What is the origin of SGLT2 inhibitor drug development?

The development of SGLT2 inhibitors was inspired by phlorizin, a naturally occurring compound found in apples, which also causes glucose to be excreted in urine. This natural discovery paved the way for synthesized, more potent versions.

What are the main SGLT2 inhibitors approved for use?

The most discussed SGLT2 inhibitor is Canagliflozin. Other approved drugs in this class include Dapagliflozin, Empagliflozin, and Ertugliflozin, with approvals generally ranging from 2013 to 2017.

How effective are SGLT2 inhibitors like Canagliflozin in reducing A1C?

Canagliflozin, particularly when used with Metformin, can lead to significant reductions in Hemoglobin A1C. Monotherapy can show a 0.7-1% absolute reduction, while combination therapy has shown up to a 1.8% reduction.

Do SGLT2 inhibitors offer benefits beyond blood sugar control?

Yes, SGLT2 inhibitors have demonstrated significant benefits, including reductions in blood pressure and improved cardiovascular outcomes, such as decreased risk of hospitalization and death for heart failure patients.

Are SGLT2 inhibitors beneficial even for people without type 2 diabetes?

Evidence suggests that SGLT2 inhibitors can improve cardiovascular outcomes and reduce heart failure hospitalizations even in individuals who do not have type 2 diabetes.

Why do pharmaceutical companies give drugs confusing names?

Pharmaceutical companies choose memorable brand names (like Jardiance) over difficult generic names to ensure doctors and patients associate the brand with the drug, potentially leading to longer sales.

Key Moments

Metabolic health & pharmacologic interventions: SGLT-2 inhibitors, metformin (AMA 53 sneak peek)

Peter Attia MD

Science & Technology4 min read28 min video

Sep 18, 2023|12,299 views|127|5

Peter Attia MD Dr. Peter Attia Early Medical The Drive Podcast The Drive Longevity Zone 2

Save to Pod

Key Moments

TL;DR

Peter Attia discusses SGLT-2 inhibitors, metformin, and GLP-1 agonists for metabolic health.

Key Insights

SGLT-2 inhibitors work by blocking glucose reabsorption in the kidneys, leading to increased glucose excretion in urine.

Naturally occurring compounds like phlorizin, found in apples, served as an early inspiration for the development of SGLT-2 inhibitors.

While Metformin is a primary treatment for type 2 diabetes, SGLT-2 inhibitors are gaining attention for potential broader benefits beyond blood sugar control.

SGLT-2 inhibitors have demonstrated potential cardiovascular benefits, including reducing hospitalization and death for heart failure patients, even in those without type 2 diabetes.

The development of specific SGLT-2 inhibitors involved modifying natural compounds to create derivatives with improved efficacy and tailored properties.

Drug brand names, often difficult to pronounce, are deliberately chosen by pharmaceutical companies to be memorable and encourage association with the product.

UNDERSTANDING SGTLT-2 INHIBITORS: MECHANISM OF ACTION

SGLT-2 inhibitors, short for sodium-glucose co-transporter protein 2 inhibitors, represent a class of drugs designed to manage blood glucose levels. Their mechanism involves the kidneys, specifically the nephron's proximal tubule, where they block the SGLT-2 protein. This protein is responsible for reabsorbing glucose and sodium back into the bloodstream from the filtered plasma. By inhibiting this reabsorption, SGLT-2 inhibitors increase the excretion of glucose and sodium into the urine, thereby lowering blood glucose levels. This action provides a novel approach to glycemic control, distinct from strategies that focus on insulin sensitivity or production.

THE ORIGINS AND DEVELOPMENT OF GLYCEMIC DRUGS

The development of modern diabetes medications often traces back to naturally occurring substances. Phlorizin, found in apple tree bark, was an early example that, when administered, caused glucose to appear in the urine, a phenomenon observed in diabetic patients. This observation, even leading Sir William Osler to taste urine for diagnosis, highlighted a pathway that could be targeted. Pharmaceutical research then focused on creating derivatives of such compounds, leading to molecules like SGLT-2 inhibitors. The resemblance between natural compounds and their synthetic counterparts, like phlorizin and modern SGLT-2 inhibitors ending in '-flozin', illustrates this drug development evolution while also explaining pharmaceutical strategies behind branding.

