At the 2021 Annual Meeting of the American Diabetes Association (ADA), the team of Professor Qu Xian of the Tenth People's Hospital affiliated to Tongji University presented a latest study that found that the new hypoglycemic drug cabrelliflozin is not inferior to metformin (click to view the original article of the report). Recently, the full text of the study was officially published in the journal Diabetes, Obesity and Metabolism. Professor Xiang Qu was invited to introduce the important findings of this research in detail and share their clinical significance.
Why did this research take place?
PCOS is a common reproductive endocrine disorder in women of childbearing age and is characterized by hyperandrogenemia, chronic anovulation, and polycystic ovaries. Often, the disease is associated with insulin resistance (IR) and other metabolic abnormalities, which are risk factors for the long-term development of type 2 diabetes mellitus (T2DM), cardiovascular disease (CVD), and metabolic syndrome. Although PCOS treatment primarily uses contraceptives containing estrogen and progesterone, some contraceptives are harmful to blood lipids and may increase the risk of thrombosis and CVD.
IR affects 50% to 80% of women with PCOS, plays an important role in the pathogenesis of PCOS, and is not associated with obesity. Previous studies have suggested that IR may lead to hyperandrogenemia by disrupting the hypothalamic-pituitary-ovarian axis, stimulating ovarian androgen secretion, and inhibiting the production of sex hormone-binding globulin (SHBG). Taking insulin sensitizers such as metformin and thiazolidinedion can significantly increase ovulation and reduce androgen levels in a dose-response manner. Therefore, targeted IR is an effective strategy for treating patients with PCOS.
Kapogliflozin is a sodium-glucose synergistic transporter 2 (SGLT2) inhibitor and partially inhibits SGLT1, mainly acting on the kidneys to inhibit its reabsorption of glucose, so that excess glucose is excreted from the urine and blood sugar is reduced. SGLT2 inhibitors can also reduce body weight, improve IR and glucose metabolism, and protect the cardiovascular system, which may be beneficial for patients with PCOS. However, there are limited data on the safety and efficacy of SGLT2 inhibitors for the treatment of PCOS. The objective of this study was to clarify the efficacy and safety of carbagliflozin in patients with IR type PCOS compared with metformin.
Research design and methodology
From July 2019 to April 2021, a single-centered, prospective, randomized, open-label (ratio 1:1) non-inferiority trial was conducted in the Department of Endocrinology of Shanghai Tenth People's Hospital, which included a total of 68 female PATIENTS with PCOS aged 18 to 45 years old, and randomized them into the carbagliflozin group (100 mg/d, n=33) or metformin group (1500-2000 mg/day, n=35) for 12 weeks.
The use of caspagliflozin is 100 mg daily before breakfast. Metformin is used by taking 500 mg 1 after breakfast and after dinner in week 1, increasing the dose to 1500 mg/day in week 2 and the maximum recommended dose of 2000 mg/day in the following weeks. All subjects received regular counselling and education about healthy lifestyles prior to randomization and throughout the study period.
The primary study outcomes were changes in the insulin resistance index (HOMA-IR) after 12 weeks of treatment, while the secondary study outcomes included changes in anthropometric measures, menstrual frequency, sex hormone levels, metabolic parameters, and body fat distribution.
Study results: Carbagliflozin is not inferior to metformin,
Some metrics improve better
A total of 59 participants in this study were followed up, including 30 cases in the carbagliflozin group and 29 cases in the metformin group.
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Primary study outcomes
BOTH GROUPS OF PCOS PATIENTS SAW SAW SIGNIFICANTLY IMPROVED AFTER 12 WEEKS OF TREATMENT, WITH THE MEAN LEAST SQUARES CHANGE OF -2.04 (95% CI: -2.89 TO -1.18) IN THE CARPAGLIFLED GROUP AND -1.23 (95% CI: -2.15 TO -0.30) IN THE METFORMIN GROUP (FIGURE 1). Conformance analysis found that cabrpagliflozin was no worse than metformin in reducing HOMA-IR (least squares mean difference: -0.85%, 95% CI: -2.19 to 0.49, Figure 2).
