Protocol for a randomized controlled trial comparing saturated and unsaturated fat sources of a ketogenic diet (KETO-IM) investigating cardiovascular, inflammatory and immune function outcomes in adults living with overweight and prediabetes or type 2 diabetes in Edmonton, Canada.

BACKGROUND: Among the general public, the ketogenic (KETO) diet is popular for weight loss and may also support glycemic control in people with type 2 diabetes (T2D). Obesity and T2D have both been associated with diminished immune responses, increasing the risk of infection. KETO diets are often high in saturated fats (SFA), which may increase cardiovascular disease (CVD) risk as well as inflammation. Substituting SFA for unsaturated fats (UFA) may improve these outcomes. This study aims to compare lipid measures, glycemia, inflammation, and immune function in people with, or at risk of developing, T2D after following KETO diets emphasizing SFA versus UFA versus a low-fat standard of care diet (LFD) for 6 months. We hypothesize that (1) circulating triglycerides (TG) will be reduced more in the two KETO groups relative to the control LFD and (2) low-density lipoprotein (LDL-C) will be lowered to a greater extent with higher UFA consumption relative to KETO rich in SFA.

METHODS: The KETO-IM study is an open-label, single-center, three parallel-arm, superiority, randomized controlled trial (RCT). It will enroll adults aged 18 to 70 years with body mass index (BMI) > 23 kg/m2 (Asian and South Asian), or > 25 kg/m2 (non-Asian) and glycated hemoglobin (HbA1c) > 5.7%, recruited by the study team from the community in Edmonton, Canada and surrounding area. Participants (175 total) will be allocated to three groups in a 1:1:1 ratio with evaluation endpoints at three and six months compared to baseline. The primary outcomes assessing CVD risk, will be plasma LDL-C and TG. Secondary outcomes of the trial include glucose metabolism, inflammation and immune function. Among the secondary outcomes, comparison of immune function will be a novel focus.

DISCUSSION: This trial will directly compare the effects of fat sources in a KETO diet to a control LFD on cardiometabolic risk, inflammation and immune function in adults of both sexes. The results of this trial can be used to guide clinical advice to patients seeking to improve lipid and glycemic control while, for the first time, comparing the effects of KETO diets on immune response.

TRIAL REGISTRATION: ClinicalTrials.gov, NCT05681468. Registered on 12 December 2022, https://clinicaltrials.gov/study/NCT05681468?titles=keto-im&rank=1 . First enrollment September 18, 2023.