Comparative Effectiveness of Antidiabetic Drugs as an Additional Therapy to Metformin in Women with Polycystic Ovary Syndrome: A Systematic Review of Metabolic Approaches

Background Metformin is commonly prescribed to treat polycystic ovary syndrome (PCOS) patients, but in some cases, it may not be effective even at high doses or may cause intolerable side effects. Therefore, recent studies have examined the impact of combining metformin with other antidiabetic medications. Methods A systematic search was performed in Scopus, PubMed, Web of Science, and Embase up to 30 June 2023. All interventional studies that assessed the efficacy of different antidiabetic agents were included. Results Among the 3488 records found in the primary search, 16 papers were included. Our study showed that dipeptidyl peptidase-4 inhibitors (DPP4i) had the most significant impact on glycemic profile, while thiazolidinediones (TZDs) had the most influence on lipid levels. However, it was observed that patients taking only metformin experienced a greater increase in high-density lipoprotein cholesterol (HDL-C) levels. Glucagon-like peptide-1 receptor agonists (GLP1RAs) effectively modified various anthropometric measurements, such as weight, body mass index, waist circumference, and waist-to-hip ratio. The effects of different antidiabetic drugs on hormone levels were inconclusive, although testosterone levels were more affected by GLP1RA, sodium-glucose cotransporter-2 inhibitors (SGLT2i), and TZDs. None of the combined therapies showed a significant change in blood pressure. Conclusion Since PCOS is a metabolic disorder, choosing the best combination of antidiabetic drugs in the clinical course of PCOS patients will be very important. Today, it seems that we need a new metabolic approach for better treatment of the metabolic aspects of these patients.


Introduction
Polycystic ovary syndrome (PCOS) is a common disorder among females of reproductive age, with an estimated prevalence of 4-20% worldwide [1,2].It is characterized by diferent metabolic and hormonal abnormalities such as oligoovulation or anovulation, hyperandrogenism, insulin resistance (IR), type 2 diabetes mellitus (T2DM), obesity, dyslipidemia, and ultrasound fndings including polycystic ovary [3,4].Rotterdam criteria are the commonly known statements for diagnosis of PCOS.It is defned if any two items of the following are present: frst evidence of oligoovulation or anovulation, second biochemical or clinical hyperandrogenism, and third polycystic ovarian morphology on ultrasound, with the exclusion of other relevant disorders [5].IR is one of the common metabolic disorders among PCOS patients, with a frequency of approximately 35-80%, independent of the body fat distribution or being obese.IR makes PCOS patients more likely to develop further complications such as T2DM [6,7].According to the Centers for Disease Control and Prevention (CDC), more than half of PCOS patients develop T2DM by age 40 [8].Since the exact pathophysiology behind PCOS has not yet been well understood, most available therapies are symptomatic, and few medications have been established for hormonal and metabolic dysregulations [4,9].
Metformin, from the family of biguanides, is usually prescribed as the frst-line drug for modifying the metabolic features of PCOS, including obesity, IR, impaired glucose metabolism, and T2DM [4,10].Metformin exerts its therapeutic efects by diminishing glucose production in the liver, inhibiting gluconeogenesis and lipogenesis, and increasing insulin sensitivity across peripheral tissues [11].Besides the metabolic parameters, metformin therapy demonstrated a signifcant impact on lowering the total testosterone, 17-hydroxyprogesterone, androstenedione, and low-density lipoprotein cholesterol (LDL-C) and increasing the possibility of pregnancy among PCOS patients [12].However, some cases do not respond efectively to metformin monotherapy, even at the highest dose, and others cannot tolerate its side efects.Te most common side efect of metformin is gastrointestinal discomfort, such as nausea, vomiting, diarrhea, and abdominal pain [13,14].Tus, recent studies have assessed the efect of other antidiabetic drugs in combination with metformin [15,16].Here, we conducted a systematic review to fnd the studies that evaluated the efcacy of hypoglycemic drugs, including dipeptidyl peptidase-4 inhibitors (DPP4i), sodium-glucose cotransporter-2 inhibitors (SGLT2i), thiazolidinediones (TZDs), and glucagon-like peptide-1 receptor agonists (GLP1RAs) as a combination therapy with metformin.Moreover, we will discuss the preference of each add-on medication regarding its efect on lipid profle, anthropometric measures, sexual hormones, glucose metabolism, IR, and blood pressure.

