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Semaglutide: A New GLP-1RA for Type 2 Diabetes Mellitus Treatment

By Saloni Dhaktode, Genetics and Genomics ’22

Author’s Note: My interest in research and biology began with understanding diabetes. This topic is close to my heart because my family is very susceptible to Type 2 diabetes, and many families of various ethnic groups in the U.S. are as well. Each patient has a unique background and lifestyle, which makes them unique in how their body handles both the condition and its treatments. My UWP 104E class with Dr. Nathaniel Williams gave me the opportunity to write this literature review and share one of the newest options available to Type 2 diabetic patients. I hope readers can learn more about how semaglutide is another step to best serving this uniqueness.

 

Introduction

The 2020 National Diabetes Statistics Report by the Centers of Disease Control (CDC) states that 34.2 million people in the United States have diabetes, either diagnosed or undiagnosed. Type 2 Diabetes Mellitus (T2D) accounts for about 90-95% of these cases. In healthy individuals, pancreatic β-cell insulin moves glucose into cells to be converted into energy, thus lowering glucose levels in the bloodstream. T2D is a chronic condition characterized by the body’s resistance to or inadequate production of β-cell insulin. This leads to uncontrolled hyperglycemia, or high blood glucose levels [1]. To compensate for rising blood glucose, the body may produce more insulin than normal, a condition known as hyperinsulinemia [8]. Since the body cannot properly respond to the accumulating insulin, hyperglycemia can persist alongside hyperinsulinemia. 

Semaglutide, a medication used to treat T2D, falls under the class of glucagon-like peptide-1 receptor agonists (GLP-1RAs). An agonist is a chemical that activates a receptor. As an agonist, semaglutide activates receptors that prompt insulin release. Hence, these types of drugs regulate glycemic levels and are also linked to the treatments of obesity and cardiovascular disease, two conditions associated with T2D [2, 3, 6, 7, 9, 10]. Previously released medications of this class include liraglutide, dulaglutide, exenatide, and lixisenatide [6]. Semaglutide was added to the list in 2017 as a longer-acting alternative. GLP-1RAs were only administered through subcutaneous injection until 2019, when the first oral form, a pill version of semaglutide, was approved by the U.S. Food and Drug Administration. The SUSTAIN and PIONEER trials conducted by Novo Nordisk led to the release of semaglutide.

With semaglutide being a relatively recent development, further clinical trials are currently ongoing. This is why semaglutide is not recommended as the first choice for T2D treatment. But it still provides a substantial option for patients who do not see improvements with or have severe adverse reactions to previous treatments, such as Metformin (usually the first choice) or sulfonylureas (which also increase insulin secretion). The National Diabetes Statistics Report indicates an increase in total diabetes cases over the years [1], which calls for new medications that can benefit patients of diverse medical backgrounds. This review analyzes the function and effects of semaglutide using various clinical trials, in order to determine the scope of the drug’s ability to combat insulin resistance and other conditions associated with T2D. 

What is Semaglutide?

Semaglutide is a GLP-1RA, a drug class that mimics the activity of the human glucagon-like peptide-1 (GLP-1) hormone. In particular, semaglutide has a 94% homology to GLP-1 [3, 5]. Glucagon, a hormone produced by pancreatic α-cells, raises blood glucose and induces insulin release to keep glycemic levels balanced. GLP-1 is called “glucagon-like” because it shares similarities with glucagon and enhances insulin secretion. GLP-1 is deficient in T2D patients, which is why semaglutide is designed as an agonist to mimic GLP-1. In this case, semaglutide activates GLP-1 receptors in the pancreas, promoting greater insulin release. By imitating GLP-1, semaglutide is able to lower glycemic levels, commonly indicated by decreased levels of Hemoglobin A1c (HbA1c), as glucose attaches to hemoglobin in the bloodstream [2, 4, 9, 10]. 

Novo Nordisk developed two forms of semaglutide: a subcutaneous injection and an oral pill. They were released and are being sold under the brand names Ozempic (injection) and Rybelsus (pill). Due to the half-life of semaglutide being 6-8 days, which is extended compared to earlier GLP-1RAs, the medication is administered once-weekly [3, 6, 7]. 

