Dual Blockade In Diabetes Mellitus

Only few studies are published using the dual blockade treatment principle to treat hypertension and nephropathy in patients with diabetes mellitus, even though the indication seems obvious. Hebert et al. were among the first to apply dual blockade to diabetic patients in a small series of only 7 patients with diabetes, hypertension and macroalbuminuria. They found arterial blood pressure significantly lowered, when adding 50 mg's of Losartan to concomitant ACE-inhibition treatment, but proteinuria was not significantly reduced [20].This was obtained in another small trial including Type 2 diabetes patients with nephropathy. Rossing et al conducted a trial of 18 patients with Type 2 diabetes, severe proteinuria (>1g/day) and hypertension, who where all treated with recommended doses of long acting ACE inhibitors among a wide variety of other antihypertensive drugs. By adding 8 mg candesartan cilexetil both blood pressure and proteinuria were significantly reduced [21]. This was also found in a second trial from the same group using the Angiotensin II receptor blocker Irbesartan in combination with concomitant ACE-inhibitor treatment in Type 1 diabetes patients with severe nephropathy and concomitant hypertension. Dual blockade was again able to significantly reduce both blood pressure and albuminuria compared to monotherapy [22].

These findings have recently been confirmed by the same study group in two small short term studies in Type 1 diabetes patients with nephropathy[23;24].

For the sake of completeness, a small trial on nephropathy should be mentioned. It included 12 patients with diabetes, out of a total number of16 severely obese patients with nephropathy. In one period, patients received lisinopril 40 mg once daily along with other antihypertensive therapy, and in the other period, losartan 50 mg was added to the previously mentioned regimen. The study failed to show any effects of dual blockade treatment over one month treatment, with a two-week washout between periods [25]. In a companion paper Agarwal and colleagues were able to find significant reduction in TGF-beta 1 levels among patients in dual blockade treatment, and the authors postulated that some renoprotection might be present, due to these findings [26]. The lack of solid evidence in these 2 trials could partially be explained by study design and size. The CALM study still stands as the largest dual blockade trial concerning diabetes patients. This randomized, double blind study was performed on 197 patients between 30 and 75 years of age who were previously diagnosed with Type 2 diabetes mellitus, hypertension and microalbuminuria. The included patients were treated with 20 mg lisinopril, or16 mg candesartan cilexetil daily, or both drugs in combination. After 4 weeks of placebo treatment, patients were treated with lisinopril or candesartan for 12 weeks. Thereafter, patients continued with either monotherapy or the combination of lisinopril and candesartan for an additional 12 weeks. All three treatments significantly reduced blood pressure from baseline to 24 weeks, with dual blockade being the most effective. There was also a significant blood pressure reduction obtained with dual blockade as compared to either lisinopril or candesartan alone. The trial also found greater reductions in the urine albumin-creatinine ratio with combination treatment (50%) compared to lisinopril alone (39%) and candesartan alone (24%). But when adjusting for diastolic blood pressure, baseline values, and weight, the differences were not significant [27]. Table 1 provides an overview of the mentioned trials.

Table 1. Selected dual blockade-trials

Study

Study drugs

N

Follow-up

Results

Hebert et al

Losartan 50 mg

7

1 week

Significant blood pressure reduction.

[20]

ACE-inhibitor

No effects on proteinuria.

Rossing et al.

Candesartan 8 mg

18

9 weeks

Significant blood pressure reduction

[21]

ACE-inhibitor

Significant reduction in albuminuria

Jacobsen et al.

Irbesartan 300 mg

21

8 weeks

Significant blood pressure reduction

[22]

ACE-inhibitor

Significant reduction in albuminuria

Jacobsen et al.

Irbesartan 300 mg

24

8 weeks

Significant blood pressure reduction

[23]

Enalapril 40 mg

Significant reduction in albuminuria

Jacobsen et al.

Benazepril 20 mg

18

8 weeks

Significant blood pressure reduction

[24]

Valsartan 80 mg

Significant reduction in albuminuria

Agarwal *

Losartan 50mg

12

1 month

No effects on blood pressure or

[25;26]

Lisinopril 40 mg

proteinuria. Improvement in GFR

significant TGF-P 1 reduction.

CALM

Candesartan 16 mg

199

12 weeks

Significant blood pressure reduction

[27]

Lisinopril 20 mg

Significant reduction in albuminuria

COOPERATE

Losartan 100 mg

245 4 yrs

Significant reduction in both end-

[38]f

Trandolapril 3 mg

stage renal disease and doubling of

serum creatinine

*] Two Studies f]Patients with non-diabetic nephropathy

Supplements For Diabetics

Supplements For Diabetics

All you need is a proper diet of fresh fruits and vegetables and get plenty of exercise and you'll be fine. Ever heard those words from your doctor? If that's all heshe recommends then you're missing out an important ingredient for health that he's not telling you. Fact is that you can adhere to the strictest diet, watch everything you eat and get the exercise of amarathon runner and still come down with diabetic complications. Diet, exercise and standard drug treatments simply aren't enough to help keep your diabetes under control.

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