DIVERSE SGTLT-2 INHIBITORS AND THEIR CHARACTERISTICS

Several SGLT-2 inhibitors are now available, including canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin. Canagliflozin, approved in 2013, has a substantial body of research, showing dose-dependent reductions in hemoglobin A1c. When used with metformin, it resulted in significant A1c decreases, moving patients from diabetic to pre-diabetic ranges. While Metformin is often the first-line treatment due to cost and efficacy, SGLT-2 inhibitors also contribute to glycemic control, with potential for weight loss and blood pressure reduction. The difference in reabsorption blockade for sodium may explain some of the observed blood pressure benefits.

BEYOND GLYCEMIC CONTROL: CARDIOVASCULAR AND RENAL BENEFITS

A significant area of interest for SGLT-2 inhibitors lies in their potential benefits extending beyond blood sugar management. Studies indicate these drugs can reduce the risk of hospitalization and death due to heart failure, even in individuals without type 2 diabetes who have reduced ejection fractions. Furthermore, they show improvements in cardiovascular outcomes for patients with heart failure and preserved ejection fraction. These broader effects suggest a multifaceted impact on metabolic and cardiovascular health, making them a topic of intense scientific inquiry and patient interest, often surpassing the public's focus on Metformin's benefits.

EXPLORING THE GERO-PROTECTIVE POTENTIAL OF SGTLT-2 INHIBITORS

The discussion around SGLT-2 inhibitors increasingly includes their potential as gero-protective agents, a subject of significant research and considerable public inquiry, similar to questions surrounding Metformin. While the intervention testing program (ITP) has highlighted specific differences, the demonstrated impact on major adverse cardiac events (MACE) is a key driver of this interest. The ability of these drugs to improve cardiovascular outcomes and potentially offer protection against decline in kidney function, even in non-diabetic populations, positions them as promising candidates for interventions aimed at promoting longevity and preserving healthspan.

THE STRATEGIC NAMING OF PHARMACEUTICALS

The complexity and occasional difficulty in pronouncing the names of pharmaceutical drugs are not accidental. Pharmaceutical companies deliberately choose brand names that are memorable to clinicians and patients alike, aiming to build strong brand recognition and customer loyalty. This strategy is designed to ensure that the product remains associated with the company even after the patent expires and generic versions become available. For instance, names like Jardiance (empagliflozin) or Januvia (sitagliptin) are far more recognizable than their generic chemical names, reflecting a calculated approach to marketing within the pharmaceutical industry.

Mentioned in This Episode

●Products

●Organizations

●Concepts

●People Referenced

Metabolic Health & Pharmacological Interventions: Key Takeaways

Practical takeaways from this episode

Do This

Understand that SGLT2 inhibitors work by preventing the kidney from reabsorbing glucose, leading to increased glucose excretion in urine.

Recognize that SGLT2 inhibitors were initially developed based on naturally occurring compounds like phlorizin found in apples.

Be aware that while Metformin is often first-line therapy for type 2 diabetes, SGLT2 inhibitors like Canagliflozin offer significant A1C reduction, especially in combination.

Consider that SGLT2 inhibitors may offer benefits beyond glycemic control, including potential reductions in blood pressure and positive cardiovascular outcomes.

Note that brand names for drugs (e.g., Jardiance, Crestor, Lipitor) are often more memorable than generic names and are intentionally chosen by pharmaceutical companies.

Avoid This

Do not solely rely on the generic names of drugs like SGLT2 inhibitors, as they can be difficult to pronounce and remember.

Do not overlook the potential benefits of SGLT2 inhibitors for non-diabetic individuals, particularly concerning heart failure and cardiovascular health.

Avoid assuming that all SGLT2 inhibitors perform identically; differences in potency and dosing exist.

Do not discount the historical methods of diagnosis, like Sir William Osler tasting urine, though modern methods are preferred.

Common Questions

SGLT2 inhibitors block the reabsorption of glucose in the kidney's proximal tubule, causing excess glucose to be excreted in the urine. This mechanism directly reduces blood glucose levels.