The Safety and Efficacy of an NAD+ Boosting Product Together With a Low Carbohydrate Diet in Adults With Mild Hypertension and Eligible for Normal-standard-of-care
Condition: Hypertension
MeSH terms: Hypertension
Study type: Interventional
Phase: Phase 2

Summary: 
      The objective of this study is to evaluate the safety and efficacy of Limitless, in
      combination with a low-carbohydrate diet, after 30 days of supplementation in an adult
      population. Changes from baseline to Day 30 post-supplementation on several parameters of
      vascular function will be examined and safety outcomes will be determined.
    

Detailed description: 
      With an aging population, and the resulting economic and health burdens, strategies to
      support healthy aging and mitigate age-associated metabolic changes are essential.

      Recent studies have demonstrated that decreases in nicotinamide adenine dinucleotide (NAD+)
      levels in multiple tissues is involved in the pathogenesis of age-associated diseases.
      Therefore, strategies to support NAD+ levels and prevent the decline of NAD+ with age have
      drawn significant attention. NAD+ precursors have also been proposed to augment NAD+ and
      support healthy aging. While NAD+ precursors share some similarities, there are differences
      in their bioavailability and safety profiles. Both nicotinamide mononucleotide (NMN) and
      nicotinamide riboside (NR) are orally bioavailable and appear to increase NAD+ levels more
      efficiently than nicotinic acid (NA). Further, a study in rodents suggests that NMN is
      retained in the body longer than NA. Unlike NMN, NA is associated with several adverse
      effects such as cutaneous flushing and nausea and hepatoxicity in sustained
      release-formulations. Recently, the first clinical study examining the safety and
      bioavailability of NMN supplementation found that single orally administered doses of 100-500
      mg were safe and well-tolerated.

      The investigational product in this study contains NMN, in addition to berberine, R-lipoic
      acid, garlic powder, agmatine, black pepper extract, fisetin and L-citrulline malate.
      Preclinical studies have shown that restoring NAD+ levels by supplementation of NMN can
      ameliorate some of the functional defects caused by its decline. Further, there are numerous
      proof-of-concept in vitro and in vivo animal studies indicating that NMN supplementation has
      beneficial biological effects. Administration of 100 mg/kg/day of NMN for 12-months mitigated
      age-associated physiological declines in energy metabolism, insulin sensitivity, and plasma
      lipid profile while age-associated body weight gain was decreased. Other animal studies have
      shown that NMN supplementation improved glucose intolerance and lipid profiles in models of
      high-fat-induced and age-induced diabetic mice. Further, 300 mg/kg/day of NMN supplementation
      for 8 weeks in old mice ameliorated age-associated nitric oxide (NO)-mediated
      endothelium-dependent dilation and oxidative stress. Despite the promising evidence in
      pre-clinical models, there have been no reports on the efficacy of NMN supplementation in
      humans. There are currently five registered clinical trials examining the role of NMN
      supplementation on metabolic parameters including glucose and insulin metabolism, lipid
      levels, body composition and hormone levels.

      The intervention for this open label study will be Limitless, a supplement containing NAD+
      boosting ingredients, in combination with a low carbohydrate diet. This study is a pilot
      study to provide information on the safety and efficacy of the intervention composed of
      Limitless and a low-carbohydrate diet on a population of participants that are not eligible
      for statin therapy. This study will inform on future research to be conducted in randomized,
      double-blind, placebo-controlled trials designed for chronic supplementation of the
      investigational product together with the diet. Vascular function will be assessed by blood
      pressure (BP), blood flow velocity and NO metabolites as well as examine outcomes related to
      NAD+ metabolism, inflammation and anti-oxidant status, glucose metabolism, lipid profile,
      physical performance, quality of life and safety. Dietary strategies to modify hypertension
      have been used as part of standard of care, including the Dietary Approaches to Stop
      Hypertension (DASH) diet. Other dietary interventions have been used to reduce BP and improve
      other cardiometabolic markers in otherwise healthy adults. Indeed, both low-carbohydrate and
      low-fat dietary interventions have been found to reduce systolic BP (SBP) and diastolic BP
      (DBP) . It is acknowledged that both dietary strategies may be beneficial to this population,
      however we have selected a low carbohydrate diet as this is hypothesized to be more
      compatible with the investigational product, Limitless, as a high-carbohydrate diet negates
      the potential benefits of the supplement. For example, the blood-sugar mediating effects of
      Berberine, are countered by the blood-sugar spike caused by a carbohydrate rich diet. The
      carbohydrate rich diet is thought to be one contributor to high blood pressure, therefore a
      low carbohydrate diet in combination with the supplement is hypothesized to produce
      beneficial improvements in blood pressure while promoting factors that support restoration of
      healthy blood flow and oxygen delivery in the body.

      Normal-standard-of-care is the recommendation in place for medical practitioners in the
      management of hypertension prior to the introduction of prescription medication plans.
      According to the most recent report from the American College of Cardiology/American Heart
      Association Task Force on Clinical Practice Guidelines, lifestyle modifications are
      recommended prior to prescribing anti-hypertensives. In Hypertension Canada's 2020
      Comprehensive Guidelines for Prevention, Diagnoses, Risk Assessment, and Treatment of
      Hypertension in Adults and Children, patients who are low risk, defined as having no other
      target organ or cardiovascular risk factors suggest an initiation of anti-hypertensive
      therapy when systolic SBP is ≥ 160 mmHg, or diastolic DBP is ≥ 100 mmHg.

      Participants in this study represent a target population who would benefit from safe and
      efficacious nutraceuticals for regulation of BP without the added burden of side effects that
      are associated with angiotensin converting enzyme (ACE) inhibitors thus limiting the
      complexities of polypharmacy. The current study population therefore allows for hypertensives
      to be enrolled if they are found to be ineligible for therapeutic plans that required
      prescription medication of ACE inhibitors. Participants will be assessed on a case-by-case
      basis to ensure that commodities and concomitant medications that may impact the safe of a
      passage of a participant thought this study will be monitored. Significant metabolic or
      physiological conditions that may affect vascular function, inflammation or glucose
      metabolism will be excluded. As well, an extensive list of exclusions in place will ensure
      that eligibility is based on establishing health and each participants' eligibility will be
      overseen by the Medical Director. Participants aged 45 to 65 years will be considered for
      enrolment to avoid complications related to advanced age and a body mass index (BMI) of and
      up to 32.9 kg/m2 will eliminate confounders related to advanced obesity. Sex-specific waist
      circumference cut-offs of less than 102 cm in men and 88 cm in women will be used to exclude
      individuals with an increased risk for obesity-related diseases.
    

Intervention name(s): Limitless
Intervention type(s): Other
Intervention description(s): Participants will be instructed to take Limitless for 30 days.
Intervention model: Single Group Assignment
Intervention model description: Open-label
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: NAD+ boosting investigational product; Mild hypertension; Limitless; Low carbohydrate diet