Metabolic and hemodynamic effects of sodium-dependent glucose cotransporter 2 inhibitors on cardio-renal protection in the treatment of patients with type 2 diabetes mellitus

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Term Occurence Count Dictionary
diabetic ketoacidosis 1 endocrinologydiseases
glipizide 2 endocrinologydiseasesdrugs
hyperglycemia 3 endocrinologydiseases
hypokalemia 1 endocrinologydiseases
pioglitazone 1 endocrinologydiseasesdrugs
sitagliptin 6 endocrinologydiseasesdrugs
Insulin 2 endocrinologydiseasesdrugs
dapagliflozin 14 endocrinologydiseasesdrugs
diabetes mellitus 6 endocrinologydiseases
hypoglycemia 5 endocrinologydiseases
metformin 7 endocrinologydiseasesdrugs
type 2 diabetes mellitus 5 endocrinologydiseases

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Insulin 11977 could have a specific usefulness in suppressing chronic diabetic vascular complications.Improvements in Insulin Secretion, Insulin Sensitivity and Glucose Toxicity with Enhanced Glucagon SecretionFerrannini et al.36
Insulin 11996 usefulness in suppressing chronic diabetic vascular complications.Improvements in Insulin Secretion, Insulin Sensitivity and Glucose Toxicity with Enhanced Glucagon SecretionFerrannini et al.36 measured whole‐body
dapagliflozin 5812 found in a phase 3 RCT using ipragliflozin18. Similarly, patients with type 2 diabetes treated with dapagliflozin 2.5–50 mg once daily, metformin or a placebo for 12 weeks showed a placebo‐adjusted mean change
dapagliflozin 5963 a placebo for 12 weeks showed a placebo‐adjusted mean change in HbA1c to a maximum −0.9% in the dapagliflozin group and −0.73% in the metformin group19. In a pooled analysis of phase 2 and 3 trials that included
dapagliflozin 9048 renal function (estimated glomerular filtration rate 30–60 mL/min/1.73 m2), who were treated with dapagliflozin and placebo for 24 weeks, respectively. Dapagliflozin at any dose did not show a significant reduction
dapagliflozin 9284 placebo30. However, interestingly, both bodyweight and blood pressure significantly decreased in the dapagliflozin group vs the placebo group. However, another RCT examining canagliflozin using 269 patients with inadequately
dapagliflozin 11476 compared with glimepiride. Long‐term durability of glycemic control over 2 years was also found in the dapagliflozin group compared with the glipizide group. In a further extension study, dapagliflozin compared with glipizide
dapagliflozin 11561 also found in the dapagliflozin group compared with the glipizide group. In a further extension study, dapagliflozin compared with glipizide showed further sustained reductions of HbA1c, bodyweight and systolic blood
dapagliflozin 13551 endogenous glucose production in 18 men with type 2 diabetes, who were randomized to receive either dapagliflozin (n = 12) or a placebo (n = 6) for 2 weeks. Dapagliflozin treatment significantly reduced fasting plasma
dapagliflozin 17297 Risk Assessment Committee has started a review of all three approved SGLT2 inhibitors (canagliflozin, dapagliflozin and empagliflozin) to evaluate the risk of DKA in type 2 diabetes, and have noted 101 cases of DKA have
dapagliflozin 18043 inhibitors. A recent review article53 reported the incidence of DKA to be <0.1% in the clinical trials using dapagliflozin effect on cardiovascular events (DECLARE) and empagliflozin, cardiovascular outcomes and mortality in
dapagliflozin 20202 increased degradation of adipose tissue and muscle mass25, 67. An interesting RCT on the effects of dapagliflozin on 24‐h blood pressure, plasma volume and hematocrit compared with hydrochlorothiazide was reported
dapagliflozin 20670 red cell counts was explained in part by an increase in plasma erythropoietin concentration in the dapagliflozin treatment group. Hydrochlorothiazide did not show any such increases59. However, further studies are
dapagliflozin 23148 hypoglycemia were found in 0.68% of patients. The incidence of adverse hypoglycemic events was 1 in 10 in the dapagliflozin group compared with the sulfonylurea group71. However, in another study, patients treated with a combination
dapagliflozin 23274 compared with the sulfonylurea group71. However, in another study, patients treated with a combination of dapagliflozin and insulin showed a higher frequency of hypoglycemia compared with the placebo group, although the
dapagliflozin 37572 increased hematocrit is proposed to be an increased erythropoietin concentration with treatment with dapagliflozin in diabetes59. In terms of renoprotective effects of SGLT2 inhibitors found in the EMPA‐REG OUTCOME
glipizide 11514 durability of glycemic control over 2 years was also found in the dapagliflozin group compared with the glipizide group. In a further extension study, dapagliflozin compared with glipizide showed further sustained
glipizide 11589 group compared with the glipizide group. In a further extension study, dapagliflozin compared with glipizide showed further sustained reductions of HbA1c, bodyweight and systolic blood pressure over 208 weeks35.
