Effect of Sodium‐Glucose Cotransport‐2 Inhibitors on Blood Pressure in People With Type 2 Diabetes Mellitus: A Systematic Review and Meta‐Analysis of 43 Randomized Control Trials With 22 528 Patients

Background The sodium‐glucose cotransporter 2 (SGLT2) inhibitors are a class of oral hypoglycemic agents. We undertake a systematic review and meta‐analysis of prospective studies to determine the effect of SGLT2 on blood pressure (BP) among individuals with type 2 diabetes mellitus. Methods and Results PubMed‐Medline, Web of Science, Cochrane Database, and Google Scholar databases were searched to identify trial registries evaluating the impact of SGLT2 on BP. Random‐effects models meta‐analysis was used for quantitative data synthesis. The meta‐analysis indicated a significant reduction in systolic BP following treatment with SGLT2 (weighted mean difference −2.46 mm Hg [95% CI −2.86 to −2.06]). The weighted mean differences for the effect on diastolic BP was −1.46 mm Hg (95% CI −1.82 to −1.09). In these subjects the weighted mean difference effects on serum triglycerides and total cholesterol were −2.08 mg/dL (95% CI −2.51 to −1.64) and 0.77 mg/dL (95% CI 0.33‐1.21), respectively. The weighted mean differences for the effect of SGLT2 on body weight was −1.88 kg (95% CI −2.11 to −1.66) across all studies. These findings were robust in sensitivity analyses. Conclusions Treatment with SGLT2 glucose cotransporter inhibitors therefore has beneficial off‐target effects on BP in patients with type 2 diabetes mellitus and may also be of value in improving other cardiometabolic parameters including lipid profile and body weight in addition to their expected effects on glycemic control. However, our findings should be interpreted with consideration for the moderate statistical heterogeneity across the included studies.

[1]  M. Mazidi,et al.  Treatment with GLP1 receptor agonists reduce serum CRP concentrations in patients with type 2 diabetes mellitus: A systematic review and meta-analysis of randomized controlled trials. , 2017, Journal of diabetes and its complications.

[2]  A. Kengne,et al.  The effects of bile acid sequestrants on lipid profile and blood glucose concentrations: A systematic review and meta-analysis of randomized controlled trials. , 2017, International journal of cardiology.

[3]  M. Mazidi,et al.  Effect of statins on serum vitamin D concentrations: a systematic review and meta‐analysis , 2017, European journal of clinical investigation.

[4]  M. Mazidi,et al.  Impact of Probiotic Administration on Serum C-Reactive Protein Concentrations: Systematic Review and Meta-Analysis of Randomized Control Trials , 2017, Nutrients.

[5]  M. Mazidi,et al.  The effect of ginger supplementation on serum C-reactive protein, lipid profile and glycaemia: a systematic review and meta-analysis , 2016, Food & nutrition research.

[6]  A. Kengne,et al.  Serum hs-CRP varies with dietary cholesterol, but not dietary fatty acid intake in individuals free of any history of cardiovascular disease , 2016, European Journal of Clinical Nutrition.

[7]  T. Mansfield,et al.  Blood pressure and glycaemic effects of dapagliflozin versus placebo in patients with type 2 diabetes on combination antihypertensive therapy: a randomised, double-blind, placebo-controlled, phase 3 study. , 2016, The lancet. Diabetes & endocrinology.

[8]  M. Pencina,et al.  Head-to-head comparison of statins versus fibrates in reducing plasma fibrinogen concentrations: A systematic review and meta-analysis. , 2016, Pharmacological research.

[9]  P. Sarafidis,et al.  Sodium-glucose cotransporter-2 inhibitors and blood pressure decrease: a valuable effect of a novel antidiabetic class? , 2015, Journal of hypertension.

[10]  R. Chen,et al.  Efficacy and safety of sodium-glucose cotransporter 2 inhibitors in type 2 diabetes: a meta-analysis of randomized controlled trials for 1 to 2years. , 2015, Journal of diabetes and its complications.

[11]  A. Sahebkar,et al.  Effect of statin therapy on paraoxonase-1 status: A systematic review and meta-analysis of 25 clinical trials. , 2015, Progress in lipid research.

[12]  G. Vlotides,et al.  Sodium-glucose cotransport inhibitors: mechanisms, metabolic effects and implications for the treatment of diabetic patients with chronic kidney disease. , 2015, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[13]  S. Del Prato,et al.  Long‐term glycaemic response and tolerability of dapagliflozin versus a sulphonylurea as add‐on therapy to metformin in patients with type 2 diabetes: 4‐year data , 2015, Diabetes, obesity & metabolism.

[14]  V. Woo,et al.  Efficacy and safety of dapagliflozin monotherapy in people with Type 2 diabetes: a randomized double‐blind placebo‐controlled 102‐week trial , 2015, Diabetic medicine : a journal of the British Diabetic Association.

[15]  K. Phan,et al.  Systematic review and meta-analysis: techniques and a guide for the academic surgeon. , 2015, Annals of cardiothoracic surgery.

