Review Article

Obesity and Pharmacokinetic Variability: Implications for Cardiovascular Therapeutics

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Abstract

Obesity, especially moderate-to-severe obesity, is strongly associated with multimorbidity, especially cardiovascular diseases, and polypharmacy. Patients with moderate to severe obesity are under-represented in large trials, so current dosing strategies are largely extrapolated from populations without obesity. Moderate and severe obesity induce complex and dynamic alterations in the gastrointestinal tract, liver and kidneys, which may affect a drug’s pharmacokinetic actions of absorption, distribution, metabolism and excretion. Drug distribution and exposure may also differ based on lipophilicity. Multimorbid patients with obesity and cardiovascular disease are frequently prescribed polypharmacy. Polypharmacy increases the risk of pharmacokinetic-based drug–drug interactions often mediated by the cytochrome P450 enzymes, whose activity can be modified by obesity. Therefore, drug response can be highly and unpredictably variable. New incretin-based therapies can affect the pharmacokinetics of orally co-administered drugs by modifying the gastrointestinal physiology. We review obesity-related pharmacokinetic changes, focusing on common cardiovascular medications. A pragmatic, personalised approach is proposed to reduce variability in response, which may ultimately improve safety and effectiveness.

Keywords

Obesity, pharmacokinetics, cardiovascular diseases, anticoagulant, antiplatelet, blood pressure-lowering drugs,

Received:

Accepted:

Published online:

DOI: https://doi.org/10.15420/ecr.2025.99

Disclosure: All authors have no conflicts of interest to declare.

Correspondence: Bianca Rocca, Department of Medicine and Surgery, LUM University, S.S. 100 Km. 18 – 70010 Casamassima (Ba), Italy. E: rocca@lum.it

Copyright:

© The Author(s). This work is open access and is licensed under CC-BY-NC 4.0. Users may copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

The global prevalence of obesity more than tripled between 1975 and 2022.1 Of particular concern is the escalating rate among children and adolescents, which increased from 4% to about 20% or more, and the growing proportion of severe forms of obesity.1–4 Obesity is one of the most prevalent cardiometabolic diseases worldwide and a major driver of cardiovascular morbidity and mortality.4,5 It frequently coexists with hypertension, type 2 diabetes, dyslipidaemia, coronary artery disease, heart failure, arrhythmias and thromboembolic disorders.4,5

There are several criteria for classifying obesity. The WHO classification identifies increasing obesity classes from 1 to 4 based on BMI expressed in kg/m2: class 1 is 30–34.9, class 2 (moderate obesity) 35–39.9, class 3 (severe obesity) ≥40 kg/m2.2 Obesity can also be classified based on total body weight (TBW) and expressed in kg, but this has major limitations. A more recent proposal of obesity classification incorporates BMI with additional anthropometric or metabolic indicators and distinguishes pre-clinical and clinical obesity, based on the absence or presence of comorbidities, respectively. In this recent classification, a BMI ≥40 kg/m² (class ≥3 according to WHO) is defined as clinical obesity, regardless of the presence of comorbidities.5 These modifications in classifications reflect the increasing recognition that obesity is already a disease with a spectrum of phenotypes and pathophysiological consequences.

Despite its limitations, we refer to the WHO classification in this article, because it is the most widely used in studies of drugs’ pharmacokinetics (PK) in relation to obesity.4,6

Moderate-to-severe obesity (WHO class 2–3) induces profound changes across organs and systems that may influence each part of the PK of a drug, which is made up of absorption, distribution, metabolism and excretion (ADME; Figure 1 ). Obesity is also a progressive disorder, with major, time-dependent alterations in body composition, tissue perfusion, hepatic and renal function and gastrointestinal physiology.7 By affecting PK parameters, those changes may alter the efficacy and/or safety of standard drug dosing regimens, which are largely developed in lean and overweight populations. The PK changes may be particularly important for patients with cardiovascular diseases (CVD) or related risk factors. Antithrombotic therapies, administered a fixed dose or adjusted per kg of TBW, have been largely developed in trials where individuals with moderate or severe obesity were largely under-represented or even absent.6 Thus, drug dosing in patients with class ≥2 obesity relies on extrapolation and data derived from non-obese cohorts, on small, underpowered subgroups or on observational analyses.8

