Telmisartan

• ONTARGET was a randomized double-blind active-controlled trial in 25,620 patients 55 or older with atherosclerotic disease or diabetes with end-organ damage. Patients were randomized to telmisartan 80 mg a day, ramipril 10 mg a day or both. At a median follow-up of 56 months the primary composite of cardiovascular death, myocardial infarction, stroke or hospitalization for heart failure occurred in 16.7 percent on telmisartan and 16.5 percent on ramipril (relative risk 1.01, 95% CI 0.94 to 1.09), and in 16.3 percent on the combination (relative risk 0.99, 95% CI 0.92 to 1.07). The conclusion was equivalence with less angioedema, and more adverse events with the combination and no added benefit (PMID: 18378520).
• TRANSCEND was a randomized double-blind placebo-controlled trial in 5,926 patients with the same risk profile who could not tolerate ACE inhibitors, usually because of cough. Over a median 56 months the primary composite occurred in 15.7 percent on telmisartan and 17.0 percent on placebo (hazard ratio 0.92, 95% CI 0.81 to 1.05, p=0.216), so the primary endpoint was not met. A secondary composite of cardiovascular death, myocardial infarction or stroke occurred in 13.0 against 14.8 percent (hazard ratio 0.87, 95% CI 0.76 to 1.00, p=0.048 unadjusted and p=0.068 after adjustment for multiplicity), and cardiovascular hospital admissions were lower (30.3 against 33.0 percent, p=0.025) (PMID: 18757085).
• On renal outcomes in ONTARGET, the composite of doubling of serum creatinine, dialysis or death was similar for telmisartan (13.4 percent) and ramipril (13.5 percent) and higher for the combination (14.5 percent, hazard ratio 1.09, 95% CI 1.01 to 1.18, p=0.037). Estimated glomerular filtration rate fell least on ramipril (-2.82 mL/min/1.73 m2) and most on the combination (-6.11), while the rise in urinary albumin was smaller on telmisartan than on ramipril (p=0.004) (PMID: 18707986).
• PRoFESS, registered as NCT00153062, was a randomized double-blind placebo-controlled trial in 20,332 patients with recent ischemic stroke. Telmisartan started a median 15 days after stroke and continued for a mean 2.5 years did not reduce the primary endpoint of recurrent stroke (8.7 against 9.2 percent, hazard ratio 0.95, 95% CI 0.86 to 1.04, p=0.23), major cardiovascular events (13.5 against 14.4 percent, p=0.11) or new-onset diabetes (1.7 against 2.1 percent, p=0.10) (PMID: 18753639). A substudy of the same trial found no difference in disability on the modified Rankin scale after a recurrent stroke or in mini-mental state scores (PMID: 18757238).

Human studies of the metabolic claims

• The TRANSCEND diabetes analysis covered 3,488 participants free of diabetes at entry. Over a median 56 months, 21.8 percent on telmisartan and 22.4 percent on placebo developed diabetes (relative ratio 0.95, 95% CI 0.83 to 1.10, p=0.51), and participants with impaired fasting glucose or impaired glucose tolerance were equally likely to return to normal glucose levels on either treatment. The authors found no evidence that telmisartan prevents diabetes in this population (PMID: 21788624).
• Pooled randomized comparisons against other angiotensin receptor blockers favour telmisartan on insulin measures by small margins: 21 trials in 1,679 patients (HOMA-IR mean difference -0.23, 95% CI -0.40 to -0.06) (PMID: 29557807); 33 trials in 2,033 hypertensive patients (insulin -10.92 percent, HOMA-IR -15.89 percent, with smaller effects in the 8 double-blind trials) (PMID: 25151319); 10 trials in 546 people with metabolic syndrome (lower fasting glucose, insulin, glycated hemoglobin and HOMA index, higher adiponectin) (PMID: 23523138); and 8 trials in 763 hypertensive patients with insulin resistance or type 2 diabetes (fasting plasma glucose -8.63 mg/dL, adiponectin +0.93 micrograms/dL) (PMID: 21848583).
• Studies of insulin action, mostly clamp-based, are mostly null. In 12 men with impaired fasting glucose given telmisartan at 160 mg a day for 3 weeks in a double-blind crossover trial, their fasting glucose fell but insulin sensitivity and substrate use during a hyperinsulinemic euglycemic clamp did not change, while insulin-stimulated adiponectin and leptin rose and TNF-alpha fell (PMID: 20630944). The same group found no change in muscle fat content measured by magnetic resonance spectroscopy in 10 similar participants (PMID: 26523653). A 138-person placebo-controlled trial in overweight or obese adults with features of metabolic syndrome but no hypertension or diabetes found no difference after 16 weeks in an insulin sensitivity index calculated from oral glucose tolerance testing, the primary measure, with clamp measurements in a subset of those participants (PMID: 20883237). One open study of 34 obese hypertensive adults reported higher clamp-measured glucose uptake and higher adiponectin after 6 months, without a control group (PMID: 22378488), and a crossover comparison with eprosartan in 50 overweight hypertensive patients found a higher glucose infusion rate on telmisartan (PMID: 19708000).
• In 35 adults with HIV, central adiposity and suppressed virus, 24 weeks of open-label telmisartan produced small losses of total and subcutaneous fat but no significant change in visceral fat (PMID: 23516440). A later 44-person randomized study found that lymph node and fat tissue fibrosis fell with continued antiretroviral therapy alone, with no additional effect of telmisartan (PMID: 29401318).

