Meta-analysis of more than 130,000 people: This super-commonly used drug in internal medicine, used for more than 3 years or greatly increases the risk of cancer, especially lung cancer!

Angiotensin receptor blockers (ARBs) are a widely used class of drugs approved for the treatment of several common conditions, including hypertension, heart failure and diabetic nephropathy, as well as for the primary prevention of cardiovascular events
.

In 2011, it was estimated that more than 200 million patients worldwide were treated with ARBs on a long-term basis

Cumulative exposure is a fundamental factor in the epidemiology of chronic diseases, especially cancer
.

Unfortunately, the relationship between cumulative exposure to ARBs and cancer risk has not been studied in regulatory agency studies or other randomized trial analyses

Cumulative exposure is a fundamental factor in the epidemiology of chronic diseases, especially cancer

Trial-level data from the ARB Trialist Collaboration, including 15 randomized controlled trials, were extracted and entered into meta-regression analysis
.

The two co-primary outcomes were the association between cumulative exposure to ARBs and the risk of all cancers combined and the association between cumulative exposure and the risk of lung cancer

The analysis included 15 randomized trials (and the ARB trialist collaboration), and the main study characteristics are shown in Table 1
.

Ultimately, a total of 74,021 patients were randomly assigned to an ARB, resulting in a total cumulative exposure of 172,389 person-years (exposed to the high daily dose or equivalent)

Meta-regression analyses examined the effect of the first co-primary outcome, cumulative exposure and hazard ratio for all cancers within the ARB group (Figure 1)
.

Overall, there was a highly significant association between cumulative exposure to ARBs and the summed risk of all cancers (slope = 0.

There was a highly significant association between cumulative exposure to ARBs and the summed risk of all cancers (slope = 0.

The effect of ARB randomization on the development of new cancers was examined according to the degree of cumulative exposure to ARBs
.

In trials with mean cumulative exposure >3 years (two telmisartan trials, one candesartan trial, and one losartan trial), there was a statistically significant excess of new cancers (7.

The excess of new cancers with mean cumulative exposure >3 years was statistically significant ⁽² fixed effects model) Figure 2 ² Figure 2

Meta-analytic hazard ratios associated with background ACE inhibitor treatment were calculated based on cumulative exposure
.

In one trial with cumulative exposure >3 years, both study arms were treated with angiotensin-converting enzyme inhibitors (i.

Figure 3 Figure 3 In the trial subgroup without ace inhibitor treatment in both study arms, a statistically significant increase in cancer incidence was again seen only when the cumulative exposure time was >3 years Figure 3

The meta-regression analysis shown in Figure 4, Panel A, examined the second co-primary outcome of cumulative exposure to ARBs and lung cancer risk
.
Likewise, there was a statistically significant relationship between cumulative exposure to ARBs and lung cancer risk; higher cumulative exposure resulted in a larger hazard ratio for lung cancer (slope 0.
16 [95% CI 0.
05-0.
27], z = 2.
93, p = 0.
003)
.
In both placebo-controlled trials (slope 0.
12 [95% CI -0.
02, 0.
28], z = 1.
68, p = 0.
09) ( Figure 4 , Panel B) and non-placebo-controlled trials (slope 0.
17 [95% CI -0.
009] , 0.
36], z = 1.
86, p = 0.
06 (using fixed-effects regression) ( Fig.
4 , panel C), there was a trend towards a positive relationship between cumulative exposure to ARBs and lung cancer risk
.

The meta-regression analysis shown in Figure 4, Panel A, examined the second co-primary outcome of cumulative exposure to ARBs and lung cancer risk
.
There was a statistically significant relationship between cumulative exposure to ARBs and lung cancer risk; higher cumulative exposure resulted in a larger hazard ratio for lung cancer (slope 0.
16 [95% CI 0.
05-0.
27], z = 2.
93, p = 0.
003 ) Figure 4 Figure 4

The effect of random assignment to ARBs on lung cancer development was examined according to the degree of cumulative exposure
.
Lung cancer excess was statistically significant in trials with mean cumulative exposure >2.
5 years (1.
2% vs 0.
9%, I ² = 0%, RR 1.
21 [95% CI 1.
02 to 1.
44], both fixed- and random-effects models p = 0.
03) ( Fig.
5 , Panel A)
.
On the other hand, in the lower cumulative exposure trial, there was no increased risk of lung cancer associated with ARBs (0.
6% vs 0.
8%, I2 ^: 40.
9%, RR 0.
86 [95% CI 0.
73 to 1.
01], p = 0.
06 using Fixed effects model, RR 0.
86 [95% CI 0.
69 to 1.
09], p = 0.
21 using random effects model) ( Figure 5 , Panel B)
.

² Figure 5 ² Figure 5

The relationship between cumulative exposure to ARBs and risk of prostate and breast cancer was also examined, neither of which showed any significant associations (p=0.
27 for prostate cancer and p=0.
71 for breast cancer for all 3 methods)
.

Taken together, cancer risk increases with cumulative exposure to ARBs
.
The excess risk of cancer begins to emerge approximately 3 years after exposure to the maximum daily dose of ARBs
.
The same relationship held for lung cancer, where the risk became statistically significant after 2.
5 years of exposure
.
The excess risk was independent of whether patients received background angiotensin-converting enzyme inhibitors and whether the trial was placebo or non-placebo-controlled
.
This analysis shows for the first time that the risk of cancer (particularly lung cancer) from ARBs increases with cumulative exposure to these drugs
.
The cancer risk associated with long-term ARB use is too high, with implications for public health
.

Cancer (particularly lung cancer) risk from ARBs increases with cumulative exposure to these drugs
.
The cancer risk associated with long-term ARB use is too high, with implications for public health
.

 

Original source:

Ilke Sipahi , et al.
Risk of cancer with angiotensin-receptor blockers increases with increasing cumulative exposure: Meta-regression analysis of randomized trials.

Ilke Sipahi

PLOS ONE | https://doi.
org/10.
1371/journal.
pone.
0263461 March 2, 2022.

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