Acetyl-L-Carnitine in Type 2 Diabetes
Condition: Diabetes Type 2; Hypertension
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2
Study type: Interventional
Phase: Phase 3

Summary: 
      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.
    

Detailed description: 
      BACKGROUND Arterial hypertension, in particular systolic hypertension, is a common component
      of the metabolic syndrome, a syndrome of hypertension, abdominal obesity, dyslipidemia,
      impaired glucose tolerance and increased urinary albumin excretion sustained by decreased
      tissue sensitivity to insulin (insulin resistance). It affects 80 to 90% of people with type
      2 diabetes and is the strongest risk factor for macrovascular and microvascular complications
      of diabetes, such as myocardial infarction, stroke, peripheral artery disease, nephropathy
      and retinopathy. Despite multi-drug therapy, reduction of systolic blood pressure to normal
      range is seldom achievable in people with type 2 diabetes. Moreover, due to increased
      vascular stiffness, reducing systolic blood pressure may decrease diastolic blood pressure to
      the extent that diastolic myocardial perfusion is impaired and the risk of ischemic event
      increased. Thus, availability of drugs that may help controlling systolic hypertension
      without appreciably affecting diastolic blood pressure would have major clinical
      implications.

      In addition to arterial hypertension, dyslipidemia is also a component of the metabolic
      syndrome that is almost invariably observed in people with type 2 diabetes and remarkably
      contributes to the excess cardiovascular risk in this population. HMGCoA inhibition by statin
      therapy, significantly ameliorates hypercholesterolemia, but only marginally affects the
      concomitant hypertriglyceridemia (probably the most typical feature of increased insulin
      resistance) and fails to significantly reduce the circulating levels of serum lipoprotein(a),
      one of the strongest predictors of coronary and cerebrovascular events in type 2 diabetics.
      Thus, availability of drugs that may help achieving a more effective amelioration of
      dyslipidemia in this population might also have important clinical implications .

      In an ongoing study in healthy subjects with decreased insulin sensitivity, we found that
      6-month treatment with acetylcarnitine - 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 acetylcarnitine is still unknown.

      Previous studies also found that L-carnitine added on background simvastatin therapy,
      marginally affected serum cholesterol, but remarkably reduced serum triglyceride and
      lipoprotein (a) levels. Whether amelioration of insulin resistance may explain at least in
      part this effect is unclear.

      Finally, all available clinical studies consistently showed that acetyl carnitine is a well
      tolerated drug that can be safely used in humans. Experimental evidence is also available
      that l-carnitine may improve statin-associated myotoxicity.

      AIMS Primary To asses the effect of 6-month therapy with acetylcarnitine compared to placebo
      on systolic blood pressure in 228 patients with type 2 diabetes, arterial hypertension and
      dyslipidemia on stable background antihypertensive, hypoglycemic, and lipid lowering therapy.

      Secondary

      A.To asses the effect of treatment on:

        -  diastolic and pulse pressure

        -  serum triglycerides and apolipoprotein(a)

        -  HOMA index (calculated during data analyses), serum insulin, leptin, adiponectin
           (pending on the findings on the other efficacy variables)

        -  blood glucose, serum cholesterol (total, HDL and LDL), non-esterified fatty acids
           (NEFA), lipoproteins A and and uric acid

        -  2-hours post oral load blood glucose profile

        -  high density C-reactive protein (hsCRP)

        -  urinary albumin excretion and estimated creatinine clearance (calculated during data
           analyses)

        -  cardiac output, peripheral resistances or large artery compliance (as assessed by
           echocardiography in a representative subgroup)

        -  24 hour sodium excretion and sodium fractional clearance, in a representative subgroup

        -  need for concomitant therapy with antihypertensive, hypoglycemic, and lipid lowering
           agents

      B.To assess whether the observed changes in systolic, diastolic or pulse pressures and in
      lipid or metabolic profile correlate with the concomitant changes in markers of insulin
      sensitivity.

      C.To monitor systolic/diastolic blood pressure and other clinical/laboratory parameters
      evaluated during the study two months after Acetyl-L-Carnitine therapy or Placebo withdrawal
      in patients completing the study and maintained on the same background medications.

      DESIGN The study will be a prospective, randomized, double-blind, placebo-controlled,
      multicenter trial.
    

Intervention name(s): acetyl-L-carnitine/statin (simvastatin); placebo
Intervention type(s): Drug; Drug
Intervention description(s): acetyl-L-carnitine: 4 tablets of 500 mg a day
simvastatin: 10 to 20 mg/day as deemed clinically appropriate and according to tolerability; placebo: 4 tablets of 500 mg a day simvastatin: 10 to 20 mg/day as deemed clinically appropriate and according to tolerability
Intervention MeSH terms: Acetylcarnitine; Simvastatin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment