Comparison between sodium-glucose cotransporter 2 inhibitors and pioglitazone as additions to insulin therapy in type 2 diabetes patients: A systematic review with an indirect comparison meta-analysis.

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hyperglycemia 1 endocrinologydiseases
hypoglycemia 26 endocrinologydiseases
metformin 3 endocrinologydiseasesdrugs
pioglitazone 7 endocrinologydiseasesdrugs
type 2 diabetes mellitus 24 endocrinologydiseases
Insulin 17 endocrinologydiseasesdrugs
diabetes mellitus 25 endocrinologydiseases

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Select Drug Character Offset Drug Term Instance
Insulin 11801 therapyInterventionsDuration (weeks)nAge (years)Male (%)BMI (kg/m2)HbA1c (%)HbA1c (mmol/mol)FPG (mg/dL) Insulin dose (units/day)Rosenstock (2002)Insulin (OADs wash out)Not reported Placebo PIO 15 mg PIO 30 mg 16 187 191 188 56.7 56.9 57.5 45.5 46.1 50.5 33.2 33.2 34.3 9.75 9.75 9.84 83.1 83.1 84.0 220.5 221.7 229.3 70.7 70.2 72.3 Mattoo
Insulin 11842 (years)Male (%)BMI (kg/m2)HbA1c (%)HbA1c (mmol/mol)FPG (mg/dL)Insulin dose (units/day)Rosenstock (2002) Insulin (OADs wash out)Not reported Placebo PIO 15 mg PIO 30 mg 16 187 191 188 56.7 56.9 57.5 45.5 46.1 50.5 33.2 33.2 34.3 9.75 9.75 9.84 83.1 83.1 84.0 220.5 221.7 229.3 70.7 70.2 72.3 Mattoo
Insulin 12051 30 mg 16 187 191 188 56.7 56.9 57.5 45.5 46.1 50.5 33.2 33.2 34.3 9.75 9.75 9.84 83.1 83.1 84.0 220.5 221.7 229.3 70.7 70.2 72.3 Mattoo (2005) Insulin ± OADsNot reported Placebo PIO 30 mg 24 147 142 58.9 58.8 42.9 43.7 31.8 32.5 8.79 8.85 72.6 73.2 203.1 204.7 0.96‡ 0.92‡Berhanu
Insulin 12209 30 mg 24 147 142 58.9 58.8 42.9 43.7 31.8 32.5 8.79 8.85 72.6 73.2 203.1 204.7 0.96‡ 0.92‡Berhanu (2007) Insulin ± MetVarious insulin regimen† Placebo PIO 45 mg 20 110 112 52.5 52.9 41.1 43.6 31.8 30.7 8.6 8.4 70.5 68.3 109.7 111.1 57.7 55.8 Charbonnel
Insulin 12376 45 mg 20 110 112 52.5 52.9 41.1 43.6 31.8 30.7 8.6 8.4 70.5 68.3 109.7 111.1 57.7 55.8 Charbonnel (2010) Insulin ± OADsVarious insulin regimen† Placebo PIO 45 mg 149 896 864 61.2 61.7 61.0 58.2 31.9 31.6 8.5 8.4 69.4 68.3 NA NA 46.7 46.5 Galle
Insulin 12534 45 mg 149 896 864 61.2 61.7 61.0 58.2 31.9 31.6 8.5 8.4 69.4 68.3 NA NA 46.7 46.5 Galle (2012) Insulin Basal and prandial insulin Placebo PIO 30 mg 24 19 20 69.6 68.9 68.4 70.0 30.3 31.5 7.7 7.4 60.7 57.4 160.5 159.9 55.37 63.96 Kharazm‐kia
Insulin 12695 30 mg 24 19 20 69.6 68.9 68.4 70.0 30.3 31.5 7.7 7.4 60.7 57.4 160.5 159.9 55.37 63.96 Kharazm‐kia (2014) Insulin Insulin NPH Placebo PIO 30 mg 16 31 31 54.8 50.2 51.6 77.4 NA NA 7.8 8.6 61.7 70.5 145.5 136.0 34.1 38.2 Data
Insulin 12702 30 mg 24 19 20 69.6 68.9 68.4 70.0 30.3 31.5 7.7 7.4 60.7 57.4 160.5 159.9 55.37 63.96 Kharazm‐kia (2014)Insulin Insulin NPH Placebo PIO 30 mg 16 31 31 54.8 50.2 51.6 77.4 NA NA 7.8 8.6 61.7 70.5 145.5 136.0 34.1 38.2 Data
Insulin 13545 therapyInterventionsDuration (weeks)nAge (years)Male (%)BMI (kg/m2)HbA1c (%)HbA1c (mmol/mol)FPG (mg/dL) Insulin dose (units/day)Wilding (2009)Insulin ± Met ± TZDNot reported Placebo Dapagliflozin 10 mg 12 23 24 58.4 55.7 69.6 54.2 34.8 35.5 8.4 8.4 68.3 68.3 165.9 156.0 90§ 93§Wilding
Insulin 13583 (years)Male (%)BMI (kg/m2)HbA1c (%)HbA1c (mmol/mol)FPG (mg/dL)Insulin dose (units/day)Wilding (2009) Insulin ± Met ± TZDNot reported Placebo Dapagliflozin 10 mg 12 23 24 58.4 55.7 69.6 54.2 34.8 35.5 8.4 8.4 68.3 68.3 165.9 156.0 90§ 93§Wilding
