Efficacy and safety of combination therapy with an α-glucosidase inhibitor and a dipeptidyl peptidase-4 inhibitor in patients with type 2 diabetes mellitus: A systematic review with meta-analysis.

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Term Occurence Count Dictionary
type 2 diabetes mellitus 19 endocrinologydiseases
acarbose 14 endocrinologydiseasesdrugs
diabetes mellitus 19 endocrinologydiseases
hypoglycemia 13 endocrinologydiseases
metformin 9 endocrinologydiseasesdrugs
miglitol 7 endocrinologydiseasesdrugs
obesity 1 endocrinologydiseases
sitagliptin 4 endocrinologydiseasesdrugs

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Select Drug Character Offset Drug Term Instance
acarbose 4024 further increase the therapeutic efficacy of DPP4 inhibitors. The α‐glucosidase inhibitors (AGIs), acarbose , miglitol and voglibose, delay carbohydrate absorption from the small intestine by inhibiting the hydrolysis
acarbose 4663 increased GLP‐1 secretion from the L‐cells9, 10. Indeed, in non‐diabetic healthy individuals, acarbose increased GLP‐1 secretion when given with sucrose11 and voglibose increased GLP‐1 secretion when
acarbose 4881 with a standardized meal12. In patients with type 2 diabetes mellitus, simultaneous administration of acarbose and sucrose resulted in increased GLP‐1 release13, and a 2‐day administration of miglitol increased
acarbose 5080 miglitol increased GLP‐1 secretion and decreased GIP secretion after a meal9. In addition, a 24‐week acarbose treatment in patients with newly diagnosed type 2 diabetes mellitus increased postprandial GLP‐1 levels14.
acarbose 5240 diabetes mellitus increased postprandial GLP‐1 levels14. However, in another study15, ingestion of acarbose with a mixed test meal failed to enhance GLP‐1 release in patients with type 2 diabetes mellitus.
acarbose 5411 patients with type 2 diabetes mellitus. Furthermore, in elderly type 2 diabetes patients treated with acarbose , just 20% of the patients showed increased GLP‐1 secretion, and no significant correlations between
acarbose 5628 GLP‐1 levels and serum glucose or insulin levels were observed16. Intriguingly, miglitol, but not acarbose , increased active postprandial GLP‐1 levels in individuals with visceral obesity (50% of the participants
acarbose 8584 ‘tenegliptin,’ ‘evogliptin,’ ‘omarigliptin,’ ‘trelagliptin,’ ‘alpha‐glucosidase inhibitor,’ ‘ acarbose ,’ ‘miglitol’ and ‘voglibose.’ The detailed search terms used in this study are provided in
acarbose 13863 voglibose 0.2–0.3 mg t.i.d.6358.671.4151.524.37.96.1Wang et al. (2015)2412Vildagliptin 50 mg bid + acarbose + metformin24546.6157.9160.424.18.98.09Placebo + acarbose + metformin24545.6754.6168.724.38.68.17Wang
acarbose 13921 et al. (2015)2412Vildagliptin 50 mg bid + acarbose + metformin24546.6157.9160.424.18.98.09Placebo + acarbose + metformin24545.6754.6168.724.38.68.17Wang et al. (2017)2524Sitagliptin 100 mg q.d. + acarbose 50
acarbose 14019 + acarbose + metformin24545.6754.6168.724.38.68.17Wang et al. (2017)2524Sitagliptin 100 mg q.d. + acarbose 50 or 100 mg t.i.d.19156.550.8178.425.98.17.4Placebo + acarbose 50 or 100 mg t.i.d.18957.851.3176.626.08.18.2BMI,
acarbose 14084 (2017)2524Sitagliptin 100 mg q.d. + acarbose 50 or 100 mg t.i.d.19156.550.8178.425.98.17.4Placebo + acarbose 50 or 100 mg t.i.d.18957.851.3176.626.08.18.2BMI, body mass index; HbA1c, glycated hemoglobin; NR,
acarbose 22154 increase in bodyweight after the addition of a DPP4 inhibitor to an AGI. A meta‐analysis that compared acarbose and placebo in patients with type 2 diabetes mellitus showed reduced body mass index in favor of acarbose8.
