The Future of GLP-1 Pills: Paradigm Shift in Obesity Management

Nelson Advisors
2 days ago
18 min read

Executive Summary

The landscape of obesity and cardiometabolic disease management is on the cusp of a profound transformation, driven by the emergence of a new generation of oral therapies. For years, the remarkable efficacy of glucagon-like peptide-1 (GLP-1) receptor agonists for weight loss and glycemic control has been inextricably linked to injectable formulations, creating a market dominated by medications like semaglutide (Wegovy) and tirzepatide (Zepbound).

However, the imminent approval of highly efficacious oral pills promises to democratise access, disrupt established supply chains, and trigger cascading effects across the entire healthcare ecosystem and beyond. This report provides a comprehensive, multi-faceted analysis of the clinical, economic, and societal forces shaping this future.

Key Findings and Strategic Implications

The analysis reveals that the next wave of oral GLP-1s, exemplified by Eli Lilly's orforglipron and Novo Nordisk's high-dose oral semaglutide, is poised to rival the efficacy of their injectable counterparts. Clinical trial data demonstrates that these investigational pills can achieve average weight loss percentages and cardiometabolic benefits consistent with established injectable therapies. This breakthrough is significant because it directly addresses several critical barriers to widespread adoption: the aversion to needles, the complex logistics of cold-chain distribution, and the limitations of a global supply chain designed for injectable pens.

The GLP-1 market is projected to expand dramatically, with global sales potentially reaching over $139 billion by 2030. The introduction of more accessible and scalable oral options could serve as a primary catalyst for this growth. However, this trajectory is not without complexity. The report identifies that the financial burden remains a central dilemma for payers and employers, who must reconcile the immense short-term budget impact of widespread coverage with the substantial long-term health cost savings from preventing obesity-related comorbidities. Furthermore, the rise of oral pills, while promising, introduces new challenges related to patient adherence and necessitates a shift in patient support strategies to manage daily dosing and common gastrointestinal side effects.

Finally, the report finds that the influence of these drugs extends far beyond the pharmaceutical sector. The pill’s widespread availability is poised to reframe obesity from a personal failing to a chronic, treatable disease, potentially reducing societal stigma. Simultaneously, it is already beginning to alter consumer behavior and disrupt the food and beverage industry, which is adapting to a new consumer preference for smaller portions and nutrient-dense foods. The future of GLP-1 pills is not merely a story of new drugs; it is a story of a transformative medical innovation that will redefine the treatment of chronic disease and reshape fundamental aspects of public health and economic activity.

The Current Landscape: From Peptide Injections to a Single Pill

Incretin Hormones and the Mechanism of Action

To comprehend the transformative potential of GLP-1 pills, it is essential to first understand the foundational biology behind this drug class. The human body naturally produces hormones known as incretins, with glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) being the most prominent. These hormones are secreted from the gut in response to food intake and play a crucial role in regulating appetite, blood sugar, and fat storage. The physiological effects are multifaceted and synergistic. GLP-1, for instance, stimulates insulin production from the pancreas in a glucose-dependent manner, meaning it only enhances insulin secretion when blood sugar levels are high. Concurrently, it reduces the release of glucagon from the liver, which prevents the liver from producing excess sugar.

Beyond their primary role in glycemic control, GLP-1s also exert a powerful effect on the central nervous system and the gastrointestinal tract. They slow gastric emptying, which delays food absorption and helps individuals feel fuller for longer after a meal. This mechanism, coupled with the activation of GLP-1 receptors in the hypothalamus, helps to suppress sensations of hunger, alleviate food cravings, and enhance feelings of satiety. The cumulative effect of these actions—on insulin, glucagon, gastric emptying, and appetite—is what drives the significant weight loss observed with these medications.

However, the native GLP-1 hormone has a very short half-life, being rapidly metabolized by the enzyme dipeptidyl peptidase 4 (DPP-4) within minutes. This inherent instability explains why the first generations of GLP-1 receptor agonists were predominantly administered as subcutaneous injections. The molecular size and structure of these peptide-based drugs made it challenging for them to be absorbed intact through the gastrointestinal tract, leading to a long-standing reliance on injectables to ensure systemic delivery and a prolonged therapeutic effect.