While there are no fatal safety issues with semaglutide, adverse effects must be considered. The most frequent effects are mild to moderate gastrointestinal events, such as nausea, vomiting and diarrhea [2, 3, 4, 5, 7, 9, 10] . A chance of hypoglycemia is always present, especially if semaglutide is taken with other antidiabetics. But most of the clinical trials reported low hypoglycemic rates [2, 4, 9, 10]. Significant increases in lipase were also reported [2, 4, 7]. Lipase is an enzyme that helps the body break down fats, but in high levels can be linked to pancreatitis. Semaglutide still requires testing with patients with histories of pancreatitis [3]. However, semaglutide exhibits a similar safety profile to other GLP-1RAs [2, 6, 7, 9, 10], so these effects are not unexpected. 

Semaglutide Administration

Subcutaneous Injection

Subcutaneous injection is the most common form of GLP-1RA medications. The injection is commercially available as Ozempic. It is applied under the patient’s skin, into the tissue layer that lies between the skin and the muscle. The tissue layer has lower blood supply, which allows the medication to enter the bloodstream slowly and in a controlled manner.  

The SUSTAIN 1 clinical trial conducted by Sorli et al. (2017) of Novo Nordisk tested the efficacy of subcutaneous semaglutide monotherapy versus placebo in T2D patients. Participants of 18 years or older with T2D were randomly assigned once-weekly subcutaneous semaglutide (0.5 mg or 1.0 mg) or volume-matched placebos. The testing period was 30 weeks. Results show that HbA1c levels significantly decreased by 1.45% with 0.5 mg and 1.55% with 1.0 mg [9]. The trial confirms subcutaneous semaglutide’s superiority versus the placebo. The Ozempic patient site prescribes a starting dose of 0.25 mg, which increases to 0.5 mg and 1.0 mg if needed. This is in accordance with the doses tested in SUSTAIN 1. 

Oral Pill 

The oral pill form of semaglutide is the first oral version of all GLP-1RAs [2, 4]. Since semaglutide is peptide-based, it is prone to proteolytic damage in the stomach. To overcome this issue, the tablet is co-formulated with sodium N-[8 (2-hydroxybenzoyl) amino] caprylate (SNAC). SNAC enhances the absorption of semaglutide across the stomach’s mucus layer and protects it from proteolytic degradation [2, 4, 6, 9]. 

The PIONEER 1 clinical trial conducted by Aroda et al. (2019) of Novo Nordisk tested the efficacy of oral semaglutide monotherapy against placebo in T2D patients. Participants of 18 years or older with T2D were randomly assigned once-daily oral semaglutide (3 mg, 7 mg, or 14 mg) or a placebo. The testing period was 26 weeks. Results indicate that the largest dose, 14 mg, led to HbA1c levels decreasing by an average of 1.5% [2]. The trial confirms oral semaglutide’s superiority at all dose levels versus the placebo. The Rybelsus patient site prescribes 7 mg or 14 mg tablets, corresponding to the doses tested in PIONEER 1. 

Oral vs. Injection

The availability of two semaglutide products raises the question of which form of administration is more effective in enhancing insulin secretion. The 1.45% to 1.55% HbA1c reductions seen in the SUSTAIN 1 trial are comparable to the 1.5% HbA1c reduction in the PIONEER 1 trial. Each of the trials differed in methods and testing duration, but the percent reductions of HbA1c are very similar, with respect to the doses each trial’s researchers deemed most effective. 

A clinical trial by Davies et al. (2017) assessed the efficacy of oral semaglutide versus subcutaneous semaglutide or placebo in T2D patients. Participants 18 years or older with T2D were randomly assigned to one of five oral semaglutide groups, an oral placebo group, or a subcutaneous semaglutide group. The oral groups’ HbA1c levels significantly reduced by an average of 1.8% and the subcutaneous group’s HbA1c levels by 1.9%. Evidently, there is very little difference between the percent reductions in both group types. [4]. This supports the similarity in HbA1c reduction between the SUSTAIN 1 and PIONEER 1 trials observed earlier. Therefore, it can be concluded that there is no significant difference between either form’s ability to effectively secrete insulin. 

Since there is no obvious advantage or disadvantage between the two forms, the choice between an injection and a pill is open to patients, according to their preference or compatibility with their bodies. The subcutaneous tissue layer has a lower blood supply, which allows semaglutide to enter the bloodstream slowly. Similarly, a semaglutide pill must be metabolized by the gastrointestinal system before entering the bloodstream. The slow absorption of both forms lowers the risk of sudden hypoglycemia in patients. Patients can also take into account (using the Rybelsus and Ozempic patient sites) that the pill (Rybelsus) must be taken once-daily on an empty stomach, as food can hinder its absorption in the stomach. In contrast, the injection (Ozempic) must be administered once-weekly with or without food. 

