Nikhil A. Sangave, PharmD

Semaglutide is a glucagon-like peptide 1 receptor agonist (GLP-1 RA) injectable used in the treatment of type 2 diabetes.

 GLP-1 agonists stimulate glucose-dependent insulin release, inhibit hepatic glucagon production, and delay gastric emptying in response to increasing blood glucose levels. In the SUSTAIN-6 trial, semaglutide showed a statistically significant 26% risk reduction in major adverse cardiovascular events (MACE) when compared to placebo.

 In addition to cardiovascular benefits, semaglutide also showed a statistically significant average weight loss up to 10.8 pounds and lowered average A1c by 1%.

 These advantages make semaglutide and other GLP agonists a preferred agent for treatment for patients with type 2 diabetes, atherosclerotic cardiovascular disease (ASCVD), and obesity.

Despite demonstrating numerous benefits, semaglutide has also been linked to an increased incidence of diabetic retinopathy (DR), which was initially reported in the SUSTAIN-6 trial.

 DR is a common microvascular complication affecting the eyes that can occur as diabetes progresses. Hyperglycemia is a contributing risk factor to DR because the increase in blood glucose can lead to osmotic stress and inflammation. If left untreated, it can eventually lead to blindness.

Although it was not designed to assess the incidence of DR, the SUSTAIN-6 trial showed a statistically significant increased risk of new onset or worsening DR, with 3% incidence in the semaglutide group as compared to 1.8% in the placebo group.

 It is worth noting that many patients who experienced retinal complications had preexisting retinopathy at baseline and no correlation was found in patients without diabetic retinopathy at baseline. Other GLP-1 RAs that have shown cardiovascular benefits are liraglutide and dulaglutide. In the LEADER trial, no statistically significant difference was found between liraglutide and placebo with respect to incidence of diabetic retinopathy.

In light of these findings, a number of observational studies have been conducted on the potential relationship between GLP1-RAs and DR. One such study, conducted by Dauner and Farley, investigated this by using the FDA Adverse Event Reporting System (FAERS) database.

 Researchers used a composite of 12 different terms to identify adverse events related to DR and used proportional reporting ratio (PRR) to identify specific GLP1-RAs with signals for the composite outcome. Although their findings showed no signal correlating the GLP1-RA drug class to the composite outcome, they did observe that semaglutide had a signal for the composite outcome. Additionally, 3 other GLP1-RAs had signals for some of the 12 individual components of the composite outcome.

It is important to note that this study has some limitations. The increased reports of DR with semaglutide use in the FAERS database does not prove causation. For example, it could simply be that semaglutide is prescribed more frequently than other GLP-1 agonists, or alternatively, prescribers who are aware of the possible link between semaglutide and DR may be more likely to report it compared to those who are unaware.Another risk of using the FAERS database is that data may not be entirely accurate, duplicate reports may have been submitted for a single incident, and data may be missing.

It has been hypothesized that this transient worsening in DR is due to the rapid A1c lowering effect of semaglutide.

 Over 40 weeks, the SUSTAIN-FORTE trial showed the potential increased benefit of a 2 mg dose of semaglutide, which lowered A1c by 2.1%. The 1 mg dose lowered A1c by 1.9%.

The FOCUS trial seeks to further investigate the long-term effects of semaglutide on DR in patients with type 2 diabetes.

 This clinical trial will measure the presence of early treatment diabetic retinopathy level progression in 1500 patients with an A1c between 7% and 10%. Patients will administer either 1 mg of semaglutide or placebo subcutaneously every week. The time frame of the trial will be 5 years and is estimated to be completed in early 2027.

While DR has been identified as a potential adverse effect of semaglutide, there remains a positive benefit-risk profile when used accordingly with the FDA-approved prescribing information. According to the American Diabetes Association guidelines, patients who have been newly diagnosed with type 2 diabetes should have a comprehensive eye exam at the time of diagnosis.