The Injectable Dominance: Approved Therapies for Weight Loss

The current market for GLP-1 weight loss medications is defined by its injectable form factors. Three drugs are currently FDA-approved for weight management: liraglutide (Saxenda), semaglutide (Wegovy) and the dual GLP-1/GIP receptor agonist tirzepatide (Zepbound). Each of these has established a benchmark for clinical efficacy. Liraglutide, for instance, has been associated with an average weight loss of approximately 8%.

Semaglutide, a long-acting GLP-1 receptor agonist administered once a week, has been shown to produce up to a 14.9% average weight loss. However, the current leader in efficacy is tirzepatide, which acts on both GLP-1 and GIP receptors. This dual-agonist mechanism has yielded the most significant weight loss results to date, with clinical trials demonstrating an average weight reduction of up to 22.5%. These established efficacy profiles set a high bar for any new oral therapy seeking to enter the market.

The First Oral GLP-1: Rybelsus and its Role

While the injectable forms dominate the weight loss landscape, Rybelsus (oral semaglutide) holds the unique distinction of being the first and, for a time, only oral GLP-1 drug on the market. Rybelsus is a daily oral tablet, but its FDA approval is strictly limited to the treatment of Type 2 diabetes to help control blood sugar levels, not for weight loss. Despite this, its ability to promote weight loss as a side effect has led to widespread off-label prescribing for that indication.

The development of Rybelsus was a significant scientific achievement, but its formulation inherited the inherent challenges of delivering a peptide orally. To be effective, it must be taken on an empty stomach with a small amount of water at least 30 minutes before the first meal, drink, or other medication of the day to ensure adequate absorption. Due to its lower bioavailability, which is approximately 1% compared to its injectable counterparts, a higher daily dose of 7 mg or 14 mg is required to achieve a therapeutic effect similar to the weekly injectable dose of 1 mg to 2 m.

This daily dosing schedule and the complex administration rules have made long-term patient adherence a significant challenge. The Rybelsus experience, while pioneering, underscored that a truly transformative oral GLP-1 for weight loss would need to overcome not just the needle barrier but also the complex dosing protocols that undermine patient convenience and adherence. This created a clear market opportunity for a new generation of oral pills that could offer the simplicity of a daily tablet without the burdensome restrictions of a peptide-based formulation.

The New Wave: Oral Therapies in the Pipeline

Eli Lilly's Orforglipron: The Non-Peptide Game-Changer

Eli Lilly's orforglipron represents a new frontier in the development of oral GLP-1 therapies. It is an investigational, once-daily, small molecule, non-peptide oral GLP-1 receptor agonist. Its designation as a "small molecule" is a critical distinction, as it allows for a different approach to oral bioavailability, a key challenge for peptide-based drugs like Rybelsus. A core advantage of orforglipron is its convenience; unlike Rybelsus, it can be taken at any time of the day "without food and water restrictions".

The efficacy of orforglipron has been demonstrated across multiple Phase 3 clinical trials, with data from the ATTAIN and ACHIEVE programs showing results that are consistent with injectable GLP-1 medicines. In the ATTAIN-1 trial, which evaluated the drug in adults with obesity, the highest dose (36 mg) led to a significant average weight loss of 12.4% (27.3 lbs) over 72 weeks. A related trial, ATTAIN-2, which studied a population with obesity and Type 2 diabetes, demonstrated a 10.5% (22.9 lbs) average weight loss on the highest dose over the same period, along with a meaningful A1C reduction of 1.8%.

Furthermore, a diabetes-focused trial, ACHIEVE-1, showed that the drug produced a 7.6% weight reduction and a 1.6% A1C reduction at 40 weeks. Across all these studies, the overall safety and tolerability profile of orforglipron was found to be consistent with the established GLP-1 class, with the most common side effects being gastrointestinal-related and generally mild to moderate in severity.

Given these compelling results, Eli Lilly has announced plans to submit orforglipron for regulatory review for obesity in 2025, with a submission for Type 2 diabetes anticipated in 2026. This strategic move positions orforglipron as a direct oral competitor to Novo Nordisk's injectable Wegovy and Zepbound, and also as a potential replacement for the less convenient Rybelsus.