Effects of Semaglutide on Conditions Associated with T2D

On Obesity 

People with obesity are at a higher risk of being diagnosed with T2D. Thus, it is important to note that semaglutide’s benefits include weight loss. GLP-1RA has been shown to stimulate satiety and reduce hunger and energy intake. These effects may be due to activation of GLP-1 receptors in the hypothalamus, the part of the brain that controls appetite. A study conducted by Blundell et al. (2017) investigated the effects of semaglutide on appetite, energy intake, and body weight in patients with obesity. The study made sure to exclude participants diagnosed with diabetes. Subjects of 18 years or older were randomized to once-weekly subcutaneous semaglutide or a placebo, both 1.0 mg doses, for 12 weeks. Subjects were allowed ad libitum (i.e. unrestricted) meals. The study shows energy intake lowered by 24% across all ad libitum meals with semaglutide versus placebo. Results also indicate lower preferences for high-fat foods and better portion control with semaglutide. Body weight was lowered by about 5.0 kg, which can be attributed to the changes in appetite [3]. Weight loss was also observed in SUSTAIN 1 and PIONEER 1 [2, 9]. These effects in conjunction with enhanced insulin secretion would particularly help obese T2D patients, who are more likely to deal with higher glycemic levels. 

It is worth noting that it is possible to have T2D without being overweight or obese. For example, the Body Mass Index (BMI) cutoff for diabetes screening is lower in some ethnic groups than others. This may be due to genetic factors rather than dietary factors. However, the PIONEER and SUSTAIN trials’ subjects were undergoing diet and exercise prior to screening, indicating that weight loss was a goal. The subjects’ mean BMI was also greater than 30.  Because T2D in non-overweight individuals is less common and harder to detect, there remains a need for more research on how T2D treatments promoting weight loss can affect them. 

On Cardiovascular Disease

T2D increases the chances of developing cardiovascular disease. In fact, it is the leading cause of death in T2D patients [7]. According to the CDC, excess blood glucose damages blood vessels over time, preventing oxygen-rich blood from reaching the heart. A study by Marso et al. (2016) for the SUSTAIN 6 trial investigated the effects of semaglutide on Major Adverse Cardiovascular Events (MACE) versus placebo. The doses administered were the same as in SUSTAIN 1. The trial confirmed the researchers’ hypothesis that semaglutide would be non-inferior to placebo. This is evidenced by a significant 26% decrease in MACE, which are a composite of cardiovascular death, non-fatal stroke, and non-fatal myocardial infarction [7].

Semaglutide with Metformin

Metformin is the preferred first-line treatment for T2D, because it has been well-studied and successfully used as such since the 1950s. It is classified as a biguanide, an oral drug that prevents glucose production in the liver and lowers insulin resistance. Dual therapy of semaglutide (both oral and subcutaneous) added to metformin is of interest because there are many T2D patients who do not see satisfactory results with metformin monotherapy. Semaglutide may be able to provide additional glycemic control. 

The PIONEER 8 trial, conducted by Zinman et al. (2019) investigated the efficacy of oral semaglutide versus placebo in T2D patients taking insulin with or without metformin. The doses administered were the same as in PIONEER 1. Results show that 14 mg of semaglutide with insulin, regardless of the presence of metformin, reduced HbA1c levels by 1.3%, which is significantly greater than the placebo’s effects [10]. An older study by Hausner et al. (2017) explored the effects of subcutaneous semaglutide on metformin in healthy subjects. No significant interactions between the two medications were found [5]. Further research must be conducted to determine whether metformin works better with semaglutide as opposed to on its own. Nevertheless, it is evident that semaglutide can be used in conjunction with metformin safely and without adjustments in dosage. 

Conclusion

The clinical trials referenced in this review have demonstrated that both subcutaneous and oral semaglutide are significantly effective in lowering Hb1Ac levels in T2D patients [2, 4, 9, 10]. In addition, semaglutide has also been proven effective in weight loss and reducing the risk of MACE [3, 7]. Semaglutide’s efficacy is a major advancement in T2D treatment and GLP-1-based therapies because of its diverse functions. Its ability to treat hyperglycemia, obesity, and cardiovascular disease; availability in oral and injection forms; and compatibility with metformin caters to T2D patients with various needs. 

Semaglutide was only recently approved, with more clinical trials being run by Novo Nordisk and other institutions today. Future research should focus on investigating the advantages of oral over subcutaneous forms and metformin-semaglutide dual therapy over metformin monotherapy. These studies would provide deeper insight into determining the best possible treatments for T2D.

