Sodium-glucose cotransporter-2 (SGLT2) inhibitors, commonly known as flozins, initially emerged as a treatment for type 2 diabetes. However, subsequent research revealed their unexpected benefits in improving heart health and slowing the progression of chronic kidney disease. While preliminary evidence suggests their potential in addressing other conditions, the underlying mechanisms remain elusive. This article delves into the weight loss mechanism of flozins and explores their broader implications.
The Discovery and Development of Flozins
In 1835, French chemists isolated phlorizin, the first SGLT2 inhibitor, from apple tree root bark. Initially studied for its potential to treat fevers, it wasn't until about 50 years later that German physician Josef von Mering discovered its ability to stimulate excess sugar excretion in the urine of animals. While this might not have seemed like a promising treatment for diabetes at the time, given that excess sugar in the urine is a symptom of the disease, it kindled interest in using flozins as antidiabetic medications.
In 1987, researchers at Yale University used phlorizin to clarify the role of high blood sugar in type 2 diabetes. They found that phlorizin restored insulin sensitivity in a rat model of diabetes, effectively curing them of the disease, whereas stopping the phlorizin treatment made insulin resistance return. This kindled interest in using flozins as antidiabetic medications.
However, phlorizin also blocks SGLT1, the main protein responsible for glucose absorption in the small intestines, leading to substantial gastrointestinal side effects like diarrhea. In 2000, Japanese researchers developed synthetic flozins that were easily absorbed into the blood after oral administration, solving the absorption problem.
Further research in the 2000s revealed the cause of familial renal glycosuria, a condition characterized by persistently high levels of glucose in the urine but otherwise normal kidney function. This condition was found to be caused by genetic mutations in the SGLT2 gene, which reduced the effectiveness of the SGLT2 pump, similar to the effect of flozins.
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These findings paved the way for clinical trials, which focused on the ability of flozins to lower blood sugar and control type 2 diabetes. After flozins were approved as diabetes drugs, further trials were conducted to ensure they did not increase the risk of cardiovascular events.
How Flozins Work
SGLT2 is a protein primarily found in the kidneys that prevents sugar and sodium chloride from being passed into the urine. SGLT2 inhibitors work by blocking SGLT2, reducing the reabsorption of glucose in the kidney and therefore lowering blood sugar. This inhibition leads to the release of glucose in the urine.
Sodium and glucose are co-transported by the SGLT-2 protein into the tubular epithelial cells across the brush-border membrane of the proximal convoluted tubule due to the sodium gradient between the tubule and the cell, providing a secondary active transport of glucose.
The most commonly used gliflozins are dapagliflozin, empagliflozin, and canagliflozin. The general structure includes a glucose sugar with an aromatic group in the β-position at the anomeric carbon.
The Weight Loss Mechanism
Flozins promote glucose excretion in the urine, leading to calorie loss and subsequent weight loss. SGLT2 inhibitors are glucose-dependent and can excrete approximately 60-100 g of glucose per day in the urine. By inhibiting SGLT2, these drugs reduce plasma glucose levels, resulting in glucosuria.
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Weight loss due to SGLT2 inhibitors has been consistently observed in several studies of type 2 diabetes regardless as a monotherapy or in combination with other hypoglycemic therapy.
Despite the calorie loss effects of SGLT2 Inhibitors, it causes less weight loss than expected due to an adaptive increase in energy intake, including compensatory increases in appetite/caloric intake. Glycosuria due to the SGLT2 inhibitors leads to lower plasma glucose and insulin levels, followed by increased fasting and post-meal glucagon concentration. Along with hormonal changes and the reduction of glucose concentration, lipid storage is mobilized to be used as an energy substrate. The body’s metabolism shifts towards utilizing fat for energy production. The metabolic adaptation towards the persistent excretion of glucose in the kidney includes: increased gluconeogenesis, suppression of tissue glucose disposal and glucose oxidation, accelerated lipolysis, increased fat oxidation, and enhances ketogenesis.
Additional Benefits of Flozins
While the blood pressure reduction associated with flozins is relatively small, it doesn't fully explain their protective effects against heart diseases. Conventional blood pressure therapy reduces the risk of heart failure by 28 percent for every 10 millimeters of mercury (mm Hg) decrease in blood pressure. However, in one trial, patients on canagliflozin had 39 percent lower rates of heart failure despite blood pressure reductions of only 3.5 mm Hg.
In 2020, a major trial demonstrated that dapagliflozin significantly reduced the risk of developing end-stage kidney disease in chronic kidney disease patients. Flozins might protect the kidney by reducing the process of overwork by surviving kidney cells. When patients take these drugs, more sodium passes along those cells, instead of being filtered out along with the extra glucose.
Post hoc analyses of human trials have suggested that they might improve liver function in patients with nonalcoholic fatty liver disease. In an analysis of national data from Taiwan, researchers found that SGLT2 inhibitor treatment was associated with a lower incidence of dementia. An ITP-funded study found that canagliflozin extended the median survival of normal male mice by 14 percent.
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Potential Risks and Side Effects
Flozins increase the risk of genital infections, since the high concentration of sugar in patients’ urine creates a good environment for pathogens to thrive. Occasionally, patients taking flozins face euglycemic diabetic ketoacidosis. Flozin therapy makes it 3.7 to 7 times more likely that people develop diabetic ketoacidosis, and most of those cases are euglycemic, with an absolute risk of approximately 0.1 percent each year you are on the drug. An even rarer but more concerning complication, also caused by sweeter urine feeding infections in the genital area, is Fournier’s gangrene, which causes large patches of skin in the genital area to die.
Gliflozins appear to increase the diuretic effect of thiazides, loop diuretics and related diuretics and may increase the risk of dehydration and hypotension. It is important to adjust the dose of antidiabetics if the treatment is combination therapy to avoid hypoglycemia.
Flozins in Combination Therapy
The combination of SGLT2 Inhibitors with other drugs that work with different mechanisms may be an effective approach for weight loss. Hollander et al. studied the coadministrations of canagliflozin and phentermine compared with placebo. The study concluded that the combination of canagliflozin and phentermine was superior in terms of weight loss when compared to placebo or canagliflozin or phentermine alone. The effect of canagliflozin and phentermine was additive and perhaps synergistic.
Another study by Lundkvist et al. explored the co-administration of dapagliflozin and exenatide, a glucagon-like-peptide-1 receptor antagonist (GLP-1 RAs). The study demonstrated a significant weight loss difference compared to placebo.