[16]  S. Matthaei,et al.  Dapagliflozin Improves Glycemic Control and Reduces Body Weight as Add-on Therapy to Metformin Plus Sulfonylurea: A 24-Week Randomized, Double-Blind Clinical Trial , 2015, Diabetes Care.

[17]  W. Wilkison,et al.  Randomized efficacy and safety trial of once‐daily remogliflozin etabonate for the treatment of type 2 diabetes , 2015, Diabetes, obesity & metabolism.

[18]  W. Wilkison,et al.  Randomized trial showing efficacy and safety of twice‐daily remogliflozin etabonate for the treatment of type 2 diabetes , 2015, Diabetes, obesity & metabolism.

[19]  P. Schumm-Draeger,et al.  Twice‐daily dapagliflozin co‐administered with metformin in type 2 diabetes: a 16‐week randomized, placebo‐controlled clinical trial , 2015, Diabetes, obesity & metabolism.

[20]  K. Mahaffey,et al.  Efficacy and Safety of Canagliflozin, an Inhibitor of Sodium–Glucose Cotransporter 2, When Used in Conjunction With Insulin Therapy in Patients With Type 2 Diabetes , 2014, Diabetes Care.

[21]  T. Heise,et al.  Effect of the sodium glucose co‐transporter 2 inhibitor canagliflozin on plasma volume in patients with type 2 diabetes mellitus , 2014, Diabetes, obesity & metabolism.

[22]  A. Kiyosue,et al.  Efficacy and safety of dapagliflozin monotherapy in Japanese patients with type 2 diabetes inadequately controlled by diet and exercise , 2014, Diabetes, obesity & metabolism.

[23]  I. Tikkanen,et al.  Empagliflozin Reduces Blood Pressure in Patients With Type 2 Diabetes and Hypertension , 2014, Diabetes Care.

[24]  Lawrence A. Leiter,et al.  Canagliflozin Provides Durable Glycemic Improvements and Body Weight Reduction Over 104 Weeks Versus Glimepiride in Patients With Type 2 Diabetes on Metformin: A Randomized, Double-Blind, Phase 3 Study , 2014, Diabetes Care.

[25]  G. Bakris,et al.  Efficacy and Safety of Canagliflozin in Patients with Type 2 Diabetes and Stage 3 Nephropathy , 2014, American Journal of Nephrology.

[26]  N. Inagaki,et al.  Efficacy and safety of canagliflozin monotherapy in Japanese patients with type 2 diabetes inadequately controlled with diet and exercise: a 24-week, randomized, double-blind, placebo-controlled, Phase III study , 2014, Expert opinion on pharmacotherapy.

[27]  Lawrence A Leiter,et al.  Dapagliflozin Added to Usual Care in Individuals with Type 2 Diabetes Mellitus with Preexisting Cardiovascular Disease: A 24‐Week, Multicenter, Randomized, Double‐Blind, Placebo‐Controlled Study with a 28‐Week Extension , 2014, Journal of the American Geriatrics Society.

[28]  Arinze Nkemdirim Okere,et al.  Dapagliflozin for the Treatment of Type 2 Diabetes Mellitus , 2014, The Annals of pharmacotherapy.

[29]  M. Monami,et al.  Efficacy and safety of sodium glucose co‐transport‐2 inhibitors in type 2 diabetes: a meta‐analysis of randomized clinical trials , 2014, Diabetes, obesity & metabolism.

[30]  G. Bakris,et al.  Blood pressure effects of sodium-glucose co-transport 2 (SGLT2) inhibitors. , 2014, Journal of the American Society of Hypertension : JASH.

[31]  A. Sahebkar Are Curcuminoids Effective C‐Reactive Protein‐Lowering Agents in Clinical Practice? Evidence from a Meta‐Analysis , 2014, Phytotherapy research : PTR.

[32]  W. White,et al.  Effects of sodium-glucose co-transporter 2 inhibitors on blood pressure: a systematic review and meta-analysis. , 2014, Journal of the American Society of Hypertension : JASH.

[33]  G. Meininger,et al.  Efficacy and safety of canagliflozin over 52 weeks in patients with type 2 diabetes on background metformin and pioglitazone , 2014, Diabetes, obesity & metabolism.

[34]  V. Woo,et al.  Dapagliflozin in patients with type 2 diabetes receiving high doses of insulin: efficacy and safety over 2 years , 2014, Diabetes, obesity & metabolism.

[35]  J. Bolinder,et al.  Dapagliflozin maintains glycaemic control while reducing weight and body fat mass over 2 years in patients with type 2 diabetes mellitus inadequately controlled on metformin , 2014, Diabetes, obesity & metabolism.

[36]  A. Sahebkar Effect of niacin on endothelial function: A systematic review and meta-analysis of randomized controlled trials , 2014, Vascular medicine.

[37]  T. Mansfield,et al.  Dapagliflozin as monotherapy in drug-naive Asian patients with type 2 diabetes mellitus: a randomized, blinded, prospective phase III study. , 2014, Clinical therapeutics.