Figure 1: Pharmacokinetic Changes in Severe-to-moderate Obesity and in Association with Weight Loss Strategies

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Moreover, patients with CVD are particularly exposed to polypharmacy (defined as the use of ≥5 drugs) due to frequent multimorbidity.9,10 Among US adults in 2017 and 2018, those with heart disease had the highest prevalence of polypharmacy (67.5%).9 In a large study, patients hospitalised for acute coronary syndrome (ACS) received a mean of 9.9 ± 2.6 drugs per day and the most represented were, in decreasing order, aspirin and a P2Y12 receptor inhibitor, statins, blood-pressure-lowering drugs, glucose-lowering drugs and benzodiazepines.11 While clinically necessary, polypharmacy increases the risk of clinically relevant drug–drug interactions (DDIs), frequently mediated by cytochrome P450 (CYP450) enzymes. The activity of some CYP450 enzymes may be altered by obesity.

This review provides a mechanistic pharmacological framework of obesity-induced changes in the ADME processes, with a special focus on drugs commonly used for CVD. It also examines the emerging influence of the approved newer incretin-based medications, including glucagon-like peptide-1 receptor agonists (GLP1RAs), that are widely used for obesity management and affect the gastrointestinal physiology in ways that may further modify the drug’s PK.12,13

Drug Absorption

Gastrointestinal Changes

Gastric pH is often mildly elevated in individuals with obesity due to the high prevalence of gastroesophageal reflux disease and consequent widespread use of proton-pump inhibitors.14 Weakly basic drugs dissolve more readily in the acidic environment of the stomach, while in a more basic environment, their solubility is reduced or may even cause drug precipitation. On the other hand, the dissolution of weakly acidic drugs is minimal in the stomach, and solubility tends to increase as the drug enters the more basic environment of the small intestine. Therefore, an elevation of gastric pH, for example after a meal or the administration of proton pump inhibitors, is expected to diminish the in vivo dissolution and absorption of weakly basic drugs but enhance the in vivo dissolution and absorption of weakly acidic drugs.15 Moreover, individuals with obesity often consume large, high-fat meals, which can increase the solubility of lipophilic compounds, gastric retention time, exposure for lipophilic drugs with high solubility in bile micelles, delay absorption for drugs requiring acidic dissolution and modify bioavailability of modified-release formulations.15

Data on the motility of gastrointestinal (GI) tracts in obese individuals are often inconsistent, possibly reflecting different experimental conditions of feeding and fasting, methods of detection and average BMI (or other body size metrics) of the participants. Gastric emptying has been reported to be either unchanged or, more often, accelerated with a reduced gastric retention time and this would increase the access of the drug into the small intestine, where most drugs are absorbed and enter the portal circulation.14,16,17 In the small intestine, a reduced transit time, lower pH and a higher intestinal contractility have been reported in individuals with class ≥2 obesity compared to individuals without obesity, which may instead decrease absorption.14,16 Of note, splanchnic blood flow and gut permeability are increased with obesity, which may increase GI absorption and systemic bioavailability.

Significant changes and disruption of the gut microbiome also occur in individuals with obesity.18 Gut dysbiosis can potentially influence the pre-systemic metabolism of xenobiotics, local biotransformation of prodrugs, enterohepatic recirculation and secondary bile acid pools relevant to lipophilic drug absorption. However, the relevance of obesity-associated changes of the microbiome in the ADME of oral drugs remains largely unknown.

