EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Diabetes has been acknowledged since ancient times. However, it was only during the late 1800s that we realized that the primary organ for blood glucose regulation was the pancreas. The 20th century witnessed insulin purification, which revolutionized the treatment of diabetes maigre; this was followed by the development of oral antidiabetic drugs. The sodium-glucose cotransporter 2 inhibitors or gliflozins are the latest class. Unique cardio- and renoprotective effects separate them from other oral antidiabetic drugs. Here, we present the history behind the development of these inhibitors, arguably the hottest and the most pleasant topic in nephrology. The first serendipity was Koninck and Stas (assistants to Prof. Van Mons, a renowned pomology expert); these researchers isolated a crystalline glycoside called phloridzin (phlorizin) from the bark of apple trees while working at their boss’s nursery. Their discovery was published in German in 1835. The second serendipity, after a half century, was from Prof. von Mering, who decided to administer phlorizin to dogs. Oskar Minkowski initially observed polyuria than glucosuria. Insightfully, von Mering postulated that phlorizin affects kidneys. In 1887, they reported that phlorizin induced glucosuria in people with diabetes. The third serendipity was that phlorizin causes several gastrointestinal side effects and has poor oral bioavailability. The first phlorizin-based drug to enter trials was T-1095. The first clinically available gliflozin was dapagliflozin, receiving approval in Europe and the United States in 2012 and 2014, respectively. The 2015 EMPA-REG Outcome trial reported extremely satisfying results that no one expected. Subsequent trials and real-world data have resulted in changes in all impactful guidelines. The impact of these agents on heart failure and chronic kidney disease seems independent of their antidiabetic properties. More than 100 years after von Mering’s original discovery, descendants of phlorizin are fast becoming the most inspiring medicine for the 21st century physician.

Key words : Diabetes, Gliflozin, History of diabetes, SGLT-2 inhibitors

Diabetes is a chronic metabolic disease that is the most common cause of end-stage kidney disease worldwide. Other notable yet inconclusive complications include hastened atherosclerosis, cardiovascular disease, noninfectious blindness, and severe neuropathy.¹

Since ancient times, diabetes has been acknow-ledged as a “sugar-in-urine disease.”² However, this acknowledgment resulted in an unfruitful quest of searching for a panacea. It was only during the late 1800s that people realized that the primary organ for blood glucose regulation was the pancreas. The 20th century witnessed insulin purification, which revolutionized the treatment of diabetes maigre or what we call today type 1 diabetes.³ Development of successful oral antidiabetic drugs (OADs) followed.

The 2010s have been witnessing a new class of OADs, namely, the sodium-glucose cotransporter 2 (SGLT-2) inhibitors or gliflozins. Their unique cardio- and renoprotective effects separate them from other OADs. Recent guidelines have installed these agents as the first line in the treatment of diabetes in patients with cardiac or kidney disease.⁴

The history of medicine is a discipline that guides our future based on meticulous research into the past. As keen students of this discipline, we dug into the history behind gliflozins, which revealed 3 serendipitous stories. Here, we share them with interested readers.

The First Serendipity: The Discovery of Phlorizin

Phlorizin, a dihydrochalcone isolated from the bark of apple trees in 1835, discovered by Belgian scientists Laurent-Guillaume de Koninck and Jean Servais Stas, is known to be the first natural product substance with SGLT inhibitory activity.

De Koninck graduated in Medicine, Pharmacy, and Natural Sciences and Jean Servais Stas was a medical doctor. Eventually, both became assistants to the professor of chemistry Jean-Baptiste Van Mons, a renowned expert in botanics, particularly pomology or the science of fruits. Van Mons also owned his gardens and nurseries for experimentation. When his apple nursery needed transplantation, Van Mons gave this task to Stas and De Koninck. In return, they were supplied with ample fresh apple tree roots.⁵ Extract from willow tree bark was in use as an analgesic and antipyretic since ancient times, with a first report of use dating back to 2000 BC. German scientist Buchner had already isolated salisilin, an antecedent of salicylic acid from willow bark as an active substance.⁶ It is plausible that Stas and De Koninck were after such an ingredient when they isolated a crystalline glycoside called phloridzine, which transformed into “phlorizin.” De Koninck published the discovery in German in 1835.⁷ However, because phlorizin does not possess features similar to salicylate, their enthusiasm for the molecule was short-lived. Following their discovery, phlorizin was also accused as one of the key reasons for a group of well-known botanical maladies named “old orchard diseases.”⁸