 After the initial exam, subsequent eye exams should be conducted annually. In patients who have recently been initiated on semaglutide, especially those with a prior history of retinopathy, prescribers should be vigilant and closely monitor for signs of new or worsening retinopathy.

1. American Diabetes Association. 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes—2021. 

2. Marso SP, Bain SC, Consoli A, et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. 

3. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. 

4. Dauner DG, Farley JF. Comparing the use of individual and composite terms to evaluate adverse drug event disproportionality: a focus on glucagon-like peptide-1 receptor agonists and diabetic retinopathy. 

5. FAERS Public Dashboard - EUA - FAQ. Accessed August 3, 2021. 

https://fis.fda.gov/extensions/FPD-FAQ/FPD-FAQ.html

6. Vilsbøll T, Bain SC, Leiter LA, et al. Semaglutide, reduction in glycated haemoglobin and the risk of diabetic retinopathy. 

7. Frías JP, Auerbach P, Bajaj HS, et al. Efficacy and safety of once-weekly semaglutide 2·0 mg versus 1·0 mg in patients with type 2 diabetes (SUSTAIN FORTE): a double-blind, randomised, phase 3B trial. 

Long-Term Effects of Semaglutide on Diabetic Retinopathy in Subjects With Type 2 Diabetes

. clinicaltrials.gov; 2021. Accessed July 22, 2021. 

https://clinicaltrials.gov/ct2/show/NCT03811561

9. Microvascular Complications and Foot Care: Standards of Medical Care in Diabetes—2021 | Diabetes Care. Accessed July 24, 2021. 

https://care.diabetesjournals.org/content/44/Supplement_1/S151

10. Safi SZ, Qvist R, Kumar S, Batumalaie K, Ismail ISB. Molecular Mechanisms of Diabetic Retinopathy, General Preventive Strategies, and Novel Therapeutic Targets. Biomed Res Int. 2014;2014:801269. doi:10.1155/2014/801269

Articles

Despite demonstrating numerous benefits, semaglutide has also been linked to an increased incidence of diabetic retinopathy, which was initially reported in the SUSTAIN-6 trial.

Semaglutide Carries Potential Risk of Worsening Diabetic Retinopathy

Diabetes mellitus (DM) is a chronic metabolic disorder that presents with consistently elevated blood glucose levels due to either a lack of insulin (T1D) or resistance to insulin (T2D). The prevalence of DM in the United States has risen over the past several decades and poses a significant disease burden if not properly treated. Failure to properly manage this disease through strict blood glucose control and medication adherence can result in microvascular and macrovascular damage with organ complications and high mortality risk.

Current treatments for T2Dinclude insulin, metformin, sulfonylureas,thiazolidinediones, glucagon-like peptide-1 (GLP-1) receptor agonists, sodium glucose co-transporter-2 (SGLT2) inhibitors, and dipeptidyl peptidase-4 (DPP-4)-inhibitors. Encouragingly, some of these medications, namely SGLT2 inhibitors and GLP-1 agonists, have exhibited additional benefits in cardiovascular and renal outcomes. Such therapies have allowed providers to address multiple disease states with one agent. While established treatments continue to show diverse benefits, there have been several novel pharmaceutical agents with different mechanisms of action that show the potential to further combat this chronic disease.

Thioredoxin-interacting protein (TXNIP) has recently been identified as a glucose-regulated protein involved in the apoptosis of pancreatic beta-cells which could indicate beta cell toxicity.

 TXNIP promotes oxidative stresswithin beta cells, inducing antiproliferative effects by causing cell cycle arrest at the G0/G1 phase. This ultimatelyincreases the risk of apoptosis in fibroblast and cardiomyocytes.

High levels of glucose stimulate TXNIP transcription and results in elevated TXNIP mRNA expression. Together, these deleterious effects of TXNIP on the body could indicate a causal relationship in glucotoxic beta-cell death associated with diabetes.