Data on CYP450 enzyme function and expression in the gut of individuals with obesity are limited. The expression of the same CYP450 enzyme can be discordant in the GI tract versus the liver, thus data on CYP450s in the liver in individuals with obesity cannot be generalised to the GI wall.19 However, in individuals with obesity, CYP3A4 expression is concordant in the liver and small intestine, and a negative correlation exists between CYP3A4 expression/biotransforming capacity and BMI.20 Indirect comparisons of data from obese and non-obese individuals suggest there is increased intestinal P-glycoprotein (P-gp) and decreased multidrug resistance-associated protein 3 (MRP3) transporters in the intestine of obese individuals, but robust data are missing.21 It must also be considered that the systemic inflammation that characterises obesity may downregulate P-gp.21 The organic anion transporting polypeptides do not seem to be affected by obesity.22 Carboxylesterase-1 expression is increased in GI adipose tissue and this may affect drugs metabolised by these enzymes.23

Thus, obesity is associated with multiple, and sometimes opposing, alterations in GI physiology. Although the net effect on absorption varies between drugs, these changes consistently increase the interindividual variability in drug exposure among patients with moderate-to-severe obesity rendering absorption difficult to predict.

Subcutaneous and Intramuscular Absorption

Intramuscular and subcutaneous absorption may be difficult in individuals with obesity. Subcutaneous absorption may be affected by the degree of obesity, the thickness of subcutaneous adipose tissue and blood supply to specific anatomical regions. Often, the length of needles used for lean individuals may be inefficient to deliver drugs in the proper subcutaneous space or in the muscular region in individuals with severe or moderate obesity.24

For subcutaneous heparin, the time to peak concentrations (Tmax) has been reported to be delayed in individuals with severe obesity, although anti–factor Xa activity appears not to be affected.14

Distribution

Obesity markedly alters drug distribution via different mechanisms that depend not only on the degree and duration of obesity, but also on the characteristics of each drug. Overall, the increased adipose mass expands the reservoir for lipophilic drugs that may undergo substantial increases in their volume of distribution (Vd). Some high lipophilic drugs nearly double their Vd in obese individuals and, as a consequence, their half-life can be considerably prolonged.25 Thus, the increased Vd may be particularly problematic with chronic treatment upon drug interruption, with prolonged persistence of drug effects in the washout period and consequent safety concerns. The increase in Vd can particularly affect the loading doses of IV drugs, which should be enhanced if Vd increases.25 However, for lipophilic drugs, Vd normalised for kg of body weight may be increased, reduced or unchanged as for digoxin, which does not show a higher Vd in obese subjects.15,16,26 Therefore, changes in Vd cannot be predicted based on a drug’s lipophilicity alone. Hydrophilic drugs show smaller Vd changes instead.

Total blood (TBV) and plasma volumes are also increased in moderate and severe obesity. However, the increase is non-linear and when referring to kg of TBW, blood and plasma volumes are reduced instead. Formulas calculating the TBV were developed when the highest degrees of obesity were less prevalent.27 Thus, at present, no validated method accurately reflects TBV and plasma volume in individuals with moderate and severe obesity.27 In principle, hydrophilic drugs may be diluted if TBV increases.

Pathophysiological changes associated with obesity, such as low-degree inflammation, can increase levels of acute-phase proteins, including C-reactive protein and α1-acid glycoprotein. This can affect drugs with a high protein-binding fraction, reducing the free fraction and, consequently, their effectiveness.28,29

Hepatic Metabolism

The liver is central for the metabolism and clearance of drugs. Oral drugs undergo a first-pass effect that affects subsequent systemic bioavailability. Hepatic blood flow may be increased to a hyperdynamic state in the initial phase of obesity, while it is reduced with non-alcoholic fatty liver disease and steatohepatitis, which are highly prevalent with severe obesity.7 These changes in liver blood supply and function can affect drug metabolism in heterogeneous and unpredictable ways.

