INTRODUCTION:

Type 2 diabetes mellitus is a chronic metabolic disorder characterized by high levels of blood sugar (hyperglycemia) resulting from insulin resistance and relative insulin deficiency. Unlike type 1 diabetes, which involves the autoimmune destruction of insulin-producing cells, type 2 diabetes typically develops gradually and is associated with lifestyle factors such as obesity, sedentary lifestyle, and poor dietary habits. Insulin resistance is a significant and central characteristic of type 2 diabetes. It emphasizes that insulin resistance plays a crucial role in the development and progression of the disease.^1,2 It occurs when the body's cells become less responsive to the effects of insulin, a hormone produced by the pancreas that helps regulate blood sugar levels.

Consequently, there is an accumulation of glucose in the bloodstream, as it fails to be utilized by cells for energy.³ Over time, the pancreas may also become unable to produce enough insulin to overcome the resistance, leading to further increases in blood sugar levels. One of the key mechanisms contributing to elevated blood sugar levels in type 2 diabetes involves the dysregulation of glucose transport into cells. In particular, a protein called the sodium-glucose cotransporter (SGLT) is involved in the reabsorption of glucose from the kidneys back into the bloodstream. In the kidneys, SGLT2 is primarily responsible for reabsorbing glucose from the urine back into the bloodstream. In people with type 2 diabetes, the kidneys may reabsorb too much glucose due to increased expression or activity of SGLT2, contributing to hyperglycemia.^4,5,6,7 Medications targeting SGLT2, such as empagliflozin and dapagliflozin, work by inhibiting the reabsorption of glucose in the kidneys, thereby promoting the excretion of glucose in the urine and lowering blood sugar levels.⁸ These drugs are commonly used as adjunct therapy in the management of type 2 diabetes, particularly in individuals who have not achieved adequate blood sugar control with other medications or lifestyle interventions.^9,10

Brenzavvy:

Brenzavvy is a recently approved medication used in the treatment of type 2 diabetes mellitus. It being developed by TheracosBio. On January 20, 2023, Brenzavvy was granted its first approval in the USA for the treatment of type 2 diabetes mellitus, As an adjunct to diet and exercise, it is employed to improve glycemic control in individuals diagnosed with type 2 diabetes mellitus. It is categorized within the class of medications known as sodium-glucose co-transporter 2 (SGLT2) inhibitor. Brenzavvy works by inhibiting SGLT2, a protein responsible for the reabsorption of glucose in the kidneys. By blocking this protein, Brenzavvy promotes the excretion of glucose in the urine, thus helping to lower blood sugar levels in people with diabetes. Like other SGLT2 inhibitors. It may be prescribed alone or in conjunction with other antidiabetic medications, such as metformin or insulin. However Brenzavvy is not recommended in patients who already suffer from type 1 diabetes mellitus, because It may increase the risk of diabetic ketoacidosis in these patients. Brenzavvy offers a unique mechanism of action, distinct from traditional antidiabetic agents. In individuals with type 2 diabetes, the kidneys play a crucial role in glucose homeostasis by reabsorbing glucose from the urine back into the bloodstream via SGLT2 transporters.¹¹ This mechanism of action is independent of insulin secretion or sensitivity, making Brenzavvy a valuable therapeutic option, particularly for patients with inadequate glycemic control despite other treatment modalities. Clinical studies have demonstrated the efficacy and safety of Brenzavvy in improving glycemic control in adults with type 2 diabetes. Additionally, it has been shown to offer additional benefits beyond glucose lowering, including reductions in body weight and blood pressure, which are important considerations in the holistic management of diabetes and its associated comorbidities. Incorporating Brenzavvy into the treatment regimen of individuals with type 2 diabetes requires careful consideration of factors such as renal function, cardiovascular risk, and potential drug interactions. Close monitoring and regular follow-up by healthcare providers are essential to optimize therapy and minimize the risk of adverse effects.^12,13 Overall, Brenzavvy represents a promising therapeutic option for the comprehensive management of type 2 diabetes mellitus, offering a novel approach to address both hyperglycemia and associated metabolic abnormalities, thereby contributing to enhance patient outcomes and overall quality of life. Brenzavvy is an orally administered tablet containing Brenzavvy as the active ingredient. Brenzavvy is a powder ranging from white to off-white or pale yellow, characterized by its minimal solubility in water but high solubility in solvents such as methanol, acetone, ethylene glycol, and propylene glycol. It also exhibits slight solubility in heptane, cyclohexane, and toluene, and does not demonstrate hygroscopic properties when crystallized. Each film-coated tablet of Brenzavvy is formulated to contain 20 mg of Brenzavvy alongside various inactive components. These include colloidal silicon dioxide, glyceryl dibehenate, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene oxide, and poloxamer 188. The tablet's film coating, known as Opadry® II Blue 85F99153, incorporates additional inactive ingredients such as FD&C Blue #1/Brilliant Blue FCF Aluminum Lake, FD&C Blue #2/Indigo Carmine Aluminum Lake, macrogol 3350, partially hydrolyzed polyvinyl alcohol, talc, and titanium dioxide.^14,15,16

Chemical name:¹⁷

(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol.

