## Introduction

Diabetes mellitus (DM) is one of the top ten causes of death and one of the fastest-growing health problems of the twenty-first century, with 463 million people living with it worldwide in 2019 and this number estimated to be 700 million by 20451. The global direct health expenditure on diabetes mellitus in 2019 was estimated at US$760 billion and is expected to increase to a projected US$ 845 billion by 20452. Type 2 diabetes mellitus (T2DM) is the most common and complex form of the disease and accounts for more than 90% of the estimated cases of diabetes, impacting the life expectancy, quality of life, and health of an individual1,3. Yet, there is no cure for T2DM, while its prevalence is largely increasing, with increased risk of complications including diabetic retinopathy, neuropathy, kidney damage, and microvascular and cardiovascular complications4,5,6,7. Cardiovascular disease (CVD) is a common complication and a major cause of morbidity and mortality in patients with T2DM8,9.

Despite the introduction of new medications, treating patients with diabetes tend to become more challenging due to the progressive nature of the disease10,11,12,13,14. The American Diabetes Association recommends lifestyle interventions (exercise, healthy eating, smoking cessation, and weight reduction) as the first step in treating newly diagnosed T2DM15. However, to achieve and maintain specific glycemic targets, the majority of patients require glucose-lowering drugs. Metformin is currently the first-line and widely used pharmacological therapy for patients with T2DM because of its potential benefits, including cardioprotective effect, loss of weight, and prevention of some comorbid diseases15,16,17,18,19,20,21,22. If lifestyle interventions and a maximally tolerated dose of metformin fail to achieve the glycemic target within 3 months follow-up, the regimen would be changed to combination therapy15.

Metformin-sulfonylurea combination therapy is the most widely used regimen in the management of T2DM23,24. Sulfonylureas are prescribed as second-line treatment options in the management of patients with T2DM, while they are still commonly prescribed as a first-line treatment as a substitute to metformin25. However, initiating treatment of T2DM with a sulfonylurea in place of metformin is associated with higher rates of ischaemic stroke, cardiovascular mortality, and hypoglycemia25,26,27,28,29,30,31. On the other side, the use of sulfonylureas as second-line treatments is associated with an increased risk of non-fatal myocardial infarction, all-cause mortality, and severe hypoglycemia, compared with metformin monotherapy; as a result, continuing metformin when introducing sulfonylureas appears to be safer than switching to another drug32. Such findings led to new requirements from licensing authorities that all new T2DM therapies should show cardiovascular efficacy and safety10.

Sodium-glucose cotransporter-2 inhibitors (SGLT2Is) are novel antidiabetic drugs that can inhibit sodium-glucose cotransporter-2 at the proximal tubule of the kidney. Those novel drugs can decrease renal glucose reabsorption, hyperglycemia, cardiovascular problems and they can increase urinary glucose excretion in patients with T2DM33,34,35,36,37,38,39. However, there is no clear evidence that shows the relative advantage of either metformin-sulphonylureas or metformin-SGLT2Is combination therapy on major treatment outcomes including CVD40. Management of T2DM remains challenging as choosing a second and/or third-line antidiabetic drug is personalized based on efficacy, risk of hypoglycemia, patient's comorbid conditions, impact on weight, side effects, and cost41. In particular, although most patients with T2DM require a combination pharmacological therapy, the choice of a best second-line drug is especially critical for the prevention of CVD. Thus, the aim of this systematic review and meta-analysis of randomized controlled trials (RCTs) was to compare the cardiovascular safety and efficacy of combination therapy of metformin-SGLT2Is and metformin-sulfonylureas in patients with T2DM.

## Methods

The protocol for this systematic review and meta-analysis has been registered at the International Prospective Register of Systematic Reviews (PROSPERO) database, ID: CRD4202015561642. We followed the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA 2015) guidelines43 for the design and reporting of the results.