 

References:

  1. American Diabetes Association. 2. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes—2020. 2019. Diabetes Care. 43(Supplement 1):S14-S31. doi:10.2337/dc20-s002
  2. Aroda, V. R., Rosenstock, J., Terauchi, Y., Altuntas, Y., Lalic, N. M., Villegas, E. C. M., … Haluzík, M. 2019. PIONEER 1: Randomized Clinical Trial of the Efficacy and Safety of Oral Semaglutide Monotherapy in Comparison With Placebo in Patients With Type 2 Diabetes. Diabetes Care [Internet]. 42(9):1724–1732. doi:10.2337/dc19-0749
  3. Blundell, J., Finlayson, G., Axelsen, M., Flint, A., Gibbons, C., Kvist, T., & Hjerpsted, J. 2017. Effects of once‐weekly semaglutide on appetite, energy intake, control of eating, food preference and body weight in subjects with obesity. Diabetes, Obesity and Metabolism [Internet]. 19(9):1242–1251. doi:10.1111/dom.12932
  4. Davies, M., Pieber, T. R., Hartoft-Nielsen, M.-L., Hansen, O. K. H., Jabbour, S., & Rosenstock, J. 2017. Effect of Oral Semaglutide Compared With Placebo and Subcutaneous Semaglutide on Glycemic Control in Patients With Type 2 Diabetes. Jama [Internet]. 318(15):1460-1470. doi:10.1001/jama.2017.14752
  5. Hausner, H., Karsbøl, J. D., Holst, A. G., Jacobsen, J. B., Wagner, F.-D., Golor, G., & Anderson, T. W. 2017. Effect of Semaglutide on the Pharmacokinetics of Metformin, Warfarin, Atorvastatin and Digoxin in Healthy Subjects. Clinical Pharmacokinetics [Internet]. 56(11):1391–1401. doi:10.1007/s40262-017-0532-6
  6. Knudsen, L. B., & Lau, J. 2019. The Discovery and Development of Liraglutide and Semaglutide. Frontiers in Endocrinology [Internet]. 10. doi:10.3389/fendo.2019.00155
  7. Marso, S. P., Bain, S. C., Consoli, A., Eliaschewitz, F. G., Jódar, E., Leiter, L. A., … Vilsbøll, T. 2016. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. New England Journal of Medicine [Internet]. 375(19):1834–1844. doi:10.1056/nejmoa1607141
  8. Shanik, M. H., Xu, Y., Škrha Jan, Dankner, R., Zick, Y., & Roth, J. 2008. Insulin resistance and hyperinsulinemia. Diabetes Care [Internet]. 31(Supplement_2). doi:10.2337/dc08-s264
  9. Sorli, C., Harashima, S.-I., Tsoukas, G. M., Unger, J., Karsbøl, J. D., Hansen, T., & Bain, S. C. 2017. Efficacy and safety of once-weekly semaglutide monotherapy versus placebo in patients with type 2 diabetes (SUSTAIN 1): a double-blind, randomised, placebo-controlled, parallel-group, multinational, multicentre phase 3a trial. The Lancet Diabetes & Endocrinology [Internet]. 5(4):251–260. doi:10.1016/s2213-8587(17)30013-x
  10. Zinman, B., Aroda, V. R., Buse, J. B., Cariou, B., Harris, S. B., Hoff, S. T., … Araki, E. 2019. Efficacy, Safety, and Tolerability of Oral Semaglutide Versus Placebo Added to Insulin With or Without Metformin in Patients With Type 2 Diabetes: The PIONEER 8 Trial. Diabetes Care [Internet]. 42(12):2262–2271. doi:10.2337/dc19-0898

How climate change will intensify infectious disease

By Shaina Eagle, Global Disease Biology ‘24 & Tammie Tam, Molecular and Medical Microbiology ‘22

Authors’ Note: We decided to partner on this paper after discovering a mutual passion for studying infectious diseases. As editors of a scientific journal and science students, we learn about the effects of climate change on our world regularly. It seemed like a natural progression to explore the effects of climate change on infectious disease.