CYP3A4 accounts for the biotransformation of most marketed drugs.30 The expression and activity of CYP3A4 have been consistently reported to be inversely related to BMI and is reduced by 10–30% in individuals with obesity compared to lean controls, with expression and activity increasing upon weight loss.14,31–34 The low activity of CYP3A4 has been related to the increased inflammation and inflammatory cytokines, such as TNF-α, which is a characteristic of obesity, which are known to down-regulate CYP3A4 gene expression.14,35 Also, CYP2C19 has been reported to be downregulated in individuals with obesity when compared to lean controls.14,34,36 This is consistent with a lower exposure to clopidogrel active metabolite in individuals with obesity.37,38 Data on CYP1A2 and CYP2D6 expression and activity in obesity are inconsistent.14,34,36 CYP2E1 and CYP2C9 have been reported to be upregulated.14,26,34 Regarding phase II enzymes, the hepatic glucuronidation is higher with obesity when compared to lean individuals, and it is reduced with weight loss.14,39

Renal Function

Obesity is typically associated with an early increase in glomerular filtration rate (GFR) (obesity-related hyperfiltration) and in renal plasma flow, followed by an increased clearance of drugs that are eliminated renally. With a prolonged disease, obesity-related glomerulopathy and possible transition to chronic kidney disease (CKD) can occur, which reduces drug clearance.7,40 This biphasic, evolving trajectory requires periodic reassessment of kidney function, which must also happen during major weight loss.

Many drugs are eliminated unchanged by the kidney. Thus, assessing renal function is central to avoid toxicity and preserve safety. Estimation of renal function by the Cockcroft–Gault formula (CG) may not be reliable in obesity class ≥2. Notably, the CG formula is based on serum creatinine concentrations and TBW and it was originally defined based on data from lean individuals; thus, whether the standard CG formula is appropriate in moderate and severe obesity is uncertain.41 Alternative methods, such as the CG including adjusted body weight rather than TBW and the de-indexed Modification of Diet in Renal Disease equation, may provide a more appropriate estimate of renal function in moderate and severe obesity when renally excreted drugs are administered, especially for drugs with a narrow therapeutic window.41 However, the best method to assess renal function in moderate or severe obesity is still up for debate.42

Implications for Specific Cardiovascular Drug Classes

Although this review is not drug-specific, obesity may introduce PK challenges for many major cardiovascular drug categories.

β-blockers

Obesity modifies the PK of several β-blockers and the magnitude and direction of changes do not depend only on the drug’s lipophilicity. The lipophilic β-blocker propranolol has been inconsistently reported to have an increased or decreased Vd, with minor effects on drug half-life; however, only a few studies included participants with severe obesity.43 Changes in GI transit and absorption, hepatic biotransformation and CYP450 (3A4, 2C19) dispositions may all variably affect the bioavailability of antihypertensive medications in patients with a very high BMI, beyond tissue distribution.44 Hydrophilic agents such as atenolol, nadolol and sotalol are less affected by adipose tissue mass and show a more stable PK also in individuals without obesity.45

Angiotensin-converting Enzyme Inhibitors and Angiotensin Receptor Blockers

Data on PK changes for this angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers for people with obesity class ≥2 are very limited and inconclusive. However, obesity may influence the bioavailability of these drugs through increased plasma protein binding. Thus, more frequent monitoring may be useful, especially in individuals with severe obesity.

Calcium Channel Blockers

There are differences in lipophilicity, hepatic metabolism and protein binding among dihydropyridine agents, such as amlodipine and nifedipine, and non-dihydropyridine agents, such as verapamil and diltiazem. A recent study involving 471 patients treated with ≥2 antihypertensive drugs showed no BMI-associated differences in serum concentration of amlodipine adjusted for the daily dose, although the vast majority of the obese population in this study had class 1 obesity.46 However, in the same study, amlodipine concentration increased in individuals with the CYP3A4 loss-of-function *22 allele. Thus, whether the reduced function of CYP3A4 reported in high-degree obesity impacts amlodipine concentrations and blood pressure control remains to be explored. No data on nifedipine and severe obesity are available. However, nifedipine is also biotransformed by the CYP3A4.47 Whether high degrees of obesity affect nifedipine concentrations in a clinically relevant way remains to be investigated. Old data for verapamil showed a significant, approximate threefold prolongation of half-life in patients weighing around 120 kg versus those with normal TBW (10.1 ± 1.8 versus 3.6 ± 0.4 hours; p<0.005) due to a marked increase in Vd (713 ± 99 versus 301 ± 33 l; p<0.005), but no change in total clearance was reported.1 However, data on patients with morbid obesity are not available. There was no correlation between TBW and total IV dose of diltiazem needed to reach the target heart rate in patients with AF and rapid ventricular response in the emergency setting.2,48

