case study 2 hcl

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HCL Technologies (A)

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About The Authors

Linda A. Hill

Tarun Khanna

Emily Truelove

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• HCL Technologies (A)  By: Linda A. Hill, Tarun Khanna and Emily Stecker

History and Growth of HCL Enterprises - A Case Study

Rishita Jain

Hindustan Computers Limited(HCL) is a multinational IT services and consulting company headquartered in Noida, Uttar Pradesh, India. HCL is a pioneer of modern computing with many firsts to its credit, including the introduction of the 8-bit microprocessor-based computer in 1978, well before its global peers.

Today, the HCL enterprise has a presence across varied sectors that include technology, healthcare, and talent management solutions, and comprises three subsidiaries- HCL Infosystems, HCL Technologies, and HCL Healthcare.

HCL - History HCL - Growth HCL - Subsidiaries & Acquisitions

HCL Technologies

Hcl infosystems, hcl healthcare, hcl talentcare.

HCL - History

HCL was established in 1976, as one of India‘s original IT startups . Originally started for making personal computers, the company was established by a group of six engineers, all former employees of Delhi Cloth & General Mills, led by Shiv Nadar.

HCL Group has formed its first three subsidiaries:

Although the company has tried to stay focused on hardware, via HCL Technologies, software and services are the main focus. In November 1991, a company called HCL Overseas Limited was incorporated as a provider of technology development services. It received the certificate of commencement of business on 10 February 1992 after which it began its operations. Two years later, in July 1994, the company name was changed to HCL Consulting Limited and eventually to HCL Technologies Limited in October 1999.

HCL TalentCare is the fourth and latest venture of HCL Corporation.

HCL - Growth

In the year 2022, HCL Enterprises generated a revenue of $1,1.48 billion. The company's revenue from operations for Q4 FY22 is $2.9 billion. HCL employed more than 208,877 professionals in 52 countries.

The company went public on 10 November 1999, with an issue of 1.42 crore shares, valued at Rs4 each.

During 2000, the company set up an offshore development center in Chennai, India, for KLA-Tencor Corporation.

In 2002, it acquired Gulf Computers Inc. On 1 July 2019, HCL Technologies acquired a few IBM products selectively. In the areas of R&D, sales, delivery, marketing, and support, HCL Technologies took full ownership of BigFix, AppScan, Commerce, Connections, Digital Experience, Notes Domino, and Unica.

HCL announced on 16 June 2020 that it had commenced operations in Sri Lanka . The company created 1,500 jobs in the country within the first 18 months of operations.

HCL - Subsidiaries & Acquisitions

HCL Technologies is currently a subsidiary of Vamasundari through a chain of intermediary companies. Vamasundari (Delhi) is owned by Shiv Nadar and in turn holding the majority of shares in most companies in the HCL group.

Between 1991 and 1999, the company expanded its software development capacities to US, European and APAC markets. In July 2018 US-based Actian was acquired by HCL Technologies and Sumeru Equity Partners for $330 million.

On 23 July 2015, CSC (NYSE: CSC) and HCL Technologies announced a joint venture agreement to form a banking software and services company, Celeriti FinTech.

In October 2017, IBM struck a strategic partnership with HCL Technologies that had the latter firm take over the development of the IBM Lotus Software's Notes, Domino, Sametime, and Verse collaboration tools.

In May 2018, HCL Technologies announced that it has joined hands with Transportation Alliance (BITA), known for incorporating blockchain in the transportation industry , to implement blockchain.

Today, HCL Technologies operate in 52 countries, including its headquarters in Noida, India.

• It has establishments in Australia, China, Hong Kong, India, Indonesia, Israel, Japan, Malaysia, New Zealand, Saudi Arabia, Singapore, South Africa, the United Arab Emirates, and Qatar.
• In Europe, it covers Belgium, Czech Republic, Denmark, Estonia, Finland, France, Germany, Italy, Netherlands, Norway, Poland, Sweden, Switzerland, Portugal, and the United Kingdom.
• In the Americas, the company has offices in Brazil, Canada, Mexico, Puerto Rico, Guatemala, and the United States.

HCL Technologies is a next-generation global technology company that helps enterprises reimagine their businesses for the digital age. Through its worldwide network of R&D facilities and co-innovation labs, global delivery capabilities, and over 150,000+ ‘Ideapreneurs’ across 49 countries, HCL delivers holistic services across industry verticals to leading enterprises, including 250 of the Fortune 500 and 650 of the Global 2000.

HCL Technologies began as the R&D Division of HCL Enterprise, a company that was a contributor to the development and growth of the IT and computer industry in India. HCL Enterprise developed an indigenous microcomputer in 1978, and a networking OS and client-server architecture in 1983. On 12 November 1991, HCL Technologies was spun off as a separate unit to provide software services.

HCL Infosystems is a Small Cap company, having a market cap of Rs 251.85 Crore operating in the IT - Hardware sector. It is a System Integration and Distribution company. It provides the distribution of technology, mobility , and consumer products. This part of HCL was formed in 1976 to produce calculators.

In June 2015, PC maker Dell announced a strategic distribution partnership with HCL Infosystems. For the quarter ended 30-06-2020, the company has reported a Consolidated sales of Rs 105.69 Crore, down 53.59 % from last quarter Sales of Rs 227.71 Crore and down 84.48 % from last year same quarter Sales of Rs 680.87 Crore Company has reported net profit after tax of Rs 36.86 Crore in the latest quarter.

HCL Healthcare, in affiliation with Johns Hopkins Medicine International, is the healthcare delivery arm of HCL Group. Starting with the country's first nationwide networked multispecialty clinics, HCL Healthcare aims to provide the whole continuum of care for chronic and acute diseases.

HCL Healthcare is determined to be the trusted long term care partner for people in health or illness.

HCL TalentCare is the newest business venture of the HCL Corporation. It is a global talent-solutions company offering integrated products and services to meet the growing demand for quality talent. The company's focus is to create development solutions that offer a career launch pad for students and a ready pool of employable talent for enterprises in the IT, Banking, Insurance and Healthcare sectors. HCL TalentCare is headquartered in Chennai and operates world-class training campuses in Hyderabad and Chennai.

HCL has also been involved in criticism and litigation for a long time, involving the H-1B visa program to replace U.S. workers with cheaper foreign labor, including the Disney collusion lawsuit, and the heavily reported case of replacing the University of California's San Francisco Medical Center IT workers.

HCL was once a garage start-up and today it's a global conglomerate. HCL was established in the year 1976 as one of India’s original IT garage start-ups. HCL is a proud corporation for its long and exciting journey from startup to become a corporation in the IT industry. It is also confident of reaching new heights in the future. All these years HCL was the face of the Indian IT industry by conscientiously setting high business standards. The goal of providing sustainable, world-class products, solutions, and services; a feat that has helped the corporation touch the lives of millions in Indian and abroad.

What is full form of HCL?

HCL stands for Hindustan Computers Limited.

What HCL company do?

HCL Technologies Ltd is a leading global IT services company. The company is primarily engaged in providing a range of software services business process outsourcing and infrastructure services.

What is the rank of HCL in India?

HCL Technologies is 8th most valued IT services company in India.

Where is the headquarters of HCL?

HCL Technologies is headquartered in Noida, India.

Who is the founder of HCL Technologies?

Shiv Nadar and Arjun Malhotra are the founders of HCL Technologies.

When was HCL Enterprise founded?

HCL Enterprise was founded in 1976.

Who is the CEO of HCL Technologies?

C Vijayakumar is the President and Chief Executive Officer of HCL Technologies.

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Case Study: Employee Innovation at HCL  

‘Employee First’ is a management approach, proposed by HCL’s CEO, Vineet Nayar. It aims to turn the organisational pyramid upside down and make management accountable to the people who create the value – the employees.

Nayar says:

“What we want at HCL is passion. We want people to be burning up with desire to pursue their interests. Fascinated by their assignments. Jumping out of their skins with excitement about what’s next. Eagerly pursuing better solutions and new initiatives. We have found that the Employees First approach produces far more passion than any motivational or recognition program. Why? Because it proves that management understands the importance of the work being done by the employees in the value zone. It demonstrates that we are actively helping them in ways that make it easier for them to do their jobs. It shows that we trust them to do what needs to be done in the way they believe it should be done. And it shows that we respect them for the value they bring to the company.”

To leverage employee-led-innovation and build a strong engagement culture, HCL has various initiatives, many of which were employee-suggested . These initiatives encourage employees to have a voice in the company and how to create value for customers. Some key initiatives are described here:

The Value Portal

The Value Portal enables and encourages innovation at grassroots level as it is where HCL employees collaborate, innovate and lead the implementation of their ideas to deliver value to HCL’s customers. It began as a pilot for four HCL customers in 2007 and has since been rolled out to 300+ HCL customers globally who see it as a key differentiator. Since the launch in April 2007 more than 5,000 HCL employees have generated over 7,000 ideas since. More than 800 ideas were implemented, delivering a total value of over $15 million to date. One example was an additional feature developed for advisors in a bank. Bank customers raise queries with the customer support team through an ‘Offline Customer Support’ service. Queries and concerns are dealt with by the customer support team and when the customer is satisfied with their answer, they can immediately leave feedback. The feature also acts as a record of queries. The feature is expected to produce annualised savings of $70,000 to the bank. Another example was the creation of a software tool that made testing new software faster and more effective, the annualised saving to the client is estimated to be $1 million.

Essentially the Value Portal is an employee idea exchange platform. Through the portal, HCL employees can suggest ideas and solutions for customer problems within a pre-defined timeline and budget. Any HCL employee can contribute suggestions and work with others across the world to develop a solution for a customer. The Portal won a Forrester Groundswell Award in the Management: Innovation System category in 2011.

MAD Jam – Celebrating the Power of Transformational Ideas

A group of HCL employees created ‘MAD Jam’ (Make a Difference Jamboree) to celebrate the best innovators at HCL that came out of the Value Portal. A couple of marketing team members were tasked by management to make innovation centre stage within HCL. They took a deep dive into existing innovation platforms such as Value Portal and the Intellectual Property Management system and found that innovation was happening within a project but was not getting the visibility beyond the project’s business unit. Armed with this insight the marketers came up with the idea for MAD JAM based on American idol – showcasing talent and innovations for everyone in the company to see.