Insulin 13749 10 mg 12 23 24 58.4 55.7 69.6 54.2 34.8 35.5 8.4 8.4 68.3 68.3 165.9 156.0 90§ 93§Wilding (2012) Insulin ± OADsNot reported Placebo Dapagliflozin 5 mg Dapagliflozin 10 mg 48 193 211 194 58.8 59.3 59.3 49.2 47.4 44.8 33.1 33.0 33.4 8.47 8.62 8.57 69.1 70.7 70.2 170.6 185.4 173.1 73.7 77.0 78.0 Rosenstock
Insulin 13975 10 mg 48 193 211 194 58.8 59.3 59.3 49.2 47.4 44.8 33.1 33.0 33.4 8.47 8.62 8.57 69.1 70.7 70.2 170.6 185.4 173.1 73.7 77.0 78.0 Rosenstock (2014) Insulin ± MetMDI Placebo Empagliflozin 10 mg Empagliflozin 25 mg 52 188 186 189 55.3 56.7 58.0 40 52 44 34.7 34.7 35.0 8.33 8.39 8.29 67.5 68.2 67.1 151.5 159.1 150.3 93.1 89.9 92.9 Neal
Insulin 14180 25 mg 52 188 186 189 55.3 56.7 58.0 40 52 44 34.7 34.7 35.0 8.33 8.39 8.29 67.5 68.2 67.1 151.5 159.1 150.3 93.1 89.9 92.9 Neal (2015) Insulin ± Met ± SUVarious insulin regimen† Placebo Canagliflozin 100 mg Canagliflozin 300 mg 52 690 692 690 63† 62† 63† 66 67 65 33.1 33.0 33.3 8.3 8.3 8.3 67.2 67.2 67.2 165.8 165.8 165.8 58§ 60§ 60§Rosenstock
Insulin 14422 300 mg 52 690 692 690 63† 62† 63† 66 67 65 33.1 33.0 33.3 8.3 8.3 8.3 67.2 67.2 67.2 165.8 165.8 165.8 58§ 60§ 60§Rosenstock (2015) Insulin ± Met ± SUBasal insulin‡ Placebo Empagliflozin 10 mg Empagliflozin 25 mg 78 170 169 155 58.1 58.6 59.9 53 55 60 31.8 32.1 32.7 8.2 8.3 8.3 66.1 67.2 67.2 142.3 138.7 145.9 47.8 45.1 48.4 Inagaki
Insulin 14648 25 mg 78 170 169 155 58.1 58.6 59.9 53 55 60 31.8 32.1 32.7 8.2 8.3 8.3 66.1 67.2 67.2 142.3 138.7 145.9 47.8 45.1 48.4 Inagaki (2016) Insulin Various insulin regimen† Placebo Canagliflozin 100 mg 16 70 76 56.1 59.7 70.0 57.9 25.99 26.88 8.85 8.89 73.2 73.7 169.1 169.9 28.1 31.1 Araki
Insulin 14814 100 mg 16 70 76 56.1 59.7 70.0 57.9 25.99 26.88 8.85 8.89 73.2 73.7 169.1 169.9 28.1 31.1 Araki (2016) Insulin ± DPP4iNot reported Placebo Dapagliflozin 5 mg 16 60 122 57.6 58.3 66.7 73.0 26.1 26.9 8.52 8.26 69.6 66.8 159.7 160.7 40.58 37.87 Ishihara
Insulin 14979 5 mg 16 60 122 57.6 58.3 66.7 73.0 26.1 26.9 8.52 8.26 69.6 66.8 159.7 160.7 40.58 37.87 Ishihara (2016) Insulin ± OADsVarious insulin regimen† Placebo Ipragliflozin 50 mg 16 87 175 59.2 58.7 58.6 62.5 26.4 25.6 8.6 8.7 70.5 71.6 160.5 159.9 Range¶Data
metformin 2754 progressive deterioration in insulin secretion and failure of oral antidiabetic drugs (OADs; including metformin and sulfonylureas) in maintaining optimal glycemic targets, many individuals with type 2 diabetes mellitus
metformin 13159 injections/day). ‡U/day/kg. BMI, body mass index; FPG, fasting plasma glucose; HbA1c, hemoglobin A1c; Met, metformin ; NA, not available; NPH, neutral protamine Hagedorn; OADs, oral antidiabetic agents; PIO, pioglitazone.John
metformin 15836 inhibitors; FPG, fasting plasma glucose; HbA1c, hemoglobin A1c; MDI, multiple daily injections; Met, metformin ; NA, not available; OADs, oral antidiabetic agents; SGLT2i, sodium–glucose cotransporter 2 inhibitors;
pioglitazone 107 Journal of Diabetes InvestigationComparison between sodium–glucose cotransporter 2 inhibitors and pioglitazone as additions to insulin therapy in type 2 diabetes patients: A systematic review with an indirect comparison
pioglitazone 714 date (ppub): 7/2018AbstractAbstractAims/IntroductionWe aimed to evaluate the efficacy and safety of pioglitazone (PIO) and sodium–glucose cotransporter 2 inhibitors (SGLT2i) as additions to insulin therapy for the
pioglitazone 11628 the included studies are presented in Tables 1 and 2.Table 1Baseline characteristics of the included pioglitazone studiesAuthor (year)Background therapyRegimen of insulin therapyInterventionsDuration (weeks)nAge (years)Male
pioglitazone 13259 metformin; NA, not available; NPH, neutral protamine Hagedorn; OADs, oral antidiabetic agents; PIO, pioglitazone .John Wiley & Sons, LtdTable 2Baseline characteristics of the included sodium–glucose cotransporter
pioglitazone 17414 bias, owing to the small number of studies included and the large heterogeneity.Figure 1Efficacy of pioglitazone (PIO) or sodium–glucose cotransporter 2 inhibitors (SGLT2i) added to insulin (INS) therapy. (a) Weighted
pioglitazone 20452 when adjusted for age and sex (WMD 4.54 kg, 95% CI: 3.41–5.67 kg; P < 0.001).Figure 2Effect of pioglitazone (PIO) or sodium–glucose cotransporter 2 inhibitors (SGLT2i) on bodyweight, insulin (INS) requirement
pioglitazone 31018 treatment.DisclosureThe authors declare no conflict of interest.Supporting informationTable S1 | Search strategy for pioglitazone ‐related studies.Table S2 | Search strategy for sodium–glucose cotransporter 2 inhibitor‐related
Select Disease Character Offset Disease Term Instance
diabetes mellitus 851 sodium–glucose cotransporter 2 inhibitors (SGLT2i) as additions to insulin therapy for the management of type 2 diabetes mellitus .Materials and MethodsWe searched PubMed, EMBASE, the Cochrane Central Register of Controlled Trials
diabetes mellitus 1188 plus insulin (SGLT2i/INS) or PIO plus insulin (PIO/INS) with placebo plus insulin (PCB/INS) in type 2 diabetes mellitus patients were included. We compared the efficacy and safety between SGLT2i/INS and PIO/INS indirectly.ResultsA
diabetes mellitus 2411 adjunctive oral agents to pre‐existing insulin therapy in individuals with inadequately controlled type 2 diabetes mellitus .J Diabetes Investig2018;9:882–892IntroductionType 2 diabetes mellitus is characterized by peripheral
diabetes mellitus 2483 inadequately controlled type 2 diabetes mellitus.J Diabetes Investig2018;9:882–892IntroductionType 2 diabetes mellitus is characterized by peripheral insulin resistance with progressive impairment in pancreatic β‐cell
diabetes mellitus 2853 metformin and sulfonylureas) in maintaining optimal glycemic targets, many individuals with type 2 diabetes mellitus eventually require insulin therapy2.Although various insulin formulations are available and the dose
diabetes mellitus 3113 glycemic targets, several OADs need to be administered to individuals with poorly controlled type 2 diabetes mellitus , despite the use of insulin therapy3, 4. This combined use of OADs with concurrent insulin treatment
diabetes mellitus 3932 combination with insulin might improve glycemic control at a reduced insulin dose in individuals with type 2 diabetes mellitus that was poorly controlled with previous insulin therapy5.Sodium–glucose cotransporter 2 inhibitors
diabetes mellitus 4662 treatment9, 10, 11, 12, 13, 14. Hence, SGLT2i are feasible adjunctive agents to insulin therapy for type 2 diabetes mellitus .Thus, the adjunctive use of either TZD (usually PIO) or SGLT2i might help improve glycemic control and
diabetes mellitus 4964 insulin doses3. However, no head‐to‐head trial has compared SGLT2i and PIO in individuals with type 2 diabetes mellitus that is inadequately controlled with insulin.In the present systematic review and meta‐analysis, we
diabetes mellitus 5208 efficacy and safety of the addition of PIO and SGLT2i to insulin therapy for the management of type 2 diabetes mellitus by carrying out an indirect comparison using studies with either the addition of PIO or SGLT2i to pre‐existing
diabetes mellitus 5382 with either the addition of PIO or SGLT2i to pre‐existing insulin therapy in individuals with type 2 diabetes mellitus .MethodsSearch strategy and Study selectionBefore this meta‐analysis, the Preferred Reporting Items