 Many studies have been conducted in mice to investigate the benefit of mutation or removal of the TXNIP gene. In one report written by Thielen and Shalev, removal of the gene in mice increased beta cell mass, decreased beta cell apoptosis, elevated insulin levels, and was shown to prevent type 1 and type 2 diabetes.

 Another report written by Chen et al noted that TXNIP-deficient mice did not have glucose-toxic beta-cell apoptosis.

Because this novel mechanism could be crucial in understanding the pathogenesis of beta cell loss in diabetes, other pharmaceutical agents with anti-TXNIP activity are being studied for the treatment of diabetes.For example, verapamil, a non-dihydropyridine calcium channel blocker traditionally used for the treatment of hypertension, has been found to have an inhibitory effect on TXNIP expression by blocking the L-type and T-type calcium channels and decreasing intracellular calcium.

 One small study (n=44) evaluated the safety and efficacy of verapamil on fasting blood glucose (FBG), hemoglobin A1c (HbA1c) and lipid profiles in patients with T2D who are taking metformin and sitagliptin. The results concluded that there was a significant decrease of 0.5% in A1c after 3 months, although changes in FBG and lipid profiles were not statistically significant.

 Although these results demonstrate that TXNIP may be a suitable therapeutic target for the management diabetes and cardiometabolic disease overall, larger trials are warranted to further substantiate this therapeutic benefit.

Another TXNIP inhibitor molecule being investigated for the treatment of diabetes is SRI-37330. In vivo studies have revealed that SRI-37330 inhibited the expression and signaling of TXNIPin mice, rat, and human islet cells.

 By preventing the induction of TXNIP, SRI-37330 reduced hepatic glucose production and reversed hepatic steatosis.

This agent is still undergoing in vivo studies and has yet to reach clinical trials to studyitssafety and efficacy in human subjects,but has shown to be highly effective in human islet cells with minimal side effects in mice.

TXNIP expression may also contribute to the comorbidities of diabetes, such as nonalcoholic fatty liver disease (NAFLD). One pathway that is targeted involves TXNIP-protein arginine methyltransferase-1 (PRMT1) and peroxisome proliferator activated receptor gamma co activator α (PGC-1α), which ultimately leads to fat accumulation in hepatocytes.

 In this cascade, elevated levels of fatty acids lead to TXNIP overexpression, which induces the TXNIP-PRMT1 interaction. This interaction induces the expression of PGC-1α, a metabolic regulator found in the liver. Increases in PGC-1α are reflected in metabolic syndrome and fatty livers.

One therapeutic combination—allopurinol and quercetin—is being studied in rats with T1D and to assess its potential in NAFLD. Both medications have significant activity in TXNIP inhibition. The results of the study demonstrated that this combination reduced blood glucose levels, hepatic stress, inflammation, and steatosis.

Such studies have brought light to this novel approach of TXNIP inhibition, which could prevent beta cell loss and protect beta cell function to potentially contribute to diabetes management and its complications. Inhibition of this protein can hopefully increase beta cell mass and even possibly reverse the detrimental effects of both T1D and T2D. Although extensive research is still necessary, these recent discoveries may pave an innovative pathway for drug targeting.

1. Wondafrash DZ, Nire’a AT, Tafere GG, Desta DM, Berhe DA, Zewdie KA. Thioredoxin-Interacting Protein as a Novel Potential Therapeutic Target in Diabetes Mellitus and Its Underlying Complications. 

2. Chen, J., Saxena, G., Mungrue, I., Lusis, A. and Shalev, A., 2008. Thioredoxin-Interacting Protein: A Critical Link Between Glucose Toxicity and beta-Cell Apoptosis. 

, [online] 57(4), pp.938-944. Available at: <https://diabetes.diabetesjournals.org/content/57/4/938> [Accessed 16 October 2021].

3. Thielen L, Shalev A. Diabetes pathogenic mechanisms and potential new therapies based upon a novel target called TXNIP. 