An American Idol for HCL Innovators

The team launched a campaign to introduce MAD Jam across HCL asking for HCLites to contribute ideas. In the first round HCL business heads chose 18 out of the total 377 ideas that were sent in. Three-minute films were made of the 18 ideas to showcase the idea and the business impact it would have and hosted on the portal. Teams then canvassed employees for votes. Two months later 9 teams from across the world were present at the Grand Finale in New Delhi. The judging panel includes two senior HCL directors, an associate partner from McKinsey and an external judge. Two winners were picked – ‘Customer On-boarding’ – a solution that drastically reduces the on-boarding cycle time of a customer in a financial institution, won best idea. ‘Mobility Solutions’ – which enabled police officers to instantly send details to the central police system from a crime scene, using mobile devices – won the Innovators’ Choice award. MAD JAM created visibility into innovation creation that had previously not been seen in this way at HCL.

Meme – Revolutionising Workplace Collaboration

Ravi Shankar, a senior VP in HR for HCL Technologies suggested B2E – business to employee social networking having looked at B2C social networking uses. At the end of 2010 he posed the idea and gathered about 20-30 supporters who started to work on the project – defining what the social network should look like and what its goals would be.

Some Pushback

When Shankar proposed the idea to top management there were concerns, particularly around uses and abuses. Shankar reassured them he would monitor but not censor, use of the network.

Connect, Share, Learn & Grow

‘Meme’ was launched in January 2011 with the management-led message of ‘connect, share, learn and grow’. It was a big success from the beginning. More than 60,000 employees are now subscribed with their own profile pages. Employees can upload photos, send messages, ‘like’ other people’s statuses, collaborate on ideas and common interests. There are currently over 1,500 groups ranging from ‘Smile a While’ where employees can play competitions, to ‘Mobile Feedback’ where employees can share feedback on different phones.

BlogHer – a gender-neutral group attracted over 100 members in 24 hours. It aims to create dialogue and suggest gender inclusive policies and practices. When a new thread is initiated, the topic gets flashed in HCL’s daily news digest sent to all employees. Anyone can then post their views. One of the outcomes from this group has been assistance in helping HR to frame flexi-timing policies at HCL. Over 50% of the active users are male.

AskHR has been particularly useful to Shankar. Here, employees can pose questions about HR and enables Shankar to test the pulse of employees and what they think about HCL. The platform has been further developed to employees can access it on their mobiles.

The Power of One is a special employee-driven initiative of the HCLT Foundation, launched in 2011. Employees get to choose what Corporate Social Responsible schemes they want to support. Each business line suggests a day where all employees and their families are encouraged to participate in community programmes.  Programmes include:

• Social Recycling – collecting and distribution of clothes, books, toys & woollens – to date, 22,000+ individuals have received clothes
• Friend-in-Need – health camps, blood donation initiatives, food-drives and community policing efforts – 870 children and 275 adults received health care in Indian slums, 5,000 individuals received blankets
• Just Like Us – creating and supporting sustainable livelihood solutions for the destitute and physically/mentally handicapped
• HCLT Youth Club – organising IT labs, sports and cultural events, vocational training and sponsorship for impoverished youth
• Renew – promotes environment-friendly programmes like tree-planting drives, 15,000 plantings have been organised so far.

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Things to know about the gender-affirming care case as the Supreme Court prepares to weigh in

FILE - A flag supporting LGBTQ+ rights decorates a desk on the Democratic side of the Kansas House of Representatives during a debate, March 28, 2023, at the Statehouse in Topeka, Kan. The U.S. Supreme Court agreed Monday to consider whether a Tennessee ban on gender-affirming care for minors is constitutional. (AP Photo/John Hanna, File)

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The U.S. Supreme Court said Monday that it will hear arguments on the constitutionality of state bans on gender-affirming care for transgender minors.

The issue has emerged as a big one in the past few years. While transgender people have gained more visibility and acceptance in many respects, half the states have pushed back with laws banning certain health care services for transgender kids.

Things to know about the issue:

What is gender-affirming care?

Gender-affirming care includes a range of medical and mental health services to support a person’s gender identity, including when it’s different from the sex they were assigned at birth.

The services are offered to treat gender dysphoria, the unease a person may have because their assigned gender and gender identity don’t match. The condition has been linked to depression and suicidal thoughts.

Gender-affirming care encompasses counseling and treatment with medications that block puberty, and hormone therapy to produce physical changes. Those for transgender men cause periods to stop, increase facial and body hair, and deepen voices, among others. The hormones used by transgender women can have effects such as slowing growth of body and facial hair and increasing breast growth.

Gender-affirming care can also include surgery, including operations to transform genitals and chests. These surgeries are rarely offered to minors .

What laws are states passing?

Over the past three years, 26 Republican-controlled states have passed laws restricting gender-affirming care for minors. Most of the laws ban puberty blockers, hormone treatment and surgery for those under 18. Some include provisions that allow those already receiving treatment to continue.

The laws also make exceptions for gender-affirming treatments that are not part of a gender transition, such as medications to stop breast growth in boys and excessive facial hair in girls.

One of the laws — in Arkansas — was nixed by a federal court and is not being enforced.

Meanwhile, at least 14 Democratic-controlled states have adopted laws intended to protect access to gender-affirming care.

The gender-affirming care legislation is a major part of a broader set of laws and policies that has emerged in Republican-controlled states that rein in rights of transgender people. Other policies, adopted in the name of protecting women and girls, bar transgender people from school bathrooms and sports competitions that align with their gender.

What have courts said so far?

Most of the bans have faced court challenges, and most are not very far along in the legal pipeline yet.

The law in Arkansas is the only one to have been struck down entirely, but the state has asked a federal appeals court to reverse that ruling.

The 6th U.S. Circuit Court of Appeals, one step below the Supreme Court, last year ruled that Kentucky and Tennessee can continue to enforce their bans amid legal challenges. The high court has agreed to hear the Tennessee case in the term that starts later this year.

The U.S. Supreme Court in April ruled that Idaho can enforce its ban while litigation over it proceeds. A lower court had put it on hold.

What does the medical community think?

Every major U.S. medical group, including the American Academy of Pediatrics and the American Medical Association, has opposed the bans and said that gender-affirming treatments can be medically necessary and are supported by evidence.

But around the world, medical experts and government health officials are not in lockstep. Some European countries in recent years have warned about overdiagnosis of gender dysphoria.

In England, the state-funded National Health Service commissioned a review of gender identity services for children and adolescents, appointing retired pediatrician Dr. Hilary Cass to lead the effort. The final version of the Cass Review , published in April, found “no good evidence on the long-term outcomes of interventions to manage gender-related distress.”

England’s health service stopped prescribing puberty blockers to children with gender dysphoria outside of a research setting, following recommendations from Cass’ interim report.

The World Professional Association for Transgender Health and its U.S. affiliate issued a statement in May saying they’re deeply concerned about the process, content and consequences of the review, saying it “deprives young trans and gender diverse people of the high-quality care they deserve and causes immense distress and harm to both young patients and their families.”

A randomized, open-label two-period crossover pilot study to evaluate the relative bioavailability in the fed state of atovaquone-proguanil (Atoguanil™) versus atovaquone-proguanil hydrochloride (Malarone®) in healthy adult participants

Open access.

• Published: 25 June 2024

Cite this article

You have full access to this open access article

• Andrea Kuemmerle 1 ,
• Denis Gossen 2 ,
• Michael W. Marx 3 ,
• Ulrike Lorch 4 ,
• Maja Szramowska 5 ,
• Ashok Kumar 6 ,
• Dharmendra Singh 6 ,
• Satinder Singh 6 ,
• Hanu Ramachandruni 1 ,
• Byju Thankachen 6 ,
• Swapnil Kore 6 ,
• Myriam El Gaaloul 1 ,
• Isabelle Borghini-Fuhrer 1 &
• Stephan Chalon   ORCID: orcid.org/0000-0002-9306-1851 1  

Atoguanil™ is a novel complex of atovaquone (ATV) and proguanil (PG) with enhanced ATV bioavailability compared to Malarone®. This pilot study assessed whether the relative bioavailability (F rel ) of ATV, PG, and the primary PG metabolite cycloguanil (CG) following a single oral dose in the fed state of Atoguanil was similar to Malarone despite a 50% lower ATV dose. This open-label, single-dose, randomized 2-period, 2-treatment, balanced crossover study was conducted between 17th November 2021 and 18th March 2022. Eligible participants (aged 18–55 years) were randomized (1:1) in period 1 to Atoguanil (ATV/PG 500/348 mg) or Malarone (ATV/PG hydrochloride 1000/400 mg) administered following a high-fat, high caloric meal. After a 24-day washout period, participants crossed treatment arms. For the doses tested, F rel was assumed similar if 90%CIs were between 80 and 125% for the geometric mean ratio of the least square mean differences for each exposure parameter. In 15 evaluable participants, F rel was similar for ATV C max (93.6% [90%CI 83.6, 104.9]) but not AUC 0-inf (77.8% [67.4, 89.8]), for PG AUC 0-inf (95.6% [92.1, 99.2]) but not C max (82.4% [75.8, 89.5]), and for both CG C max (100.8% [95.0, 107.0]) and AUC 0-inf (102.9% [98.4, 107.7]). Nine adverse events occurred; all were of mild severity and not considered treatment related. At the doses tested, ATV F rel was lower following Atoguanil versus Malarone based on AUC 0-inf , though when adjusted for dose F rel increased by 156%. Both drugs were well tolerated with no safety concerns. ClinicalTrials.gov: NCT04866602 (April 26th, 2021)

Avoid common mistakes on your manuscript.

Introduction

Most deaths from malaria occur in African children under 5 years of age with Plasmodium falciparum infection (World Health Organization  2023 ). Thus, preventing P. falciparum malaria in children is a key intervention in reducing the risk of mortality and morbidity associated with severe malaria.