Antiarrhythmic Drugs

A recent review of the available evidence, which included seven cohort studies and two PK studies, reported that obesity may affect the PK of amiodarone and sodium channel blockers, such as flecainide, disopyramide and propafenone, suggesting a need for a higher dose of amiodarone in extremely obese patients (>40 kg/m2), while people with obesity were less responsive to class I antiarrhythmic drugs.2 Data on potassium channel blockers, such as dofetilide, sotalol, dronedarone, vernakalant and ibutilide, are more conflicting.2 However, studies are heterogeneous with respect to BMI and confounding factors, such as multimorbidity, concomitant medications, routes of administration, classification and degrees of obesity.

Oral Anticoagulants

Morbidly obese patients require a longer time to achieve a therapeutic international normalised ratio (INR), and need about weekly maintenance doses of oral anticoagulant that are 20% higher than those without obesity.49 Thus, more frequent INR testing is advised.9 Peak and trough concentrations of full-dose apixaban and rivaroxaban show a wide variability in patients with class 3 obesity, with drug concentrations outside the ‘on-treatment’ concentration intervals measured in the main phase 3 randomised controlled trials (RCTs).50–53 Assessment of direct oral anticoagulant (DOAC) levels with drug-specific assays has been suggested in individuals with class ≥2 obesity.9 However, simulations based on population PK models, mostly derived from RCTs’ available data for the anti-Xa DOACs, did not show any major impact of extreme TBWs as covariates significantly affecting PK/PD.54–56

Parenteral Anticoagulants

Unfractionated heparin (UFH) dosing nomograms based on TBW were developed with poor representation of individuals with moderate and severe obesity. For patients with class ≥2 obesity (or TBW>160), conventional nomograms based on TBW tend to generate overdosing compared to normal, overweight or class 1 obese patients, based on aPTT or anti-Xa measurements.6 It may be valuable to use body metrics other than TBW to adjust dosing. In an RCT of patients with obesity undergoing cardiopulmonary bypass, UFH dosing adjustment was randomised between ideal body weight (IBW) and TBW metrics. IBW-adjusted dosing resulted in about 15% lower doses in a superior on-target range.57 In patients undergoing catheter ablation of AF, a UFH dosing based on IBW showed a more rapid achievement and maintenance of therapeutic anticoagulation levels compared to TBW, irrespective of BMI.58 Thus, body size metrics other than TBW may improve UFH dosing, avoiding overdosing, sparing the use of protamine as an antidote and possible bleeding complications.

Dosing low-molecular-weight heparin (LMWH) in patients with extreme TBW is challenging, as anticoagulation can fall outside the target range when a standard regimen that was developed for lean individuals is used.59,60 Plasma anti-Xa activity is the reference biomarker often used as a surrogate for clinical efficacy of LMWH.59–61 This coagulation assay can be used to assess whether levels are within the expected target range, which was developed for individuals with a normal weight.9 Underdosing is possible using a fixed, standard, prophylactic LMWH dose in obesity class ≥2 and a higher fixed dose or a TBW-adjusted LMWH in prophylaxis may be better for adequate anticoagulation.6 A population PK model predicted optimal anti-Xa levels for nadroparin in the prophylaxis of morbid obesity when administered per kg of TBW rather than as standard fixed dosing.62 In a systematic review, the TBW-based LMWH dosing suggested in post-surgical or medical patients with obesity was for enoxaparin 0.5 mg/kg once or twice a day and for tinzaparin 75 IU/kg once a day.63 A higher fixed prophylactic LMWH dose has also been suggested to provide superior efficacy and safety.64,65