. 2018;25(2):75-80. doi:10.1097/MED.0000000000000391

4. Shalev A. Minireview: Thioredoxin-interacting protein: regulation and function in the pancreatic β-cell. 

. 2014;28(8):1211-1220. doi:10.1210/me.2014-1095

5. Malayeri A, Zakerkish M, Ramesh F, Galehdari H, Hemmati AA, Angali KA. The Effect of Verapamil on TXNIP Gene Expression, GLP1R mRNA, FBS, HbA1c, and Lipid Profile in T2DM Patients Receiving Metformin and Sitagliptin. 

6. Thielen LA, Chen J, Jing G, et al. Identification of an Anti-diabetic, Orally Available Small Molecule that Regulates TXNIP Expression and Glucagon Action. 

7. Park M-J, Kim D-I, Lim S-K, et al. Thioredoxin-interacting protein mediates hepatic lipogenesis and inflammation via PRMT1 and PGC-1α regulation in vitro and in vivo. 

8. Wang W, Wang C, Ding X-Q, et al. Quercetin and allopurinol reduce liver thioredoxin-interacting protein to alleviate inflammation and lipid accumulation in diabetic rats. 

TXNIP inhibition could prevent beta cell loss and protect beta cell function to potentially contribute to diabetes management and its complications. 

TXNIP inhibitors: A New Class of Agents for Diabetes Treatment 

Advancements in technology have provided patients with many new pathways to manage their cardiovascular health. Telehealth has introduced new ways to enable remote health care delivery in an attempt to provide better access, improved quality, and lower costs to patients, especially during the coronavirus disease 2019 (COVID-19) pandemic.

 In recent years, digital health devices have offered pathways for patients to record and send data, which may ultimately encourage the patient to be more interactive in their disease management.

Alivecor, Apple, coala, eko, iRhythm, Omron, and Oculus

 are some of the companies that have a stake in cardiac digital health devices. Generally, cardiac devices are wearables that can track blood pressure, heart rate, electrocardiography (ECG), fitness, and sleep patterns.

 Most wearable devices are used alongside a companion app to record data, allowing physicians to monitor cardiac function and screen for heart abnormalities via email or in real time through a dashboard that can be shared directly with the patient.

Additionally, medication adherence plays a critical role in treating cardiovascular disease, making pharmacists key players in disease management after initial diagnosis. To keep secondary cardiovascular events at bay, pharmacists can perform counseling and medication therapy management to help the physician better understand a patient’s prognosis. The implementation of digital health devices may add new dimensions to the existing processes and could allow pharmacists to incorporate daily cardiovascular parameters into patient evaluations. 

Although studied as beneficial add-ons to current treatment, digital health devices have been used alongside telehealth as standard treatment during the COVID-19 pandemic.

 Prior to the recent public health emergency, trusted telehealth platforms and digital devices were limited to those that were compliant with the Health Insurance Portability and Accountability Act (HIPAA). With the Department of Health and Human Services temporarily waiving the penalties affiliated with not following HIPAA, there has been a disorganized adaptation of multiple digital and telehealth services during the pandemic.

This shift has given foresight into digital health-based models and a better perception into adjustments that need to be made as technology and health care continue to blend.

High smartphone ownership across all demographics may reduce health-related inequalities,

 but the use of smartphone compatible devices does not address patients facing other barriers. In a study comparing a smartphone coaching application to a smartphone tracking application, most participants in both control and intervention groups spoke English as a primary language and had 4 years or more of college education.

Additionally, in Treskes, et al, for patients who opted out of the intervention of a smartphone health monitoring device versus a regular follow up, one of the reasons classified was “fear of not being able to cope with technology.”

 Whether the issue is education, language, older age, low health literacy, or low socioeconomic status, according to the 

European Journal of Preventive Cardiology, 

these patients have a lower likelihood of going online to communicate with a physician or even using a mobile device to track their health.