Search Strategy.
Tis study was planned, performed, and reported based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [17].Te protocol of this systematic review was registered at PROSPERO (CRD42023462716).We systematically searched databases, including Scopus, MEDLINE (PubMed), Web of Science, and Embase, for articles published up to the end of June 2023.Te search string used keywords such as metformin, polycystic ovary syndrome, and clinical trial.Te details of each database's search line are shown in Supplementary File 1.

Inclusion and Exclusion
Criteria.All randomized clinical trials (RCTs) that assessed the efect of metformin in combination with other antidiabetic drugs on anthropometric, metabolic, and hormonal parameters among PCOS patients were included.Tere is no restriction for blindness, follow-up duration, race, country, and publication year.
Only English articles were included.We excluded the studies that assumed other drugs as the main intervention and assessed the efect of metformin as an add-on medication.Duplicate records, conference proceedings, in vivo and in vitro experiments, and studies with insufcient data or poor quality were also excluded.

Screening Process and Data
Extraction.Two reviewers (MM and SM-T) independently screened the primary results of the literature review according to the predetermined criteria for inclusion and exclusion.Te following information was extracted from the eligible articles by two independent reviewers (MH and MM): frst author, date of publication, country, the exact design of the study (blindness and arms of the trial), demographic characteristics of the participants, intervention and the duration of it, dose of the consumed medications, and the outcome of the patients.Any disagreement surrounding the screening process or data extraction was resolved by consultation with the third reviewer (HR).

Quality Assessment.
Te quality of the included articles was evaluated using the National Institute of Health (NIH) quality assessment tool for controlled intervention studies [18].Tis scale consists of 14 questions and qualifes studies as poor, fair, or good.Two independent reviewers (MH and SM-T) assessed the quality of the studies, and controversies were reconciled via consensus with the third reviewer (HR).

Study Selection.
A total of 3488 records were found from the primary search in the mentioned databases.After duplicate removal, 1648 reports remained.According to the title and abstract screening, 52 articles were eligible for further assessment through the full text.Finally, 16 RCTs were eligible for inclusion in the systematic review.Figure 1 demonstrates the study selection process.

Study Characteristics.
Te details of the 16 included studies are summarized in Table 1.A total of 878 PCOS patients were investigated between 2004 and 2023.Te lowest and highest sample sizes of the included studies were 23 [23] and 137 [15], respectively.Most of the included studies have used the Rotterdam criteria for diagnosing PCOS.Included studies utilized diferent levels of blindness as follows: 13 reports open-label, 1 single-blind, and 2 double-blind.Te duration of the intervention varied from 8 weeks to 24 weeks.In all included citations, the control group consumed diferent dosages of metformin varying from 850 to 2000 mg per day.On the other hand, in most cases, for the intervention group, an antidiabetic drug was added to the same dosage of metformin that had been consumed in the control group.Te impact of diferent antidiabetic agents, including DPP4i, SGLT2i, GLP1RA, and TZDs, on glycemic and lipid profles, anthropometric measures, and sexual hormones was investigated.All
According to the NIH quality assessment tool, 12 out of 16 included studies in this review qualifed as good and 4 as fair.Te details of the quality assessment process are demonstrated in Supplementary File 2.
According to the available literature, the low number of studies on each add-on medication, on the one hand, and the great heterogeneity of the included studies due to diferent patients' conditions, on the other hand, persuade us not to conduct a meta-analysis.

Efects of Antidiabetic Drugs as an Add-On Medication to
Metformin on Blood Pressure.Tree studies have examined the changes in systolic and diastolic blood pressure (SBP and DBP) [20,23,25].Te impact of rosiglitazone [20], saxagliptin [23], and liraglutide [25] has been evaluated as an add-on drug to metformin.Table 2 demonstrates the details of blood pressure alteration following the mentioned drugs.