The World Health Organization recommends seasonal malaria chemoprevention (SMC) for children aged 3 months to 5 years in areas with highly seasonal malaria transmission (World Health Organization 2022 ). A monthly dose of sulfadoxine-pyrimethamine + amodiaquine (SPAQ) is administered for 3 to 4 consecutive months to reduce malaria cases, hospitalizations, and deaths (Adjei et al. 2022 ). SMC deployment is currently limited to the sub-Sahel region due to a high prevalence of SPAQ-resistant P. falciparum in southern, central, and eastern Africa (Amimo et al. 2020 ). Moreover, the increased prevalence of molecular markers of drug resistance in areas where SPAQ is currently deployed for SMC is concerning (Ndiaye et al. 2023 ).

The antimalarial drug Malarone® is a fixed-dose combination of atovaquone (ATV) and proguanil (PG), formulated as the hydrochloride salt (PG HCl ). The combination is active against P. falciparum liver and blood stages, being registered for P. falciparum malaria prophylaxis and the treatment of uncomplicated malaria or uncomplicated P. falciparum malaria (Croft 2010 ; Nakato et al. 2007 ; Blanshard and Hine 2021 ). Malarone has a favorable safety profile and good tolerability (Nakato et al. 2007 ; Blanshard and Hine 2021 ; Bustos et al. 1999 ; Overbosch 2003 ). Despite the patent for Malarone expiring in 2013, generic ATV-PG HCl has not been considered for use in chemoprevention in malaria endemic regions because of its high cost.

The hydroxynaphthoquinone ATV is a competitive inhibitor of ubiquinol, disrupting the parasite mitochondrial electron transport chain at the bc1 complex. Elimination is mainly via the liver through bile clearance (Zsila and Fitos 2010 ), with no evidence of metabolization and an elimination half-life of ~50–84 h (Rolan et al. 1997 ; Nixon et al. 2013 ). ATV is highly protein bound (> 99.5%) and lipophilic (log P 5.1) with poor oral bioavailability (Nixon et al. 2013 ). Administration with a high-fat meal increases the area under the concentration–time curve (AUC) by 3.3-fold and maximum concentration (C max ) by 5.3-fold (Rolan et al. 1994 ). However, even when taken with food, as per the Malarone label recommendation, ATV maximum bioavailability was 23% (Hussein et al. 1996 ). Because of the low exposures achieved, ATV monotherapy has limited efficacy and parasite resistance readily emerges (Looareesuwan et al. 1996 ). However, antimalarial efficacy is enhanced synergistically when ATV is combined with PG, reducing the risk of recrudescence and ATV resistance emergence (Looareesuwan et al. 1996 ; Lin et al. 2021 ). Nevertheless, the high ATV dose and a relatively expensive manufacturing process results in a high cost-of-goods for Malarone , limiting its use for malaria prevention in endemic countries.

Proguanil is a biguanide derivative that is converted to 4-chlorophenyl biguanide and the active metabolite cycloguanil (CG), a parasite dihydrofolate reductase (DHFR) inhibitor. Metabolism is via cytochrome P450 (CYP) 2C19 and CYP3A4 (Pudney et al. 1999 ). Genetic polymorphism in CYP2C19 results in higher PG and lower CG plasma concentrations in poor metabolizers (Beerahee 1999 ). The synergy between ATV and PG does not appear to result from DHFR inhibition. Rather, PG enhances the ATV provoked collapse in mitochondrial membrane potential without affecting electron transport inhibition (Srivastava and Vaidya 1999 ). This explains why ATV-PG HCl does not require dose adjustment in populations with a high prevalence of poor PG metabolizers and retains efficacy against PG-resistant parasites (Hussein et al. 1996 ; Srivastava and Vaidya 1999 ).

To enhance ATV bioavailability and potentially reduce the required dose, a novel complex of ATV with PG free base has been developed (Atoguanil™). Atoguanil dissociates into ATV and PG in vivo when it comes into contact with gastro-intestinal fluids. The resulting ATV is found to be more polar and more soluble in aqueous media compared to free ATV from Malarone , resulting in better absorption and bioavailability in vivo . ATV from Atoguanil showed a more than three-fold higher dissolution (over 90%) compared to ATV from Malarone . In a preclinical pharmacokinetic study in the rabbit, this difference in dissolution translated into an approximately twofold increase in ATV oral bioavailability with Atoguanil compared to Malarone , and similar findings were reported in rats (Medicines for Malaria Venture, data on file).

This pilot study in healthy participants compared the pharmacokinetic (PK) profiles and drug exposures for ATV, PG, and CG obtained after Atoguanil or Malarone administration, containing an ATV dose of 500 mg or 1000 mg, respectively. The aim was to determine whether a twofold reduction in the ATV dose with Atoguanil was feasible while maintaining appropriate therapeutic exposure. Such an improved bioavailability would potentially lead to a significant cost reduction with Atoguanil versus Malarone , increasing affordability for use in malaria chemoprevention, including SMC, in endemic regions.

Study design

This open-label, single-dose, randomized 2-period, 2-treatment balanced crossover pilot study evaluated the PK profile and relative bioavailability (F rel ) of single-dose Atoguanil tablets in healthy adults relative to Malarone in the fed state.

Study drugs were Atoguanil (Ipca Laboratories Ltd, Mumbai, India), comprising ATV 500 mg plus PG free base 348 mg administered as four tablets of 125:87 mg; and Malarone (GSK, Ware, UK) comprising ATV 1000 mg plus PG HCl 400 mg (equivalent to PG 348 mg free base) administered as four tablets of 250:100 mg. The Malarone dose administered was the approved dose for treating acute uncomplicated malaria as chemoprevention currently requires a full course of antimalarial treatment (World Health Organization 2022 ). The Atoguanil ATV dose was reduced from 1000 to 500 mg, anticipating similar ATV exposures after oral administration of Atoguanil and Malarone . Exposure to PG from Atoguanil was predicted to be similar to that from Malarone . Thus, PG dose (free base) in Atoguanil matched the PG dose (hydrochloride) in Malarone .

As Malarone is administered with food or a milky drink, the fed condition was selected to assess bioavailability for both formulations. The study was conducted at Richmond Pharmacology Ltd (London, UK) between 17th November 2021 and 18th March 2022 (ClinicalTrials.gov: NCT04866602 registered 26th April, 2021; EudraCT number 2021-003422-69).

The primary objective was to determine the F rel of ATV, PG, and CG derived from a single oral dose of Atoguanil compared to a single oral dose of Malarone in the fed state at the doses administered. Secondary objectives were to further describe the single-dose PK properties of ATV, PG, and CG in healthy participants following a single dose of Atoguanil or Malarone in the fed state, to assess the safety and tolerability of Atoguanil , and further document the safety/tolerability of Malarone .

The study conformed to Good Clinical Practice as per the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use Good Clinical Practice Guidelines, the Declaration of Helsinki, and all applicable local laws and guidance. All participants provided informed signed consent before undertaking any study procedure. The study protocol including one amendment were reviewed and approved by the London Bridge Research Ethics Committee.

Participants

Eligible participants were male and female, including those of child-bearing potential, aged between 18 and 55 years, with bodyweight 50 to 80 kg and a body mass index 18 to 25 kg/m 2 . Participants were in good health, non-smokers, with no significant medical history, or clinically relevant abnormalities at screening based on physical examination, vital signs, clinical laboratory evaluations, or electrocardiogram (ECG). All participants had to use highly effective contraception, unless post-menopausal or sterilized. Pregnant and lactating women or partners of pregnant or lactating women were excluded. Key exclusion criteria were known hypersensitivity to ATV or PG, any significant underlying disease, condition or infection, including HIV, hepatitis B and drug and food allergies, current or history of psychiatric illness, any condition affecting drug absorption, a history of photosensitivity, a history or clinical evidence of substance or alcohol abuse, receipt of an investigational drug within 90 days or 5 half-lives, any moderate/strong inhibitor/inducer of CYP450 within 30 days or 5 half-lives, or any other drug in the previous 7 days or 10 half-lives or herbal supplement within 30 days, or any other significant disease or disorder considered to put the participant at risk.

Participants were screened within 30 days of trial start (Day −1). In period 1, participants were randomized (1:1) to Atoguanil or Malarone according to a computer-generated randomization schedule with cross-over to the other treatment in period 2. For each study period, study medication was administered on Day 1, participants discharged on Day 4, and outpatient follow-up visits conducted on Days 8, 15, and 22. There was a minimum 24-day washout period between each study period. Post-screening procedures are shown in Table 1 .

Before treatment administration, participants fasted overnight for at least 10 h, then consumed an FDA-type high-fat/calorie breakfast (796 kcal, 45.2 g/406.8 kcal of fat). Study drug was administered at completion of the breakfast being consumed entirely within 30 min of serving and with 240 mL of water. No additional food was allowed for 4 h post-dose, and additional water intake was not allowed 1 h before and after dosing. Participants were asked to not lie fully recumbent for 2 h post-dosing. Blood samples were collected for determination of ATV, PG, and CG plasma concentrations using a validated method. The lower limit of quantification (LLOQ) was 100 ng/mL for ATV, 5.00 ng/mL for PG and 1.50 ng/mL for CG.

The primary endpoints were F rel for ATV at the doses tested for C max , the AUC from time zero to last detectable plasma concentration (AUC 0-t ), AUC from time zero to 72 h (AUC 0-72h ), AUC from time zero to 168 h (AUC 0-168h ), and AUC from time zero to infinity (AUC 0-inf ). Also, the F rel for PG and CG for C max and AUC 0-inf at the doses tested were primary endpoints. Although AUC 0-inf is recommended as the most relevant measure for assessing F rel (United States Food and Drug Administration 2022 ), as ATV has a long terminal half-life (t 1/2 ), additional AUC endpoints were considered in case AUC 0-inf could not be calculated.

Secondary PK endpoints were time to maximum plasma concentration (T max ), terminal rate constant (λ z ), terminal half-life (t 1/2 ), apparent volume of distribution during the terminal phase (Vz/F), apparent total plasma clearance (Cl/F), and percentage of AUC due to extrapolation from the last measured value to infinity (%AUC extrap ).