acarbose 22260 acarbose and placebo in patients with type 2 diabetes mellitus showed reduced body mass index in favor of acarbose 8. Some AGIs have been reported to reduce appetite and change the gut hormone levels in postprandial
metformin 13570 voglibose 0.2 mg t.i.d.7562.364.0NR24.48.17.52Su et al. (2014)2212Vildagliptin 50 mg bid + AGI + metformin 26048.65NR167.9NR9.0NRPlacebo + AGI + metformin26049.67NR159.6NR8.7NRTajima et al. (2013)2312Sitagliptin
metformin 13617 t.i.d.7562.364.0NR24.48.17.52Su et al. (2014)2212Vildagliptin 50 mg bid + AGI + metformin26048.65NR167.9NR9.0NRPlacebo + AGI + metformin 26049.67NR159.6NR8.7NRTajima et al. (2013)2312Sitagliptin 50 mg + voglibose 0.2–0.3 mg t.i.d.7062.360.0152.723.97.98.2Placebo
metformin 13874 0.2–0.3 mg t.i.d.6358.671.4151.524.37.96.1Wang et al. (2015)2412Vildagliptin 50 mg bid + acarbose + metformin 24546.6157.9160.424.18.98.09Placebo + acarbose + metformin24545.6754.6168.724.38.68.17Wang et al. (2017)2524Sitagliptin
metformin 13932 (2015)2412Vildagliptin 50 mg bid + acarbose + metformin24546.6157.9160.424.18.98.09Placebo + acarbose + metformin 24545.6754.6168.724.38.68.17Wang et al. (2017)2524Sitagliptin 100 mg q.d. + acarbose 50 or 100 mg
metformin 20001 HbA1c levels, showed a greater reduction than that in other studies. In addition, concurrent use of metformin , which is known to augment GLP‐1 secretion from L‐cells27, might be ascribed to the observed greater
metformin 21543 24. In contrast to the former two studies, the latter two studies recruited patients with concomitant metformin therapy. However, the discrepancy might not be explained by background metformin therapy, because, even
metformin 21624 patients with concomitant metformin therapy. However, the discrepancy might not be explained by background metformin therapy, because, even if a DPP4 inhibitor was added on to pre‐existing metformin therapy, the PPG‐lowering
metformin 21708 explained by background metformin therapy, because, even if a DPP4 inhibitor was added on to pre‐existing metformin therapy, the PPG‐lowering effect was much greater than the FPG‐lowering effect34, 35, 36, 37, 38.Weight
metformin 23520 might increase the risk of hypoglycemia47. DPP4 inhibitors, when used alone or in combination with metformin , are unlikely to cause hypoglycemia because of the glucose‐dependent mode of action with regard to
miglitol 4034 increase the therapeutic efficacy of DPP4 inhibitors. The α‐glucosidase inhibitors (AGIs), acarbose, miglitol and voglibose, delay carbohydrate absorption from the small intestine by inhibiting the hydrolysis of
miglitol 4975 administration of acarbose and sucrose resulted in increased GLP‐1 release13, and a 2‐day administration of miglitol increased GLP‐1 secretion and decreased GIP secretion after a meal9. In addition, a 24‐week acarbose
miglitol 5610 correlations between serum GLP‐1 levels and serum glucose or insulin levels were observed16. Intriguingly, miglitol , but not acarbose, increased active postprandial GLP‐1 levels in individuals with visceral obesity
miglitol 8600 ‘evogliptin,’ ‘omarigliptin,’ ‘trelagliptin,’ ‘alpha‐glucosidase inhibitor,’ ‘acarbose,’ ‘ miglitol ’ and ‘voglibose.’ The detailed search terms used in this study are provided in Appendix S1.Data
miglitol 22909 open‐label, parallel, three‐arm study on overweight Japanese patients with type 2 diabetes mellitus, miglitol alone or miglitol/sitagliptin combination, but not sitagliptin alone, reduced the total body fat mass
miglitol 22927 three‐arm study on overweight Japanese patients with type 2 diabetes mellitus, miglitol alone or miglitol /sitagliptin combination, but not sitagliptin alone, reduced the total body fat mass and miglitol/sitagliptin
miglitol 23024 or miglitol/sitagliptin combination, but not sitagliptin alone, reduced the total body fat mass and miglitol /sitagliptin reduced visceral fat mass45. Therefore, DPP4i/AGI combination therapy might be one of the
sitagliptin 8320 ClinicalTrials.gov. The keywords of search terms were as follows: ‘DPP4 inhibitor,’ ‘vildagliptin,’ ‘ sitagliptin ,’ ‘linagliptin,’ ‘alogliptin,’ ‘saxagliptin,’ ‘gemigliptin,’ ‘dutogliptin,’ ‘gosogliptin,’
sitagliptin 22936 three‐arm study on overweight Japanese patients with type 2 diabetes mellitus, miglitol alone or miglitol/ sitagliptin combination, but not sitagliptin alone, reduced the total body fat mass and miglitol/sitagliptin reduced