### Data sources and searches

We searched MEDLINE-PubMed (http://www.ncbi.nlm.nih.gov/pubmed/), Embase (http://www.embase.com/), The Cochrane Library (http://www.cochranelibrary.com/), and ClinicalTtrials.gov (https://www.clinicaltrials.gov/) for completed studies that reported the safety and/or efficacy of metformin-SGLT2Is versus metformin-sulfonylureas combination therapies for patients with T2DM. We included RCTs without restriction on year of publication, but published in English language, up to 15 August 2019. The RCTs were needed to have at least a 1-year follow-up of patients. The keywords we used in different combinations using Boolean Operators were: metformin, biguanide, sodium-glucose co-transporter- 2 inhibitors, SGLT-2 inhibitors, dapagliflozin, canagliflozin, empagliflozin, ertugliflozin, sulfonylurea, gliclazide, glimepiride, glyburide, glibenclamide, glipizide, tolbutamide, type 2 diabetes mellitus, T2DM, cardiovascular outcomes, and randomized controlled trials (Supplementary file 1). All potentially eligible studies were considered for this review, irrespective of the primary outcomes. Manual searching was performed to find out additional eligible trials from the reference lists of key articles.

### Eligibility

We formulated the study’s eligibility criteria using the PICOS (participants, interventions, comparison, outcomes, and study designs) description model44:

• Participants

• Patients with T2DM

• Man or woman of any age

• Who was taking a combination therapy of metformin-sulfonylurea or metformin-SGLT2Is

• Intervention

• A combination of metformin with any of the SGLT2Is, which could be dapagliflozin, canagliflozin, empagliflozin, or ertugliflozin.

• Comparator

• A combination of metformin with any of sulfonylureas compounds, which could be gliclazide, glipizide, glyburide, glibenclamide, or glimepiride.

• Outcomes

• Primary endpoints

• All-cause mortality

• Secondary endpoints

• Cardiovascular mortality

• Non-fatal myocardial infarction

• Non-fatal stroke

• Hypoglycemia

• Changes in HbA1c

• Change in body weight,

• Changes in fasting plasma glucose (FPG)

• Changes in systolic blood pressure (SBP

• Changes in diastolic blood pressure (DBP)

• Changes in low-density lipoprotein cholesterol (LDL-C)

• Changes in high-density lipoprotein cholesterol (HDL-C)

• Study design

• RCTs

• At least one-year duration of follow-up

• Published in English language

### Study selection

Two independent authors examined the title and abstract of all searched studies. From the title and abstract of all studies identified by the database search, those studies duplicated and not meet the inclusion criteria were excluded. The full texts of the remaining studies were further reviewed. Disagreements were resolved by consensus and if persisted, we arbitrated through discussion with a third author.

### Data extraction

Two independent authors extracted the needed data from each RCTs. These include name of the first author, year of publication, trial registration, mean age of the participant, baseline average body weight, HbA1c, interventions, comparators, number of participants randomized, duration of follow-up, and patient-important outcomes. Data on the mean change of HbA1c (%), body weight (Kg), FPG (mmol/L), SBP (mmHg), DBP (mmHg), HDL-C (mmol/L), and LDL-C (mmol/L) were collected from baseline for continuous outcomes. The status and number of events were captured for the two groups, which include, death, hypoglycemia, adverse events (AEs), SAEs, SAEs related to study drugs, genital mycotic infection (GMI), and adverse cardiovascular events.

### Assessment of risk of bias

We used the Cochrane risk of bias tool45 to assess the risk of bias in each included study and the risks were judged by two independent authors as “Low”, “Unclear”, or “High” based on the critical domains, including random sequence generation, allocation concealment, blinding, incomplete outcome data, and selective reporting. Disagreements were resolved by consensus and if persisted, we arbitrated through discussion with a third author.

### Statistical analysis

We carried out meta-analysis using the computer software packages RevMan 5.346 to compare the cardiovascular safety and efficacy between the two combination therapies. Pooled results of continuous patient-important outcomes i.e., HbA1c, FPG, blood pressure, body weight, HDL-C, and LDL-C were reported using a mean difference (MD) with 95% confidence interval (CI). Pooled results of binary outcomes i.e. all-cause mortality, AEs, AEs related to study drug, SAEs, SAEs related to study drug, hypoglycemic event, worsening of coronary artery disease, acute myocardial infarction (AMI), aortic aneurism, coronary artery occlusion (CAO) and GMI were summarized using risk ratio (RR) with 95% CI.