metformin 5850 ipragliflozin18. Similarly, patients with type 2 diabetes treated with dapagliflozin 2.5–50 mg once daily, metformin or a placebo for 12 weeks showed a placebo‐adjusted mean change in HbA1c to a maximum −0.9% in the
metformin 6003 placebo‐adjusted mean change in HbA1c to a maximum −0.9% in the dapagliflozin group and −0.73% in the metformin group19. In a pooled analysis of phase 2 and 3 trials that included monotherapy or add‐on studies
metformin 6936 ipragliflozin once daily in combination with other oral hypoglycemic drugs, such as sulfonylureas21, metformin 22 or pioglitazone23. Consistently, a similar add‐on RCT study (phase 3) was reported that used 100
metformin 7121 was reported that used 100 and 300 mg canagliflozin as compared with a placebo in patients with both metformin plus sulfonylurea for 26 weeks24. HbA1c significantly reduced in the canagliflozin vs the placebo groups
metformin 7399 safety of canagliflozin vs glimepiride in patients with type 2 diabetes inadequately controlled with metformin 25 in a 52‐week, phase 3, non‐inferiority RCT, and only canagliflozin 300 mg was found to be superior
metformin 7703 100 mg were studied for 26 weeks in patients with type 2 diabetes who were inadequately treated with metformin 26. Only canagliflozin 300 mg showed statistical superiority to sitagliptin in lowering HbA1c (−0.88
metformin 10306 sitagliptin 100 mg, both once daily in a study using type 2 diabetes patients inadequately controlled with metformin and sulfonylureas. In this randomized, double‐blind, active‐controlled, phase 3 trial, canagliflozin
pioglitazone 6951 once daily in combination with other oral hypoglycemic drugs, such as sulfonylureas21, metformin22 or pioglitazone 23. Consistently, a similar add‐on RCT study (phase 3) was reported that used 100 and 300 mg canagliflozin
sitagliptin 7590 was found to be superior to glimepiride. Similarly, canagliflozin 300 mg compared with a placebo and sitagliptin 100 mg were studied for 26 weeks in patients with type 2 diabetes who were inadequately treated with
sitagliptin 7776 inadequately treated with metformin26. Only canagliflozin 300 mg showed statistical superiority to sitagliptin in lowering HbA1c (−0.88 vs −0.73%). Furthermore, in the Continuous Glucose Monitoring study27,
sitagliptin 10199 hypoglycemic drugs33, 34, 35. Glucose‐lowering effects of canagliflozin 300 mg were compared with sitagliptin 100 mg, both once daily in a study using type 2 diabetes patients inadequately controlled with metformin
sitagliptin 10546 in the control of HbA1c. Then in a subsequent assessment, canagliflozin was found to be superior to sitagliptin for the long‐term durability of glycemic control33. Furthermore, the stable and continuous reductions
sitagliptin 15297 improvements in liver function, such as improved serum levels of liver enzymes compared with the placebo and sitagliptin groups. These reductions might be closely related to improvements in fatty liver in patients with type
sitagliptin 21470 diabetes mellitus study26PlaceboIpragliflozinPlaceboEmpagliflozinIpragliflozinDapagliflozinPlacebo/ sitagliptin CanagliflozinNo. patients 322 n (%) 509 n (%) 2,333 n (%) 4,687 n (%) 8,505 n (%) 728 n (%) 183 n
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diabetes mellitus 201 glucose cotransporter 2 inhibitors on cardio‐renal protection in the treatment of patients with type 2 diabetes mellitus Alternative Title: Kashiwagi and MaegawaAtsunori KashiwagiHiroshi Maegawa1Kusatsu General HospitalKusatsuJapan2Department
diabetes mellitus 5393 reported to be 80–100 g/day5. In a phase 2 randomized clinical trial (RCT)17, patients with type 2 diabetes mellitus were treated with 12.5–100 mg ipragliflozin once daily for 12 weeks. Glycated hemoglobin (HbA1c) levels
diabetes mellitus 18564 coexistence of ketoacidosis.Hemodynamic and Renal Effects with Blood Pressure LoweringHypertension and type 2 diabetes mellitus are major risk factors for cardiovascular events, and frequently coexist. For example, 56% of Japanese
diabetes mellitus 21321 eventsAdverse eventsPooled analysis of ipragliflozin20EMPA‐REG OUTCOME trial13STELLA‐ELDER70Japanese type 2 diabetes mellitus 102Lavalle‐Gonzalez FJ. Type 2 diabetes mellitus study26PlaceboIpragliflozinPlaceboEmpagliflozinIpragliflozinDapagliflozinPlacebo/sitagliptinCanagliflozinNo.