sitagliptin 22969 patients with type 2 diabetes mellitus, miglitol alone or miglitol/sitagliptin combination, but not sitagliptin alone, reduced the total body fat mass and miglitol/sitagliptin reduced visceral fat mass45. Therefore,
sitagliptin 23033 miglitol/sitagliptin combination, but not sitagliptin alone, reduced the total body fat mass and miglitol/ sitagliptin reduced visceral fat mass45. Therefore, DPP4i/AGI combination therapy might be one of the favorable
Select Disease Character Offset Disease Term Instance
diabetes mellitus 183 with an α‐glucosidase inhibitor and a dipeptidyl peptidase‐4 inhibitor in patients with type 2 diabetes mellitus : A systematic review with meta‐analysisAlternative Title: Min et al.Se Hee MinJeong‐Hwa YoonSeokyung
diabetes mellitus 2709 have challenged the traditional ‘insulinocentric’ understanding of the pathophysiology of type 2 diabetes mellitus as characterized by impaired insulin secretion and action. Presently, the pathophysiology of type 2
diabetes mellitus 2827 as characterized by impaired insulin secretion and action. Presently, the pathophysiology of type 2 diabetes mellitus is recognized as a more complex one, encompassing defective β‐cell responses to incretin hormones,
diabetes mellitus 4294 monosaccharides8. As such, AGIs are used to reduce postprandial glucose (PPG) levels in patients with type 2 diabetes mellitus 8. Interestingly, AGIs decrease carbohydrate absorption in the proximal gut and result in the delivery
diabetes mellitus 4831 voglibose increased GLP‐1 secretion when given with a standardized meal12. In patients with type 2 diabetes mellitus , simultaneous administration of acarbose and sucrose resulted in increased GLP‐1 release13, and a
diabetes mellitus 5139 after a meal9. In addition, a 24‐week acarbose treatment in patients with newly diagnosed type 2 diabetes mellitus increased postprandial GLP‐1 levels14. However, in another study15, ingestion of acarbose with a mixed
diabetes mellitus 5330 ingestion of acarbose with a mixed test meal failed to enhance GLP‐1 release in patients with type 2 diabetes mellitus . Furthermore, in elderly type 2 diabetes patients treated with acarbose, just 20% of the patients showed
diabetes mellitus 6186 synergistic) effect on glucose control with complementary mechanism of action in patients with type 2 diabetes mellitus . In an animal study with prediabetic db/db mice, combined treatment with voglibose and a DPP4 inhibitor
diabetes mellitus 6663 safety of the combination of DPP4 inhibitor and AGI in patients with inadequately controlled type 2 diabetes mellitus .MethodsWe carried out a systematic review and meta‐analysis following the predeveloped protocol by
diabetes mellitus 7247 inhibitor to AGI (DPP4i/AGI) and the addition of a placebo to AGI (PCB/AGI) in patients with type 2 diabetes mellitus were regarded as eligible for inclusion. Among the initially retrieved studies, we included only studies
diabetes mellitus 19502 resulted in significant reductions in HbA1c levels relative to the placebo in patients with type 2 diabetes mellitus who received an AGI therapy. However, substantial heterogeneity (I2 = 95.7%) was found in the magnitude
diabetes mellitus 20837 insulinotrophic effect of GIP is reduced, but glucagonotrophic effect is preserved in patients with type 2 diabetes mellitus 30, the opposite actions of both agents on GIP levels might not adversely affect glycemic control.Both
diabetes mellitus 21993 dose or adding another class of antidiabetic drugs in patients with inadequately controlled type 2 diabetes mellitus . The current meta‐analysis found no increase in bodyweight after the addition of a DPP4 inhibitor
diabetes mellitus 22199 DPP4 inhibitor to an AGI. A meta‐analysis that compared acarbose and placebo in patients with type 2 diabetes mellitus showed reduced body mass index in favor of acarbose8. Some AGIs have been reported to reduce appetite
diabetes mellitus 22890 a 24‐week, open‐label, parallel, three‐arm study on overweight Japanese patients with type 2 diabetes mellitus , miglitol alone or miglitol/sitagliptin combination, but not sitagliptin alone, reduced the total body
diabetes mellitus 25245 show the efficacy and safety of the addition of a DPP4 inhibitor to an AGI in patients with type 2 diabetes mellitus . Second, because we could not compare the outcomes among DPP4 inhibitor plus AGI, placebo plus AGI,