Safety endpoints were the frequency of treatment-emergent adverse events, serious adverse events and adverse events of special interest, and the proportion of participants with clinically relevant changes in laboratory safety tests, vital signs (supine), or ECG (as triplicate) parameters. Adverse events of special interest were alanine transaminase (ALT) or aspartate transaminase (AST) > 3× the upper limit of normal (ULN) plus total bilirubin > 1.5×ULN, ALT or AST >8×ULN, or >3×ULN and symptomatic, uncorrected QT interval prolongation >500 msec, decline in hemoglobin ≥ 25% from baseline or an absolute value < 10 g/dL, clinically relevant decrease in neutrophil count, and platelet count ≥ 25% from baseline or an absolute value < 80 × 10 9 /L.

Statistical analysis

For this pilot study with first administration of Atoguanil in humans, no formal statistical power calculation was done, and 16 participants were enrolled to have at least 14 participants complete. A previous assessment of Malarone PK in healthy adult participants indicated intersubject coefficient of variation (CV%) values of 20–23% for ATV and PG C max and PG AUC 0-inf , but > 30% for ATV AUC 0-inf , suggesting that the proposed sample size would not allow for a formal bioequivalence assessment (Beerahee 1999 ). Thus, this study was conducted as an exploratory investigation to inform the design of a subsequent formal bioequivalence study.

The safety population included all randomized participants who received at least one dose of study treatment and was used for the safety analyses. The PK population was used for the PK analyses and included participants in the safety population with sufficient blood samples for calculation of at least one PK parameter.

PK parameters were estimated using non-compartmental analysis based on individual plasma concentration data, and the actual time of drug administration and blood sampling using Phoenix WinNonlin Version 8.3 (Certara, St Louis, USA). Samples below the LLOQ prior to the first quantifiable concentration were set to zero and those after the first quantifiable concentration were set to missing and omitted from the analysis. AUC was calculated using the linear/log trapezoidal method, applying the linear trapezoidal rule up to C max and the log trapezoidal rule for the remainder of the curve. Other PK parameters were calculated according to standard equations and summarized using descriptive statistics.

F rel at the doses tested was assessed as the ratio of the geometric means for exposure parameters expressed as a percentage, i.e., ( Atoguanil / Malarone) × 100%. F rel was calculated for ATV using for C max , AUC 0–t , AUC 0–72h , AUC 0–168h , and AUC 0–inf and for PG and CG using C max and AUC 0-inf . Using the bioequivalence module within Phonenix WinNonlin, a linear mixed effect model was used to obtain the geometric means ratios, with the logarithm of the PK parameter as the response variable, the sequence, treatment, and period as fixed effects, and the subject within sequence as the random effect. Least square mean differences ( Atoguanil − Malarone ) were extracted from the model with 90% confidence intervals (CI). Mean ratios were reported with two-sided 90%CI after back transformation from the log-scale. For this pilot study, bioavailability was assumed to be similar if the 90%CI limits for the F rel for each exposure parameter did not exceed 80% to 125%. A post hoc analysis was performed to determine dose-adjusted F rel as the ratio of the geometric means for exposure parameters expressed as a percentage following formula: (( Atoguanil ×1000)/( Malarone ×500)) ×100%.

Adverse events were classified using the Medical Dictionary for Regulatory Activities (MedDRA, version 24.1). Adverse event severity was classified using a categorical grading system (mild/moderate/severe) based on a global clinical assessment by a trained research physician. All safety endpoints were analyzed using descriptive statistics using SAS Version 9.4 (SAS Institute, Cary, NC, USA).

Of 38 individuals screened, 22 were excluded (5 reserve participants, 7 laboratory findings, 7 withdrew consent, 4 BMI/weight, 1 ECG, 1 medical history; including 3 re-screenings). All 16 enrolled participants completed the study and were included in the safety and PK populations. Mean (SD) age was 27.8 (4.9) years and 50% (8/16) were female; all females were of child-bearing potential (Table 2 ). The pre-specified threshold for a period 2 pre-dose ATV concentration > 5% of C max was observed for one participant, who was excluded from the analysis of F rel for both periods (modified PK population of 15 subjects). There were no other exclusions.

• Pharmacokinetics

PK parameters

Following peak ATV plasma concentrations, plasma levels declined in a multiphasic manner and remained quantifiable up to 504 h post-dose in both treatment groups (Fig. 1 ). Measurable concentrations of PG and CG were present until at least 72 h post-dose with a T lag of between 0.13 and 0.25 h with PG and 1.00 and 0.72 h for CG, reflecting the rapid metabolic conversion (Fig. 1 ). Median T max of ATV after administration of Atoguanil and Malarone was 4.5 h for both products. PK parameters for ATV, PG, and CG following Atoguanil or Malarone are summarized in Table 3 .

Mean (SD) plasma concentrations for ATV, PG, and CG over time following oral administration of Atoguanil (ATV 500 mg PG 348 mg) or Malarone (ATV 1000 mg plus PG hydrochloride 400 mg) in the presence of food (PK population, n = 16). ATV, atovaquone; PG, proguanil; CG, cycloguanil; SD, standard deviation

Relative bioavailability

Geometric means and intersubject variability (CV%) and the analysis of F rel for PK exposure measures are shown in Table 4 . At the doses tested, Malarone treatment gave rise to higher ATV exposure values when compared to Atoguanil with moderate CV%. ATV F rel following Atoguanil was 93.6% (90%CI 83.6, 104.9) for C max and 77.8% (90%CI 67.4, 89.8) for AUC 0-inf . Thus, in this pilot study, at the doses tested F rel between Atoguanil 500 mg and Malarone 1000 mg was similar for ATV C max , but not for AUC 0-inf . When correcting for the ATV dose, based on AUC 0-inf the F rel of Atoguanil was 156% compared to Malarone .

At the doses tested, PG C max was lower following Atoguanil versus Malarone (82.4% 90%CI [75.8, 89.5]), though AUC 0-inf values were similar for the two formulations (Table 4 ). PK exposure parameters for CG were similar for Atoguanil and Malarone (Table 4 ).

Following Atoguanil , four adverse events (3 COVID-19 infection, 1 soft tissue infection) occurred in 25.0% (4/16) of participants. Following Malarone , five adverse events (1 diarrhea, 3 headache, 1 contact dermatitis) occurred in 25.0% (4/16) of participants. All adverse events were of mild severity, two cases of headache were treated symptomatically with fluid/analgesics, and all resolved by period end. None of the adverse events was considered related to study medication. There were no serious adverse events or deaths. There were no adverse events of special interest reported.

There were no clinically significant changes in biochemistry, hematology, or coagulation parameters. There were no clinically relevant changes in ECG parameters. One participant receiving Malarone had a single reading of a transient prolongation of Fridericia-corrected QT interval of 454 msec (53 msec increase from baseline) at 6 h post-dose on Day 1, which was not observed in nine repeated readings and not considered clinically relevant. No clinically relevant observations were made for physical examination or vital signs.

This open-label, single-dose, standard non-replicated randomized 2-period, 2-treatment balanced crossover pilot study evaluated the oral PK profile and F rel of a novel formulation of ATV-PG ( Atoguanil ) relative to ATV-PG HCl ( Malarone ) in healthy adults in the fed state. In vitro dissolution data of Malarone vs Atoguanil tablets in two discriminating dissolution media showed dissolution rates for Atoguanil were about 2 to 2.5 times that of Malarone (Medicines for Malaria Venture, data on file). Also, a study in rabbits showed similar bioavailability of 50 mg/kg Atoguanil to 100 mg/kg Malarone with the ratio for ATV AUC 0-inf being 99.6% (95%CI 96.4, 103.0) (personal communication, Byju Thankachen). Thus, the maximum theoretical systemic exposure to ATV from Atoguanil was expected to be approximately twofold higher than for the Malarone . In this study, the proposed Atoguanil ATV dose was 500 mg, anticipating similar ATV exposures after oral administration of the Malarone ATV dose of 1000 mg.

PK parameters for ATV, PG, and CG following Malarone were consistent with previous reports in healthy participants in the fed state (Gillotin et al. 1999 ). At the doses tested, F rel was similar between Atoguanil and Malarone for C max (93.6% [90%CI 83.6, 104.9]), but not for AUC 0-inf (77.8% [90%CI 67.4, 89.8]). The PG dose in Atoguanil was similar to that in Malarone , and PG and CG exposures were expected to be similar. This was the case except for the PG C max , with an F rel of 82.4% (95%CI 75.8, 89.5).

The preferred study design for evaluating the F rel is the cross-over study design. As ATV has a half-life of up to 116 h, a minimum wash-out interval of 24 days between the administration of two single doses was used. However, one participant had an ATV concentration > 5% of C max in the second period and data from both periods were excluded from the F rel analysis (modified PK data set).

The individual ATV concentration–time profiles following Malarone showed some transient plateau and secondary peaks after 24 h, observed nominally around the time the participants would be administered food. This observation may account for the higher ATV AUC following administration of Malarone versus Atoguanil . However, as the ATV dose in Atoguanil was 500 mg versus 1000 mg in Malarone , the dose-adjusted F rel for ATV was improved by 156% with Atoguanil based on AUC 0-inf . The ATV AUC 0-inf following administration of Atoguanil also showed a reduced variability compared to Malarone , with CV% values of 26.8% and 48.7%, respectively.

Only nine treatment-emergent adverse events were reported, with no apparent differences observed between the treatment groups. All adverse events were mild and not considered treatment related. No clinically relevant abnormalities were observed for clinical laboratory tests, hematology, vital signs, or ECG. Overall, the Atoguanil safety and tolerability profile was acceptable and comparable to that of Malarone .

Key limitations were that this is a pilot study with moderate intersubject variability observed for exposure parameters. The ATV AUC 0-inf CV% observed in our study was largely above 30%, confirming previous data in healthy participants (Beerahee 1999 ). This suggests that a replicate design in which the reference product is given more than once, or even a two-stage design, would probably be required for a formal bioequivalence study (United States Food and Drug Administration 2022 ). According to the European Medicines Agency guidelines, widening the conventional 20% acceptance range for bioequivalence based on high variability is possible for C max but not AUC, and only if a replicate design is conducted (Committee for Medicinal Products for Human Use 2010 ). In contrast, the US Food and Drug Administration allows widening of the bioequivalence acceptance criteria for both C max and AUC, as well as applying slightly different approaches to estimate within-subject variation for the reference product above 25% (Endrenyi and Tothfalusi 2019 ). Importantly, this study used a high-fat, high calorific meal. As there was moderate intersubject variability in ATV exposures following Malarone and transitory secondary peaks in ATV concentrations around the time the participants were administered food, the possibility that there would be similar F rel between Atoguanil and Malarone following a low-fat meal or a milky drink as per normal Malarone dosing recommendations cannot be discounted, but this was not evaluated in this study. In terms of relevance to the target population, perennial malaria chemoprevention is recommended for children up to 24 months of age, and SMC is recommended for children under 5 years old. However, the safety and effectiveness of Malarone has not been confirmed in children weighing less than 11 kg. This study was necessarily conducted in healthy adults for ethical reasons.