Human studies in other conditions

• In hypertensive patients with Alzheimer's disease, a 20-patient randomized comparison of telmisartan against amlodipine over 6 months found no change in cognitive test scores on telmisartan while the amlodipine group worsened on the Alzheimer's Disease Assessment Scale, with higher regional cerebral blood flow in several areas on telmisartan (PMID: 21929736). These are small, short, single-centre studies with active comparators rather than placebo.
• A pharmacoepidemiology study of insurance claims for 5.62 million people aged 60 or over found moderate or high telmisartan exposure associated with a lower incidence of Alzheimer's disease in African Americans (hazard ratio 0.77, 95% CI 0.65 to 0.91, p=0.0022) but not in non-Hispanic European Americans (hazard ratio 0.97, 95% CI 0.89 to 1.05, p=0.411). The authors call for randomized trials to establish whether the association is causal (PMID: 36331056).
• In a 12-week randomized placebo-controlled add-on trial in schizophrenia, 54 patients on olanzapine or clozapine were randomized to add telmisartan at 80 mg a day or placebo, and 43 completed. The total Positive and Negative Syndrome Scale score fell 4.1 points on telmisartan and rose 0.4 on placebo (p=0.038), with no difference on subscale scores or any cognitive measure (PMID: 28851055).
• An open-label randomized trial in Buenos Aires of 158 patients hospitalized with COVID-19 reported lower C-reactive protein at days 5 and 8 and lower 30-day mortality with telmisartan added to standard care, but it was stopped early because recruitment fell and it was not blinded (PMID: 34189447). An open-label phase 2b trial of 294 adults with mild or moderate COVID-19 in Cote d'Ivoire found that adding telmisartan to lopinavir-ritonavir did not improve a composite virological and inflammatory endpoint at day 11 (PMID: 39443527). A small double-blind placebo-controlled pilot in outpatients reported lower inflammatory markers and higher MasR expression with telmisartan at 40 mg a day (PMID: 41339688).

Animal and cell studies behind the longevity interest

• A genetic deletion study, which did not use telmisartan, found that mice lacking the Agtr1a gene that encodes the AT1a receptor lived markedly longer than wild-type mice, had less cardiac and vascular injury and less oxidative damage, and showed more mitochondria and higher Nampt and sirtuin 3 in the kidney (PMID: 19197138). This is the strongest lifespan result in the AT1 field and it used a knockout, not a drug.
• On mouse lifespan, the National Institute on Aging Interventions Testing Program tested atorvastatin plus telmisartan in genetically heterogeneous UM-HET3 mice at three sites and found no increase in lifespan in males or females; females on that combination weighed significantly less than controls from 12 months of age (PMID: 41843349).
• A cell senescence study used human endothelial cells cultured to the twelfth passage: telmisartan lowered reactive oxygen species, raised DDAH expression and activity, lowered asymmetric dimethylarginine, raised nitric oxide metabolites and delayed senescence; blocking PPAR-gamma with GW9662 or PPAR-gamma small interfering RNA removed the effect, while the angiotensin receptor blocker eprosartan had none (PMID: 18250362). A separate cell study reported that telmisartan reduced NADPH oxidase changes and delayed senescence of late endothelial progenitor cells exposed to angiotensin II (PMID: 21841319).
• Rodent studies of metabolism and exercise found that telmisartan prevented high-fat-diet obesity in wild-type mice and in hypertensive rats but not in PPAR-delta knockout mice, without changing food intake (PMID: 20176998), and raised running endurance, post-exercise oxygen consumption and slow-twitch fibre numbers in wild-type but not PPAR-delta-deficient mice (PMID: 20477906). In white fat of mice on a high-fat diet, telmisartan raised adiponectin messenger RNA through an AMPK-dependent and partly PPAR-gamma-independent route (PMID: 22819702), and a cell study found telmisartan raised human adiponectin gene transcription independently of PPAR-gamma (PMID: 17399685).
• In organ damage models, telmisartan reduced proteinuria, glomerulosclerosis and interstitial fibrosis in obese Zucker rats, a model of type 2 diabetic kidney disease, in studies run by Boehringer Ingelheim researchers (PMID: 18008027), and prevented hypertension, dyslipidemia, cardiac hypertrophy and oxidative stress markers in streptozotocin-treated rats (PMID: 22001983).