There is also a lack of synchronization between the tech industry and health care, which will not change unless manufacturers address regulations around device development and data exchange protections, as well as credible studies showing improved health care outcomes.

 Additionally, the financial burden and time investment for training health care professionals to review data from these devices may be an opportunity cost.

 If manufacturers incorporated quality of life and health care outcomes studies for patients and providers, the integration of such devices into the provider workflow could be streamlined.

Finally, patient and physician-related barriers may be alleviated if the roles and responsibilities of pharmacists are shifted as digital health advancements continue to occur. Pharmacists are readily accessible health care professionals in the community who could play a significant role in digital health communication as “translators” to further assist patients and providers in understanding how to use data from various apps and devices.

, digital health could also introduce a new “digital pharmacist” role, a pharmacist who specializes in educating patients and training health care professionals on digital health devices.

As manufacturers continue to develop digital health devices at an unregulated pace, multiple devices have the potential to become important components in cardiovascular disease management. With or without the possibility of introducing a “digital pharmacist,” the COVID-19 pandemic has shown that more research needs to go into addressing the divide between technology and health care before digital health devices can be incorporated seamlessly into practice.

Narla, A., Paruchuri, K. and Natarajan, P., 2020. Digital health for primary prevention of cardiovascular disease: Promise to practice. 

Patel, P., 2020. Telehealth - Impacting Access, Cost and Quality - Perficient Blogs. [online] Perficient Blogs. Available at <https://blogs.perficient.com/2015/01/05/telehealth-impacting-access-cost-and-quality-2/>

Keesara S, Jonas A, Schulman K. Covid-19 and Health Care’s Digital Revolution. New England Journal of Medicine. 2020;382(23):e82. doi:10.1056/nejmp2005835

Cardiology — Digital.Health. Digital.Health. https://www.digital.health/cardiology. Published 2020. Accessed November 19, 2020.

Crilly P, Hassanali W, Khanna G et al. Community pharmacist perceptions of their role and the use of social media and mobile health applications as tools in public health. Research in Social and Administrative Pharmacy. 2019;15(1):23-30. doi:10.1016/j.sapharm.2018.02.005

Persell S, Peprah Y, Lipiszko D et al. Effect of Home Blood Pressure Monitoring via a Smartphone Hypertension Coaching Application or Tracking Application on Adults with Uncontrolled Hypertension. JAMA Network Open. 2020;3(3):e200255. doi:10.1001/jamanetworkopen.2020.0255

Treskes R, van Winden L, van Keulen N et al. Effect of Smartphone-Enabled Health Monitoring Devices vs Regular Follow-up on Blood Pressure Control Among Patients After Myocardial Infarction. JAMA Network Open. 2020;3(4):e202165. doi:10.1001/jamanetworkopen.2020.2165

Frederix I, Caiani E, Dendale P et al. ESC e-Cardiology Working Group Position Paper: Overcoming challenges in digital health implementation in cardiovascular medicine. European Journal of Preventive Cardiology. 2019;26(11):1166-1177. doi:10.1177/2047487319832394

Vatanka P, Lofton J. Re-envisioning the Pharmacist's Role in the Era of Digital Health—CPhA's Inaugural Digital Health Conference.

Aungst T. Creating a 'Digital Pharmacist' for the Future of Pharmacy Care — The Digital Apothecary. The Digital Apothecary. https://www.thedigitalapothecary.com/pharmacy-innovation-news/2019/3/23/creating-a-digital-pharmacist-for-the-future-of-health-care. Published 2019.

In recent years, digital health devices have offered pathways for patients to record and send data, which may ultimately encourage the patient to be more interactive in their disease management.
 