We used Mantel–Haenszel method47 to pool effect estimates of dichotomous outcomes and inverse variance for continuous outcomes. The analysis was conducted using a random-effects meta-analyses model as it assumes the observed estimates of the treatment can vary across studies because of the real differences in the treatment effect in each study as well as sampling variability (chance)48. We used Cochrane Q test49 to assess heterogeneity between studies, and I2 testing50 to quantify heterogeneity between studies, with values > 50% representing moderate-to-high heterogeneity. We carried out sensitivity and subgroup analysis by duration of the RCTs. We couldn’t conduct funnel plot and Egger test to check any possible reporting bias because the number of studies included in the meta-analyses are insufficient (less than 10 trials). We considered statistical analysis with a p-value < 0.05 statistically significant.

## Results

### Search results

We searched a total of 3,190 citations through the databases, of which we assessed 30 full-text studies for eligibility and found nine of them51,52,53,54,55,56,57,58,59 fulfilled the inclusion criteria. We excluded the rest 21 full-text articles23,24,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78 mainly for they did not include SGLT2Is or sulfonylureas as a combination therapy; included a combination of more than two glucose-lowering drugs; included single glucose-lowering drug; data were driven from review or post hoc analysis of previous RCTs; had no active comparator; or had a duration of interventions less than a year (Fig. 1).

### Study characteristics

Table 1 summarizes the characteristics of the nine RCTs included. Four RCTs51,54,56,59 used two different doses of SGLT2Is. The meta-analysis included all results of both doses for dichotomous outcomes but only a high dose of SGLT2Is for continuous outcomes.

### Participant characteristics

From the nine RCTs, we polled and included 10,974 patients with T2DM who were in either of the two combination therapies at least for a year (Table 1).

### Methodological quality and risk of bias

The studies were found to be “low risk of bias” when these studies were subjected to the Cochrane Collaboration’s Tool for Quality Assessment of Randomized Controlled Trials (Fig. 2).

### Efficacy and safety assessments

#### All-cause mortality

All the nine included RCTs involving 10,974 participants assessed all-cause mortality/death events between intervention and control groups. Our meta-analysis of pooled results revealed no significant difference in all-cause mortality/death events between patients with T2DM who were on metformin-SGIT2Is and metformin-sulphonylureas combination therapies (RR = 0.93, 95% CI [0.52, 1.67], p = 0.81), with statistically non-significant heterogeneity between studies (I2 = 9%) (Fig. 3). Subgroup analysis by duration of follow-up showed no significant difference in risk of death between the two groups, year 1 (RR = 0.66, 95% CI [0.12, 3.71], p = 0.64, year 2 (RR = 1.25, 95% CI [0.47, 3.32], p = 0.66, and year 4 (RR = 0.80, 95% CI [0.35, 1.84], p = 0.60) (S2).

#### Cardiovascular events

Two trials55,57 evaluated the cardiovascular efficacy of metformin-SGIT2I versus metformin-sulphonylureas combination therapies. The studies followed-up 1,628 participants for coronary artery disease (CAD) and acute myocardial infarction (AMI). After 2 years follow-up, there was no significant difference observed in CAD (RR = 3.01, 95% CI [0.31, 28.92], p = 0.34) and AMI (RR = 0.63, 95% CI [0.08, 5.09], p = 0.66) between the two arms. One of the two trials57 further evaluated 814 patients for coronary artery occlusion (CAO) and aortic aneurism and reported no significant difference in the risk of developing these diseases between the two arms (S3).

Of the nine trials included, eight trials followed-up 8,399 participants for changes in SBP and five trials followed-up 5,804 participants for changes in DBP from the baseline. The report showed a significant decreases for both SBP (MD = − 4.77, 95% CI [− 5.39, − 4.16] mmHg, p < 0.001) and DBP (MD = − 2.07, 95% CI [− 2.74, − 1.40] mmHg, p < 0.001) in patients taking metformin-SGIT2I combination therapy (Figs. 4 and 5).

