Handbook of Diabetes, 4th Ed., Excerpt #18: Hypertension in Diabetes

Angiotensin-converting enzyme (ACE) is responsible for most AII production from AI, but other enzymes such as chymases may also operate and be upregulated in the presence of ACEI drugs. ACE2 is a newly described enzyme not inhibited by ACEI and responsible for production of angiotensin 1 – 7.

By blocking AII action at the type 1 receptor, angiotensin receptor blocking agents (ARB) may upregulate the type 2 receptor but also increase angiotensin 1 – 7 production via ACE2.

Finally, both spironolactone and eplerenone block aldosterone action by direct antagonism at its receptor.

With the development of a direct renin inhibitor (aliskiren), blockade of the RAS is possible at almost all levels. Theoretically, the choice of agent should be determined by where in the RAS it is active and the likely consequences of blockade in terms of physiological outcome. In practice, however, because the agents were developed historically, there is much more information about ACEI and ARB.

ACEI

In experimental animals, ACEI reduce glomerular intracapillary pressure and subsequent glomerulosclerosis. In humans, they reduce microalbuminuria over and above their blood pressure lowering effect. In type 1 diabetes, a meta-analysis of 12 trials in 698 normo- or mildly hypertensive patients showed that ACEI treatment gave an odds ratio of 0.38 (95% CI 0.25 – 0.57) for progression to clinical nephropathy, and 3.07 (2.15 – 4.44) for regression to normoalbuminuria. At 2 years, albuminuria was 50.5% (29.2 – 65.5%) lower in treated patients versus placebo. In type 1 patients with clinical nephropathy, captopril use for 4 years was associated with a 50% reduction in the numbers doubling serum creatinine or who reached a combined endpoint of death, dialysis or kidney transplantation (Figure 19.4). There are few other studies of antihypertensive therapy using cardiovascular endpoints in type 1 diabetes.

For patients with type 2 diabetes at high risk of vascular disease, ramipril use for 4.5 years in the MICRO-HOPE Study reduced overall albumin:creatinine ratio and the numbers developing microalbuminuria and clinical nephropathy (incidence reduced by 13% and 14% respectively). There was also a 25% (95% CI 12 – 36%) relative risk reduction in fatal and non-fatal MI and stroke. More recently, the ADVANCE study of a perindopril and indapamide combination showed a 21% and 18% risk reduction in new microalbuminuria and worsening nephropathy respectively in 11,140 type 2 patients at high vascular risk. However, the observed risk reduction for fatal and non-fatal MI and stroke was not statistically significant at 8% (95% CI − 4 to 19%). Most of the patients in these studies were hypertensive. Why the results differ is not clear but may relate to the fact that many control patients in ADVANCE were taking open label perindopril.

ARB

Short-term studies in type 1 diabetes suggest equal potency for albuminuria reduction with similar blood pressure lowering for ARB and ACEI. ARB have been most extensively used in type 2 diabetes where a similar reduction in microalbuminuric patients developing clinical nephropathy on the ARB irbesartan to the meta-analysis of ACEI in type 1 diabetes was seen (HR 0.32; 95% CI 0.15 – 0.65).

For clinical nephropathy, two large trials showed a significant reduction of 16 – 20% in the numbers reaching a combined endpoint of doubling of serum creatinine, end-stage renal disease or death. However, neither of these studies of ARB has shown a significant impact on cardiovascular mortality or morbidity alone.

Renin inhibitors

Aliskiren is the only agent currently in this class and has been shown to reduce both blood pressure and albuminuria when used in combination with an ARB. No data are available on renal or cardiovascular endpoints.

Aldosterone antagonists

Spironolactone and eplerenone have been shown to benefit patients with heart failure and who are already on an RAS-blocking agent. In diabetes, they further reduce albuminuria when added to either an ACEI or ARB, although with a risk of hyperkalemia. There are no hard endpoint data on their use in diabetic patients.

Side effects

All RAS-blocking agents can cause hyperkalemia and regular serum potassium monitoring is required when initiating or adjusting therapy. An acute reduction in GFR can occur as part of the lowering of glomerular pressure.

An increase in serum creatinine of up to 35% of baseline is acceptable but above this either a reduction in concomitant diuretic dose or investigation for possible renal artery stenosis should be considered. Although many type 2 patients at postmortem have evidence of renal artery atheroma and stenosis, this is functional in only a minority of individuals. If there is a suspicion of stenosis from a rapid deterioration in renal function after RAS blockade, renal arterial Doppler ultrasound or renal angiography should be undertaken. Trials have shown no real benefit of angioplasty or stenting on rate of decline of GFR. Some patients may experience hypotension with the first dose of an RAS-blocking drug. Because of this the first dose should be given at night.

Combination/dual blockade

Because of the potential of a theoretical lack of complete RAS blockade using either an ACEI or an ARB alone, studies using both drugs together have been undertaken in diabetic patients with nephropathy. Most of these are of short duration and whilst they have shown an increased benefit in terms of lowering blood pressure and albuminuria, there was a significant incidence of hyperkalemia. The recently published ONTARGET study of long-term dual blockade (telmisartan plus ramipril) versus either agent alone in over 25,000 patients, nearly 7000 of whom had type 2 diabetes, found worse renal outcomes, so at present combination therapy cannot be recommended routinely.

Hyporeninemic hypoaldosteronism (also known as type IV renal tubular acidosis) is more common in people with diabetes with developing nephropathy and is probably a result of tubulointerstitial disease. It often only becomes apparent when patients are challenged with RAS-blocking agents and they become markedly hyperkalemic.

Calcium channel blockers

There are two groups: dihydropyridine and non-dihydropyridine; both are vasodilators and useful in systolic hypertension (Table 19.3). However, they can increase albuminuria in nephropathy and are less effective than ARB in preserving renal function in patients with type 2 diabetes and clinical nephropathy.

The non-dihydropyridines also slow heart rate and for this reason they should not be used with ß-blockers. They can worsen heart failure. Verapamil has been shown to be less effective in reducing albuminuria than the ACEI trandolapril.