Conclusions

In this pilot study, the ATV F rel following Atoguanil (ATV 500 mg PG 348 mg) or Malarone (ATV 1000 mg plus PG hydrochloride 400 mg) at the doses tested was not similar when both treatments were administered with high-fat/high caloric meal, based on AUC 0-inf . However, given that Malarone contains twice the ATV dose of Atoguanil, the dose-adjusted F rel of Atoguanil was 156% compared to Malarone . Both drugs were well tolerated with no safety concerns. However, the feasibility of halving the ATV dose required with the Atoguanil formulation compared with Malarone was not established.

Data availability

De-identified participant data are available on reasonable request and with completion of a signed data access agreement from ( https://www.mmv.org/about-us/contact-us ) referencing this publication. Data will be available for at least five years from publication of this study.

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Acknowledgements

The authors acknowledge the support of André-Marie Tchouatieu, Helen Demarest, from Medicines for Malaria Venture, Fraser Peck and Lucy Fulford Smith from Richmond Pharmacology Ltd, and Susan Podmore, independent consultant. Naomi Richardson (Magenta Communications Ltd) wrote the first draft of this article and provided editorial and graphic design services and was funded by Medicines for Malaria Venture.

Open access funding provided by Medicines for Malaria Venture MMV Funding for the conduct of this study and support for preparation of this manuscript was provided by Medicines for Malaria Venture. This work was supported, in whole or in part, by the Bill & Melinda Gates Foundation (grant number INV-007155). Under the grant conditions of the Foundation, a Creative Commons Attribution 4.0 Generic License has already been assigned to the Author Accepted Manuscript version that might arise from this submission.

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Conceptualization: Andrea Kuemmerle, Myriam El Gaaloul, Ulrike Lorch, Ashok Kumar, Dharmendra Singh, Satinder Singh, Hanu Ramachandruni, Byju Thankachen, Swapnil Kore, Isabelle Borghini-Fuhrer, Stephan Chalon; methodology: Andrea Kuemmerle, Ulrike Lorch, Hanu Ramachandruni, Isabelle Borghini-Fuhrer, Stephan Chalon; formal analysis and investigation: Andrea Kuemmerle, Denis Gossen, Michael Marx, Ulrike Lorch, Maja Szramowska, Isabelle Borghini-Fuhrer, Stephan Chalon; writing—review and editing: Andrea Kuemmerle, Denis Gossen, Michael Marx, Ulrike Lorch, Maja Szramowska, Ashok Kumar, Dharmendra Singh, Satinder Singh, Hanu Ramachandruni, Byju Thankachen, Swapnil Kore, Myriam El Gaaloul, Isabelle Borghini-Fuhrer, Stephan Chalon; resources: Ulrike Lorch, Maja Szramowska, Byju Thankachen, Dharmendra Singh, Ashok Kumar, Swapnil Kore; supervision: Andrea Kuemmerle, Myriam El Gaaloul, Ulrike Lorch, Isabelle Borghini-Fuhrer, Stephan Chalon. The authors declare that all data were generated in-house and that no paper mill was used.

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Correspondence to Stephan Chalon .

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Ethical approval.

All participants provided informed signed consent before undertaking any study procedure. The study protocol including one amendment were reviewed and approved by the London Bridge Research Ethics Committee.

Competing interests

HR, MEG, IB-F, and SC are employees of MMV. AK was employed at Medicines for Malaria Venture (MMV) when the study was designed and conducted and is a current employee of Novartis, Biomedical Research, Basel, Switzerland; the content of this paper is the responsibility of the individual authors and neither the study nor this publication is associated with Novartis, Biomedical Research. DG is the owner and director of Mangareva SRL, which received financial support from MMV to review and interpret the study results. MM is an employee of ICON Clinical Research, Langen, Germany, which received financial support from MMV to monitor the study. UL is an employee of Richmond Pharmacology Ltd, which received financial support from MMV to conduct the study. MS is an employee of PharmaKinetic Ltd which received financial support from MMV to perform the pharmacokinetic analysis. AK, DS, BT, and SK are employees of IPCA Laboratories Limited, Mumbai, India. SS was employed at IPCA Laboratories Limited when the study was designed and conducted and is a current employee of Aragen Life Sciences, Hyderabad, India; the content of this paper is the responsibility of the individual authors and neither the study nor this publication is associated with Aragen Life Sciences.

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Kuemmerle, A., Gossen, D., Marx, M.W. et al. A randomized, open-label two-period crossover pilot study to evaluate the relative bioavailability in the fed state of atovaquone-proguanil (Atoguanil™) versus atovaquone-proguanil hydrochloride (Malarone®) in healthy adult participants. Naunyn-Schmiedeberg's Arch Pharmacol (2024). https://doi.org/10.1007/s00210-024-03245-x

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DOI : https://doi.org/10.1007/s00210-024-03245-x

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Fantastic beasts and where not to find them —

The mythical griffin was not inspired by a horned dinosaur, study concludes, the mythological creatures are instead "chimeras of big cats and raptorial birds.".

Jennifer Ouellette - Jun 25, 2024 7:42 pm UTC

The gryphon, or griffin , is a legendary creature dating back to classical antiquity, sporting the body, legs, and tail of a lion and the wings, head, and front talons of an eagle. Since the 1980s, a popular "geomyth" has spread that the griffin's unique appearance was inspired by the fossilized skeleton of a horned dinosaur known as Protoceratops . It's a fascinating and colorful story, but according to the authors of a new paper published in the journal Interdisciplinary Science Reviews, there is no hard evidence to support such a connection.

"Everything about griffin origins is consistent with their traditional interpretation as imaginary beasts, just as their appearance is entirely explained by them being [mythological] chimeras of big cats and raptorial birds," said co-author Mark Witton , a paleontologist at the University of Portsmouth. "Invoking a role for dinosaurs in griffin lore, especially species from distant lands like Protoceratops , not only introduces unnecessary complexity and inconsistencies to their origins, but also relies on interpretations and proposals that don’t withstand scrutiny.”

There are representations of griffin-like creatures in ancient Egyptian art dated to before 3000 BCE, while in ancient Greek and Roman texts the creatures were associated with gold deposits in Central Asia. By the Middle Ages, griffins were common figures in medieval iconography and in heraldry. The hippogriff named Buckbeak in Harry Potter and the Prisoner of Azkaban is a related mythical creature, the product of a griffin and a mare.

It was the legendary link to Central Asian gold deposits that intrigued classical folklorist Adrienne Mayor in the 1980s. Drawing on Greek and Latin texts and related artworks, she suggested (beginning with a 1989 paper in Cryptozoology) that nomadic prospectors stumbled across fossilized skeletons of Protoceratops and brought tales of strange beaked quadrupeds to other regions as they traveled southeast along ancient trade routes. The dinosaur's bony neck frill might have been interpreted in early illustrations as mammal-like external ears, with its beak indicating a creature that was part-bird, leading to the eventual addition of wings.

Over the last 30 years, Mayor's hypothesis has gained traction in the popular media and within certain academic circles; it's now one of the most famous and widely touted examples of geomythology. It's not an entirely crazy idea, even if its origins lie in the pseudoscientific field of cryptozoology . After all, people as far back as Paleolithic times certainly used fossils as decorative ornaments or talismans, and there are bona fide cases of such "geomyths": For example, British ammonites were modified into "snake stones"; shark teeth were interpreted as snake tongues; and "winged" brachiopods became "stone swallows" in historic China.

The case for skepticism

But Witton and fellow Portsmouth paleontologist Richard Hing were skeptical because of the lack of any material evidence to support the connection between the griffin and Protoceratops . And they weren't alone. Paleontologist Paul Sereno once dismissed Mayor's claims as "sophomoric" and questioned her understanding of how fossils are found, identified, and interpreted, per the authors. So they set out to conduct the first detailed assessment of Mayor's claims, re-examining historical fossil records—including the distribution of sites where Protoceratops fossils have been found—and classical sources, as well as consulting with historians and archaeologists about the supposed link.

“It is important to distinguish between fossil folklore with a factual basis—that is, connections between fossils and myth evidenced by archaeological discoveries or compelling references in literature and artwork—and speculated connections based on intuition," said Hing . "There is nothing inherently wrong with the idea that ancient peoples found dinosaur bones and incorporated them into their mythology, but we need to root such proposals in realities of history, geography, and palaeontology. Otherwise, they are just speculation.”

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Contribution of matrix metalloproteinase-2 and matrix metalloproteinase-9 to upper tract urothelial cancer risk in taiwan.

1. Introduction

2. materials and methods, 2.1. recruitment of utuc patients and non-utuc control groups, 2.2. genotyping methodology of mmp-2 rs243865 and rs2285053, 2.3. genotyping methodology of mmp-9 rs3918242, 2.4. transcriptional expression of mmp-2 and mmp-9, 2.5. translational expression of mmp-2 and mmp-9, 2.6. statistical analysis methodology, 3.1. demographic characteristics of the utuc population, 3.2. the genotyping outcomes for the utuc patients and non-utuc control groups, 3.3. the allelic frequency distribution analyzing outcomes for the utuc patients and non-utuc control groups, 3.4. the mrna and protein expression levels of mmp-2 and mmp-9, 3.5. the associations of snps with the risks of metastasis in utuc patients, 4. discussion, 5. conclusions, author contributions, institutional review board statement, informed consent statement, data availability statement, acknowledgments, conflicts of interest.