Two trials51,56 assessed the change in HDL-C and LDL-C levels from baseline between the two arms. Both HDL-C and LDL-C levels were reduced in patients who received metformin-sulphonylureas combination therapies. However, the pooled effect was not statistically significant between the two arms in HDL-C (MD = 4.32, 95% CI [− 4.00, 12.64] mmol/L, p = 0.32), I2 = 99%) and LDL-C (MD = 3.63, 95% CI [− 3.96, 11.22] mmol/L, P = 0.35, I2 = 88%) (S14 & S15) respectively.

With pooled data from the nine trials, we found no statistically significant difference in the risk of developing adverse events between the two arms (RR = 1.00, 95% CI [0.99, 1.02], p = 0.66, I2 = 0% (Fig. 6). We performed a sensitivity analysis by removing the highest weighted study52 and found no significant difference in the risk of developing adverse events between the two arms (RR = 1.00, 95% CI [0.98, 1.02], I2 = 0%). The result of the subgroup analysis was consistent at different duration of follow-up (RR = 0.98, 95% CI [0.94, 1.03] at 1 year, RR = 1.00, 95% CI [0.97, 1.04] at 2 years and RR = 1.01, 95% CI [0.98, 1.04] at 4 years, with p = 0.57 for subgroup difference (S4). Seven RCTs assessed the risk of adverse events related to study drug, of which two RCTs showed lower risk in patients on metformin-sulphonylureas combination therapies but the pooled analysis showed no statistically significant difference (RR = 0.97, 95% CI [0.85, 1.10], p = 0.60, I2 = 69%, (S5). Subgroup analysis of the seven RCTs showed that risk of adverse events related to study drug was similar across different duration of the study, RR = 1.09, 95% CI [0.94, 1.26] at year one, RR = 0.94, 95% CI [0.75, 1.21] at year two, and RR = 0.89, 95% CI [0.73, 1.10] at year four.

All included trials assessed the risk of serious adverse events during the study period, where our analysis of the pooled data showed no significant difference between the two groups (RR = 0.96, 95% CI [0.79, 1.17], with statistically significant heterogeneity across trials (I2 = 68%, p = 0.001) (Fig. 7). Consistently, subgroup analysis showed no significant difference between the two groups at year 1 (95% CI (RR = 0.92 [0.53, 1.59], I2 = 75%), year 2 (RR = 0.98 [0.69, 1.40], I2 = 80%), and year four (RR = 1.02 [0.87, 1.20], I2 = 0%), with subgroup differences of p = 0.92 and I2 = 0% (S6).

Five trials assessed the risk of serious adverse events related to study drug. The pooled result of these trials showed that serious adverse events related to study drug were less frequent on patients taking metformin-sulphonylureas combination, but the pooled result was not significant at 95% CI (RR = 1.34 [0.75, 2.36] (S7).

#### Hypoglycemic events

We analyzed hypoglycemic events on pooled results of the nine trials involving 10,794 T2DM patients, considering the occurrence of at least one hypoglycemic event during the follow-up period. Patients under metformin-SGIT2I combination therapy were found to experience significantly fewer hypoglycemic events as compared to patients under metformin-sulphonylureas combination therapy (RR = 0.13, 95% CI [0.10, 0.17], P < 0.001) I2 = 67%, p = 0.002) (Fig. 8). We performed sensitivity analysis by removing two low weighted trials58,59. However, the result of the remaining trials was similar to the nine trials in risk of hypoglycemia (RR = 0.13, 95% CI [0.10, 0.18, P < 0.001) with increased between study heterogeneity (I2 = 73%, P = 0.009). To see the robustness of the result, we did subgroup analysis at different duration of follow-up. However, the risk of experiencing hypoglycemic events was consistently more frequent under patients on metformin-sulfonylureas combination therapy at 95% CI RR = 0.12[0.08, 0.19], p < 0.001 at year one, RR = 0.15[0.10, 0.22], p < 0.001 at year two and RR = 0.10[0.07, 0.15], p < 0.001 at year four respectively. On the other hand, patients on metformin-SGLT2I were found to experience significantly higher GMI than patients on metformin-sulfonylureas combination therapy RR = 5.00, 95% CI [3.94, 6.33], p < 0.001 (S8).