Novo Nordisk's High-Dose Oral Semaglutide

In a parallel effort to maintain its market leadership, Novo Nordisk is also developing a high-dose (50 mg) oral semaglutide specifically for weight management, a substantial increase from the 14 mg maximum dose of Rybelsus. The OASIS 1 Phase 3 trial, a 68-week study, demonstrated the efficacy of this new formulation. Results showed that patients taking the 50 mg dose achieved a clinically meaningful weight loss of 15.1%, compared to a 2.4% reduction with placebo. This result is highly competitive and effectively places the efficacy of this pill on par with its injectable counterpart, Wegovy, which has an average weight loss of up to 14.9%. Novo Nordisk submitted this investigational obesity pill for FDA approval in April 2025, ahead of Lilly' planned submission for orforglipron for obesity.

The Small Molecule Advantage and The Next Frontier

The development of small molecule oral GLP-1s like orforglipron marks a significant strategic shift in the competitive landscape. The small-molecule nature of orforglipron enables it to be more readily manufactured at a large scale, potentially alleviating the supply chain bottlenecks and shortages that have plagued the injectable GLP-1 market. This scalability offers the potential to launch the drug globally without the supply constraints that have limited access to injectables. The convenience of a once-daily pill without food and water restrictions directly targets the primary reasons for patient reluctance with both Rybelsus and the injectable pen. The competitive calculus is no longer simply about which drug is the most effective; it is about which drug can deliver a comparable level of efficacy with the most convenience and accessibility.

This strategic evolution is further complicated by the emergence of next-generation therapies with even greater potential. Eli Lilly's retatrutide, a triple agonist targeting GLP-1, GIP, and glucagon receptors, has shown even higher efficacy in early trials, with weight loss of up to 24.2% at 48 weeks. Similarly, Amgen's MariTide is a monoclonal antibody with the potential for once-monthly dosing, and its Phase 2 trials demonstrated up to 20% weight loss. These developments raise the bar for what is considered a landmark result and suggest that the long-term competition will be fought on multiple fronts, efficacy, delivery mechanism, and dosing frequency, with the pill serving as a foundational and highly strategic entry point for mass market penetration.

Clinical Efficacy and Patient Experience: A Comparative Analysis

Head-to-Head: Oral vs. Injectable Efficacy

The advent of highly effective oral GLP-1s presents a compelling alternative to established injectable therapies. A direct comparison of the clinical data reveals that the new oral formulations are poised to deliver a level of efficacy that is consistent with or comparable to their injectable counterparts, effectively closing a long-standing gap in the market.

For instance, the OASIS 1 Phase 3 trial showed that Novo Nordisk's investigational 50 mg oral semaglutide led to a 15.1% weight loss, a result that rivals the 14.9% average weight loss seen with injectable Wegovy.Similarly, Eli Lilly's orforglipron, a non-peptide oral agonist, demonstrated an average weight loss of 12.4% in the ATTAIN-1 trial, a result considered clinically meaningful by experts. While Rybelsus, the first-generation oral semaglutide, has a lower therapeutic dose and is not indicated for weight loss, a clinical study found that it produced weight loss of 5.9 kg at 6 months, a result not statistically different from the 6.5 kg loss seen with injectable semaglutide in a real-world setting.

Furthermore, the efficacy of oral formulations extends to cardiometabolic benefits. Oral semaglutide has been shown to be "nearly equally effective" in achieving and maintaining glycemic targets for Type 2 diabetes as its injectable version. A landmark study demonstrated that oral semaglutide reduced the risk of cardiovascular death, heart attack, or stroke by 14% over four years, a result in line with the outcomes of injectable GLP-1 trials. In addition, orforglipron has also shown clinically meaningful benefits on cardiovascular risk factors such as non-HDL cholesterol, triglycerides, and systolic blood pressure.