 

Introduction

A changing climate impacts all living organismsincluding the ones you can’t see. While climate change has made a name for itself through its more visible effects, it is equally affecting a hidden dynamic forceinfectious diseases. Climate change is altering the movement of existing pathogens, fostering the emergence of new pathogens, and in turn, changing host-pathogen interactions. As the level of greenhouse gasses, like CO2, increases, shifts in temperature and precipitation patterns are producing more frequent and intense climate disasters from the raging wildfires burning the West to the floods drowning Southeast Asia [1, 2]. Besides damages from climate disasters, humans are actively destroying habitats and expanding the ecosystem boundaries where humans and the wild interact [4]. As a result, climate change is speeding up biodiversity loss, as zoonotic pathogens are spilling over from one host species to another which is threatening more species, including humans [5]. At the same time, pathogens adapted to warmer, more humid climates are creeping into historically cooler, dryer zones [3]. As sea levels rise, Arctic ice and permafrost thaw and release ancient microbial foes [6]. Consequently, infectious diseases are expected to be on the rise.

By the disease triangle model, an infectious disease event occurs when the right host, pathogen, and environment interact with each other [7]. Climate change is expected to affect all three of these factors. If even one part of the disease triangle is thrown off, the disease cannot take root. However, if complementary components are introduced and complete the disease triangle, the disease can take off and spread. The latter is what researchers are concerned about with how climate change may affect the prevalence and emergence of infectious diseases. For instance, if a new pathogen moves into a region where there is a compatible host and optimal environment, it can devastate an ecosystem unprepared for it. Similarly, if a host is weakened because it becomes unsuitable to the changing environment, an existing pathogen can wreck the current population of the host species and the health of the ecosystem.

While the basis of how infectious diseases arise can be simplified by the disease triangle model, infectious diseases come in a range of different combinations of causative pathogens, host species, transmission methods, and severity of symptoms. For instance, pathogens can be bacterial, viral, parasitic, or fungal and can infect plants, animals, and/or humans. How well they affect their host species, however, depends on the strength of their host’s defense. Once the pathogen is established in a host population, pathogens can be transmitted through many means within and between species, such as: direct contact, aerosolized particles, or through an insect vector acting as the intermediary agent transmitting the pathogen between individuals. Due to all these different factors, climate change will not affect all host-pathogen interactions in the same way, presenting different challenges for scientists to tackle. As a result, researchers are working to predict and understand how different aspects of climate change are affecting different host-pathogen interactions that will impact human society. These aspects include plant pathogens on agriculture, wildlife pathogens in zoonotic events leading to the transmission of disease between animals and humans, and environmental changes on existing human pathogens.

Climate Change Effects on Plant-Pathogen Interactions in Agriculture

Climate change is negatively affecting both ends of plant-pathogen interactions, allowing plant pathogens to pose a significant threat to global food security. While predictive models anticipate an increase in crop yield over the next few decades, they often do not consider the detrimental effects of emerging plant pathogens that may hinder such progress [8]. Plant immunity is expected to be less efficient at higher temperatures, which poses an issue as plants will potentially have to face new pathogens as the planet warms [9]. As temperatures increase with latitude, pathogens adapted for higher temperatures are expected to move poleward, especially those that travel through airborne dispersal or on insect vectors [10].

Climate Change can compromise Plant Immunity

Although plants mainly have nonspecific defense mechanisms capable of fending off a variety of pathogens, climate-change-induced abiotic stressors, such as temperature, may negatively impact a plant’s ability to fight against both existing and novel pathogens. In plants, there are two main lines of immune defense. When plant cell surface receptors detect common features shared by all pathogens known as pathogen-associated molecular patterns (PAMP), PAMP-triggered immunity (PTI) is induced, which initiates a signaling cascade that produces reactive oxygen species to damage the infected cells and upregulates resistance genes to inhibit microbial growth [9, 11]. When receptors within the plant cell detect virulent proteins called effectors, effector-triggered immunity (ETI) is induced, causing resistance genes to be upregulated, and a form of apoptosis called hypersensitive response occurs [9, 11].

The rising temperature and shifting precipitation patterns characteristic of climate change can compromise plant immunity. There have been a few studies on how temperature affects PTI, where elevated temperatures may impair some aspects of PTI but enhance it in other ways [12]. While researchers are still looking into PTI, ETI is better studied and can provide a better idea on how climate change can affect plant immunity. Increasing temperatures and humidity alters ETI-related genes and suppresses the hypersensitive response [9, 12]. For example, tomatoes infected by the fungal pathogen Cladosporium fulvum develop leaf mold, and typically, effectors injected into tomato leaf cells activate ETI which upregulates resistance genes specific against C. fulvum. However, under high temperatures greater than 30oC, ETI is unable to be properly activated [9]. Furthermore, at humidity levels greater than 95 percent, the tomato is not able to respond by ETI and efficiently upregulate its resistance genes against C. fulvum effectors [9]. Therefore, higher temperatures and humidity may find plants to have unfavorable odds against plant pathogens under climate change.