Implementation of Digital Health Technologies in Cardiovascular Disease Management during the COVID-19 Pandemic

Digital health strategically leverages digital technologies, empowering patients to manage their illnesses, reduce health risks, and promote health and wellness. This era of digital innovation within our health care system provides new alternatives for managing chronic conditions, diagnosing diseases earlier, and promoting prevention. The extensive scope of digital health encompasses technologies such as mobile health (mHealth) apps, artificial intelligence (AI)-enabled medical devices, and smart connected devices.

One emerging technology—smart inhalers&mdash;is becoming one of the greatest opportunities for clinical pharmacy engagement. Traditional inhalers have long been the mainstay of therapy for patients with chronic respiratory diseases. Their ability to deliver medication (ie bronchodilators and corticosteroids) directly to the lungs and significantly reduce systemic adverse effects has been well established, making them an effective and ideal treatment option.

However, health care professionals still face several challenges associated with managing respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD). The efficacy of inhalers can be negatively impacted by incorrect inhaler technique and poor adherence. A recent study showed worsening dyspnea, greater health condition impairment, and an increased frequency of exacerbations associated with incorrect inhaler technique and non-adherence.

Furthermore, incorrect inhaler technique and non-adherence places an immense burden on the cost of health care for patients with respiratory diseases. In patients with chronic diseases in the United States, the excess costs associated with non-adherence alone are estimated to be $300 billion annually.

 The management and prevention of respiratory diseases are suggested to be among the most cost-effective health interventions available; however, many patients do not optimize their medication therapies.

Inadequate inhaler technique or non-adherence to their medication, consequently, may result in the progression of their condition and unnecessary health care expenses for respiratory disease patients. The CDC states that if all COPD patients were completely compliant with their medication, exacerbations could be decreased by 25% to 30% annually, saving $4 billion per year.

Smart inhalers have the potential to address the challenges faced by patients and health care professionals in the management of respiratory diseases. With digital features designed to connect with mobile applications, smart inhalers and mobile applications work simultaneously to monitor medication schedules and subsequent dosing. Smart inhalers can monitor adherence; accurately record the time, date, and location of each dosage administered; send dosage reminders; and provide access to readily shareable data via Bluetooth. Several smart devices either have sensors built into the body of the inhaler or provide external sensors that can be attached to traditional inhalers.

As the smart inhaler market grows, pharmacists will need to develop a baseline proficiency in the use of digital technology to support patients and health care professionals with tools in the management of respiratory diseases. Nonetheless, approaches to managing respiratory diseases with smart inhalers should be supported by clinical outcomes, be designed as a cost-effective system, and mirror the needs of patients and health care professionals before they can be widely accepted in practice.

Here is a look at some of the smart inhalers currently on the market in the United States:

Smart inhalers available internationally:

Digital Health Center of Excellence. U.S. Food and Drug Administration. https://www.fda.gov/medical-devices/digital-health. Published 2020. Accessed November 7, 2020.

Greene, G. and Costello, R., 2019. Personalizing medicine - could the smart inhaler revolutionize treatment for COPD and asthma patients?. 

Ngo CQ, Phan DM, Vu GV, et al. Inhaler Technique and Adherence to Inhaled Medications among Patients with Acute Exacerbation of Chronic Obstructive Pulmonary Disease in Vietnam. 

. 2019;16(2):185. Published 2019 Jan 10. doi:10.3390/ijerph16020185

Lareau SC, Yawn BP. Improving adherence with inhaler therapy in COPD. 

. 2010;5:401-406. Published 2010 Nov 24. doi:10.2147/COPD.S14715

. 2nd ed. Sheffield: European Respiratory Society, p.6.

Pal S. Epidemiology of Chronic Lung Diseases. Uspharmacist.com. https://www.uspharmacist.com/article/epidemiology-of-chronic-lung-diseases. Published 2020. Accessed November 7, 2020.

An Analysis Of The Smart Inhalers Market. Medical Product Outsourcing. https://www.mpo-mag.com/contents/view_online-exclusives/2020-06-09/an-analysis-of-the-smart-inhalers-market/. Published 2020. Accessed November 7, 2020.