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Wang, B.-R.; Ma, H.-H.; Chang, C.-H.; Liao, C.-H.; Chang, W.-S.; Mong, M.-C.; Yang, Y.-C.; Gu, J.; Bau, D.-T.; Tsai, C.-W. Contribution of Matrix Metalloproteinase-2 and Matrix Metalloproteinase-9 to Upper Tract Urothelial Cancer Risk in Taiwan. Life 2024 , 14 , 801. https://doi.org/10.3390/life14070801

Wang B-R, Ma H-H, Chang C-H, Liao C-H, Chang W-S, Mong M-C, Yang Y-C, Gu J, Bau D-T, Tsai C-W. Contribution of Matrix Metalloproteinase-2 and Matrix Metalloproteinase-9 to Upper Tract Urothelial Cancer Risk in Taiwan. Life . 2024; 14(7):801. https://doi.org/10.3390/life14070801

Wang, Bo-Ren, Hung-Huan Ma, Chao-Hsiang Chang, Cheng-Hsi Liao, Wen-Shin Chang, Mei-Chin Mong, Ya-Chen Yang, Jian Gu, Da-Tian Bau, and Chia-Wen Tsai. 2024. "Contribution of Matrix Metalloproteinase-2 and Matrix Metalloproteinase-9 to Upper Tract Urothelial Cancer Risk in Taiwan" Life 14, no. 7: 801. https://doi.org/10.3390/life14070801

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• Introduction
• Conclusions
• Article Information

ADHD indicates attention-deficit/hyperactivity disorder; CVD, cardiovascular disease.

a Controls were derived from the same base cohort as the cases; thus, a case with a later date of CVD diagnosis could potentially serve as a control for another case in the study.

Crude odds ratios (ORs) were based on cases and controls matched on age, sex, and calendar time. Adjusted ORs (AORs) were based on cases and controls matched on age, sex, and calendar time and adjusted for country of birth, educational level, somatic comorbidities (type 2 diabetes, obesity, dyslipidemia, and sleep disorders), and psychiatric comorbidities (anxiety disorders, autism spectrum disorder, bipolar disorder, conduct disorder, depressive disorder, eating disorders, intellectual disability, personality disorders, schizophrenia, and substance use disorders).

The solid lines represent the adjusted odds ratios, and the shaded areas represent the 95% CIs. In restricted cubic splines analysis, knots were placed at the 10th, 50th, and 90th percentiles of ADHD medication use.

eTable 1. International Classification of Diseases (ICD) Codes from the Swedish National Inpatient Register

eTable 2. Type of Cardiovascular Disease in Cases

eTable 3. Risk of CVD Associated With ADHD Medication Use Across Different Average Defined Daily Doses

eTable 4. Risk of CVD Associated With Cumulative Duration of Use of Different Types of ADHD Medications

eTable 5. Sensitivity Analyses of CVD Risk Associated With Cumulative Use of ADHD Medications, Based On Different Cohort, Exposure, and Outcome Definitions

eFigure. Risk of CVD Associated With Cumulative Use of ADHD Medications, Stratified by Sex

Data Sharing Statement

• Long-Term ADHD Medications and Cardiovascular Disease Risk JAMA Medical News in Brief December 26, 2023 Emily Harris
• Long-Term Cardiovascular Effects of Medications for ADHD—Balancing Benefits and Risks of Treatment JAMA Psychiatry Editorial February 1, 2024 Samuele Cortese, MD, PhD; Cristiano Fava, MD, PhD

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Zhang L , Li L , Andell P, et al. Attention-Deficit/Hyperactivity Disorder Medications and Long-Term Risk of Cardiovascular Diseases. JAMA Psychiatry. 2024;81(2):178–187. doi:10.1001/jamapsychiatry.2023.4294

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Attention-Deficit/Hyperactivity Disorder Medications and Long-Term Risk of Cardiovascular Diseases

• 1 Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
• 2 Unit of Cardiology, Heart and Vascular Division, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden
• 3 School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
• 4 Department of Applied Health Science, School of Public Health, Indiana University, Bloomington
• 5 Department of Psychological and Brain Sciences, Indiana University, Bloomington
• Editorial Long-Term Cardiovascular Effects of Medications for ADHD—Balancing Benefits and Risks of Treatment Samuele Cortese, MD, PhD; Cristiano Fava, MD, PhD JAMA Psychiatry
• Medical News in Brief Long-Term ADHD Medications and Cardiovascular Disease Risk Emily Harris JAMA

Question   Is long-term use of attention-deficit/hyperactivity disorder (ADHD) medication associated with an increased risk of cardiovascular disease (CVD)?

Findings   In this case-control study of 278 027 individuals in Sweden aged 6 to 64 years who had an incident ADHD diagnosis or ADHD medication dispensation, longer cumulative duration of ADHD medication use was associated with an increased risk of CVD, particularly hypertension and arterial disease, compared with nonuse.

Meaning   Findings of this study suggest that long-term exposure to ADHD medications was associated with an increased risk of CVD; therefore, the potential risks and benefits of long-term ADHD medication use should be carefully weighed.

Importance   Use of attention-deficit/hyperactivity disorder (ADHD) medications has increased substantially over the past decades. However, the potential risk of cardiovascular disease (CVD) associated with long-term ADHD medication use remains unclear.

Objective   To assess the association between long-term use of ADHD medication and the risk of CVD.

Design, Setting, and Participants   This case-control study included individuals in Sweden aged 6 to 64 years who received an incident diagnosis of ADHD or ADHD medication dispensation between January 1, 2007, and December 31, 2020. Data on ADHD and CVD diagnoses and ADHD medication dispensation were obtained from the Swedish National Inpatient Register and the Swedish Prescribed Drug Register, respectively. Cases included individuals with ADHD and an incident CVD diagnosis (ischemic heart diseases, cerebrovascular diseases, hypertension, heart failure, arrhythmias, thromboembolic disease, arterial disease, and other forms of heart disease). Incidence density sampling was used to match cases with up to 5 controls without CVD based on age, sex, and calendar time. Cases and controls had the same duration of follow-up.

Exposure   Cumulative duration of ADHD medication use up to 14 years.

Main Outcomes and Measures   The primary outcome was incident CVD. The association between CVD and cumulative duration of ADHD medication use was measured using adjusted odds ratios (AORs) with 95% CIs.

Results   Of 278 027 individuals with ADHD aged 6 to 64 years, 10 388 with CVD were identified (median [IQR] age, 34.6 [20.0-45.7] years; 6154 males [59.2%]) and matched with 51 672 control participants without CVD (median [IQR] age, 34.6 [19.8-45.6] years; 30 601 males [59.2%]). Median (IQR) follow-up time in both groups was 4.1 (1.9-6.8) years. Longer cumulative duration of ADHD medication use was associated with an increased risk of CVD compared with nonuse (0 to ≤1 year: AOR, 0.99 [95% CI, 0.93-1.06]; 1 to ≤2 years: AOR, 1.09 [95% CI, 1.01-1.18]; 2 to ≤3 years: AOR, 1.15 [95% CI, 1.05-1.25]; 3 to ≤5 years: AOR, 1.27 [95% CI, 1.17-1.39]; and >5 years: AOR, 1.23 [95% CI, 1.12-1.36]). Longer cumulative ADHD medication use was associated with an increased risk of hypertension (eg, 3 to ≤5 years: AOR, 1.72 [95% CI, 1.51-1.97] and >5 years: AOR, 1.80 [95% CI, 1.55-2.08]) and arterial disease (eg, 3 to ≤5 years: AOR, 1.65 [95% CI, 1.11-2.45] and >5 years: AOR, 1.49 [95% CI, 0.96-2.32]). Across the 14-year follow-up, each 1-year increase of ADHD medication use was associated with a 4% increased risk of CVD (AOR, 1.04 [95% CI, 1.03-1.05]), with a larger increase in risk in the first 3 years of cumulative use (AOR, 1.08 [95% CI, 1.04-1.11]) and stable risk over the remaining follow-up. Similar patterns were observed in children and youth (aged <25 years) and adults (aged ≥25 years).

Conclusions and Relevance   This case-control study found that long-term exposure to ADHD medications was associated with an increased risk of CVDs, especially hypertension and arterial disease. These findings highlight the importance of carefully weighing potential benefits and risks when making treatment decisions about long-term ADHD medication use. Clinicians should regularly and consistently monitor cardiovascular signs and symptoms throughout the course of treatment.

Attention-deficit/hyperactivity disorder (ADHD) is a common psychiatric disorder characterized by developmentally inappropriate inattentiveness, impulsivity, and hyperactivity. 1 , 2 Pharmacological therapy, including both stimulants and nonstimulants, is recommended as the first-line treatment for ADHD in many countries. 1 , 3 The use of ADHD medication has increased greatly in both children and adults during the past decades. 4 Although the effectiveness of ADHD medications has been demonstrated in randomized clinical trials (RCTs) and other studies, 5 , 6 concerns remain regarding their potential cardiovascular safety. 7 Meta-analyses of RCTs have reported increases in heart rate and blood pressure associated with both stimulant and nonstimulant ADHD medications. 5 , 7 - 9

As RCTs typically evaluate short-term effects (average treatment duration of 75 days), 7 it remains uncertain whether and to what extent the increases in blood pressure and heart rate associated with ADHD medication lead to clinically significant cardiovascular disease (CVD) over time. Longitudinal observational studies 10 - 12 examining the association between ADHD medication use and serious cardiovascular outcomes have emerged in recent years, but the findings have been mixed. A meta-analysis 13 of observational studies found no statistically significant association between ADHD medication and risk of CVD. However, the possibility of a modest risk increase cannot be ruled out due to several methodological limitations in these studies, including confounding by indication, immortal time bias, and prevalent user bias. Additionally, most of these studies had an average follow-up time of no more than 2 years. 13 , 14 Thus, evidence regarding the long-term cardiovascular risk of ADHD medication use is still lacking.