Climate Change can introduce new Plant Pathogens

Armed with a less effective immune system, plants may also have to face new pathogens to which they are not adapted. Typically, plant microbes, including existing plant pathogens, compete against new plant pathogens and prevent them from establishing. However, with climate change, plant microbes face a changing environment which they are not adapted to, allowing new pathogens more suited to the environment to sweep in. For instance, the bacterial pathogen Agrobacterium tumefaciens is responsible for crown gall disease in many plant species like fruit crops, but when exposed to temperatures greater than 32oC, its virulent genes are downregulated, rendering it nonpathogenic [9]. While this seems great for these fruit crops, they now face the threat of new pathogens that can fill roles vacated by native beneficial and pathogenic microbes that can’t survive well in the new environment. Although new pathogens may not be adapted to the plant hosts of the region, it is possible for them to acquire virulent genes from existing pathogens through horizontal gene transfer, the mechanism where bacteria can share pieces of DNA with other bacteria [13]. Meanwhile, plants can’t adapt as quickly and are limited now by an immune system that has adapted to familiar pathogens but not novel pathogens, providing ample opportunity for the new pathogen to proliferate.

Climate Change can Exacerbate Existing Vector-borne Plant Diseases

Since effectiveness of immunity and susceptibility to new pathogens under climate change do vary by plant species, some plants like cassava, which is a starchy root vegetable grown throughout the tropics that provides nutrition for over half a billion people, are quite hardy and resistant to stressors like changing temperature and precipitation levels [14, 15]. Yet, plants, such as cassava, that are susceptible to diseases transmitted by insect vectors still face a different challenge brought about by climate change. For example, cassava is affected by two major pathogens across Africa, cassava mosaic virus and cassava brown streak virus, which are transmitted by the insect vectors, whiteflies and mealybugs, respectively [16]. As temperature increases, the populations of whiteflies and mealybugs boom, leading to the destruction of cassava crop and ultimately resulting in famine and a collapsed economy for communities that rely on the crop for food and income [17]. 

Combatting Effects of Climate Change on Plant-Pathogen Interaction

As illustrated, climate change impacts many aspects of plant-pathogen interactions, many of which are still unknown but it’s certain from current findings that the impact is most likely large. Fortunately, much of the predicted effects of climate change on plant-pathogen interactions have yet to take root, so it’s pertinent to employ techniques to prevent and manage any negative effects that are already in place. Besides cultivating crop strains resistant against specific pathogenic species, humans have a huge hand in staving off diseases in crops through the use of pesticides and fungicides. To manage and prevent disease, crop growers can switch between different fungicides or use multi-site targeting fungicide to minimize the chance of developing resistance among pests and pathogens [18]. Climate change may also affect pesticide and fungicide uptake. As CO2 concentration increases, plants are expected to grow bigger, so more pesticide and fungicide will be necessary for better uptake [18]. Ideally, once these strategies are properly in place, plant pathogens will no longer be a threat to global food security. 

Climate Change and Wildlife Infectious Disease

Besides threatening global food security, climate change is producing more natural disasters that are intensifying the habitat destruction and biodiversity loss that was initiated by human-driven forces such as urban expansion and wildlife trade. This has increased the prevalence and transmission of existing and novel wildlife infectious diseases [19]. Additionally, with increasing temperatures, pathogens are expanding into new territories. As a result of the increasing interaction between humans and wildlife, zoonotic diseases, a subsection of wildlife diseases capable of infecting humans, are expected to increase in frequency and infect humans at a higher rate.  

Climate change is great for ticks and mosquitoes

All pathogens are adapted to living at certain temperatures. For pathogens that have evolved to live in warmer climates, they may find themselves moving northward as the temperature there rises due to climate change. This particularly affects pathogens that are transmitted by arthropod vectors, which have previously been kept at bay by colder winters and lower average temperatures in the global North [25]. Arthropod vectors, such as ticks and mosquitoes, may harbor new diseases that Northern hosts have never encountered before, and consequently do not have immunity to. Blood-sucking vectors transmit diseases between different species by first feeding on an infected host, and then transferring the disease with a bite directly into the bloodstream of a naive host, which can be a human or another animal [26]. As pathogens adapt to the changing global climate, species across the globe will be threatened.