diabetes mellitus 11195 our electronic literature search, of which six eligible RCTs involving 2,938 participants with type 2 diabetes mellitus who were randomized into PIO or placebo groups, and eight eligible RCTs involving 4,288 participants
diabetes mellitus 11326 randomized into PIO or placebo groups, and eight eligible RCTs involving 4,288 participants with type 2 diabetes mellitus randomized into SGLT2i or placebo groups were finally enrolled in our meta‐analysis. Flow charts of
diabetes mellitus 22947 between the two groups (RR 1.15, 95% CI: 0.97–1.35; P = 0.102).DiscussionMost individuals with type 2 diabetes mellitus treated with OADs eventually require insulin therapy to manage the progressive deterioration in glycemic
diabetes mellitus 23337 27. This complicated clinical situation is commonly exemplified by individuals with advanced type 2 diabetes mellitus who require high doses of insulin or require a novel strategy for better glycemic control11, 28. The
diabetes mellitus 23765 glycemic control, with similar hypoglycemic risks and insulin‐sparing effects in individuals with type 2 diabetes mellitus inadequately controlled with insulin. However, SGLT2i treatment achieved a greater reduction in bodyweight
diabetes mellitus 24720 efficacy in glycemic control when added to insulin therapy in individuals with poorly controlled type 2 diabetes mellitus .Most individuals with type 2 diabetes mellitus are obese or overweight29, which might aggravate insulin
diabetes mellitus 24767 therapy in individuals with poorly controlled type 2 diabetes mellitus.Most individuals with type 2 diabetes mellitus are obese or overweight29, which might aggravate insulin resistance and result in dose escalation or
diabetes mellitus 25093 Therefore, insulin‐induced weight gain is an important issue in the management of individuals with type 2 diabetes mellitus , particularly in cases poorly controlled with insulin therapy30. In the present meta‐analysis, SGLT2i/INS
diabetes mellitus 25637 weight gain, SGLT2i might serve as a better option for obese or overweight individuals with type 2 diabetes mellitus , particularly those regarding the bodyweight gain accompanying insulin therapy.Intensification of the
diabetes mellitus 27083 hypoglycemia should also be carefully considered during treatment selection in individuals with type 2 diabetes mellitus , and most guidelines highlight the importance of minimizing this risk34. Hence, the selection of a treatment
diabetes mellitus 29010 both agents (i.e., PIO and SGLT2i) showed improved cardiovascular outcomes in patients with type 2 diabetes mellitus at high cardiovascular risk in their corresponding CVD outcome trials (PROactive study for PIO, Empagliflozin
diabetes mellitus 29945 according to the result of meta‐regression analysis. Fifth, the long‐term complications of type 2 diabetes mellitus and some major safety concerns, including genital infection, euglycemic ketoacidosis and edema, were
diabetes mellitus 30332 adjunctive OADs to pre‐existing insulin therapy in individuals with inadequately controlled type 2 diabetes mellitus . PIO and SGLT2i treatment both led to a significant reduction in HbA1c and FPG levels, and increased
diabetes mellitus 30864 provide important evidence for selecting OADs to improve glycemic control in individuals with type 2 diabetes mellitus receiving insulin treatment.DisclosureThe authors declare no conflict of interest.Supporting informationTable S1
