ACE inhibitors and ARBs in the prevention of type 2 diabetes

• a meta-analysis was conducted of 12 randomized controlled clinical trials of angiotensin-converting enzyme inhibitors (ACE inhibitors) or angiotensin receptor blockers (ARBs), identified through a MEDLINE search and a review of reports from scientific meetings, to study the efficacy of these medications in diabetes prevention (1)
  • the meta-analysis showed that ACE inhibitors and ARBs were associated with reductions in the incidence of newly diagnosed diabetes by 27% and 23%, respectively, and by 25% in the pooled analysis
  • the study authors concluded that the use of an ACE inhibitor or ARB should be considered in patients with pre-diabetic conditions such as metabolic syndrome, hypertension, impaired fasting glucose, family history of diabetes, obesity, congestive heart failure, or coronary heart disease
• a further meta-analysis found that the association of antihypertensive drugs with incident diabetes is lowest for ARB and ACE inhibitors followed by calcium channel blockers and placebo, beta blockers and diuretics in rank order (2)

Notes:

• mechanisms of action to as to how these medications may prevent type 2 diabetes are not known. Some theories regarding possible mechanisms are briefly outlined:
  • ACE inhibitors not only block the conversion of angiotensin I to angiotensin II, but also increase bradykinin levels through inhibition of kininase II-mediated degradation
    • higher kinin levels lead to:
      • an increased production of prostaglandins (prostaglandin E1 and prostaglandin E2) and nitric oxide, which improve exercise-induced glucose metabolism and muscle sensitivity to insulin. This in conjunction with the peripheral vasodilatory actions of ACE inhibitors and ARBs, leads to an improvement in skeletal muscle blood flow, the primary target for insulin action and an important determinant of glucose uptake
        • the consequence of these changes may be to lead to to an increase in the surface area for glucose exchange between the vascular bed and skeletal muscles
  • these agents may have an effect on adipocyte function
    • increased levels of angiotensin II may inhibit pre-adipocyte differentiation into mature adipocytes, and this impair fat cells’ ability to store fat - there is then a shunting of fats to the liver, skeletal muscle, and pancreas, which worsens insulin resistance. Thus if angiotensin II levels are reduced with an ACE inhibitor or blocking the angiotensin II receptor with an ARB may promote differentiation of pre-adipocytes to mature adipocytes, which serve as a sump for fat - thus reducing insulin resistance
  • may facilitate a protective effect on the pancreatic beta cell via inhibiting the vasoconstrictive effect of angiotensin II in the pancreas and increasing islet blood flow
• DREAM study
  • among persons with impaired fasting glucose levels or impaired glucose tolerance, the use of ramipril for 3 years did not significantly reduce the incidence of diabetes or death but did significantly increase regression to normoglycemia (3)

Reference:

1. Abuissa H et al. Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers for prevention of type 2 diabetes: a meta-analysis of randomizedclinical trials. J Am Coll Cardiol 2005; 46: 979-95
2. Elliott WJ, Meyer PM. Incident diabetes in clinical trials of antihypertensive drugs: a network meta-analysis. Lancet. 2007 Jan 20;369(9557):201-7
3. Bosch J et al. Effect of ramipril on the incidence of diabetes. N Engl J Med. 2006 Oct 12;355(15):1551-62