The pharmacological research of the renin-angiotensin-aldosterone system is known for having brought major therapeutic breakthroughs in cardiovascular, renal, and diabetic medicine.

       Since the 80s ACE-Inhibitors were already available for the treatment of hypertension. For about 15 to 20 years Angiotensin Receptor blockers (ARBs) began a similar journey in clinical medicine. ACE-Inhibitors and ARBs are proposed in the vast majority of guidelines that address the issue of cardiovascular and renal protection in type 2 diabetics, based on a landmark study in type 1 diabetic individuals with captopril, where the randomization process failed, so inducing a higher number of probably sicker patients in the control group, and other follow-up studies with ARBs in type 2 diabetic individuals. These studies were all highly publicized, and the end-points were all surrogates for type 2 diabetic complications, but not genuine, real world diabetic complications such as amputations, loss of vision, myocardial infarction, strokes, heart failure, renal failure requiring chronic dialysis or transplantation, and cardiovascular death.  The only large and long-term study comparing single drugs for the treatment of hypertension, with many type 2 diabetics – the ALLHAT study showed a “disturbing” victory of a cheap diuretic over the other anti-hypertensive drugs, including an ACE-Inhibitor; this study became highly criticized and ostracized because of its virtues: a head to head comparison of single drugs in the treatment of hypertension in diabetics and non-diabetics.

       There was never one single head to head clinical trial comparing the potential benefits, or harms, of ACE-Inhibitors versus ARBs in type 2 diabetic individuals. These two drugs, in many clinical/pharmacology studies have become known as having cardiovascular and renal benefits independent of, or beyond their blood pressure lowering effects. These studies were, again, all based on surrogate markers of disease such as proteinuria, estimated glomerular filtration rate, parameters of endothelial function and etc…

       Aliskiren, the first direct renin inhibitor, came to the market in 2007 without any single long-term study to assess its safety or effectiveness, just because of its “wonderful” pharmacological actions at the root of the renin-angiotensin-aldosterone system, lowering both plasma renin activity and blood pressure levels. Dozens of medical authorities envisioned Aliskiren as the perfect pill for the treatment of hypertension in type 2 diabetics. The PHARMA became so confident in this molecule that initiated a large prospective randomised (6.000 patients) study to assess the benefits of Aliskiren added on top of ACE-I or ARBs treatment of high risk type 2 diabetics – the ALTITUDE study. This study had now an early end, because actually Aliskiren harmed instead of benefitting these patients. The patients taking Aliskiren had significantly more Strokes, renal dysfunction, hyperkalemia, hypotension.

       I have learned across the years to be very careful about all dogmas in medicine, namely when they relate to common&complex diseases like hypertension and type 2 diabetes. Life (and the complex systems theory) has taught me that there are no magic single (deterministic) "cure" for them.

       The dogma of increased cardio-renal protection with ACE-Inhibitors or Angiotensin Receptor Blockers independent of, or beyond, blood pressure control is one good example of this.

       And it is very easy to start a dogma based on easy to achieve surrogates markers of disease processes. The AVOID study - published in the prestigious New England Journal of Medicine - started to heavily increase the prescriptions of Aliskiren based solely on its anti-proteinuric effect when added to Losartan.

       These dogmas make-me remember of what said Dr. William Osler:

       "The higher the ignorance, the higher the dogmatism"

       All Best,

       Joey