Type 2 diabetic patients not only have carbohydrate disturbances but also are commonly hypertensive, have lipid abnormalities, are often overweight, and not surprisingly have a high incidence of cardiovascular events. They are prone to chronic kidney disease, which amplifies their risk even further. Thus, diabetic patients are oftentimes selected targets for pharmacological intervention and appropriately so. They have an increased frequency of cardiovascular events in a day and age when regulatory agencies demand ‘hard' endpoints for medication trials. Furthermore, they represent a genuine need and physicians desperately want to reach out and help them.

The renin-angiotensin-aldosterone system (RAAS) has received intense attention in the last half century [1] and particularly its role in diabetes has been thoroughly scrutinized [2]. In terms of patient-oriented research, the development of angiotensin-converting enzyme (ACE) inhibitors opened a highly attractive therapeutic avenue for diabetic patients. The Collaborative Study Group published that captopril reduced a combined endpoint of death, dialysis, and transplantation in type 1 diabetic patients by 50% [3]. Both groups in that study received the best treatments of the day and captopril 25 mg three times daily was compared to placebo. Systolic and diastolic blood pressure was to be held below 140 and 90 mm Hg by the trial physicians. Amazingly, the blood pressure decrease observed in the study was the same in both groups, 7 ± 11 and 5 ± 11 mm Hg, respectively. Either the trial physicians were incredibly adroit in lowering blood pressure in the placebo group or captopril 75 mg/day did not lower blood pressure. Thereafter, this experiment was repeated with a new class of RAAS inhibitors, the AT1 receptor blockers (ARB), with similarly favorable results for patients with type 2 diabetes [4,5]. Suffice it to say that ‘something special' has been associated with these agents that implying a magical action of RAAS above and beyond lowering blood pressure. Identifying such effects clinically, however, has been elusive [6]. Figure 1 summarizes a review of the putative advantages of ‘dual blockade' as explained on a popular website.

Fig. 1

A common schema of the putative advantages afforded by ‘double blockade' of the RAAS. Recent trails suggest that this view should be revised. Diagram adapted from: http://www.escardio.org/communities/councils/ccp/e-journal/volume9/Pages/Dual-RAAS-suppression-clinical-practice.aspx#.UooxfI2IIog.

Fig. 1

A common schema of the putative advantages afforded by ‘double blockade' of the RAAS. Recent trails suggest that this view should be revised. Diagram adapted from: http://www.escardio.org/communities/councils/ccp/e-journal/volume9/Pages/Dual-RAAS-suppression-clinical-practice.aspx#.UooxfI2IIog.

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The dynamics of the RAAS are complex and the pharmacology of available agents does not guarantee uniform inhibition at all times. Furthermore, the discovery of various additional components, such as AT2 receptors, ACE2, further breakdown products of angiotensin (Ang 1-7, Ang 3-8, Ang 1-12), the renin receptor, and virtually a host of additional pathways (Mas) led to the attractive conclusion that blocking these systems at more than one point could be desirable. Several landmark studies were performed that did not have as their sole aim to test the notion that ACE plus ARB would be better than either compound alone, but nonetheless gave some insight into this issue.

The ONTARGET investigators did not focus solely on patients with diabetes, but did concentrate on particularly high-risk patients. They assigned 8,576 to receive ramipril 10 mg, 8,542 to receive telmisartan 80 mg, and 8,502 to receive both drugs, a courageous study indeed. The primary composite outcome was death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for heart failure. Treatment with ramipril or telmisartan led to similar results, while the combination was associated with more adverse events without an increase in benefit. Blood pressure at entry was 142/82 mm Hg. The mean blood pressure was reduced by 6.4/4.3 mm Hg in the ramipril group, by 7.4/5.0 mm Hg in the telmisartan group, and by 9.8/6.3 mm Hg in the combination-therapy group. Hyperkalemia (>5.5 mmol/l) was significantly higher in the combination-therapy group and occurred in 480 patients. In the combination-therapy group, an increased number of patients withdrew because of hypotensive symptoms, syncope, or renal impairment, to compared to the other groups. The number of deaths was numerically higher in the combination group, albeit not statistically significantly so. No specific causes of death were identified that were unique to the combination group. Could overly aggressive blood pressure lowering have been responsible for the disappointing results?