The following table provides a comprehensive overview of the comparative efficacy data for key oral and injectable GLP-1 and multi-agonist therapies:

Drug (Brand/Active Ingredient)	Formulation	Frequency	Average Weight Loss (%)	Average Weight Loss (lbs)	HbA1c Reduction (%)	Source/Trial Name
Rybelsus (Oral Semaglutide)	Oral tablet	Daily	5.9 kg (~13 lbs)	-	-1.4%	Real-world study
Ozempic (Inj. Semaglutide)	Injectable	Weekly	3 kg (~6.6 lbs)	-	-	Meta-analysis
Wegovy (Inj. Semaglutide)	Injectable	Weekly	14.9%	-	-	Clinical data
Orforglipron (Investigational)	Oral pill	Daily	12.4%	27.3 lbs	-	ATTAIN-1
Orforglipron (Investigational)	Oral pill	Daily	10.5%	22.9 lbs	-1.8%	ATTAIN-2
Oral Semaglutide 50mg (Investigational)	Oral tablet	Daily	15.1%	-	-	OASIS 1
Zepbound (Inj. Tirzepatide)	Injectable	Weekly	22.5%	-	-	Clinical data
Saxenda (Inj. Liraglutide)	Injectable	Daily	~8%	-	-	Clinical data

Side Effects and Tolerability

A primary consideration for patient experience and long-term adherence is the side effect profile of these medications. The clinical data indicates that the most common adverse events are remarkably consistent across both oral and injectable GLP-1 formulations: they are predominantly gastrointestinal symptoms, including nausea, vomiting, diarrhoea and constipation. In clinical trials for injectable Wegovy, 44% of patients reported nausea, a rate that is notably high. Similarly, Phase 3 trials for orforglipron showed that nausea was the most common adverse event, with reported rates as high as 36.4% in one trial. Other common side effects include abdominal pain, headaches, and fatigue. While serious but rare side effects such as pancreatitis, gallbladder disorders, and acute kidney injury can occur, the vast majority of patients experience mild to moderate GI symptoms that tend to diminish over time as the body adjusts to the medication.

The Economic and Market Impact of Oral Formulations

Market Size and Growth Forecasts

The GLP-1 drug class has already achieved blockbuster status, and forecasts suggest its growth will be nothing short of explosive. The market was valued at $53.46 Billion in 2024 and is projected to reach $156.71 Billion by 2030, representing a compound annual growth rate (CAGR) of 17.46%. Another analysis projects global sales to reach as high as $139 Billion by 2030, a significant increase from an earlier forecast. These figures underscore the immense commercial potential of this drug class, which is being driven by unprecedented efficacy in weight reduction, glycemic control, and a broadening range of indications.

The market is currently dominated by a duopoly of Novo Nordisk and Eli Lilly, with the latter recently surpassing Novo Nordisk to capture an estimated 57% of the market in the second quarter of 2025. The introduction of oral options is seen as a "game-changer" for market expansion, with the potential to attract a new patient population that has been reluctant to use injectables. Oral pills are also generally cheaper to produce, which could facilitate broader global access and further accelerate market penetration. The competitive environment is intensifying, with over 60 companies and 65+ GLP-1 agonists in various stages of development, all vying for a share of this rapidly expanding market.

The Cost Conundrum: Payers, Employers, and Patients

Despite the immense demand and clinical value, the high cost of GLP-1 drugs remains a central barrier to access. List prices can exceed $1,000 a month, placing a significant financial burden on patients without insurance. While manufacturers offer savings programs and some patients with private or employer-covered insurance may pay as little as $10, the majority of people do not pay the full list price, but still face substantial out-of-pocket costs. Over half of adults taking these drugs reported having difficulty paying for them, even when they had some form of coverage.

This financial challenge is even more pronounced for payers and employers who bear the primary cost of coverage. A central dilemma exists between the significant upfront costs and the uncertain, long-term health benefits. The analysis shows that while GLP-1s can deliver impressive long-term health improvements and prevent thousands of cases of diabetes and cardiovascular disease, their current prices far exceed standard benchmarks for cost-effectiveness. For instance, one study found that tirzepatide would require a 30% price reduction to meet cost-effectiveness thresholds, while semaglutide would need to cost 80% less. The short-term budget impact is immense, with one state projecting to spend $1.3 Billion on GLP-1 drugs in a single year.