hyperglycemia 2624 peripheral insulin resistance with progressive impairment in pancreatic β‐cell function, leading to hyperglycemia 1. Due to the progressive deterioration in insulin secretion and failure of oral antidiabetic drugs (OADs;
hypoglycemia 2072 −5.67 to −3.41 kg; P < 0.001). PIO/INS showed non‐significant trends toward a higher risk of hypoglycemia (relative risk 1.15, 95% CI: 0.97 to 1.35; P = 0.102) and higher reduction of total daily insulin
hypoglycemia 3254 insulin therapy3, 4. This combined use of OADs with concurrent insulin treatment minimizes the risk of hypoglycemia associated with insulin use, and might help reduce the insulin dose, while simultaneously facilitating
hypoglycemia 4363 suggests that SGLT2i can improve glycemic control, while also resulting in weight loss and reduced risk of hypoglycemia 7, 8. The addition of SGLT2i to insulin treatment improves glycemic control and reduces bodyweight, and
hypoglycemia 4516 treatment improves glycemic control and reduces bodyweight, and is associated with a similar risk of hypoglycemia , as compared with placebo treatment9, 10, 11, 12, 13, 14. Hence, SGLT2i are feasible adjunctive agents
hypoglycemia 6930 proportion of patients achieving the therapeutic goal of HbA1c <7.0% (<53.0 mmol/mol); and the risk of hypoglycemia at the final end‐point of each study. For studies wherein the change from baseline was not reported,
hypoglycemia 7272 was converted to mg/dL by using the following formula: 1 mmol/L = 18 mg/dL. The definitions of hypoglycemia are shown in Tables S3 and S4. In addition to the outcome measures, the two authors (YKC and CHJ) also
hypoglycemia 9096 dichotomous outcomes, including the proportion of participants achieving target HbA1c values and the risk of hypoglycemia . We evaluated the validity of the methods for the analysis of indirect comparisons and determined an
hypoglycemia 20572 or sodium–glucose cotransporter 2 inhibitors (SGLT2i) on bodyweight, insulin (INS) requirement and hypoglycemia risk. (a) Weighted mean differences (WMDs) in changes in bodyweight from baseline. (b) Weighted mean
hypoglycemia 20775 Weighted mean differences (WMDs) in changes in insulin dose from baseline. (c) Relative risks (RRs) of hypoglycemia . The tops of each figure represent the comparison of treatment (PIO/INS or SGLT2i/INS) vs PCB/INS, and
hypoglycemia 22524 22 and eight SGLT2i studies (n = 4,239)9, 11, 12, 13, 14, 24, 25, 26 were analyzed for the risk of hypoglycemia (Figure 2c). The unadjusted indirect comparison showed that the risk for hypoglycemia was higher in
hypoglycemia 22611 the risk of hypoglycemia (Figure 2c). The unadjusted indirect comparison showed that the risk for hypoglycemia was higher in the PIO/INS group than in the SGLT2i/INS group (RR 1.24, 95% CI: 1.06–1.44; P = 0.006).
hypoglycemia 22796 95% CI: 1.06–1.44; P = 0.006). After adjusting for age, sex, BMI and baseline HbA1c, the risk of hypoglycemia was not significantly different between the two groups (RR 1.15, 95% CI: 0.97–1.35; P = 0.102).DiscussionMost
hypoglycemia 23182 time2. However, therapies that depend on insulin supplementation are also associated with risks of hypoglycemia , weight gain and loss of effectiveness11, 27. This complicated clinical situation is commonly exemplified
hypoglycemia 25939 levels, as an aggressive insulin regimen might lead to complications, such as weight gain, edema and hypoglycemia 2, 10. Therefore, there is a need for other OADs as add‐on therapy with an insulin‐sparing effect.