Some insight might be provided by the ACCORD Study Group [7]. These investigators enrolled 4,733 high-risk participants with type 2 diabetes to undergo blood pressure lowering of systolic blood pressure to 140 mm Hg, the standard guideline, or down to 120 mm Hg, a level recommended by some experts. Various medications were allowed. Combinations of drugs were common; however, the combination of ACE inhibitors plus ARB was not included in the trial. The blood pressure separation was astonishingly good with systolic blood pressure falling from an initial 140 mm Hg in both groups to 134 mm Hg in the standard-care group and to 120 mm Hg in the intensive-treatment group. Nonetheless, 120 mm Hg compared with <140 mm Hg did not reduce the rate of fatal and non-fatal major cardiovascular events. As a matter of fact, ONTARGET may have been a harbinger of these results, since the additional blood pressure lowering in the ONTARGET ACE plus ARB group should have reduced cardiovascular risk rather than elevating it. Compared to the standard-care group, the intensive-therapy group had significantly more serious adverse events attributed to antihypertensive treatment, as well as higher rates of hypokalemia and elevations in serum creatinine levels. A favorite surrogate endpoint, proteinuria, was reduced in the intensive group, apparently without further benefit to these patients. Death rates from cardiovascular or non-cardiovascular causes were not different between the groups.

The ROADMAP Trial investigators also focused on type 2 diabetes [8]. They assigned 4,447 patients to olmesartan 40 mg/day or placebo. ACE inhibitors assignment and other ARB were excluded from the trial. The investigators selected a surrogate endpoint, namely the prevention of microalbuminuria. Renal and cardiac events were secondary endpoints. Blood pressure at entry was 137/81 mm Hg. The mean value in the olmesartan group was 126/74 mm Hg, while the value in the placebo group was 129/76 mm Hg. Olmesartan indeed delayed microalbuminuria slightly, although if this surrogate endpoint has clinical meaning is debatable. Glomerular filtration rate decreased 5 ml/min in the olmesartan group and 2 ml/min in the placebo group over 3 years. Cardiovascular endpoints were complex. Slightly fewer patients in the olmesartan group than in the placebo group had non-fatal cardiovascular events. However, a significantly greater number had fatal cardiovascular events. The difference appeared to be related to a significantly higher rate of death from cardiovascular causes in the olmesartan group than in the placebo group among patients with preexisting coronary heart disease.

Another heroic attempt to clarify matters was conducted by the ALTITUDE investigators [9]. These investigators tested the utility of the renin inhibitor, aliskiren. They assigned 8,561 type 2 diabetic patients to aliskiren 300 mg/day or placebo as an adjunct to ACE inhibitor or ARB care. A composite cardiovascular and renal endpoint was selected. The trial was discontinued prematurely after 18.3% of the aliskiren group had reached the primary endpoint compared to 17.1% in the placebo group. About 41% of patients had a baseline systolic blood pressure >140 mm Hg, and 12% had a diastolic blood pressure >85 mm Hg. Oddly, blood pressure actually increased about 3 mm Hg in both groups, although this increase was less in the group given aliskiren. Glomerular filtration rate decreased 5 ml/min over the 42 months of observation in both groups. Potassium increased in both groups, more so in the aliskiren group, although the highest mean value of 4.65 mmol/l does not raise concern. Nonetheless, hyperkalemia (5.5 mmol/l) was the most common adverse event reported by investigators and the most common adverse event leading to discontinuation of the study drug. The investigators very appropriately underscored the need to go beyond surrogate biomarkers and obtain risk-benefit data from clinical endpoint trials to better inform clinical decisions.

