Weekly DPP-4 Inhibitors: ‘Trelagliptin & Omarigliptin’, Overlooked or Underrated? A Potential Game Changer for Diabetes Care in Developing Countries

Author: Dr. Farhat Naz

“Trelagliptin and Omarigliptin” What revolution these novel once weekly DPP-4 inhibitors can bring to diabetes management?

Trelagliptin and Omarigliptin are exciting developments in diabetes management, representing a significant advancement in the class of DPP-4 inhibitors. These medications are unique. They need to be taken only once a week. This is unlike traditional DPP-4 inhibitors like Sitagliptin or Vildagliptin that require daily dosing. This innovative dosing schedule offers several potential benefits and revolutionary implications for the management of type 2 diabetes:

1. Improved Patient Compliance

Simplified Regimen: Once weekly dosing reduces the pill burden, making easier for patients to adhere to their medication schedule

Reduced Forgetfulness: Patients are less prone to miss doses, which is particularly beneficial for those managing multiple medications or co-morbidities.

2. Enhanced Glycemic Control

Steady Efficacy: These drugs maintain consistent DPP-4 inhibition over a week, helping to stabilize glucose levels without daily fluctuations

Comparable Potency: Clinical trials suggest that their efficacy in reducing HbAlc is comparable to daily DPP- inhibitors. This makes them an equally effective choice.

3. Potential for Better Quality of Life

Convenience: A weekly routine aligns with lifestyle preferences, particularly for active individuals or elderly patients who struggle with daily regimens

Fewer Dosage Adjustments: Simplified dosing minimizes the need for frequent changes, reducing healthcare visits and enhancing patient satisfaction

4. Lower Risk of Hypoglycemia

Similar to other DPP-4 inhibitors, these weekly options have a low risk of causing hypoglycemia. This risk is especially low when they are used as monotherapy or combined with agents like Metformin.

5. Market Evolution

Broader Adoption: Weekly dosing convenience can lead more patients to choose DPP-4 inhibitors over other classes like Sulfonylureas or Insulin. This is especially true in early-stage diabetes.

Cost-Effectiveness: Long-term savings result from improved compliance and reduced complications due to consistent glycemic control.

6. Challenges to Address

Safety Data: Long-term safety data for once-weekly agents is still being collected. The goal is to match the robust profiles of their daily counterparts.

Individualized Therapy: They are not ideal for all patients, especially those requiring rapid dose titration.

Trelagliptin and Omarigliptin hold the potential to revolutionize diabetes care. They can improve adherence, simplify management and enhance patient outcomes. These benefits make them an exciting addition to the diabetes therapeutic arsenal, particularly for patients prioritizing convenience and stability.

HOW Weekly Anti diabetic Medications ARE Revolutionizing Diabetes ManagemenT?

Weekly anti diabetic medications have been introduced. Particularly notable are the once-weekly DPP-4 inhibitors like Trelagliptin and Omarigliptin. The GLP-1 receptor agonists such as Dulaglutide and Semaglutide also stand out. This marks a turning point in diabetes management. These novel therapies offer improved compliance and potential clinical benefits. However, their adoption raises questions about cost and availability. This is especially concerning in resource-limited setting.

Q1: How Do Weekly Anti diabetics Work?

Mechanism of Action

DPP-4 Inhibitors (e.g., Omarigliptin, Trelagliptin):

These inhibit the enzyme dipeptidyl peptidase-4, which degrades incretin hormones like GLP-1. By prolonging incretin activity, they enhance insulin secretion and suppress glucagon release, stabilizing post-meal blood glucose levels.

GLP-1 Receptor Agonists (e.g., Dulaglutide, Semaglutide):

These mimic the incretin hormone GLP-1. They stimulate insulin secretion and suppress glucagon. Additionally, they slow gastric emptying and promote satiety. This combination leads to weight loss benefits.

Q2. Are Weekly Anti-diabetics as Effective as Daily Therapies?

Efficacy Comparison

• Weekly GLP-1 Agonists:

HbA1c reduction: 0.8-1.5%

Additional benefits: Significant weight loss (~3-4 kg on average) and cardiovascular protection.

Drawbacks: Injectable format and potential side effects like nausea.

• Weekly DPP-4 Inhibitors:

HbA1c reduction: 0.5-1% (comparable to daily DPP-4 inhibitors).

• Weight neutral but lower efficacy compared to GLP-1 agonists.
• Advantage: Oral administration, better tolerability.

Debate Point:

While GLP-1 agonists are more potent, their injectability and side effect profile may deter some patients. On the other hand, weekly DPP-4 inhibitors offer a gentler, non-invasive alternative, ideal for those prioritizing simplicity over maximum efficacy.

Q4: How Do Weekly Therapies Compare in Cost?

