The Paleolithic diet and chronic disease risk: a GRADE-assessed systematic review and dose-response meta-analysis of prospective cohort studies and randomized controlled trials

This systematic review and meta-analysis evaluate the effects of the Paleolithic diet on cardiometabolic parameters and chronic disease outcomes by combining evidence from interventional and observational studies. We analyzed 19 randomized controlled trials (RCTs) and 12 prospective cohort studies identified through systematic searches. Both random-effects and fixed-effects meta-analyses, along with dose-response evaluations, were conducted for cohort studies. A fixed-effects model was applied when fewer than five comparisons were available to ensure model stability with limited data. Meta-analysis of RCTs demonstrated significant improvements in cardiometabolic markers including, fasting insulin [Weighted Mean Differences (WMD −1.01 [−1.45, −0.57], <i>p</i> &lt; 0.001], total cholesterol (WMD −0.15, [−0.24, −0.07], <i>p</i> &lt; 0.001), low-density lipoprotein cholesterol (WMD −0.24, [−0.40, −0.08], <i>p</i> = 0.003), triglycerides (WMD −0.16, [−0.24, −0.08], <i>p</i> &lt; 0.001), body weight (WMD −1.74, [−2.57, −0.91], <i>p</i> &lt; 0.001), body mass index (WMD −1.12, [−1.42, −0.82], <i>p</i> &lt; 0.001), and diastolic blood pressure (WMD −3.28, [−4.55, −2.01], <i>p</i> &lt; 0.001). Cohort studies revealed 10% lower all-cause mortality risk (RR: 0.90, 95% CI: 0.87–0.94, <i>p</i> &lt; 0.001), 10% reduced cancer mortality (RR: 0.90, 95% CI: 0.85–0.97, <i>p</i> = 0.004), and 16% lower coronary heart disease incidence (RR: 0.84, 95% CI: 0.70–1.00, <i>p</i> = 0.05) among high adherers. The Paleolithic diet may provide significant benefits for cardiometabolic health and potentially lower the risk of chronic disease.