Pharmacokinetic and interaction studies

A Boehringer Ingelheim program gave single oral doses of 1 to 160 mg and intravenous doses of 10 to 160 mg to healthy young men, 7 days of dosing to healthy elderly volunteers and up to 28 days to hypertensive patients; plasma concentrations rose more than proportionally with oral dose, steady state was reached in 5 to 7 days, the terminal phase lasted more than 20 hours, and the most frequent adverse event was headache, which also occurred on placebo (PMID: 11014323). A population pharmacokinetic model built on 1,566 samples from 20 healthy volunteers and 129 hypertensive patients found that oral clearance fell with age and with higher dose (PMID: 15618736). In 12 healthy men, telmisartan at 120 mg a day raised steady-state digoxin area under the curve by 22 percent and peak concentration by 50 percent, while trough levels stayed within the predefined no-interaction range (PMID: 11185636).

Common effects in trials

Telmisartan was studied for safety in more than 3,700 patients with hypertension. In placebo-controlled trials of 1,041 patients on telmisartan monotherapy for up to 12 weeks the overall rate of adverse events was similar to placebo. In the label's table covering 1,455 patients on telmisartan and 380 on placebo, the events at 1 percent or more and more frequent than placebo were upper respiratory tract infection (7 against 6 percent), back pain (3 against 1 percent), sinusitis (3 against 2 percent), diarrhea (3 against 2 percent) and pharyngitis (1 against 0 percent). Treatment was stopped for adverse events in 2.8 percent of 1,455 telmisartan patients and 6.1 percent of 380 placebo patients, and cough occurred at the same rate as placebo, 1.6 percent (US prescribing information for telmisartan tablets).

In the cardiovascular outcome trials

In TRANSCEND, over 4 years and 8 months of follow-up, 8.4 percent on telmisartan and 7.6 percent on placebo stopped for adverse events, and the only serious adverse events at least 1 percent more common on telmisartan were intermittent claudication (7 against 6 percent) and skin ulcer (3 against 2 percent) (US prescribing information for telmisartan tablets; PMID: 18757085). In ONTARGET, telmisartan caused less cough than ramipril (1.1 against 4.2 percent, p<0.001) and less angioedema (0.1 against 0.3 percent, p=0.01) but more symptomatic hypotension (2.6 against 1.7 percent, p<0.001) (PMID: 18378520).

The combination with an ACE inhibitor

Adding telmisartan to ramipril in ONTARGET produced no extra benefit and more harm: symptomatic hypotension in 4.8 percent against 1.7 percent on ramipril alone, syncope in 0.3 against 0.2 percent and renal dysfunction in 13.5 against 10.2 percent (PMID: 18378520). The renal analysis of the same trial found the composite of doubling of serum creatinine, dialysis or death in 14.5 percent of the combination group against 13.5 percent on ramipril (hazard ratio 1.09, 95% CI 1.01 to 1.18, p=0.037), and the largest fall in estimated glomerular filtration rate in the combination group (PMID: 18707986). This is the basis of the label's instruction to avoid combined use of renin-angiotensin system inhibitors.

Postmarketing reports

The label lists, from reports after approval: anemia, eosinophilia, thrombocytopenia, abdominal pain, diarrhea, dyspepsia, nausea, asthenia, chest pain, edema, fatigue, abnormal liver function, anaphylactic reaction, hypersensitivity, raised creatine phosphokinase and uric acid, hyperkalemia, hypoglycemia in diabetic patients, hyponatremia, myalgia, dizziness, headache, syncope, renal impairment including acute renal failure, erectile dysfunction, cough, angioedema with fatal outcome, drug eruption, urticaria, hypotension including postural hypotension, and rare cases of rhabdomyolysis (US prescribing information for telmisartan tablets).

Animal toxicology

There was no evidence of carcinogenicity when telmisartan was fed to mice and rats for up to 2 years at doses providing systemic exposures more than 100 times and more than 25 times the exposure in people taking the maximum recommended human dose, and genotoxicity assays, among them bacterial mutagenicity, a hamster cell gene mutation test, a human lymphocyte cytogenetic test and a mouse micronucleus test, showed no telmisartan-related effects (US prescribing information for telmisartan tablets).