diabetes mellitus 25433 inhibitor plus AGI, placebo plus AGI, placebo plus DPP4 inhibitor and placebo alone in patients with type 2 diabetes mellitus who were naïve to DPP4 inhibitors or AGIs, we could not determine whether the glucose‐lowering effect
diabetes mellitus 26267 groups.In conclusion, the addition of a DPP4 inhibitor to patients with inadequately controlled type 2 diabetes mellitus with AGI therapy achieved a clinically significant improvement in glycemic control without increasing
diabetes mellitus 26525 hypoglycemia. Therefore, this combination should be a viable option in the pharmacological therapy for type 2 diabetes mellitus .DisclosureYMC received research grants from AstraZeneca and LG Chemical. The authors declare no conflict
hypoglycemia 2204 glucose and 2‐h postprandial plasma glucose levels, with no increase in bodyweight. The risks of hypoglycemia and gastrointestinal adverse events were similar between DPP4i/AGI and PCB/AGI.ConclusionsThe addition
hypoglycemia 2497 with an AGI achieved better glycemic control without further increasing the risk of weight gain and hypoglycemia .J Diabetes Investig2018;9:893–902IntroductionRecent research findings over the past two decades have
hypoglycemia 9205 plasma glucose (FPG) levels, 2‐h PPG levels and bodyweight. The safety outcomes were the risk of hypoglycemia and gastrointestinal (GI) adverse events. The following information was additionally extracted from
hypoglycemia 11688 between treatment groups were calculated. For the analysis of dichotomous outcomes, such as the risk of hypoglycemia , relative risks (RR) and their corresponding 95% CIs were calculated. The random effects model of meta‐analysis
hypoglycemia 18104 (P = 0.440).Safety OutcomesFour out of five studies were included for the meta‐analysis for the risk of hypoglycemia (Figure 4a).21, 23, 24, 25 Pooled analysis of the four studies did not show a significant increase
hypoglycemia 18244 Pooled analysis of the four studies did not show a significant increase or decrease in the risk of hypoglycemia in the DPP4i/AGI group compared with the PCB/AGI group (RR 1.4, 95% CI: 0.4 to 4.6). The test for heterogeneity
hypoglycemia 18469 was not significant (P = 0.891).Figure 4Meta‐analysis for safety outcomes. (a) Relative risk of hypoglycemia with dipeptidyl peptidase‐4 inhibitor plus α‐glucosidase inhibitor (DPP4i/AGI) vs placebo plus
hypoglycemia 23223 one of the favorable therapeutic options for overweight/obese type 2 diabetes patients.The risk of hypoglycemia was not increased when adding DPP4 inhibitors to AGI therapy. In general, AGI monotherapy does not cause
hypoglycemia 23341 not increased when adding DPP4 inhibitors to AGI therapy. In general, AGI monotherapy does not cause hypoglycemia 46. However, when AGI is combined with sulfonylureas or insulin, it might increase the risk of hypoglycemia47.
hypoglycemia 23448 hypoglycemia46. However, when AGI is combined with sulfonylureas or insulin, it might increase the risk of hypoglycemia 47. DPP4 inhibitors, when used alone or in combination with metformin, are unlikely to cause hypoglycemia
hypoglycemia 23553 hypoglycemia47. DPP4 inhibitors, when used alone or in combination with metformin, are unlikely to cause hypoglycemia because of the glucose‐dependent mode of action with regard to the regulation of insulin and glucagon
hypoglycemia 23926 50. Therefore, theoretically, the addition of DPP4 inhibitors to AGI should not increase the risk of hypoglycemia , which was in accordance with the present results.Flatulence, diarrhea and abdominal pain are frequent
hypoglycemia 26415 clinically significant improvement in glycemic control without increasing the risk of weight gain and hypoglycemia . Therefore, this combination should be a viable option in the pharmacological therapy for type 2 diabetes
obesity 5712 miglitol, but not acarbose, increased active postprandial GLP‐1 levels in individuals with visceral obesity (50% of the participants had impaired glucose tolerance or diabetes)17. These inconsistent results might
type 2 diabetes mellitus 176 therapy with an α‐glucosidase inhibitor and a dipeptidyl peptidase‐4 inhibitor in patients with type 2 diabetes mellitus : A systematic review with meta‐analysisAlternative Title: Min et al.Se Hee MinJeong‐Hwa YoonSeokyung
type 2 diabetes mellitus 2702 decades have challenged the traditional ‘insulinocentric’ understanding of the pathophysiology of type 2 diabetes mellitus as characterized by impaired insulin secretion and action. Presently, the pathophysiology of type 2