The thermal mismatch hypothesis explains that species adapted to the cold are at high risk from infectious diseases as their habitats warm, and vice versa [20]. The risk of this increases as parasites and other wildlife pathogens are adapting to survive a wide range of environments. The Arctic is one region especially susceptible to fluctuations in temperature and the spread of disease. The Arctic’s temperature is increasing nearly double anywhere else on the planet, and an unusually warm summer in the Arctic would put local species and the humans that rely on them at risk of zoonotic diseases [21]. Encephalitis, a disease that causes inflammation of the brain, is spreading northward into Arctic Russia as temperatures warm and the ticks that carry the disease can survive for longer periods of the year [21]. Similarly, Lyme disease, normally found in climates like those of the upper Midwest or Northeast of the United States, is now reported in areas of the Russian Arctic, due to a tick species better suited to the cold climate [21].

Shorter, warmer winters and longer, drier summers are easier for cold-blooded ticks and mosquitoes to survive. And as temperatures rise globally, vectors’ viable habitat expands, and thus, so does the range of disease, as mosquitoes and ticks will bring vector-borne diseases into previously temperate locations. The ranges of many vector-borne diseases will shift to higher latitudes and altitudes, where they previously were not found or could not survive. Furthermore, the seasons of transmission in historically warmer and more tropical climates will lengthen [22]. Certain aspects of the ticks’ reproduction, such as developmental cycle and egg production, speed up as temperature increases [22]. This is significant because the number of ticks maturing to be capable of spreading disease and further reproducing will increase, and as tick numbers increase, so will the risk of disease.

Increasing temperatures are expected to increase vector abundance as well as their survival. Changes in precipitation rates will also affect the transmission of vector-borne diseases. More rain creates more puddles, which serve as the perfect breeding ground for mosquitoes, while drought will increase the number of containers storing stagnant water, which if not properly stored can also serve as a vector breeding ground.

Zoonotic diseases and spillover

Over time, thousands of bacterial, viral, and fungal pathogens that once circulated within host species spilled over into the human population, causing illness. Increasing interaction between humans and wildlife and the loss of biodiversity characteristic of climate change will put human populations at the risk of increased emergence and transmission of zoonotic diseases.

Zoonotic diseases are those that are transmitted between animals and humans, such as rabies, Lyme disease, and COVID-19. The transmission of zoonotic diseases, zoonotic spillover, is a significant public health concern for humans as nearly 75 percent of emerging infectious diseases [20] originate from wildlife reservoir species. Reservoir species are those through which a disease circulates without killing it off entirely, thus allowing it to spread to humans if direct or indirect cross-species contact occurs. 

The rates of zoonotic spillover are increased in areas where humans live in close vicinity to wildlife. Factors such as deforestation, land-use change, and increasing population density push humans closer and closer to wildlife species’ habitats [23]. These areas, known as boundary zones, are areas where two or more different ecosystems meet. It has long been hypothesized that boundary zones are associated with the emergence and spillover of zoonotic disease, because they support increased contact of humans and wildlife species as well as species that are more likely to transmit zoonotic pathogens. These bridge species are generalist, meaning that they can move through a wider variety of ecosystems and encounter a wider variety of pathogens. This in turn increases the diversity of zoonoses that have the chance to spill over as well as the rate of spillover in and around these ecosystem boundaries [23].

As discussed, areas of high biodiversity, such as boundary zones between ecosystems, are often attributed to the emergence and spread of zoonotic disease. However, decreasing biodiversity has also been acknowledged as increasing the spread of pathogens in human populations. A new study explains that the reason for this apparent contradiction is that species that are more likely to be host species of zoonotic pathogens are more commonly found in areas where humans live [24]. It is the diversity of host species such as bats, rodents, and livestock that influence zoonotic emergence and spillover, rather than total species diversity. With decreasing biodiversity, the species that are left behindsuch as those with small bodies and fast life histories (early maturation, high rates of reproduction, and mortality)are those likely to transmit zoonotic pathogens [24]. There is also a dilution effect, when the buffer of non-reservoir species declines, meaning that the transmission of zoonotic diseases is increased.

Climate Change on Existing Human Pathogens

Besides the downstream effects of plant and wildlife infectious diseases on human society and health, climate change is expected to also directly affect the human population by impacting existing human-pathogen interactions. In the Arctic, ice and permafrost is melting at an unprecedented rate due to rising temperatures, reviving dormant pathogens, such as anthrax and smallpox, and introducing old and unknown human diseases [6]. Warmer water and more frequent storms are also generating outbreaks of water-borne infectious diseases such as cholera [27]. With warmer winters and hotter summers, climate change is affecting seasonal weather patterns and thus driving the prevalence and severity of certain seasonal infectious diseases like the flu [28]. These are just a few examples, as there are many more climate-related environmental changes and human infectious diseases being similarly affected. 