Discussion
Te current review study aims to fnd the best choice for an add-on medication to metformin in PCOS patients.Since PCOS is a metabolic disorder associated with an increased risk of multiple metabolic complications, choosing the best combination of antidiabetic drugs in the clinical course of PCOS patients will be very important.Terefore, selecting a second agent as a metformin add-on therapy should be based on the patient's clinical characteristics.
According to the available literature, the impact of diferent groups of antidiabetic drugs, including DPP4i, SGLT2i, GLP1RA, and TZDs, on glycemic and lipid profles, anthropometric measures, sexual hormones, and blood pressure was evaluated.As we were unable to conduct a meta-analysis, we determined the best option for combining with metformin based on the consensus of the studies included.Te glycemic profle was reported to be afected most by exenatide [22,27] and saxagliptin [23,28] as an addon medication to metformin in PCOS patients.
Rosiglitazone infuenced the lipid profle of PCOS patients more than other antidiabetic agents [15,26].However, HDL-C is reported to increase more among groups consuming metformin alone [15,28].It is worth mentioning that rosiglitazone was withdrawn from the European market in 2010 due to an increased risk of heart attacks.Te United States Food and Drug Administration (FDA) restricted access to rosiglitazone in 2011.However, the FDA removed its prescribing restrictions in 2013 based on studies that reduced the suspicion of the cardiovascular risks of rosiglitazone [33].
TZDs or glitazones are a group of drugs with insulinsensitizing properties.TZDs reduce IR in the liver and peripheral tissues by activating the nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPARc).Tey were also reported to afect dyslipidemia state [19,22] positively.Among patients with T2DM, TZDs, in combination with metformin, were found to be more efective in controlling hyperglycemia than metformin alone.However, metformin monotherapy is more efective in lowering weight [34].Among PCOS patients, the efcacy of pioglitazone and rosiglitazone, in combination with metformin, has been investigated.Two studies that evaluated pioglitazone showed inconsistent results.Ali et al. found that combination therapy appears to be more efective than metformin monotherapy in improving IR through diminishing interleukin 6 (IL-6) and interleukin 8 (IL-8) levels [19].While Sohrevardi et al. showed no signifcant diference between combination therapy and each drug monotherapy [16], results of a Chinese network meta-analysis suggested that a combination therapy is more efective than metformin alone in reducing IR, total testosterone, and TG levels [35].Rosiglitazone, in addition to metformin, was shown to modulate the lipid profle among obese PCOS patients and is a good choice in patients with severe IR, which do not respond to metformin.Moreover, the combination therapy efectively managed endocrinal abnormalities and modifed menstrual patterns among obese patients [15,26].However, a study in nonobese PCOS patients without IR found no more benefcial efects than metformin alone [20].No serious side efects have been reported for pioglitazone or rosiglitazone.
DPP4i are a class of glucose-lowering drugs that act by inhibiting GLP1 degradation.Tey reduce the serum levels of the DPP4 enzyme by 70-90%, increasing the circulating levels of GLP1 [36].In patients with T2DM, the combination International Journal of Endocrinology of DPP4i and metformin reported better glycemic outcomes than metformin alone.However, there is no signifcant diference in weight change.Beyond these, other add-on medications to metformin, such as TZDs, SGLT2i, and GLP1RA, were more efective in modulating glycemic profle and body weight [34].Among PCOS patients, two studies evaluated sitagliptin's efectiveness, and two others assessed saxagliptin as an adjunct to metformin.Sitagliptin, in addition to metformin, is reported to be a good choice for improving the fertilization rate but not the pregnancy rate.It exerts its efect by increasing the growth diferentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15) expressions [21].Sitagliptin, in addition to metformin, is more efective than metformin monotherapy in preventing weight regain in PCOS patients who previously consumed liraglutide [24].Te most frequent adverse efect of the individuals consuming sitagliptin and metformin was mild to moderate gastrointestinal complaints.Saxagliptin, in addition to metformin, indicated desirable results in modulating diferent aspects of prediabetic and diabetic PCOS patients, especially glycemic profle [23,28].Tis combination treatment did not show any additional adverse efects to the gastrointestinal side efects of metformin alone.
GLP1RAs are a group of antidiabetic medications that exert their efect by mimicking the action of the GLP1 hormone.GLP1 and glucose-dependent insulinotropic polypeptide (GIP) are both incretin hormones that stimulate insulin secretion after glucose administration.Tis medication benefts T2DM patients through diferent mechanisms, such as increasing insulin excretion, delaying gastric emptying, inhibiting glucagon production, and decreasing pancreatic beta cell apoptosis [37].According to the halftime, GLP1RAs are categorized into short-acting drugs (half-life of 2-4 hours), such as exenatide and beinaglutide, and long-acting ones (half-time more than 12 hours) such as liraglutide [38].When added to metformin monotherapy, GLP1RAs, especially long-acting ones, were reported to induce better hypoglycemic efects than other antidiabetic agents, such as DPP4i and SGLT2i [34,39].Te combination therapy of exenatide and metformin reported better results than metformin alone in modulating anthropometric indexes, insulin sensitivity, and menstrual cycle frequency among overweight and obese PCOS patients [22,27].
Recently, once weekly subcutaneous injection of semaglutide as a potent GLP1RA approved for long-term weight management has been shown to produce signifcant weight loss in patients with overweight or obesity and have favorable efects on cardiometabolic risk factors.Also, the FDA's approval of oral semaglutide, the frst oral GLP1RA, signals a paradigm shift in treating patients with T2DM.However, to our knowledge, there is no study on semaglutide benefts on the anthropometric factors in combination with metformin in PCOS patients [40].
In addition, the combination therapy indicated higher remission rates of prediabetic PCOS patients than metformin monotherapy (64% and 32%, respectively) [29].As in all the abovementioned studies, the exenatide was consumed through subcutaneous injections.Pain and itching at the injection site was a common side efect.Mild gastrointestinal reactions were also another common adverse event.Beinaglutide as an adjunct to metformin exerts better shortterm efects than metformin alone in modifying diferent anthropometrics, metabolic, and hormonal profles [30].Similar to exenatide, because of subcutaneous administration of beinaglutide, induration and pruritus at the injection site were the common tolerable adverse events.In combination with metformin, liraglutide appears superior to metformin monotherapy in weight loss among obese PCOS  is not yet recommended. 2GLP1RA's such as exenatide, liraglutide, and beinaglutide. 3However, testosterone levels were more afected by rosiglitazone, liraglutide, beinaglutide, and canaglifozin when used as an additional medication to metformin.
8 International Journal of Endocrinology cases [25].Tis combination was more efective than metformin alone in improving hyperandrogenemia and reproductive disorders.However, combination therapy has no more benefcial efect on modulating glucose metabolism and IR [31].Mild and moderate gastrointestinal complaints were the most common adverse reactions to this combination therapy.SGLT2i are medications that primarily block glucose reabsorption in the proximal convoluted tubules, leading to lower blood sugar levels [41].According to the results of a meta-analysis surrounding adding medications to metformin, SGLT2i was found to be more efcacious than other antidiabetic medications in managing T2DM.Although genital tract infections were more frequent among SGLT2i [42], unfortunately, up to date, only one clinical trial assessed the efectiveness of SGLT2i combined with metformin versus metformin alone.Canaglifozin and metformin exert no diferent outcomes from metformin monotherapy in weight control, insulin sensitivity, androgen excess, and menstrual frequency [32].Further investigations are needed to better clarify the efcacy of SGLT2i in addition to metformin among PCOS patients.
It should be noted that the use of any of the mentioned antidiabetic drugs, including TZDs [43], DPP4i [44], GLP1RA [45], and SGLT2i [46], is prohibited during pregnancy, and metformin alone should be prescribed.
Finally, it is important to note that lifestyle modifcation is one of the pivotal interventions in the management of PCOS patients at early stages [47,48].Some studies have demonstrated the greater impact of lifestyle modifcation than metformin therapy in modulating obesity and menstrual frequency among PCOS patients [49,50].Most of the included studies in this systematic review assessed the people with normal diet and physical activity levels and did not measure the impact of lifestyle modifcation.It is suggested that further investigations assess the efect of lifestyle modifcation in addition to the abovementioned therapies.