hypoglycemia 26980 compared with in the SGLT2i/INS group (Figure 2b).In addition to the efficacy of a treatment, the risk of hypoglycemia should also be carefully considered during treatment selection in individuals with type 2 diabetes mellitus,
hypoglycemia 27239 importance of minimizing this risk34. Hence, the selection of a treatment that is less likely to cause hypoglycemia is vital. SGLT2i and TZDs both carry a lower risk of hypoglycemia compared with other add‐on treatments,
hypoglycemia 27305 treatment that is less likely to cause hypoglycemia is vital. SGLT2i and TZDs both carry a lower risk of hypoglycemia compared with other add‐on treatments, such as sulfonylureas, while offering similar glycemic control8,
hypoglycemia 27451 treatments, such as sulfonylureas, while offering similar glycemic control8, 35. However, we found that hypoglycemia was more common in the PIO/INS and SGLT2i/INS groups than in the respective PCB/INS group (Figure 2c),
hypoglycemia 27728 mild in severity. Previous studies have reported that although PIO is related to a low incidence of hypoglycemia , concomitant therapy with insulin could increase the risk of hypoglycemia36, 37. Similarly, hypoglycemia
hypoglycemia 27802 related to a low incidence of hypoglycemia, concomitant therapy with insulin could increase the risk of hypoglycemia 36, 37. Similarly, hypoglycemia often occurs when individuals receive SGLT2i as an add‐on to background
hypoglycemia 27833 hypoglycemia, concomitant therapy with insulin could increase the risk of hypoglycemia36, 37. Similarly, hypoglycemia often occurs when individuals receive SGLT2i as an add‐on to background therapy with insulin7, 38,
hypoglycemia 27972 individuals receive SGLT2i as an add‐on to background therapy with insulin7, 38, whereas the incidence of hypoglycemia during SGLT2i treatment is generally low38. Furthermore, in this meta‐analysis, there was a non‐significant
hypoglycemia 28128 Furthermore, in this meta‐analysis, there was a non‐significant trend towards a higher risk of hypoglycemia in the PIO/INS group compared with the SGLT2i/INS group (Figure 2c). This result is consistent with
hypoglycemia 28752 treatment, the methods used for insulin dose titration (Tables 1, 2 and S5) and the definition of hypoglycemia (Table S3) were inconsistent among the included studies. Third, although the cardiovascular benefit
hypoglycemia 30656 that PIO and SGLT2i treatments confer comparable efficacy, with similar insulin dose reduction and hypoglycemia risk. Thus, in the absence of a head‐to‐head comparison, the results of the present study provide
hypoglycemia 31173 strategy for sodium–glucose cotransporter 2 inhibitor‐related studies.Table S3 | The definitions of hypoglycemia in the included studies.Table S4 | Methodological quality assessment.Table S5 | The insulin titration
type 2 diabetes mellitus 844 sodium–glucose cotransporter 2 inhibitors (SGLT2i) as additions to insulin therapy for the management of type 2 diabetes mellitus .Materials and MethodsWe searched PubMed, EMBASE, the Cochrane Central Register of Controlled Trials
type 2 diabetes mellitus 1181 SGLT2i plus insulin (SGLT2i/INS) or PIO plus insulin (PIO/INS) with placebo plus insulin (PCB/INS) in type 2 diabetes mellitus patients were included. We compared the efficacy and safety between SGLT2i/INS and PIO/INS indirectly.ResultsA
type 2 diabetes mellitus 2404 adjunctive oral agents to pre‐existing insulin therapy in individuals with inadequately controlled type 2 diabetes mellitus .J Diabetes Investig2018;9:882–892IntroductionType 2 diabetes mellitus is characterized by peripheral
type 2 diabetes mellitus 2846 including metformin and sulfonylureas) in maintaining optimal glycemic targets, many individuals with type 2 diabetes mellitus eventually require insulin therapy2.Although various insulin formulations are available and the dose
type 2 diabetes mellitus 3106 maintain glycemic targets, several OADs need to be administered to individuals with poorly controlled type 2 diabetes mellitus , despite the use of insulin therapy3, 4. This combined use of OADs with concurrent insulin treatment
type 2 diabetes mellitus 3925 combination with insulin might improve glycemic control at a reduced insulin dose in individuals with type 2 diabetes mellitus that was poorly controlled with previous insulin therapy5.Sodium–glucose cotransporter 2 inhibitors
type 2 diabetes mellitus 4655 treatment9, 10, 11, 12, 13, 14. Hence, SGLT2i are feasible adjunctive agents to insulin therapy for type 2 diabetes mellitus .Thus, the adjunctive use of either TZD (usually PIO) or SGLT2i might help improve glycemic control and
