Telmisartan: Effect on the Liver and Kidneys

Telmisartan is often described as a drug with “organ-protective” properties. For the kidneys this is partly true, but with important caveats, and for the liver the situation is even more complex: it is precisely this organ that is responsible for eliminating the drug. The editorial team examined what is known about telmisartan's effect on both organs and where the evidence ends.

The drug's path through the body

After oral intake, telmisartan is rapidly absorbed, and bioavailability depends on the dose and is estimated in the prescribing information at roughly 40–60%. The drug binds almost completely to plasma proteins, primarily albumin, and thanks to its high lipophilicity has a large volume of distribution.

Unlike many other drugs, telmisartan is practically not metabolized by the cytochrome P450 system. The main route of its transformation is conjugation with glucuronic acid, resulting in an inactive acylglucuronide. This reduces the likelihood of interactions through the cytochromes but makes the drug dependent on the state of the liver.

More than 97% of the dose taken, according to the official prescribing information, is excreted with bile and feces. Only a very small fraction is excreted through the kidneys. It is precisely this feature that determines why the drug behaves differently in liver and kidney pathology.

The half-life is more than 20 hours, so a steady-state concentration is established after about a week of regular intake. In people with impaired liver function, the blood concentration can rise substantially, which is the basis of the restrictions in the guidelines.

Liver: the main organ of elimination

Since telmisartan is eliminated predominantly with bile, any disturbance of bile outflow sharply changes its pharmacokinetics. Therefore obstructive diseases of the biliary tract (mechanical jaundice, tumors blocking the ducts, and so on) are included among the contraindications in the official prescribing information.

In people with mild and moderate liver failure, the bioavailability of the drug increases, and blood concentrations can be several times higher than in healthy people. The European prescribing information for such patients provides for a restriction of the maximum daily dose, and severe liver failure is a contraindication.

As for direct hepatotoxicity, it is not characteristic of telmisartan. In the post-marketing period, isolated cases of impaired liver function and elevated liver enzymes were reported, most of which, according to the prescribing information, were registered in Japan. Such reactions are considered rare.

For people who simultaneously use other potentially hepatotoxic substances — for example, oral anabolic steroids with 17-alpha-alkylation — the risks add up. In such a situation the problem lies not so much in telmisartan as in the total load on the liver and the possible cholestasis, which alters the elimination of the drug.

• Contraindications: biliary tract obstruction, severe liver failure.
• Caution: mild and moderate liver failure, cholestatic conditions.
• Monitoring: liver tests as clinically indicated, especially with symptoms (jaundice, itching, darkening of the urine).

Kidneys: protection and expected changes

Angiotensin II constricts primarily the efferent arteriole of the renal glomerulus, maintaining the filtration pressure. When its action is blocked, the pressure in the glomerulus decreases. For a kidney suffering from hyperfiltration (in diabetes, obesity, hypertension), this is a protective effect: the leakage of protein into the urine is reduced and the sclerosis of the glomeruli is slowed.

The nephroprotective properties of RAAS blockers are best proven for diabetic nephropathy with albuminuria. For telmisartan, important studies are DETAIL, where it was not inferior to enalapril regarding the dynamics of the glomerular filtration rate in type 2 diabetes, and AMADEO, where telmisartan reduced proteinuria more strongly than losartan.

The flip side of the same mechanism is an expected small rise in creatinine after the start of treatment. It reflects a decrease in intraglomerular pressure rather than kidney damage. Guidelines on hypertension and chronic kidney disease usually consider acceptable a rise in creatinine of up to about 30% from the baseline level, provided that it then stabilizes.

The second natural change is a tendency toward a rise in potassium, since RAAS blockade reduces aldosterone production. In people with preserved kidney function this rarely has clinical significance, but in chronic kidney disease, diabetes, and the use of potassium-sparing agents the risk of hyperkalemia increases.

When the kidney risk increases

The most dangerous situation is bilateral renal artery stenosis or stenosis of the artery of a single kidney. In such patients the glomerular filtration largely depends on angiotensin II, and its blockade can cause an acute worsening of kidney function.

The second risk situation is dehydration. Vomiting, diarrhea, intense sweating, a strict fluid-restricted diet, and excessive doses of diuretics reduce the volume of circulating blood. Against this background, a RAAS blocker “takes away” the kidney's compensation mechanism, and creatinine can rise sharply.

The third factor is combinations. The ONTARGET study showed that combining telmisartan with ramipril adds no protection but more often leads to renal dysfunction and hyperkalemia. Similar conclusions were reached in the ALTITUDE (with aliskiren) and VA NEPHRON-D (losartan with lisinopril) studies. Therefore dual RAAS blockade is not recommended today.

Finally, non-steroidal anti-inflammatory drugs, which are often used by athletes and people with joint pain, constrict the afferent arteriole of the glomerulus. In combination with a RAAS blocker and a diuretic, this forms the so-called “triple threat” to the kidneys, especially in older people.

It is worth remembering that telmisartan is not removed by hemodialysis. In patients on dialysis it can be used, but under careful blood pressure monitoring, since the risk of hypotension is especially high there.

Fatty liver disease: what studies say

Thanks to its partial PPAR-gamma activity and RAAS blockade, which is involved in fibrogenesis, telmisartan has been studied as a possible agent in non-alcoholic (metabolically associated) fatty liver disease. In experimental models, angiotensin II activates the hepatic stellate cells that produce collagen.

Small clinical studies, in particular the work of Georgescu and colleagues (2009) in patients with hypertension and steatohepatitis, showed a decrease in transaminase activity and a certain improvement in histological indicators with telmisartan compared with valsartan.

However, these studies were small, short, and had no hard endpoints. Modern guidelines on fatty liver disease do not consider telmisartan a treatment for this condition. The drug may be an appropriate choice for blood pressure control in such patients, but it does not replace weight reduction and lifestyle correction.

Thus, telmisartan's “hepatoprotective” reputation is largely based on mechanistic and pilot data. For the kidneys the evidence base is much stronger, but it concerns specific groups — primarily people with diabetes and albuminuria.

Editorial conclusions

Telmisartan barely burdens the kidneys as an elimination route and in certain conditions protects them by reducing intraglomerular pressure and proteinuria. A small rise in creatinine at the start of treatment is expected and does not mean damage.

The liver, on the contrary, is the drug's “bottleneck”: biliary tract obstruction and severe liver failure are contraindications, and with moderate impairment the dose is limited.

The greatest risks for the kidneys are connected not with the drug itself but with circumstances: dehydration, renal artery stenosis, combination with NSAIDs, diuretics, or other RAAS blockers.

We also recommend familiarizing yourself with the materials “Tests While Taking Telmisartan”, “Who Should Not Take Telmisartan” and “Nebivolol: Effect on the Liver and Kidneys”.

References

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