The Second Serendipity: Glucoretic Effects of Phlorizin

Prof. Freiherr Josef von Mering was born into a wealthy family, enabling him a prolific education. However, the family’s financial status declined over the years, and, in response, von Mering resorted to multitasking in various fields of medicine. He was a pioneer for physicians working closely with the industry. He introduced the infamous sleep and, unfortunately, suicide drug veronal (barbital), some lipid formulations to replace cod liver oil, and Kraft kakao as nutritional supplements for children. Interestingly, it is less known that he was also the inventor behind today’s most widely used analgesic paracetamol.⁹

Fifty years after its discovery, Herr von Mering was interested in phlorizin again. Von Mering decided to administer phlorizin to dogs, and why he did this was never understood. However, we can speculate that his relations with Dr. Hermann Von Fehling, mainly known for the “Fehling’s reagent” via his coresearcher Minkowski, directed Mering’s studies in that path.⁹ Another speculation would be that von Mering was aware of the diuretic action of the apple tree and was experimenting to see whether phlorizin had such an effect. Diuretic effects of apple leaves and fruits had first been recorded by Dioscorides in his famous work “Materia Medica” centuries ago.¹⁰ Unfortunately, no such insight from either Mering or Minkowski is available to us.

Dogs given oral or subcutaneous phlorizin developed polyuria and glucosuria, becoming diabetic.¹¹ In 1886, von Mering reported that phlorizin decreased glycemia in dogs and assumed that the substance “may induce glucosuria by changing something in the kidney.” Furthermore, a year later, he noted that, in people with diabetes, phlorizin (15-20 g) induced glucosuria of 6% to 8%.¹² This is the first-ever report of phlorizin as an OAD candidate.

The Mering-Minkowski collaboration proved that pancreatectomy induces diabetes in dogs, an excellent premise for the discovery of insulin in the upcoming years. They also demonstrated that phlorizin acts in the kidney after they showed phlorizin lost its blood glucose-lowering capacity after nephrectomy in pancreatectomized dogs.¹³

The sodium-glucose cotransport with SGLT-1 and SGLT-2 receptors was later enlightened by Dr. Robert Kellogg Crane, whose team also proved that phlorizin is a potent inhibitor of both.¹⁴

The Third Serendipity: Cardiovascular and Renal Benefits of Gliflozins

In the 1930s, phlorizin failed as an OAD because of its intolerable gastrointestinal side effects, due to SGLT-1 inhibition and poor oral bioavailability. Several pharmaceutical companies began extensive research to develop novel phlorizin-based analogs. In 1999, an orally available selective SGLT-2 inhibitor, T-1095, was created. T-1095 was an O-glucoside analog of phlorizin and has an important place in history because it is the first phlorizin derivative used in treating diabetes in a modern sense. Other O-glucoside products, sergliflozin, remogliflozin, and AVE2268, were developed. None of them prevailed. Scientists then turned their attention to other phlorizin derivatives, namely C-glucosides, because of their pharmacokinetic stability and incomplete pharmacological selectivity for SGLT-2.¹⁵ Consequently, in 2008, Meng and colleagues developed dapagliflozin as a C-glucoside analog.¹⁶ The first clinically available gliflozin is dapagliflozin, which received European Medicines Agency and US Food and Drug Administration approval in 2012 and 2014, respectively. Empagliflozin and canagliflozin soon followed.

The Food and Drug Administration requires all OADs to have trials addressing major cardiac adverse events after the notorious rosiglitazone experience.¹⁷ The EMPA-REG trial in 2015 was the first trial to report an unexpected 38% reduction in cardiac mortality, 35% reduction in hospitalization for heart failure, and a prolonged interval to doubling of serum creatinine or end-stage renal disease.¹⁸ These extremely satisfying results that no one expected was welcomed with joy. However, supported by subsequent trials and real-world data, all credible guidelines have changed. Furthermore, the effects of these agents on heart failure and chronic kidney disease seem to be independent of their antidiabetic properties.¹⁹ For a clinician, this was the most pleasant serendipity of gliflozins.

More than 100 years after von Mering’s original discovery, descendants of phlorizin are fast becoming the most inspiring medicine for the 21st century physician (Figure 1).

Volume: 21 Issue: 6 June 2023 - Supplement - 2

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