Decreased insulin sensitivity (or insulin resistance) is a major risk factor for type 2
diabetes mellitus and renal and cardiovascular disease. It is the key component and,
possibly, a pathogenetic factor of the metabolic syndrome - a clustering of arterial
hypertension, obesity, impaired glucose tolerance, dyslipidemia, coagulation abnormalities,
albuminuria and increased cardiovascular risk - that may precede or accompany type 2
diabetes.
Insulin function and the abnormalities associated with insulin resistance, may have a major
role in preventing type 2 diabetes and, in the long-term, diabetes micro- and macrovascular
complications. Carnitine is involved in lipids and carbohydrates metabolism and
acetyl-L-carnitine (ALC), an intramitochondrial carrier of acylic group, may modulate cell
fuel substrate utilization. Studies found that carnitine may improve insulin sensitivity and
glucose disposal in healthy subjects and in patients with type 2 diabetes. A recent study
found that a primed constant infusion of acetyl-L-carnitine (ALC) may increase glucose
utilization in type 2 diabetic patients, possibly restoring the glycogen synthase activity.
In a previous pilot study in healthy subjects with decreased insulin sensitivity, the
investigators found that 6-month treatment with Acetyl-L-Carnitine - an ester of l-carnitine
- improved the glucose disposal rate, taken as a marker of insulin sensitivity. Amelioration
of insulin sensitivity was associated with a significant and clinically relevant reduction in
systolic blood pressure without appreciable changes in diastolic blood pressure. Whether
blood pressure reduction reflected the amelioration of insulin sensitivity or, rather, a
direct, specific effect of Acetyl-L-Carnitine is still unknown.The antihypertensive effect
ensued progressively and slowly waned after treatment withdrawal as documented by a slow and
progressive increase in blood pressure levels toward baseline levels over the recovery
period. This finding provided convincing evidence that blood pressure reduction throughout
the observation period was not explained by a "trial effect", but reflected a true treatment
effect. Blood pressure was a secondary efficacy variable of the study and mechanisms
underlying the antihypertensive effect of Acetyl-L-Carnitine (such as reduced peripheral
resistances, decreased cardiac output, increased artery compliance and/or enhanced sodium
excretion), in this population were not assessed.
Acetyl-L-Carnitine was well tolerated in all of the patients and may provide a novel
therapeutic tool for the treatment of arterial hypertension, and of dyslipidemia and could be
safely used in people with type 2 diabetes.
Thus, the investigators designed a prospective, randomized, double-blind, placebo-controlled
trial to investigate whether Acetyl-L-Carnitine added-on stable and standardized blood
pressure and lipid lowering therapy may help further improving control of hypertension and
dyslipidemia and, therefore, decreasing the overall cardiovascular risk in hypertensive
patients with type 2 diabetes.
Phase:
Phase 3
Details
Lead Sponsor:
Mario Negri Institute for Pharmacological Research
Collaborators:
Leadiant Biosciences, Inc. Sigma Tau Pharmaceuticals, Inc.