Now come the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) study investigators [10]. Similar to the ONTARGET investigators, they studied ACE inhibitor, ARB alone, or the combination in patients with type 2 diabetes. They used losartan 100 mg/day, in their patients, who were then randomized to lisinopril 10-40 mg/day or placebo. The primary endpoint was a decrease in glomerular filtration rate, end-stage renal disease, or death. The secondary endpoint was the first occurrence of a glomerular filtration rate decline or end-stage renal disease. The investigators focused on these renal endpoints rather than cardiovascular endpoints in general, probably because of the propensity to employ the combination treatment in chronic kidney disease patients. Safety endpoints were mortality, hyperkalemia, and acute kidney injury. This study was also discontinued prematurely. A total of 152 primary endpoint events occurred in the monotherapy group and 132 in the combination-therapy group, a non-significant difference. There was even a trend towards a benefit from combination treatment with respect to the secondary endpoint. Total mortality or cardiovascular endpoints were not different between treatments. However, what led to study discontinuation were hyperkalemic events (6.3 per 100 patient-years, compared to 2.6 per 100 patient-years) and the occurrence of acute kidney injury. Both dismal endpoints were highly significantly different between the groups. The enrolled patients had a reduced glomerular filtration rate (54 ml/min) at entry, which distinguishes them from the other studies. The blood pressures were 137/72 mm Hg in both groups. After adjustment of the lisinopril or placebo dose, the combination group had a slightly lower blood pressure than the monotherapy group, but only by 2 mm Hg. The decrease in systolic blood pressure in the patients was from 140 to 130 mm Hg. Diastolic blood pressure decreased from about 74 to 70 mm Hg. Interestingly, proteinuria after 1 year's treatment was reduced in half by the combination treatment, compared to placebo plus losartan, evidently without helping these patients. This result puts another nail in the coffin of the proteinuria surrogate endpoint in patients with type 2 diabetes.

These trials are very diverse, tested different hypotheses, and although the focus was for the most part on patients with type 2 diabetes, the patient populations were diverse. ONTARGET, ACCORD, and ROADMAP focused primarily on cardiovascular outcomes. ALTITUDE included a focus on cardiovascular and the kidney while NEPHRON-D was primarily concerned with kidney disease. The results of all these trials are disappointing to physicians and are particularly painful for nephrologists. Can we find explanations? From ONTARGET and ACCORD, we could get the impression that blood pressure goals (blood pressures that we may have had at age <20 years) are not such a great idea after all. Messerli et al. have drawn sufficient attention to this problem [11]. Nonetheless, the blood pressure differences, aside from ACCORD, in the studies were not great and blood pressure even increased slightly in ALTITUDE. Are the patients given combination RAAS blockade endangered by hyperkalemia? A potassium value of 5.5 mmol/l scares non-nephrologist physicians but should not be lethal. In ACCORD, hypokalemia appears to have been a problem. Patients selected for clinical trials tend to be ‘professors' cases' (not too sick). Nevertheless, these patients may be sicker than the cardiovascular risk patients selected for other clinical questions. Helpful would be an adjudicated investigation of all adverse endpoints in these studies presented as a meta-analysis. Such an investigation would require the cooperation amongst all these investigators and perhaps a detailed chart review and further follow-up of each individual case, particularly of those who died. Otherwise, combined blockade of the RAAS is dead in the water, at least for nephrologists. Our intrepid cardiologist colleagues are exploring concomitant antihyperkalemia treatments to maintain the safety of mineralocorticoid receptor blockade in heart failure patients receiving ACE inhibitors or ARB (or perhaps even both) treatments [12]. This strategy would probably not appeal to nephrologists. Where are we left with figure 1? Evidently, not too much!

No disrespect is meant to any of the investigators responsible for these studies. Each featured impeccable design and was conducted in an excellent fashion. The hypotheses tested were reasonable at the time and the outcomes, although disappointing, provide us with important lessons. To paraphrase Donald Rumsfeld, ‘there are unknowns and then there are unknown unknowns'. So, we found out what it was that we did not know we didn't know. That is what hypothesis testing is all about and that is why rigorous clinical trials are important.

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