat burning, and reduce appetite, and a daily intake of 100 mg was estimated to increase energy expenditure by around 100 calories a day, which could consequently lower the risk of developing obesity.
“As genetic variants are fixed at conception, individuals with genetic variants that are associated with higher plasma caffeine concentrations will, on average, be exposed to higher caffeine concentrations throughout their life compared with people with variants associated with lower plasma caffeine.”
The team also noted that considering the extensive intake of high-sugar caffeine drinks worldwide, randomised controlled trials are warranted to assess whether non-caloric caffeine containing beverages might also play a role in reducing the risk of obesity and type 2 diabetes.