In relation to the therapeutic LMWH dosing, a meta-analysis included studies of patients with obesity on heparin for venous thromboembolism (VTE), AF or coronary artery disease and compared full, body-weight-based standard (1 mg/kg) versus reduced (<1 mg/kg; average 0.8 mg/kg) dosing.66 The reduced dose showed similar efficacy (VTE recurrence: OR 0.86; 95% CI [0.11–6.84]), and higher safety (major bleeding OR 0.30; 95% CI [0.10–0.89]) versus the conventional full dose. A comprehensive review supports reduced body-weight-based enoxaparin dosing (~0.8 rather than 1/mg/kg) in morbid obesity, although data are based on anti-Xa levels.63 A recent registry of VTE treatment showed fewer complications with a reduced dose of LMWH.67 Enoxaparin at a standard per kg dose (1 mg/kg twice daily) is recommended for ACS.68 However, based on previous studies, bleeding increases in patients weighing >150 kg receiving 1 mg/kg twice daily enoxaparin versus a reduced median dose of 0.65 mg/kg twice daily.6 Consistently, an in silico PK/pharmacodynamic (PD) model predicted that obese children have approximately 20% higher peak anti-Xa concentrations under standard TBW–based dosing compared to non-obese children due to reduced weight-normalised clearance. Moreover, enoxaparin was better dosed using fat-free mass calculation.69 However, clinical outcome data are limited and studies are largely observational and based on laboratory measurements.

Antiplatelet Drugs

Aspirin PD is similar in individuals with class 1 obesity versus those without obesity, while individuals with class ≥2 obesity on 100 mg acetylsalicylic acid (ASA) once daily (mean BW 111 ± 21 kg and BMI 39.4 ± 5.1 kg/m2) show significantly lower inhibition of platelet cyclooxygenase activity than non-obese individuals.70,71 Residual, uninhibited ex vivo cyclooxygenase activity in peripheral platelets appears log-linearly associated with BMI, with a hindered response at BW >110 kg or BMI >35 kg/m2.71 Consistently, patients on 100 mg once-daily ASA and average body weight >102 kg or BMI >38 kg/m2 or in the highest quartiles of BMI or weight showed lower platelet inhibition versus non-obese individuals, while doubling the once-daily low dose re-established an optimal platelet inhibition.72–74 Among 1,002 pregnant women on low-dose aspirin for eclampsia, class 3 obesity was associated with significantly reduced platelet inhibition compared to women with lower BMIs.75 In silico PK/PD model and simulations of low-dose aspirin predicted a reduced platelet inhibition in moderate-to-severe obesity due to a severe reduction in systemic bioavailability.76,77 According to the model, either doubling the low dose to 200 mg once daily or using a twice-daily low-dose regimen restored normal platelet inhibition.76 Whether these optimised regimens are able to restore the PD response and translate into an improved clinical benefit-risk profile remains to be established.

P2Y12 Inhibitors

Low formation of clopidogrel active metabolite (AM) has been reported in patients with obesity.6 A PK/PD in silico model for clopidogrel indicated that TBW significantly and inversely affects AM concentration and platelet inhibition, especially for patients with class ≥2 obesity.78,79 Model simulations predicted that higher loading and maintenance doses of clopidogrel would be needed in severely obese subjects to achieve adequate platelet inhibition.78 For BMI >35 kg/m2 associated with intermediate or poor metaboliser status of the CYP2C19 alleles, the model predicts a clopidogrel maintenance daily dose of 300 mg and 450 mg, respectively.78 Importantly, class 3 obesity is associated with reduced CYP2C19 activity that is independent of its allele disposition, which returns to almost normal values after weight loss.36 An in silico PK/PD model developed for prasugrel showed that high BMIs had no influence.80

Class 1 obesity does not appear to affect ticagrelor PD and responsiveness, while data for class ≥2 obesity are limited.81 A PK/PD model developed in healthy and post-ACS individuals in China indicated that TBW, diet and sex were the major covariates affecting ticagrelor response.82 Plasma concentration of ticagrelor, its AM and platelet function at peak and trough in patients from two RCTs showed that BMI inversely correlated with ticagrelor and its AM concentrations.83 These data are also consistent with the reduced function of CYP3A4 in moderate and severe obesity, considering that ticagrelor is biotransformed by CYP3A4 into an active metabolite, which is more potent than the parent drug and contributes to its final antiplatelet effect.