Examining the long-term cardiovascular risk associated with ADHD medicine use is clinically important given that individuals with a diagnosis of ADHD, regardless of whether they receive treatment, face an elevated risk of CVD. 15 Additionally, a substantial proportion of young individuals with ADHD continues to have impairing symptoms in adulthood, 16 necessitating prolonged use of ADHD medication. Notably, studies have indicated a rising trend in the long-term use of ADHD medications, with approximately half of individuals using ADHD medication for over 5 years. 17 Furthermore, evidence is lacking regarding how cardiovascular risk may vary based on factors such as type of CVD, type of ADHD medication, age, and sex. 13 Therefore, there is a need for long-term follow-up studies to address these knowledge gaps and provide a more comprehensive understanding of the cardiovascular risks associated with ADHD medication use. This information is also crucial from a public health perspective, particularly due to the increasing number of individuals receiving ADHD medications worldwide. 4

This study aimed to assess the association between cumulative use of ADHD medication up to 14 years and the risk of CVD by using nationwide health registers in Sweden. We hypothesized that longer cumulative use of ADHD medication would be associated with increased CVD risk. In addition, we aimed to examine whether the associations differ across types of ADHD medication, types of CVD, sex, and age groups.

We used data from several Swedish nationwide registers linked through unique personal identification numbers. 18 Diagnoses were obtained from the National Inpatient Register, 19 which contains data on inpatient diagnoses since 1973 and outpatient diagnoses since 2001. Information on prescribed medications was retrieved from the Swedish Prescribed Drug Register, which contains all dispensed medications in Sweden since July 2005 and includes information on drug identity based on the Anatomical Therapeutic Chemical (ATC) classification, 20 dispensing dates, and free-text medication prescriptions. Socioeconomic factors were obtained from the Longitudinal Integrated Database for Health Insurance and Labour Market studies. 21 Information on death was retrieved from the Swedish Cause of Death Register, 22 which contains information on all deaths since 1952. The study was approved by the Swedish Ethical Review Authority. Informed patient consent is not required for register-based studies in Sweden. The study followed the Reporting of Studies Conducted Using Observational Routinely Collected Health Data–Pharmacoepidemiological Research ( RECORD-PE ) guideline. 23

We conducted a nested case-control study of all individuals residing in Sweden aged 6 to 64 years who received an incident diagnosis of ADHD or ADHD medication dispensation 15 between January 1, 2007, and December 31, 2020. The diagnosis of ADHD ( International Statistical Classification of Diseases and Related Health Problems, Tenth Revision [ ICD-10 ] code F90) was identified from the National Inpatient Register. Incident ADHD medication dispensation was identified from the Swedish Prescribed Drug Register and was defined as a dispensation after at least 18 months without any ADHD medication dispensation. 24 Baseline (ie, cohort entry) was defined as the date of incident ADHD diagnosis or ADHD medication dispensation, whichever came first. Individuals with ADHD medication prescriptions for indications other than ADHD 25 and individuals who emigrated, died, or had a history of CVD before baseline were excluded from the study. The cohort was followed until the case index date (ie, the date of CVD diagnosis), death, migration, or the study end date (December 31, 2020), whichever came first.

Within the study cohort, we identified cases as individuals with an incident diagnosis of any CVD (including ischemic heart diseases, cerebrovascular diseases, hypertension, heart failure, arrhythmias, thromboembolic disease, arterial disease, and other forms of heart disease; eTable 1 in Supplement 1 ) during follow-up. For each case, the date of their CVD diagnosis was assigned as the index date. Using incidence density sampling, 26 up to 5 controls without CVD were randomly selected for each case from the base cohort of individuals with ADHD. The matching criteria included age, sex, and calendar time, ensuring that cases and controls had the same duration of follow-up from baseline to index date. Controls were eligible for inclusion if they were alive, living in Sweden, and free of CVD at the time when their matched case received a diagnosis of CVD, with the index date set as the date of CVD diagnosis of the matched case ( Figure 1 ). Controls were derived from the same base cohort as the cases. Thus, a case with a later date of CVD diagnosis could potentially serve as a control for another case in the study. 26

The main exposure was cumulative duration of ADHD medication use, which included all ADHD medications approved in Sweden during the study period, including stimulants (methylphenidate [ATC code N06BA04], amphetamine [ATC code N06BA01], dexamphetamine [ATC code N06BA02], and lisdexamfetamine [ATC code N06BA12]) as well as nonstimulants (atomoxetine [ATC code N06BA09] and guanfacine [ATC code C02AC02]). Duration of ADHD medication use was derived from a validated algorithm that estimates treatment duration from free text in prescription records. 25 The cumulative duration of ADHD medication use was calculated by summing all days covered by ADHD medication between baseline and 3 months prior to the index date. The last 3 months before the index date were excluded to reduce reverse causation, as clinicians’ perception of potential cardiovascular risks may influence ADHD medication prescription. This time window was chosen because routine psychiatric practice in Sweden limits a prescription to a maximum 3 months at a time. 27 Individuals with follow-up of less than 3 months were excluded.

We conducted conditional logistic regression analyses to estimate odds ratios (ORs) for the associations between cumulative durations of ADHD medication use and incident CVD. Crude ORs were adjusted for all matching variables (age, sex, and calendar time) by design. Adjusted ORs (AORs) were additionally controlled for country of birth (Sweden vs other), highest educational level (primary or lower secondary, upper secondary, postsecondary or postgraduate, or unknown; individuals aged <16 years were included as a separate category), and diagnoses of somatic (type 2 diabetes, obesity, dyslipidemia, and sleep disorders) and psychiatric comorbidities (anxiety disorders, autism spectrum disorder, bipolar disorder, conduct disorder, depressive disorder, eating disorders, intellectual disability, personality disorders, schizophrenia, and substance use disorders; eTable 1 in Supplement 1 ) before baseline. The association between cumulative ADHD medication use and incident CVD was assessed using both continuous and categorical measures (no ADHD medication use, 0 to ≤1, 1 to ≤2, 2 to ≤3, 3 to ≤5, and >5 years). To capture potential nonlinear associations, we used restricted cubic splines to examine ADHD medication use as a continuous measure throughout follow-up. 28 The associations were examined in the full sample and stratified by age at baseline, that is, children or youth (<25 years old) and adults (≥25 years old). Furthermore, to evaluate the association with dosage of ADHD medication, we estimated the risk of CVD associated with each 1-year increase in use of ADHD medication across different dosage groups categorized by the average defined daily dose (DDD; for instance, 1 DDD of methylphenidate equals 30 mg) during follow-up. 29

In subgroup analyses, we examined the associations between ADHD medication use and specific CVDs, including arrhythmias, arterial disease, cerebrovascular disease, heart failure, hypertension, ischemic heart disease, and thromboembolic disease (eTable 1 in Supplement 1 ). Additionally, we investigated the associations with CVD risk for the most commonly prescribed ADHD medications in Sweden, ie, methylphenidate, lisdexamfetamine, and atomoxetine, while adjusting for other ADHD medication use. We also examined sex-specific associations.

To further examine the robustness of our findings, we conducted 4 sensitivity analyses. First, we restricted the sample to ever users of ADHD medication to reduce unmeasured confounding between ADHD medication users and nonusers. Second, we assessed ADHD medication exposure over the entire follow-up period without excluding the 3 months prior to the index date. Third, to capture fatal cardiovascular events, we additionally included death by CVD in the outcome definition. Finally, we constructed a conditional logistic regression model that adjusted for propensity scores of ADHD medication use. Data management was performed using SAS, version 9.4 (SAS Institute Inc) and all analyses were performed using R, version 4.2.3 (R Foundation for Statistical Computing).

The study cohort consisted of 278 027 individuals with ADHD aged 6 to 64 years. The incidence rate of CVD was 7.34 per 1000 person-years. After applying exclusion criteria and matching, the analysis included 10 388 cases (median [IQR] age at baseline, 34.6 (20.0-45.7) years; 6154 males [59.2%] and 4234 females [40.8%]) and 51 672 matched controls (median [IQR] age at baseline, 34.6 [19.8-45.6] years; 30 601 males [59.2%] and 21 071 females [40.8%]) ( Figure 1 and Table 1 ). Median (IQR) follow-up in both groups was 4.1 (1.9-6.8) years. Among the controls, 3363 had received a CVD diagnosis after their index dates. The most common types of CVD in cases were hypertension (4210 cases [40.5%]) and arrhythmias (1310 cases [12.6%]; eTable 2 in Supplement 1 ). Table 1 presents the sociodemographic information and somatic and psychiatric comorbidities in cases and controls. In general, cases had higher rates of somatic and psychiatric comorbidities and a lower level of educational attainment compared with controls.

A similar proportion of cases (83.9%) and controls (83.5%) used ADHD medication during follow-up, with methylphenidate being the most commonly dispensed type, followed by atomoxetine and lisdexamfetamine. Longer cumulative duration of ADHD medication use was associated with an increased risk of CVD compared with nonuse (0 to ≤1 year: AOR, 0.99 [95% CI, 0.93-1.06]; 1 to ≤2 years: AOR, 1.09 [95% CI, 1.01-1.18]; 2 to ≤3 years: AOR, 1.15 [95% CI, 1.05-1.25]; 3 to ≤5 years: AOR, 1.27 [95% CI, 1.17-1.39]; and >5 years: AOR, 1.23 [95% CI, 1.12-1.36]) ( Figure 2 ). The restricted cubic spline model suggested a nonlinear association, with the AORs increasing rapidly for the first 3 cumulative years of ADHD medication use and then becoming stable thereafter ( Figure 3 ). Throughout the entire follow-up, each 1-year increase in the use of ADHD medication was associated with a 4% increased risk of CVD (AOR, 1.04 [95% CI, 1.03-1.05]), and the corresponding increase for the first 3 years was 8% (AOR, 1.08 [95% CI, 1.04-1.11]). We observed similar results when examining children or youth and adults separately ( Figure 2 ). The restricted cubic spline model suggested a similar nonlinear association, with higher AORs in children or youth than in adults, but the 95% CIs largely overlapped ( Figure 3 ). Furthermore, similar associations were observed for females and males (eFigure in Supplement 1 ). The dosage analysis showed that the risk of CVD associated with each 1 year of ADHD medication use increased with higher average DDDs. The risk was found to be statistically significant only among individuals with a mean dose of at least 1.5 times the DDD (eTable 3 in Supplement 1 ). For example, among individuals with a mean DDD of 1.5 to 2 or less (eg, for methylphenidate, 45 to ≤60 mg), each 1-year increase in ADHD medication use was associated with a 4% increased risk of CVD (AOR, 1.04 [95% CI, 1.02-1.05]). Among individuals with a mean DDD >2 (eg, for methylphenidate >60 mg), each 1-year increase in ADHD medication use was associated with 5% increased risk of CVD (AOR, 1.05 [95% CI, 1.03-1.06]).