type 2 diabetes mellitus 2820 mellitus as characterized by impaired insulin secretion and action. Presently, the pathophysiology of type 2 diabetes mellitus is recognized as a more complex one, encompassing defective β‐cell responses to incretin hormones,
type 2 diabetes mellitus 4287 monosaccharides8. As such, AGIs are used to reduce postprandial glucose (PPG) levels in patients with type 2 diabetes mellitus 8. Interestingly, AGIs decrease carbohydrate absorption in the proximal gut and result in the delivery
type 2 diabetes mellitus 4824 sucrose11 and voglibose increased GLP‐1 secretion when given with a standardized meal12. In patients with type 2 diabetes mellitus , simultaneous administration of acarbose and sucrose resulted in increased GLP‐1 release13, and a
type 2 diabetes mellitus 5132 secretion after a meal9. In addition, a 24‐week acarbose treatment in patients with newly diagnosed type 2 diabetes mellitus increased postprandial GLP‐1 levels14. However, in another study15, ingestion of acarbose with a mixed
type 2 diabetes mellitus 5323 study15, ingestion of acarbose with a mixed test meal failed to enhance GLP‐1 release in patients with type 2 diabetes mellitus . Furthermore, in elderly type 2 diabetes patients treated with acarbose, just 20% of the patients showed
type 2 diabetes mellitus 6179 perhaps synergistic) effect on glucose control with complementary mechanism of action in patients with type 2 diabetes mellitus . In an animal study with prediabetic db/db mice, combined treatment with voglibose and a DPP4 inhibitor
type 2 diabetes mellitus 6656 efficacy and safety of the combination of DPP4 inhibitor and AGI in patients with inadequately controlled type 2 diabetes mellitus .MethodsWe carried out a systematic review and meta‐analysis following the predeveloped protocol by
type 2 diabetes mellitus 7240 of DPP4 inhibitor to AGI (DPP4i/AGI) and the addition of a placebo to AGI (PCB/AGI) in patients with type 2 diabetes mellitus were regarded as eligible for inclusion. Among the initially retrieved studies, we included only studies
type 2 diabetes mellitus 19495 inhibitor resulted in significant reductions in HbA1c levels relative to the placebo in patients with type 2 diabetes mellitus who received an AGI therapy. However, substantial heterogeneity (I2 = 95.7%) was found in the magnitude
type 2 diabetes mellitus 20830 insulinotrophic effect of GIP is reduced, but glucagonotrophic effect is preserved in patients with type 2 diabetes mellitus 30, the opposite actions of both agents on GIP levels might not adversely affect glycemic control.Both
type 2 diabetes mellitus 21986 increasing the dose or adding another class of antidiabetic drugs in patients with inadequately controlled type 2 diabetes mellitus . The current meta‐analysis found no increase in bodyweight after the addition of a DPP4 inhibitor
type 2 diabetes mellitus 22192 of a DPP4 inhibitor to an AGI. A meta‐analysis that compared acarbose and placebo in patients with type 2 diabetes mellitus showed reduced body mass index in favor of acarbose8. Some AGIs have been reported to reduce appetite
type 2 diabetes mellitus 22883 mass. In a 24‐week, open‐label, parallel, three‐arm study on overweight Japanese patients with type 2 diabetes mellitus , miglitol alone or miglitol/sitagliptin combination, but not sitagliptin alone, reduced the total body
type 2 diabetes mellitus 25238 enough to show the efficacy and safety of the addition of a DPP4 inhibitor to an AGI in patients with type 2 diabetes mellitus . Second, because we could not compare the outcomes among DPP4 inhibitor plus AGI, placebo plus AGI,
type 2 diabetes mellitus 25426 inhibitor plus AGI, placebo plus AGI, placebo plus DPP4 inhibitor and placebo alone in patients with type 2 diabetes mellitus who were naïve to DPP4 inhibitors or AGIs, we could not determine whether the glucose‐lowering effect
type 2 diabetes mellitus 26260 ethnic groups.In conclusion, the addition of a DPP4 inhibitor to patients with inadequately controlled type 2 diabetes mellitus with AGI therapy achieved a clinically significant improvement in glycemic control without increasing
type 2 diabetes mellitus 26518 hypoglycemia. Therefore, this combination should be a viable option in the pharmacological therapy for type 2 diabetes mellitus .DisclosureYMC received research grants from AstraZeneca and LG Chemical. The authors declare no conflict

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