Improves insulin resistance
△ Represented the change in indicators before and after treatment in patients with PCOS; △ cabriplin -△ metformin represented the difference in primary outcomes of the reduction in HOMA-IR at 12 weeks between the carbagliflozin group and the metformin group
Figure 2. HOMA-IR changes from baseline at week 12
After adjusting for possible confounding factors at the baseline, the model assessed the populations that fit the protocol
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Secondary study outcomes
Both kapogliflozin and metformin significantly improve menstrual conditions in patients with PCOS, reduce body weight and overall lipid levels, and lower serum triglyceride levels. In addition, compared with metformin, caspagliflozin has a significant advantage in reducing uric acid and dehydroepiandrosterone sulfate (DHEAS) levels (Table 1).
Table 1. Secondary outcomes after 12 weeks of treatment
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security
The main adverse events in the carbagliflozin group and metformin group were vulvar itching (9.09%) and gastrointestinal reactions (55.55%), respectively, and no serious adverse events occurred in both groups.
discuss
This study confirmed that both cabrigliflozin and metformin significantly improved HOMA-IR in PCOS patients with IR. The two have different underlying mechanisms: metformin inhibits hepatic gluconeogenesis in patients with PCOS, increasing the absorption and utilization of glucose by surrounding tissues, while kapogliflozin works by inhibiting renal glucose reabsorption and inducing urinary glucose excretion.
Reduce body weight
This study also showed that both kapogliflozin and metformin can reduce body weight and BMI as well as waist and hip circumference in PATIENTS with PCOS with IR. Many previous studies have reported weight loss in patients with T2DM by inhibiting renal glucose reabsorption, enhancing lipolysis, fatty acid oxidation, and adipose tissue browning. Consistent with previous studies, weight loss in the caspagliflozin group was primarily due to a decrease in fat content rather than a decrease in lean body mass. Notably, the average weight loss of pcOS patients in both the cabrigliflozin and metformin groups appeared to be higher than in previous short-term trials, possibly because patients in this study received healthy lifestyle education and exercised regularly and ate a balanced diet throughout the study period.
Lowers uric acid
In this study, the decrease in uric acid in the cabrigliflozin group was greater than in the metformin group, which was also consistent with previous studies. The underlying mechanism may be related to the renal SLC2A9 transporter, which converts glucose into uric acid. Therefore, a higher concentration of glucose in the urine may lead to an increase in the exchange of glucose with uric acid in the apical membrane of tubular cells. There is growing evidence that serum uric acid levels in patients with PCOS are significantly higher than in patients without PCOS, and that hyperuricemia exacerbates IR. Therefore, a decrease in uric acid levels associated with caspagliflozin in this study may be beneficial in patients with PCOS with hyperuricemia, but needs to be further confirmed in larger sample sizes and longer studies.
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Regulates the menstrual cycle and androgen levels
Menstrual disorders are the main clinical feature of PCOS. After 12 weeks of treatment, the menstrual cycle status of both the carbalaflozin group and the metformin group improved compared to baseline. In addition, DHEAS levels in the cabreachflozin group decreased significantly. Previous studies have shown that approximately 40% to 60% of patients with PCOS have adrenal hyperandrogenism, which is characterized by elevated DHEAS levels. Therefore, a decrease in DHEAS levels in the kagliflozin group may be beneficial in patients with PCOS with adrenal hyperandrogenemia. The underlying mechanism by which kapogliflozin lowers DHEAS is unclear and may be related to its lowering of uric acid.
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Good safety and tolerance
In terms of safety, caspagliflozin is generally well tolerated in patients with PCOS with IR, and after 12 weeks of treatment, the group did not develop genital fungal infections or urinary tract infections. Compared with the metformin group, the incidence of vulvar pruritus associated with osmotic diuresis increased in the cabernet group, which is consistent with previous reports. The high incidence of adverse events in this study may be explained by the all-female study population and the presence of a comprehensive record (including temporary responses) and information bias, as this study was open-label, but all adverse events were generally self-limiting and mild.
In summary, in this study, caspagliflozin was well tolerated, and its efficacy was similar to that of metformin in reducing HOMA-IR, weight loss, and improving the menstrual cycle in Chinese PCOS patients with IR. In addition, carbagliflozin has certain advantages in reducing uric acid and DHEAS compared to metformin, suggesting that SGLT2 inhibitors can be considered an effective drug for the treatment of PCOS patients with IR.
参考文献：Cai M, Shao X, Xing F, Zhang Y, Gao X, Zeng Q, Dilimulati D, Qu S, Zhang M. Efficacy of canagliflozin versus metformin in women with polycystic ovary syndrome: A randomized, open-label, noninferiority trial. Diabetes Obes Metab. 2022 Feb; 24(2): 312-320.
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