When examining the risk for specific CVDs, we found that long-term use of ADHD medication (compared with no use) was associated with an increased risk of hypertension (AOR, 1.72 [95% CI, 1.51-1.97] for 3 to ≤5 years; AOR, 1.80 [95% CI 1.55-2.08] for >5 years) ( Table 2 ), as well as arterial disease (AOR, 1.65 [95% CI, 1.11-2.45] for 3 to ≤5 years; AOR, 1.49 [95% CI 0.96-2.32] for >5 years). However, we did not observe any statistically significant increased risk for arrhythmias, heart failure, ischemic heart disease, thromboembolic disease, or cerebrovascular disease ( Table 2 ). Furthermore, long-term use of methylphenidate (compared with no use) was associated with an increased risk of CVD (AOR, 1.20 [95% CI, 1.10-1.31] for 3 to ≤5 years; AOR, 1.19 [95% CI, 1.08-1.31]) for >5 years; eTable 4 in Supplement 1 ). Compared with no use, lisdexamfetamine was also associated with an elevated risk of CVD (AOR, 1.23 [95% CI, 1.05-1.44] for 2 to ≤3 years; AOR, 1.17 [95% CI, 0.98-1.40] for >3 years), while the AOR for atomoxetine use was significant only for the first year of use (1.07 [95% CI 1.01-1.13]; eTable 4 in Supplement 1 ).

In sensitivity analyses, we observed a similar pattern of estimates when the analysis was restricted to ever users of ADHD medications. Significantly increased risk of CVD was found when comparing ADHD medication use for 1 year or less with use for 3 to 5 or less years (AOR, 1.28 (95% CI, 1.18-1.38) or for use for more than 5 years (AOR, 1.24 [95% CI, 1.13-1.36]) (eTable 5 in Supplement 1 ). When assessing ADHD medication use across the entire follow-up period, and compared with no use, the pattern of estimates was similar to the main analysis (3 to ≤5 years: AOR, 1.28 [95% CI, 1.18-1.39]; >5 years: AOR, 1.25 [95% CI, 1.14-1.37]) (eTable 5 in Supplement 1 ). The analysis that included cardiovascular death as a combined outcome also had results similar to the main analysis. Moreover, when adjusting for propensity scores of ADHD medication use, the findings remained consistent (eTable 5 in Supplement 1 ).

This large, nested case-control study found an increased risk of incident CVD associated with long-term ADHD medication use, and the risk increased with increasing duration of ADHD medication use. This association was statistically significant both for children and youth and for adults, as well as for females and males. The primary contributors to the association between long-term ADHD medication use and CVD risk was an increased risk of hypertension and arterial disease. Increased risk was also associated with stimulant medication use.

We found individuals with long-term ADHD medication use had an increased risk of incident CVD in a dose-response manner in the first 3 years of cumulative ADHD medication use. To our knowledge, few previous studies have investigated the association between long-term ADHD medication use and the risk of CVD with follow-up of more than 2 years. 13 The only 2 prior studies with long-term follow-up (median, 9.5 and 7.9 years 30 , 31 ) found an average 2-fold and 3-fold increased risk of CVD with ADHD medication use compared with nonuse during the study period, yet 1 of the studies 30 included only children, and participants in the other study 31 were not the general population of individuals with ADHD (including those with ADHD and long QT syndrome). Furthermore, both studies were subject to prevalent user bias. Results from the current study suggest that the CVD risk associated with ADHD medication use (23% increased risk for >5 years of ADHD medication use compared with nonuse) is lower than previously reported. 30 , 31 Furthermore, we observed that the increased risk stabilized after the first several years of medication use and persisted throughout the 14-year follow-up period.

The association between ADHD medication use and CVD was significant for hypertension and arterial disease, while no significant association was observed with other types of cardiovascular events. To our knowledge, only 1 previous study 12 has examined the association between ADHD medication use and clinically diagnosed hypertension, and it found an increased risk, although the increase was not statistically significant. Furthermore, increased blood pressure associated with ADHD medication use has been well documented. 7 , 9 One study 32 found that blood pressure was mainly elevated during the daytime, suggesting that the cardiovascular system may recover at night. However, the cross-sectional nature of that study cannot preclude a long-term risk of clinically diagnosed hypertension associated with ADHD medication use. We also identified an increased risk for arterial disease. To date, no previous study has explored the association between ADHD medication use and arterial disease. A few studies have reported that ADHD medication may be associated with changes in serum lipid profiles, but the results were not consistent. 33 , 34 Further research is needed on the potential implications of ADHD medications for individuals’ lipid profiles. We did not observe any association between ADHD medication use and the risk of arrhythmias. A recent systematic review of observational studies of ADHD medication use reported an elevated risk of arrhythmias, but the finding was not statistically significant. 13 A review of RCTs also found that the use of stimulants was associated with an average increase in heart rate of 5.7 beats/min, 9 but no evidence of prolonged QT interval or tachycardia was found based on electrocardiograms. 7 Additionally, it is worth noting that some individuals receiving ADHD medications might be prescribed antiarrhythmic β-blockers to alleviate palpitation symptoms, thus potentially attenuating an association between ADHD medications and arrhythmias. Nevertheless, the absence of an association between ADHD medication use and clinically diagnosed arrhythmias in the present study does not rule out an increased risk for mild arrhythmias or subclinical symptoms, as palpitations and sinus tachycardia are not routinely coded as arrhythmia diagnoses. Further research is necessary to replicate our findings.

Regarding types of ADHD medication, findings of the present study suggest that increasing cumulative durations of methylphenidate and lisdexamfetamine use were associated with incident CVD, while the associations for atomoxetine were statistically significant only for the first year of use. Previous RCTs have reported increased blood pressure and heart rate with methylphenidate, lisdexamfetamine, and atomoxetine, 5 , 35 , 36 but the mechanisms behind these adverse effects are still a topic of debate; there might be differences in cardiovascular adverse effects in stimulants vs nonstimulants. 37

We found that the association between cumulative duration of ADHD medication use and CVD was similar in females and males. Previous investigations exploring sex-specific association found higher point estimates in females, although the differences were not statistically significant. 13 Research has indicated that females diagnosed with ADHD may demonstrate different comorbidity patterns and potentially have different responses to stimulant medications compared with males. 38 - 40 Therefore, additional studies are needed to explore and better understand the potential sex-specific differences in cardiovascular responses to ADHD medications.

A strength of this study is that data on ADHD medication prescriptions and CVD diagnoses were recorded prospectively, so the results were not affected by recall bias. The findings should, however, be interpreted in the context of several limitations. First, our approach for identification of patients with CVD was based on recorded diagnoses and there could be under ascertainment of cardiovascular diagnoses in the registers used. This means that some controls may have had undiagnosed CVD that did not yet require medical care, which would tend to underestimate associations between ADHD medication use and CVD. Second, exposure misclassification may have occurred if patients did not take their medication as prescribed. This misclassification, if nondifferential, would tend to reduce ORs such that the estimates we observed were conservative. Third, while we accounted for a wide range of potential confounding variables, considering the observational nature of the study and the possibility of residual confounding, we could not prove causality. It is possible that the association observed might have been affected by time-varying confounders. For example, other psychotropic medications and lifestyle factors could have affected both ADHD medication use and the occurrence of cardiovascular events. 41 , 42 Confounding by ADHD severity is also a potential factor to consider, as individuals with more severe ADHD symptoms may have more comorbidities and a less healthy lifestyle, which could affect the risk of CVD. Fourth, the study did not examine the risk of CVD among individuals with preexisting CVD. Individuals with preexisting CVD represent a distinct clinical group that requires careful monitoring; thus, evaluating the risk among them necessitates a different study design that carefully considers the potential impact of prior knowledge and periodic monitoring. Finally, the results by type of ADHD medication and type of CVD need to be replicated by studies with larger sample sizes.

The results of this population-based case-control study with a longitudinal follow-up of 14 years suggested that long-term use of ADHD medication was associated with an increased risk of CVD, especially hypertension and arterial disease, and the risk was higher for stimulant medications. These findings highlight the importance of carefully weighing potential benefits and risks when making treatment decisions on long-term ADHD medication use. Clinicians should be vigilant in monitoring patients, particularly among those receiving higher doses, and consistently assess signs and symptoms of CVD throughout the course of treatment. Monitoring becomes even more crucial considering the increasing number of individuals engaging in long-term use of ADHD medication.

Accepted for Publication: August 29, 2023.

Published Online: November 22, 2023. doi:10.1001/jamapsychiatry.2023.4294

Open Access: This is an open access article distributed under the terms of the CC-BY License . © 2023 Zhang L et al. JAMA Psychiatry .

Corresponding Authors: Zheng Chang, PhD ( [email protected] ) and Le Zhang, PhD ( [email protected] ), Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Nobels väg 12A, 171 65 Stockholm, Sweden.

Author Contributions: Dr Zhang and Prof Chang had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Zhang, Johnell, Larsson, Chang.

Acquisition, analysis, or interpretation of data: Zhang, Li, Andell, Garcia-Argibay, Quinn, D'Onofrio, Brikell, Kuja-Halkola, Lichtenstein, Johnell, Chang.

Drafting of the manuscript: Zhang.

Critical review of the manuscript for important intellectual content: All authors.

Statistical analysis: Zhang, Li.

Obtained funding: Larsson, Chang.

Administrative, technical, or material support: Garcia-Argibay, D'Onofrio, Kuja-Halkola, Lichtenstein, Chang.

Supervision: Andell, Lichtenstein, Johnell, Larsson, Chang.

Conflict of Interest Disclosures: Dr Larsson reported receiving grants from Takeda Pharmaceuticals and personal fees from Takeda Pharmaceuticals, Evolan, and Medici Medical Ltd outside the submitted work. No other disclosures were reported.

Funding/Support: This study was supported by grants from the Swedish Research Council for Health, Working Life, and Welfare (2019-01172 and 2022-01111) (Dr Chang) and the European Union’s Horizon 2020 research and innovation program under grant agreement 965381 (Dr Larsson).

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Data Sharing Statement: See Supplement 2 .

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