type 2 diabetes mellitus 4957 insulin doses3. However, no head‐to‐head trial has compared SGLT2i and PIO in individuals with type 2 diabetes mellitus that is inadequately controlled with insulin.In the present systematic review and meta‐analysis, we
type 2 diabetes mellitus 5201 the efficacy and safety of the addition of PIO and SGLT2i to insulin therapy for the management of type 2 diabetes mellitus by carrying out an indirect comparison using studies with either the addition of PIO or SGLT2i to pre‐existing
type 2 diabetes mellitus 5375 studies with either the addition of PIO or SGLT2i to pre‐existing insulin therapy in individuals with type 2 diabetes mellitus .MethodsSearch strategy and Study selectionBefore this meta‐analysis, the Preferred Reporting Items
type 2 diabetes mellitus 11188 through our electronic literature search, of which six eligible RCTs involving 2,938 participants with type 2 diabetes mellitus who were randomized into PIO or placebo groups, and eight eligible RCTs involving 4,288 participants
type 2 diabetes mellitus 11319 were randomized into PIO or placebo groups, and eight eligible RCTs involving 4,288 participants with type 2 diabetes mellitus randomized into SGLT2i or placebo groups were finally enrolled in our meta‐analysis. Flow charts of
type 2 diabetes mellitus 22940 between the two groups (RR 1.15, 95% CI: 0.97–1.35; P = 0.102).DiscussionMost individuals with type 2 diabetes mellitus treated with OADs eventually require insulin therapy to manage the progressive deterioration in glycemic
type 2 diabetes mellitus 23330 effectiveness11, 27. This complicated clinical situation is commonly exemplified by individuals with advanced type 2 diabetes mellitus who require high doses of insulin or require a novel strategy for better glycemic control11, 28. The
type 2 diabetes mellitus 23758 glycemic control, with similar hypoglycemic risks and insulin‐sparing effects in individuals with type 2 diabetes mellitus inadequately controlled with insulin. However, SGLT2i treatment achieved a greater reduction in bodyweight
type 2 diabetes mellitus 24713 comparable efficacy in glycemic control when added to insulin therapy in individuals with poorly controlled type 2 diabetes mellitus .Most individuals with type 2 diabetes mellitus are obese or overweight29, which might aggravate insulin
type 2 diabetes mellitus 24760 insulin therapy in individuals with poorly controlled type 2 diabetes mellitus.Most individuals with type 2 diabetes mellitus are obese or overweight29, which might aggravate insulin resistance and result in dose escalation or
type 2 diabetes mellitus 25086 Therefore, insulin‐induced weight gain is an important issue in the management of individuals with type 2 diabetes mellitus , particularly in cases poorly controlled with insulin therapy30. In the present meta‐analysis, SGLT2i/INS
type 2 diabetes mellitus 25630 insulin‐associated weight gain, SGLT2i might serve as a better option for obese or overweight individuals with type 2 diabetes mellitus , particularly those regarding the bodyweight gain accompanying insulin therapy.Intensification of the
type 2 diabetes mellitus 27076 of hypoglycemia should also be carefully considered during treatment selection in individuals with type 2 diabetes mellitus , and most guidelines highlight the importance of minimizing this risk34. Hence, the selection of a treatment
type 2 diabetes mellitus 29003 although both agents (i.e., PIO and SGLT2i) showed improved cardiovascular outcomes in patients with type 2 diabetes mellitus at high cardiovascular risk in their corresponding CVD outcome trials (PROactive study for PIO, Empagliflozin
type 2 diabetes mellitus 29938 covariates according to the result of meta‐regression analysis. Fifth, the long‐term complications of type 2 diabetes mellitus and some major safety concerns, including genital infection, euglycemic ketoacidosis and edema, were
type 2 diabetes mellitus 30325 options as adjunctive OADs to pre‐existing insulin therapy in individuals with inadequately controlled type 2 diabetes mellitus . PIO and SGLT2i treatment both led to a significant reduction in HbA1c and FPG levels, and increased
type 2 diabetes mellitus 30857 study provide important evidence for selecting OADs to improve glycemic control in individuals with type 2 diabetes mellitus receiving insulin treatment.DisclosureThe authors declare no conflict of interest.Supporting informationTable S1

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