Cost Analysis

GLP-1 Agonists: Typically $850-$1,200 per month, making them less accessible in low-income settings.

DPP-4 Inhibitors: Estimated at $500-$600 per month (based on daily options like Sitagliptin), potentially more affordable than GLP-1 agonists.

Debate Point:

The higher cost of GLP-1 agonists reflects their additional benefits (weight loss, cardiovascular protection). For third-world countries, the affordability of DPP-4 inhibitors makes them a more realistic option, despite their comparatively modest efficacy.

Q5: Are These Medications feasible in Third-World Countries?

Challenges:

1. Affordability: Limited healthcare budgets often prioritize more affordable generic medications.
2. Infrastructure: Injectable GLP-1 agonists require proper storage and administration training. They are marketed in prefilled injector pens. They are administered subcutaneously and require healthcare monitoring.
3. Healthcare Access: Long-term treatment plans can be disrupted due to inconsistent medication supply.

Opportunities:

• DPP-4 Inhibitors: Oral, weekly regimens offer a practical and scalable solution for resource-limited settings.
• Policy Changes: Subsidies, generic versions, and public-private partnership can improve access to these therapies.

The Way Forward

The advent of weekly anti-diabetic medications represent a paradigm shift in diabetes care. For developed nations, GLP-1 receptor agonists provide unmatched efficacy and additional benefits, making them a first-line choice for many. In contrast, weekly DPP-4 inhibitors offer convenience and tolerability. They have also shown better safety profile in renal impairment. There is also lesser risk of hypoglycemia compared to GLP 1 agonists. They can be a preferable alternative for elderly and countries with underdeveloped health infrastructure. They are affordable, making them ideal for lower-income regions.

what is the mechanism of action of weekly anti diabetic drugs?

Mechanism of Action: DPP-4 Inhibitors vs. GLP-1 Agonists

1. What Are Incretins?

Incretins are a group of hormones. They include primarily GLP-1 (Glucagon-like peptide-1) and GIP (Glucose-dependent insulinotropic peptide). The intestines secrete these hormones in response to food intake.

These hormones:

Stimulate insulin secretion in a glucose-dependent manner.

Inhibit glucagon release, which reduces glucose production by the liver.

Slow gastric emptying and promote satiety.

Incretins have a short half-life due to rapid degradation by the enzyme DPP-4 (Dipeptidyl Peptidase-4).

2. DPP-4 Inhibitors: Mechanism of Action

• DPP-4 inhibitors (e.g., Sitagliptin, Omarigliptin) block the activity of the DPP- 4 enzyme, preventing the breakdown of incretins.
• This leads to increased levels of active GLP-1 and GIP, prolonging their effect.

The result is enhanced insulin secretion, reduced glucagon secretion, and better postprandial glucose control.

• They are oral medications and are weight-neutral.

GLP-1 Receptor Agonists: Mechanism of Action

• GLP-1 receptor agonists (e.g., Semaglutide, Dulaglutide) mimic the action of endogenous GLP-1 by directly activating the GLP-1 receptor.
• They provide the same benefits as incretins but at supra physiologic levels, leading to stronger effects:

Substantial insulin secretion stimulation.

Marked glucagon suppression.

Delayed gastric emptying.

Appetite suppression, which promotes weight loss

These are administered via injection (except oral daily Semaglutide).

ARE WEEKLY DPP-4 INHIBITORS OVERLOOKED?

In developing countries, DPP-4 inhibitors are generally more practical due to their affordability and oral formulation.

Argument 1: DPP-4 Inhibitors Are Overlooked

1. Efficacy Bias:

DPP-4 inhibitors are often seen as less effective compared to GLP-1 receptor agonists and SGLT2 inhibitors. Their modest HbA1c reduction (0.5-1%) might not impress clinicians aiming for aggressive glycemic control.

GLP-1 receptor agonists, with additional benefits like weight loss and cardiovascular protection, overshadow DPP-4 inhibitors in guidelines and prescribing preferences.

2. Lack of Headlines:

GLP-1 receptor agonists like Semaglutide (OZEMPIC)dominate the conversation with bold claims like “game-changers” for diabetes, obesity, and cardiovascular health. DPP-4 inhibitors rarely feature in such headlines, making them seem less innovative.

3. Marketing and Awareness:

Pharmaceutical companies invest heavily in promoting newer drug classes. DPP-4 inhibitors have been around longer. Thus, weekly DPP4 inhibitors received lesser attention from both the medical community and the media.

4. Misconceptions:

• They are sometimes misperceived as “just oral options” when GLP-1 agonists can also be oral (e.g., oral Semaglutide). This comparison diminishes the perceived uniqueness of DPP-4 inhibitors.

Why DPP-4 Inhibitors Deserve More Recognition?