The Compounder Problem and Regulatory Hurdles

The high cost and persistent supply shortages of FDA-approved GLP-1s have created a robust black market for compounded and unapproved versions of these medications. The FDA has issued strong warnings against these unapproved versions, citing a lack of review for safety and efficacy. The agency has received hundreds of adverse event reports associated with compounded semaglutide and tirzepatide, including instances requiring hospitalisation. These unapproved products may be counterfeit, contain incorrect or harmful ingredients, or lack the proper dosage, posing a serious health risk to consumers.

The widespread availability of a highly efficacious, scalable, and potentially lower-cost oral pill serves a strategic purpose beyond simply expanding the market. By providing a convenient and more accessible alternative, the pill could effectively marginalise the black market for compounded and unapproved drugs. This would allow pharmaceutical companies to regain control of the supply chain, re-establish safety and quality standards, and provide a legitimate, regulated alternative for a patient population that is otherwise forced to seek out risky, unapproved products. The pill, therefore, is not just a commercial product but a strategic asset in the broader effort to ensure patient safety and maintain regulatory control of a transformative drug class.

Broader Societal and Public Health Implications

Reframing Obesity as a Chronic Disease

The widespread adoption of GLP-1s, particularly in a convenient pill form, has the potential to fundamentally reframe the public perception of obesity. For decades, obesity has been widely viewed as a matter of personal responsibility or a moral failing, driven by a lack of willpower to eat less and exercise more. This narrative has contributed to significant external and internalised stigma, leading to discrimination in employment, education, and healthcare.

However, the medical community increasingly recognises obesity as a complex, chronic disease with multiple neuroendocrine pathways and hormonal imbalances that affect hunger, satiety, and metabolism. The efficacy of GLP-1s in quieting the "food noise", the intrusive, anxiety-provoking thoughts about food that many patients experience, provides powerful physiological evidence that obesity is not simply a behavioural issue. The availability of a simple, effective oral pill validates the medical community's view that obesity is a chronic condition that requires long-term, pharmacological management, much like hypertension or hyperlipidemia.This medical validation can help reduce the stigma that has long been a barrier to seeking and receiving care, empowering patients to view their condition as a treatable disease rather than a personal failure.

Ripple Effects on the Food and Beverage Industry

The dramatic reduction in appetite and food intake among GLP-1 users is already sending ripple effects through the food and beverage industry. Early evidence suggests that consumers on these medications spend significantly less money on groceries and shift their purchasing habits away from snacks, alcohol, and carbohydrates. This change in consumer behaviour is not just a passing trend; it reflects a fundamental change in the body's neuroendocrine signalling and a shift in food preferences. The industry has begun to take notice. Some restaurants are reviewing their menus and portion sizes, while brands are developing new products or adding "GLP-1 friendly" labels that highlight attributes such as high protein and fibre. The long-term impact on agriculture is also being considered, with some experts suggesting that slowing food demand may require a greater focus on nutritionally dense foods rather than simply production volume. The introduction of widely accessible oral pills could accelerate this transformation, compelling the industry to pivot its strategies to align with the evolving dietary needs and preferences of a large and growing segment of the population.

Beyond Weight Loss: Ancillary Health Benefits

While the spotlight on GLP-1s has largely been on their weight loss capabilities, their proven benefits extend far beyond cosmetic changes. A growing body of evidence demonstrates their protective effects against a wide range of chronic diseases. GLP-1s have been shown to significantly reduce cardiovascular events and mortality, with a meta-analysis from 2024 confirming that the odds of major adverse cardiac events and all-cause mortality were reduced in patients on these drugs. Notably, the SOUL trial demonstrated that oral semaglutide reduced the composite risk of cardiovascular death, heart attack, or stroke by 14% over a four-year period, proving that the benefits of the class are not exclusive to injectables.