Statins

Many statins are biotransformed by CYP3A4, so it can be hypothesised that there is reduced biotransformation of CYP3A4-dependent statins in patients with severe obesity, and this may reduce their safety. However, biotransformation of statins also involves other transporters and PK data on statins in severe obesity are not available.

The Effect of Incretins on Drug Absorption, Distribution, Metabolism and Excretion

GLP-1 receptor agonists (GLP-1RAs), such as exenatide, liraglutide, dulaglutide and semaglutide, and dual glucose-dependent insulinotropic polypeptide/GLP-1R co-agonists, such as tirzepatide, are approved for the treatment of obesity.12 Those drugs delay gastric emptying, cause substantial weight loss and metabolic remodelling that can influence different steps of PK, and create new, potentially clinically relevant interactions. Gastroparesis is increased approximately fourfold by GLP-1RAs as compared to bupropion-naltrexone when used for weight loss.84 Gastric emptying half-time is prolonged by about twofold and 1.5-fold by short- and long-acting GLP-1RAs, respectively, with a high inter-individual and time-dependent variability.85 Consequently, absorption and systemic exposure of co-administered oral drugs, expressed as Tmax, Cmax and area under the curve (AUC), can be affected by GLP1-RAs, also in relation to the specific ADME and chemical characteristics of the co-administered drug.

Specifically, minor and non-clinically relevant (<30%) increases in Tmax and AUC have been reported for warfarin, some statins and ACEi when co-administered with GLP-1RAs.86 However, physiologically based PK modelling showed that co-administration of GLP1-RAs doubles dabigatran, but not rivaroxaban, AUC, and increases by 64% valsartan AUC and by 90% rosuvastatin AUC. The exposure to very high drug concentrations may favour bleeding while on dabigatran and myopathy while on rosuvastatin.87 Considering the recent approval of the new incretion-related therapies, data are still limited. Beyond gastric motility, the changes in motility of the first part of the intestine may be relevant for orally administered drugs that are absorbed in the initial part of the GI tract.87

No direct effects of GLP-1RAs and tirzepatide on different CYP450 activities have been documented so far, and direct effects are unlikely since these drugs are not biotransformed by CYP450s.88 Indirect PK-related effects on CYP450 activity can be exerted by GLP-1RAs and tirzepatide through reduction in the inflammatory status, improved renal function (hyperfiltration) and weight loss, but the clinical relevance of these effects remains unknown.88

In summary, in patients with a high level of obesity and CVD who are being treated with GLP-1RAs or dual agonists, all orally co-administered drugs, especially those with a low therapeutic index, may require adaptive and individualised dosing strategies, combined with monitoring, if available, to optimise safety and efficacy (Figure 2).

Figure 2: Practical Algorithm for Using Drugs in Obese Individuals

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Conclusion

Moderate and severe obesity introduce profound variability in drug disposition that varies between individuals. For cardiologists, these changes are highly relevant, given the prevalence of obesity among patients with hypertension, heart failure, coronary disease, arrhythmias and thromboembolic conditions. Cardiovascular drugs differ substantially in their PK susceptibility to obesity-related changes, especially those occurring in patients with the highest levels of obesity. However, patterns are often unpredictable since they involve many aspects: route of administration, lipophilicity of the drug, hepatic and intestinal metabolisms, protein binding, weight loss co-medication and renal elimination.

As obesity prevalence rises globally, integrating obesity-specific PK principles into cardiovascular care will be increasingly necessary, as shown in Figure 2. Unfortunately, PK data on moderate and severe obesity remain limited and their clinical impact has often been unexplored. Future research should prioritise structured PK studies in individuals with severe obesity, particularly for drugs with narrow therapeutic windows to personalise treatment, reduce variability in response and ensure the best effectiveness and safety in daily practice.

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