1. Unique Advantages:

Oral Convenience: Unlike injectable GLP-1 agonists, DPP-4 inhibitors are oral medications (e.g., Sitagliptin, Omarigliptin). This makes them an attractive option for patients who fear needles or have difficulty adhering to injectable regimens.

2. Weight Neutrality: While GLP-1 agonists induce weight loss, some patients prefer weight neutrality, especially if weight loss is undesirable.

3. Tolerability: They have an excellent safety profile. They cause fewer gastrointestinal side effects compared to GLP-1 agonists. This makes them suitable for patients sensitive to medication side effects.

4.Cost-Effectiveness:

They are more affordable than GLP-1 receptor agonists. This makes them an accessible choice for low and middle-income countries. They are also suitable for patients with financial constraints

5. Broad Suitability:

They are suitable for a wide range of patients. This includes the elderly and those with renal impairment. Many other medications are contraindicated or require dose adjustments in these cases.

In the context of global diabetes care, DPP-4 inhibitors offer a pragmatic and effective option. They deserve a more prominent place in the treatment arsenal, especially for low-resource settings. The medical community must recognize their value and ensure they are not overlooked midst the buzz surrounding newer therapies.

WHICH COUNTRIES HAVE APPROVED WEEKLY DPP-4 INHIBITORS?

Weekly DPP-4 inhibitors like Omarigliptin and Trelagliptin are primarily approved and utilized in Japan since 2015. Their decade-long use offers valuable insights into their efficacy and safety. They have broader implications for diabetes management, especially in third-world countries. Bangladesh has approved Trilagliptin and Omarigliptin in 2023. These drugs are also being used and gaining momentum in other Asian markets like South Korea, Pakistan and India

Japan’s Experience with Weekly DPP-4 Inhibitors

Once weekly DPP-4 inhibitors were approved and marketed in Japan in 2015. Trelagliptin Succinate (Zafatek) by Takeda (50mg &100mg)

Omarigliptin (Merizev) by Merck & CO (12.5&25mg)

After over a decade of use, Japan provides a rich dataset on these drugs’ real-world efficacy:

1. Clinical Effectiveness:

• Weekly DPP-4 inhibitors achieve HbA1c reductions similar to daily counterparts (~0.8%-1%), making them highly effective for managing Type 2 Diabetes Mellitus (T2DM)
• Studies confirm stable glycemic control without significant hypoglycemia or weight gain

2. Safety Profile:

• Minimal adverse effects, like mild infections, were noted. These are consistent with those observed in other DPP-4 inhibitors

3. Patient Adherence:

• The once-weekly dosing improves adherence and reduces the cognitive burden on patients compared to daily.

Key Insight: Japan’s innovation in weekly regimens has improved adherence and quality of life for diabetes patients. Omarigliptin is specially proven beneficial for use in patients with renal impairment. However, limited global approval and availability restrict their broader influence.

Potential Benefits for Third-World Countries

1. Ease of Use:
   • For populations with limited healthcare access, weekly regimens reduce the need for frequent visits and improve long-term adherence.
2. Cost Efficiency:
   • While initially costlier than daily generics, the reduced frequency of administration can lower logistical and dispensing costs.
3. Suitability for Rural Areas:
   • Patients in remote areas benefit significantly from reduced medication frequency, minimizing travel for prescription refills.

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Challenges in Global Adoption

1. Regulatory and Market Barriers:
   • Weekly DPP-4 inhibitors are primarily approved in Japan, with limited availability elsewhere due to regulatory constraints
2. Economic Concerns:
   • Despite cost-saving potential, their affordability compared to generic options like metformin remains a challenge for widespread use in resource-limited settings.

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Lessons from Japan: Gains and Losses

1. Gains:
   • Japan has pioneered a convenient, effective treatment that improves adherence and long-term outcomes.
   • The country has amassed extensive safety and efficacy data, enabling further innovation.
2. Losses:
   • Limited export has prevented global recognition and utilization.
   • Competing therapies like GLP-1 receptor agonists overshadow the role of weekly DPP-4 inhibitors internationally.

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Conclusion

Weekly DPP-4 inhibitors provide a practical solution for diabetes management. They are particularly beneficial for third-world countries. In these regions, adherence and access are critical. While Japan has demonstrated their efficacy and safety, global adoption will require addressing cost, availability, and regulatory hurdles. These therapies have the potential to revolutionize diabetes care, making treatment more accessible and sustainable worldwide.

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References

1. Meta-analysis of Omarigliptin’s efficacy and safety in T2DM: E-enMps://www.e-enm.org/journal/view.php?doi=10.3803/EnM.2023.1839).
2. Clin​E-enM on the effectiveness of weekly DPP-4 inhibitors: Source.
3. Japan’s regulatory landscape and global availability issues: Source.

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