Arctic ice melting and permafrost thawing brings new and familiar threats

Every decade as the ocean’s temperature rises by 0.13oC, the Arctic ice melts by about 13 percent on average, which is thereby accelerating how fast the nearby Arctic permafrost, or frozen soil, is thawing and reviving dormant microbes [29, 30, 31, 6]. From the thawing permafrost, researchers have found novel viruses and bacteria but none so far that can infect humans [6]. For now, scientists are only aware of known human pathogens that may emerge. In 2016, an anthrax outbreak in Siberia has been linked to thawing permafrost releasing hardy anthrax spores. Besides anthrax, scientists are also worried about other known human pathogens, like smallpox, being released. Since the 1970s, the deadly smallpox has been considered eradicated. However, smallpox may still remain on frozen corpses as the virus can withstand freezing conditions [32]. Although scientists have not been able to isolate viable smallpox viruses, they have been able to extract their viral DNA from previously infected frozen corpses [32]. Nonetheless, the thawing permafrost in the Arctic may still contain threats from old and new human pathogens that have yet to be revealed as researchers continue digging into the matter.

Cholera, algal blooms, and changing tides

Besides melting ice, the warming ocean, home to many water-borne pathogens, is changing tidal patterns and intensifying and increasing the frequency of storms. Moreover, warmer water is also promoting algae bloom, which the bacterial causative agent of cholera, Vibrio cholerae, can be found in [33, 34]. As a result, hurricanes, which are becoming stronger due to warming water, are driving V. cholerae to wash up onto shores and coastal cities and contaminate water sources [27, 35]. Since V. cholerae is transmitted through contaminated food and water, hurricanes and algae blooms have both been linked to cholera outbreaks. During infection, V. cholerae proliferates in the human intestine and produces a toxin that causes diarrhea, vomiting, dehydration, a drop in blood pressure, and, if left untreated, can lead to death within 18 hours [36]. In communities that lack a stable health system, a treatable disease such as cholera may end up fatal when hospitals and clinics are overwhelmed by multiple coinciding disease outbreaks such as COVID-19 [37]. 

Influenza seasons become more severe

On a more global scale, the effects of seasonal changes is expected to worsen the severity of the flu season. Influenza is commonly known for its mild nature and annual appearance in the winter. While a warmer winter may create a milder flu season by making transmission of the virus less effective and thus affecting less individuals, more individuals are set to become susceptible to the flu the next season due to the lack of acquired immunity during the previous season, allowing the following winters to see more severe and earlier flu seasons [28]. Interestingly, during the warmest winters experienced, the 2017-18 flu season had the highest influenza mortality rates in recent history [38]. To account for this, scientists found that climate change is also affecting rapid weather variability in the fall preceding flu season, which is correlated with severe flu seasons [38]. Although COVID-19 restrictions in the past year have led to a dramatic decline in flu cases during the flu season, flu cases are picking back up once again, so the public must continue to remain vigilant and vaccinated if they want to avoid future severe flu seasons [39]. 

Conclusion

There is no more obvious of an example of the interactions between climate change and infectious disease than the last two years. Questions still remain regarding the origin and circulation of SARS-CoV-2 leading up to its explosion into a global pandemic [40], but a World Health Organization investigation distinguished bats as the virus’ reservoir host and identified a wet market in Wuhan as a probable center of outbreak [40]. Many of the underlying causes of climate change, such as deforestation and loss of habitat, are also linked to the emergence of infectious diseases. Researchers suspect the outbreak of COVID-19 could be connected to deforesting the tropics, changing agricultural practices, and increasing contact between reservoir and intermediate species, as well as wild animals and humans [41].

With no corner of the globe untouched by COVID-19, a clear and thorough understanding of how climate change and infectious disease affect each other is necessary for mitigating this pandemic and preventing the next one. Ultimately, any action taken towards reducing climate change will likely have a positive impact on reducing the risks of emerging infectious diseases. Recognizing that climate change and global health are interconnected is necessary for avoiding any future disastrous consequences.

Infectious disease emerges at the intersection of host, pathogen, and environment—and climate change is interacting with all three. This presents a multifaceted challenge, as a solution for plant immunity to fungal pathogens likely will not be the same as a solution for the increasing transmission of vector-borne wildlife viruses. Climate change, from rising greenhouse gasses to biodiversity loss, is dredging up new diseases and making existing ones worse. As host susceptibility, pathogen survival, and environment structures change, it would not be surprising to see more global pandemics in the future.

 

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