Molecular weight:

464.94 g/mol.

Molecular formula:

C₂₄H₂₉CIO₇

Structural formula:

Figure 1: Structure of Brenzavvy

Mechanism of action:

Brenzavvy, a prominent member of the sodium-glucose cotransporter 2 (SGLT2) inhibitors class, exerts its primary action by impeding the activity of the SGLT2 transporter localized in the renal tubules of the kidneys. In individuals grappling with type 2 diabetes mellitus, characterized by an abundance of glucose in the blood stream owing to insulin resistance or inadequate insulin secretion. this transporter typically facilitates the reabsorption of glucose from urine back into the circulation. Nonetheless, Brenzavvy 's antagonism of the SGLT2 transporter disrupts this process, fostering heightened elimination of glucose through the urine and effectively mitigating elevated blood glucose levels. In essence, through its selective blockade of the SGLT2 transporter in the kidneys, Brenzavvy enhances the excretion of glucose in urine, thereby contributing to the amelioration of hyperglycemia in individuals afflicted with type 2 diabetes mellitus.¹⁸

Pharmacokinetics: Brenzavvy's pharmacokinetics remain consistent between healthy individuals and those with type 2 diabetes mellitus. When taken in a fasted state, it reaches a peak plasma concentration (Cmax) of 134 ng/mL and an area under the curve (AUC0-∞) of 1,162 ng·h/mL. Its pharmacokinetics do not show time-dependent behavior, with about a 20% accumulation upon repeated dosing. Peak plasma concentrations typically reached 2 to 4 hours post-administration, though this can be delayed with food or certain medications.¹⁹ It has a high plasma protein binding of 93% and an estimated volume of distribution of 262 liters. Brenzavvy is primarily metabolized by UGT1A9 and to a lesser extent by CYP3A, with the main metabolite being the inactive 3′-O-glucuronide. Clearance is around 19.1 L/h, and the terminal elimination half-life is approximately 12 hours. Most of the drug (91.6%) is recovered after administration, with 51.1% excreted in feces as Brenzavvy and 40.5% in urine as the metabolite. Age, gender, race, and body weight have minimal impact on its pharmacokinetics, but dosage adjustments may be necessary in renal impairment cases. Overall, Brenzavvy 's profile includes rapid absorption, strong protein binding, minimal hepatic processing, mainly renal excretion, and consistent behavior across patient populations, aiding in effective management of type 2 diabetes mellitus.²⁰

Pharmacodynamics: Both adults with type 2 diabetes mellitus (T2DM) and healthy participants exhibited dose-dependent increases in urinary glucose elimination (UGE) and enhanced urine volume following administration of one or more doses of Brenzavvy. The attainment of near-maximal UGE occurred with a 20 mg dose of Brenzavvy, with sustained elevation of UGE observed with subsequent doses. Even at doses five times higher than recommended, Brenzavvy did not induce clinically significant prolongation of the QTc interval. However, the use of Brenzavvy has been associated with adverse effects including genital mycotic infections, necrotizing fasciitis of the perineum, pyelonephritis, urosepsis, and ketoacidosis. Furthermore, patients treated with Brenzavvy experienced a higher incidence of lower limb amputations compared to those receiving a placebo. Notably, the use of Brenzavvy may elevate the risk of hypoglycemia in individuals receiving insulin or insulin secretagogues.²¹

Adverse drug reaction of Brenzavvy:²²

Brenzavvy, like all medications, can potentially cause adverse drug reactions (ADRs) in some individuals. Here's a comprehensive overview of the adverse reactions associated with Brenzavvy:

1. Genitourinary Infections: One of the most commonly reported adverse effects of Brenzavvy is an increased risk of genitourinary infections, including urinary tract infections (UTIs), genital mycotic infections (such as yeast infections in women and balanitis in men), and urinary frequency. The increased glucose excretion in the urine creates a more favorable environment for bacterial and fungal growth, leading to these infections.