#### Glycated hemoglobin A1c

All the nine RCTs involving 9,180 participants assessed the changes in HbA1c (%) from baseline between the two arms. The pooled data of these trials showed significant difference in the mean difference of HbA1c between patients on metformin-SGLT2I and metformin-sulfonylureas combination therapies; MD = − 0.10, 95% CI [− 0.17, − 0.03] %, p = 0.005), I2 = 63%, p = 0.006) (Fig. 9). Interestingly, subgroup analysis by duration of follow-up showed a reduction of HbA1c from baseline was not statistically significant between the two groups at year-one, with MD = − 0.01[− 0.13, 0.11] %, I2 = 67%. However, metformin-SGLT2I induced a greater reduction in HbA1c from baseline after 2 years (MD = − 0.12[− 0.20, − 0.05] %, p = 0.001) and after 4 years (MD = − 0.24[− 0.37, − 0.10] %, p = 0.0007) (S9).

#### Bodyweight

All trials included in the meta-analysis assessed the change in body weight from baseline between the two groups. The pooled result showed that body weight of patients in the metformin-SGLT2I was significantly reduced from baseline compared to patients in the metformin-sulfonylureas (MD = − 4.57, 95% CI [− 4.74, − 4.39] kg, p < 0.001) (Fig. 10). We conducted a sensitivity analysis by removing the low weighted56 and the high weighted53 study and the result was consistent with the nine studies. Surprisingly, subgroup analysis also showed consistent results following different duration of follow-up that the mean difference of change in body weight from baseline at year one (MD = − 4.52 [− 4.79, − 4.24] kg, p < 0.001, at year two (MD = − 4.56 [− 4.81, − 4.31] kg, p < 0.001, and at year four (MD = − 4.76[− 5.27, − 4.26] kg, p < 0.0000, respectively (S10).

#### Fasting plasma glucose

Eight trials assessed the change in FPG level from baseline between the intervention and control. The pooled result showed that FPG level was significantly reduced from baseline with patients in the metformin-SGLT2I combination therapies (MD = − 0.55, 95% CI [− 0.69, − 0.41] mmol/L, p < 0.001, I2 = 57%) (Fig. 11). We conducted sensitivity analysis by removing one outlier with a low weighted study58. But the result was consistent with the eight study (MD = − 0.55, 95% CI [− 0.67, − 044], p < 0.001). Subgroup analysis of seven trials also showed consistent results following different duration of intervention and control that the mean difference of change in FPG level from baseline at year one (MD = − 0.47 [− 0.63, − 0.30] mmol/L, p < 0.001, I2 = 0%), at year two (MD = − 0.56 [− 0.74, − 0.38] mmol/L, p < 0.001, I2 = 59% and at year four (MD = − 0.70[− 0.98, − 0.42] mmol/L, p < 0.001) (S11).

## Discussion

The result of this systematic review and meta-analysis showed that the risk of all-cause mortality/death events was not statistically significant between patients in the metformin-SGLT2I and metformin-sulfonylureas combination therapies. In agreement with our findings, a previous study reported a non-significant difference in all-cause mortality and cardiovascular death between the two arms40. Similarly, study77 also revealed a lower and statistically nonsignificant cardiovascular death and all-cause mortality in T2DM patients who were on metformin-sulfonylurea combination therapy. However, another study29 reported that the use of sulfonylureas as a second-line drug has significantly associated with an increased risk of myocardial infarction and all-cause mortality.

The goal of durable glycemic control is to reduce the long-term risk of diabetes-related cardiovascular morbidity and mortality57. Recent studies showed that SGLT2Is have been shown to decrease cardiovascular events in treating high-risk patients with T2DM34. Likewise, the addition of empagliflozin to metformin therapy improves in patients with established CVD or heart failure78. Even though the current meta-analysis of metformin-SGLT2I combination showed a favorable effect on cardiovascular outcomes (acute myocardial infarction, aortic aneurism, coronary artery occlusion, and atherosclerosis), the pooled analysis was not statistically significant.