Strengths, Limitations, and Suggestions
Several review articles are regarding the efcacy of various antidiabetic agents in PCOS patients.However, to the best of our knowledge, this is the frst systematic review surrounding the efcacy of an additional medication to metformin.However, there is limited evidence to conduct a meta-analysis, but we have found the best choices as an adjunct for each aspect of PCOS.Further studies on all the abovementioned categories of drugs, especially SGLT2i, are needed to better clarify the best add-on medication to metformin.Besides, all included studies have a 6-month or lower duration of treatment, and we cannot compare the efcacy of the long-term combination therapy and metformin monotherapy.Tus, further long-term trials are needed to discover more accurate results regarding the effcacy and side efects of combination therapies.

Conclusion
Since PCOS is a metabolic disorder, choosing the best combination of antidiabetic drugs in the clinical course of PCOS patients will be very important.Today, it seems that we need a new metabolic approach for better treatment of these patients.

Figure 2 :
Figure2: Flow diagram for preferred add-on medications according to the included studies in the systematic review.1 Saxagliptin is not yet recommended. 2GLP1RA's such as exenatide, liraglutide, and beinaglutide.3However, testosterone levels were more afected by rosiglitazone, liraglutide, beinaglutide, and canaglifozin when used as an additional medication to metformin.

Table 2 :
Changes in diferent aspects of PCOS patients following diferent antidiabetic drugs as an add-on medication to metformin.