Blakey JD, Bender BG, Dima AL, Weinman J, Safioti G, Costello RW. Digital technologies and adherence in respiratory diseases: the road ahead. 

. 2018;52(5):1801147. Published 2018 Nov 22. doi:10.1183/13993003.01147-2018

Propeller Health Sensor to Be Co-Packaged With Recently Approved Enerzair® Breezhaler® Asthma Medication in Europe. Businesswire.com. https://www.businesswire.com/news/home/20200706005585/en/Propeller-Health-Sensor-Co-Packaged-Approved-Enerzair%C2%AE-Breezhaler%C2%AE. Published 2020. Accessed November 7, 2020.

Teva Announces Availability of ProAir® Digihaler® (albuterol sulfate 117 mcg) Inhalation Powder for Patients with Asthma and COPD. Businesswire.com. https://www.businesswire.com/news/home/20200713005034/en/Teva-Announces-Availability-of-ProAir%C2%AE-Digihaler%C2%AE-albuterol-sulfate-117-mcg-Inhalation-Powder-for-Patients-with-Asthma-and-COPD. Published 2020. Accessed November 7, 2020.

Teva Launches Two Digital Inhalers in the U.S., AirDuo® Digihaler® (fluticasone propionate and salmeterol) Inhalation Powder and ArmonAir® Digihaler® (fluticasone propionate) Inhalation Powder. Businesswire.com. https://www.businesswire.com/news/home/20200921005170/en/Teva-Launches-Two-Digital-Inhalers-in-the-U.S.-AirDuo%C2%AE-Digihaler%C2%AE-fluticasone-propionate-and-salmeterol-Inhalation-Powder-and-ArmonAir%C2%AE-Digihaler%C2%AE-fluticasone-propionate-Inhalation-Powder. Published 2020. Accessed November 7, 2020.

How It Works | Hailie™. hailie. https://www.hailie.com/pages/how-it-works. Published 2020. Accessed November 7, 2020.

FindAir — Smart Inhaler. Findair.eu. https://findair.eu/#Produkt. Published 2020. Accessed November 7, 2020.

Lupin launches "Adhero," first-of-its-kind connected Smart Device in India to support treatment of Respiratory Disease - Lupin. Lupin. https://www.lupin.com/portfolio/lupin-launches-adhero-first-of-its-kind-connected-smart-device-in-india-to-support-treatment-of-respiratory-disease/. Published 2020. Accessed November 7, 2020.

3M Designs an 'Intelligent Inhaler' System for COPD, Asthma and Other Respiratory Ills - Lung Disease News. Lung Disease News. https://lungdiseasenews.com/2016/04/22/3m-designs-intelligent-inhaler-system-copd-asthma-respiratory-ills/. Published 2020. Accessed November 7, 2020.

BreatheSmart® Mobile App Virtual Tour - HeroTracker® Sensors. Coherohealth.com. https://coherohealth.com/BreatheSmart/demo/sensors.php. Published 2020. Accessed November 7, 2020.

Pharma company Opko acquires smart inhaler startup for at least $10M. MobiHealthNews. https://www.mobihealthnews.com/32207/pharma-company-opko-acquires-smart-inhaler-startup-for-at-least-10m. Published 2020. Accessed November 7, 2020.

Inspair | Biocorp. Biocorpsys.com. https://biocorpsys.com/en/our-products/connected-devices/inspair/. Published 2020. Accessed November 7, 2020.

Pneuma Respiratory debuts smartphone-compatible inhaler. MobiHealthNews. https://www.mobihealthnews.com/content/pneuma-respiratory-debuts-smartphone-compatible-inhaler. Published 2020. Accessed November 7, 2020.

Amiko | Upgrading respiratory care. Amiko. https://amiko.io/. Published 2020. Accessed November 7, 2020.

Smart inhalers have the potential to address the challenges faced by patients and health care professionals in the management of respiratory diseases.