2. Dehydration and Hypotension: Brenzavvy acts as a diuretic, promoting increased urinary volume and frequency. In some individuals, this diuretic effect can lead to dehydration, electrolyte imbalances, and low blood pressure (hypotension), especially in elderly patients or those with pre-existing kidney impairment.

3. Diabetic Ketoacidosis (DKA): Although rare, the use of SGLT2 inhibitors like Brenzavvy has been associated with an increased risk of diabetic ketoacidosis (DKA), particularly in patients with type 1 diabetes or those with type 2 diabetes who have underlying insulin deficiency. DKA is a serious condition characterized by high levels of ketones in the blood, metabolic acidosis, and hyperglycemia.

4. Hyperkalemia: Brenzavvy may lead to elevated levels of potassium in the blood (hyperkalemia), especially in patients with impaired kidney function or those taking medications that increase potassium levels (such as potassium-sparing diuretics or potassium supplements).

5. Bone Fractures: Some studies have suggested a possible association between the use of SGLT2 inhibitors and an increased risk of bone fractures, particularly in women. The exact mechanism behind this association is not fully understood and requires further investigation.

Table 1: Recent clinical trial data of Brenzavvy:²³

Clinical trial phase and nct no.	Status of study	Intervention	Population and age group	Clinical trial design	Study completion
I NCT03417076	Withdrawn	Bexagliflozin	0, 18 Years to 55 Years (Adult)	Single Group Assignment, Open Label,	September 16, 2018
I NCT02820298	Completed	Bexagliflozin	25, 18 Years to 65Years (Adult, Older Adult)	Randomized, Crossover Assignment, Open Label,	August 29, 2016
III NCT02836873	Completed	Bexagliflozin, placebo	312, 20 Years and older (Adult, Older Adult)	Randomized, Parallel Assignment, Triple (Participant, Investigator, Outcomes Assessor)	January 11, 2018
III NCT02558296	Completed	Bexagliflozin, placebo	1700, 40 Years and older (Adult, Older Adult)	Randomized, Parallel Assignment, Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)	October 23, 2019
III NCT03115112	Completed	Bexagliflozi, Sitagliptin, Placebo for Sitagliptin, Placebo for bexagliflozin	386, 18 Years and older (Adult, Older Adult)	Randomized, Parallel Assignment, Quadruple, (Participant, Care Provider, Investigator, Outcomes Assessor)	October 31, 2018
III NCT02769481	Completed	Bexagliflozin, Placebo for Bexagliflozi, Glimepiride, placebo for Glimepiride	426, 18 Years and older (Adult, Older Adult)	Randomized, Parallel Assignment, Quadruple, (Participant, Care Provider, Investigator, Outcomes Assessor)	June 14, 2019
II NCT02390050	Completed	Bexagliflozin tablet, Bexagliflozin tablet placebo	292, 20 Years and older (Adult, Older Adult)	Randomized, Parallel Assignment, Quadruple, (Participant, Care Provider, Investigator, Outcomes Assessor)	June 3, 2016

CONCLUSION:

Brenzavvy highlights its potential as a valuable addition to the armamentarium of antidiabetic agents. As a highly selective SGLT2 inhibitor, Brenzavvy offers not only effective glycemic control but also notable cardiovascular and renal benefits. Through a comprehensive analysis of clinical trials and real-world evidence, this review underscores the favorable outcomes in reducing HbA1c levels, body weight, and blood pressure, while also decreasing the risk of cardiovascular events and progression of diabetic kidney disease. Despite these promising findings, it is essential to acknowledge the need for continued monitoring of safety profiles, particularly regarding the risk of genital mycotic infections and diabetic ketoacidosis. Additionally, cost considerations and accessibility may influence its widespread adoption, especially in resource-constrained settings.

In short, Brenzavvy emerges as a compelling therapeutic option in the management of type 2 diabetes mellitus, offering multifaceted benefits beyond glycemic control. Future research should focus on long-term outcomes, comparative effectiveness, and addressing remaining questions to optimize its use in diverse patient populations. As we continue to refine our understanding of this novel agent, it holds great promise in improving the lives of individuals living with type 2 diabetes mellitus.

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Received on 14.03.2024 Revised on 27.05.2024

Accepted on 02.07.2024 Published on 07.12.2024

Available online on December 30, 2024

Res.J. Pharmacology and Pharmacodynamics.2024;16(4):328-331.

DOI: 10.52711/2321-5836.2024.00056

Breaking Ground: A Review of Brenzavvy - The newly approved treatment for type 2 Diabetes mellitus