Lowering blood pressure is significantly important to reduce the risk of CVD and death in many patients with T2DM. A 10-mmHg reduction in systolic blood pressure decreased the risk of major CVD events by 20%79. SGLT2Is induced a greater reduction in systolic and diastolic blood pressure73. Similar with the other findings, the pooled result of our study showed a reduction in both systolic and diastolic blood pressure with patients in the metformin-SGLT2Is combination therapy as compared with metformin-sulfonylureas, which might be due to the effect of SGLT2Is reducing renal glucose reabsorption and increasing urinary excretion51. Consistent with our findings, previous studies reported a greater increase from baseline in HDL-C and LDL-C in patients who were on SGLT2Is groups as compared with sulfonylureas51,54,56.

The result of this meta-analysis showed that the overall incidence of AEs was similar across the two arms, which is consistent with a trial reported by elsewhere59. However, metformin-SGLT2Is combination was associated with a higher episode of GMI which is similar to other meta-analysis reported an increased risk of GMI with SGLT2Is73. In addition, for both genders, the proportion of patients reporting symptoms of GMI was higher in the SGLT2Is group than in the sulfonylureas58. However, these infections respond to standard antimicrobial treatment and their incidence declines with time57. SAEs such as ketoacidosis, bone fractures, and pyelonephritis were rarely reported with metformin-SGLT2Is53, while the pooled result of the current study did not find a statistically significant difference between metformin-SGLT2I and metformin-sulfonylureas combinations. Even though the pooled analysis did not find statistically significant results, AEs related to study drug was observed more in patients with metformin-SGLT2Is, but more SAEs related to study drug in metformin-sulfonylureas. This might be due to the hypoglycemic effect of sulfonylureas and GMI as a result of SGLT2Is respectively.

Sulfonylureas as second-line drugs are associated with an increased risk of severe hypoglycemia79, and our study is in support of this. The hypoglycemic effect of sulfonylureas might be due to its insulin-dependent mechanism of action, while the less hypoglycemic effect of SGLT2Is is due to the non-insulin dependent mechanism of action.

Obesity is one of the main risk factors for T2DM and representing a major worldwide health problem. Lowering body weight is an important part of T2DM management. SGLT2Is has been associated with an added benefit of weight loss in patients with T2DM, whereas sulfonylureas are reported to increase body weight80. In support of this evidence, our study showed a 4.57 kg weight loss in metformin-SGLT2Is group than the metformin-sulfonylureas. The weight loss caused by SGLT2Is is probably due to the loss of calories via urine and glucose-induced osmotic diuresis51.

Long term glycemic control is the major goal of diabetes management to prevent both microvascular and macrovascular complications of DM81. Both metformin-SGLT2Is and metformin-sulfonylureas combinations are effective to control HbA1c for a short duration of follow-up. However, for a long duration of follow-up, metformin-SGLT2Is are more effective than metformin-sulfonylureas73. Our finding is consistent with this evidence where both groups were equally effective for a one-year duration of follow-up; however, as the duration of follow-up increases to 4 years, metformin-SGLT2Is combination showed a significant reduction from baseline in HbA1c. Eight previously conducted trials reported a higher reduction of FPG in patients randomized to metformin-SGLT2Is51,52,53,54,56,57,58,59, and our pooled result is in support of their finding as it showed reduction of FPG under patients on metformin-SGLT2Is.

This study reported important information about cardiovascular safety, efficacy, and cardiovascular risk factors control between the two combination therapies. However, we acknowledge that available studies are very limited and heterogeneous. There remains a need for additional long-term trials comparing the overall safety, efficacy, and cost-effectiveness of metformin-SGLT2Is and metformin-sulfonylureas combination therapies.

## Conclusion

Combination therapy of metformin and sodium-glucose cotransporter-2 inhibitors are a safe and efficacious alternative to combination therapy of metformin and sulfonylureas for patients with T2DM who are at risk of cardiovascular comorbidity. However, there remains a need for additional long-term randomized controlled trials as available studies are very limited and heterogeneous.