Furthermore, GLP-1s are demonstrating a broader therapeutic potential. The FDA has already approved the use of semaglutide for chronic kidney disease in adults with Type 2 diabetes and Zepbound for moderate to severe obstructive sleep apnea in adults with obesity. These drugs have also shown benefits in improving kidney function and treating conditions like metabolic dysfunction-associated steatohepatitis (MASH), formerly known as NAFLD. Researchers are also exploring their potential applications in neurodegenerative diseases like Alzheimer's and Parkinson's, and even for addiction management, which could further broaden their utility and drive demand.

These ancillary benefits reshape the framework for how these drugs are evaluated. Rather than being seen as a luxury or a cosmetic intervention, their ability to prevent and manage costly comorbidities positions them as a strategic investment in long-term public health. For payers and employers, this shifts the conversation from a question of how to afford the high short-term budget impact to a recognition that these drugs can generate significant long-term savings by reducing the incidence of expensive, obesity-related health conditions. The pill's potential for lower cost and wider access could accelerate this shift in perspective, making the economic case for broad coverage even more compelling.

Future Outlook and Recommendations

Key Drivers for Future Growth

The future of GLP-1 pills for weight loss is poised for exponential growth, driven by a confluence of powerful factors. The most significant of these is the convenience of oral administration, which directly addresses the major psychological barrier of needle aversion that has prevented millions of patients from accessing these life-changing therapies. The next-generation pills, like orforglipron, further enhance this convenience by removing the complex food and water restrictions associated with first-generation oral therapies.

Secondly, the potential for lower manufacturing costs and increased scalability of small-molecule oral pills stands to resolve the persistent supply chain issues that have plagued the GLP-1 market. This scalability could enable a much broader and more rapid global launch, ensuring that demand can be met. Third, the

proven efficacy of oral pills on par with their injectable counterparts removes any potential trade-off between convenience and clinical outcome. Patients will soon have a choice between a daily pill and a weekly injection without compromising on weight loss or cardiometabolic benefits. Finally, the

expanding indications for these drugs beyond diabetes and obesity into areas like heart failure, MASH, and even neurodegenerative disorders will increase their addressable patient population and further entrench their role as a cornerstone of chronic disease management.

Remaining Challenges and Unanswered Questions

Despite the promising outlook, several challenges and unresolved questions remain. The long-term safety profile of these medications is still being studied, particularly regarding their effects on the pancreas and other organs. While short-term data is reassuring, the implications of decades-long use are not yet fully understood. Additionally, whether the real-world adherence for a daily pill will be superior to a weekly injection remains an open question. The high rates of gastrointestinal side effects could still pose a significant challenge to long-term compliance, regardless of the administration route.

Perhaps the most significant challenge is the development of sustainable coverage models. Given the high cost and the medical consensus that these drugs must be used indefinitely to maintain their benefits, payers and employers face a central conundrum. How can they create economically viable, long-term coverage plans for a drug that millions may need for life? This is a question that will require innovative solutions and a re-evaluation of traditional drug coverage strategies.

Recommendations

Based on this analysis, the following recommendations are offered for key stakeholders in the healthcare ecosystem:

For Pharmaceutical Companies: The primary focus should be on demonstrating the long-term health-economic value of oral therapies to secure favorable and comprehensive coverage from payers. This requires shifting the narrative from a short-term budget impact to a long-term investment that prevents costly comorbidities. Companies should also invest in patient support programs that are specifically tailored to the nuances of oral medication, focusing on managing gastrointestinal side effects and reinforcing the importance of long-term adherence.
For Healthcare Providers: The widespread availability of oral GLP-1s provides an opportunity to expand access to a wider range of patients. Providers should embrace a holistic approach, combining medication with essential lifestyle interventions like a balanced diet and regular exercise to maximise weight loss, preserve muscle mass, and improve overall health. Patient education is paramount, ensuring that individuals understand the potential side effects and the need for long-term use to maintain benefits.
For Payers and Employers: It is recommended to shift the framework from a short-term budget constraint to a long-term investment in employee and member health. The use of strategic medical management tools, such as prior authorisation and step therapy, can ensure responsible prescribing and help guide patients toward effective, long-term solutions while controlling costs. Investing in complementary programs that support lifestyle changes can also help improve health outcomes and potentially mitigate some of the long-term cost burden.

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