diabetes mellitus 21371 ipragliflozin20EMPA‐REG OUTCOME trial13STELLA‐ELDER70Japanese type 2 diabetes mellitus102Lavalle‐Gonzalez FJ. Type 2 diabetes mellitus study26PlaceboIpragliflozinPlaceboEmpagliflozinIpragliflozinDapagliflozinPlacebo/sitagliptinCanagliflozinNo.
diabetes mellitus 25967 treatment can only be observed after long‐term good control of hyperglycemia in both type 1 and type 2 diabetes mellitus patients76, 77. In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study, patients with
diabetic ketoacidosis 16889 Administration warned that SGLT2 inhibitors for the treatment of diabetes might result in an increased risk for diabetic ketoacidosis (DKA), with mild‐to‐moderate glucose elevations (euglycemic DKA)49. Euglycemic DKA is defined as
hyperglycemia 8739 of glucose in proximal renal tubular cells. Therefore, the usefulness of SGLT2 inhibitors to control hyperglycemia is affected by the glomerular filtration rate of the patients30, 31, 32. A RCT study was carried out
hyperglycemia 17031 mild‐to‐moderate glucose elevations (euglycemic DKA)49. Euglycemic DKA is defined as DKA without marked hyperglycemia . Most cases of DKA are reported in insulin‐treated type 2 diabetes patients. The European Medicines
hyperglycemia 25927 intensive glucose control with medical treatment can only be observed after long‐term good control of hyperglycemia in both type 1 and type 2 diabetes mellitus patients76, 77. In the Action to Control Cardiovascular
hypoglycemia 8230 al.28 reported that the ipragliflozin treatment improved the entire 24‐h glucose AUC without causing hypoglycemia . Finally, Japanese patients with type 2 diabetes inadequately controlled with sulfonylureas were randomly
hypoglycemia 22413 & Sons, LtdHypoglycemiaMonotherapy of any SGLT2 inhibitor is not a cause of clinically significant hypoglycemia . If SGLT2 inhibitors are used in combination with either sulfonylureas or insulin, hypoglycemia becomes
hypoglycemia 22509 significant hypoglycemia. If SGLT2 inhibitors are used in combination with either sulfonylureas or insulin, hypoglycemia becomes a clinical problem in general practice68, 69. However, patients treated with multiple oral hypoglycemic
hypoglycemia 23038 (STELLA‐ELDER) has been reported (Table 2)70. Adverse drug reactions of special interest related to hypoglycemia were found in 0.68% of patients. The incidence of adverse hypoglycemic events was 1 in 10 in the dapagliflozin
hypoglycemia 23329 study, patients treated with a combination of dapagliflozin and insulin showed a higher frequency of hypoglycemia compared with the placebo group, although the dose of insulin was generally 50% of the original dose68.Skin
hypokalemia 30536 extensively discussed, and SGLT2 inhibitors have a similar effect as loop diuretics without induction of hypokalemia 66, 81. SGLT2 inhibitors increase glucose concentration, and gradually decrease Cl– concentration in
type 2 diabetes mellitus 194 sodium‐dependent glucose cotransporter 2 inhibitors on cardio‐renal protection in the treatment of patients with type 2 diabetes mellitus Alternative Title: Kashiwagi and MaegawaAtsunori KashiwagiHiroshi Maegawa1Kusatsu General HospitalKusatsuJapan2Department
type 2 diabetes mellitus 5386 generally reported to be 80–100 g/day5. In a phase 2 randomized clinical trial (RCT)17, patients with type 2 diabetes mellitus were treated with 12.5–100 mg ipragliflozin once daily for 12 weeks. Glycated hemoglobin (HbA1c) levels
type 2 diabetes mellitus 18557 coexistence of ketoacidosis.Hemodynamic and Renal Effects with Blood Pressure LoweringHypertension and type 2 diabetes mellitus are major risk factors for cardiovascular events, and frequently coexist. For example, 56% of Japanese
type 2 diabetes mellitus 21314 eventsAdverse eventsPooled analysis of ipragliflozin20EMPA‐REG OUTCOME trial13STELLA‐ELDER70Japanese type 2 diabetes mellitus 102Lavalle‐Gonzalez FJ. Type 2 diabetes mellitus study26PlaceboIpragliflozinPlaceboEmpagliflozinIpragliflozinDapagliflozinPlacebo/sitagliptinCanagliflozinNo.
type 2 diabetes mellitus 25960 medical treatment can only be observed after long‐term good control of hyperglycemia in both type 1 and type 2 diabetes mellitus patients76, 77. In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study, patients with

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