[38]  J. Rosenstock,et al.  Efficacy and safety of empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, as add‐on to metformin in type 2 diabetes with mild hyperglycaemia , 2013, Diabetes, obesity & metabolism.

[39]  H. Häring,et al.  Empagliflozin as Add-on to Metformin Plus Sulfonylurea in Patients With Type 2 Diabetes , 2013, Diabetes Care.

[40]  G. Charpentier,et al.  Efficacy and safety of canagliflozin in patients with type 2 diabetes mellitus inadequately controlled with metformin and sulphonylurea: a randomised trial , 2013, International journal of clinical practice.

[41]  A. Januszewicz,et al.  Efficacy and safety of canagliflozin compared with placebo and sitagliptin in patients with type 2 diabetes on background metformin monotherapy: a randomised trial , 2013, Diabetologia.

[42]  T. Mansfield,et al.  Correction: Dapagliflozin add-on to metformin in type 2 diabetes inadequately controlled with metformin: a randomized, double-blind, placebo-controlled 102-week trial , 2013, BMC Medicine.

[43]  J. Rosenstock,et al.  Canagliflozin Compared With Sitagliptin for Patients With Type 2 Diabetes Who Do Not Have Adequate Glycemic Control With Metformin Plus Sulfonylurea , 2013, Diabetes Care.

[44]  E. Ferrannini,et al.  A Phase IIb, randomized, placebo‐controlled study of the SGLT2 inhibitor empagliflozin in patients with type 2 diabetes , 2013, Diabetes, obesity & metabolism.

[45]  K. Mahaffey,et al.  Rationale, design, and baseline characteristics of the Canagliflozin Cardiovascular Assessment Study (CANVAS)--a randomized placebo-controlled trial. , 2013, American heart journal.

[46]  N. Inagaki,et al.  Efficacy and safety of canagliflozin in Japanese patients with type 2 diabetes: a randomized, double-blind, placebo-controlled, 12-week study , 2013, Diabetes, obesity & metabolism.

[47]  D. de Zeeuw,et al.  Dapagliflozin a glucose-regulating drug with diuretic properties in subjects with type 2 diabetes , 2013, Diabetes, obesity & metabolism.

[48]  T. Hoffmann,et al.  Cost effectiveness of patient education for the prevention of falls in hospital: economic evaluation from a randomized controlled trial , 2013, BMC Medicine.

[49]  A. Kiyosue,et al.  Efficacy and safety of dapagliflozin as a monotherapy for type 2 diabetes mellitus in Japanese patients with inadequate glycaemic control: a phase II multicentre, randomized, double‐blind, placebo‐controlled trial , 2013, Diabetes, obesity & metabolism.

[50]  G. Bakris,et al.  Efficacy and safety of canagliflozin in subjects with type 2 diabetes and chronic kidney disease , 2013, Diabetes, obesity & metabolism.

[51]  S. Del Prato,et al.  [Dapagliflozin versus glipizide as add-on therapy in patients with type 2 diabetes who have inadequate glycemic control with metformin]. , 2013, Deutsche medizinische Wochenschrift.

[52]  K. Kim,et al.  Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise , 2013, Diabetes, obesity & metabolism.

[53]  Kanxing Zhao,et al.  Plasminogen activator inhibitor-1 4G/5G polymorphism and retinopathy risk in type 2 diabetes: a meta-analysis , 2013, BMC Medicine.

[54]  C. Clar,et al.  Systematic review of SGLT2 receptor inhibitors in dual or triple therapy in type 2 diabetes , 2012, BMJ Open.

[55]  J. Rosenstock,et al.  Effects of Dapagliflozin, an SGLT2 Inhibitor, on HbA1c, Body Weight, and Hypoglycemia Risk in Patients With Type 2 Diabetes Inadequately Controlled on Pioglitazone Monotherapy , 2012, Diabetes Care.

[56]  S. Schwartz,et al.  Canagliflozin improves glycaemic control over 28 days in subjects with type 2 diabetes not optimally controlled on insulin , 2012, Diabetes, obesity & metabolism.

[57]  J. Rosenstock,et al.  Dose-Ranging Effects of Canagliflozin, a Sodium-Glucose Cotransporter 2 Inhibitor, as Add-On to Metformin in Subjects With Type 2 Diabetes , 2012, Diabetes Care.

[58]  R. Henry,et al.  Dapagliflozin, metformin XR, or both: initial pharmacotherapy for type 2 diabetes, a randomised controlled trial , 2012, International journal of clinical practice.

[59]  V. Woo,et al.  Long-Term Efficacy of Dapagliflozin in Patients With Type 2 Diabetes Mellitus Receiving High Doses of Insulin , 2012, Annals of Internal Medicine.

[60]  J. Kullberg,et al.  Effects of dapagliflozin on body weight, total fat mass, and regional adipose tissue distribution in patients with type 2 diabetes mellitus with inadequate glycemic control on metformin. , 2012, The Journal of clinical endocrinology and metabolism.

[61]  K. Yoon,et al.  Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with glimepiride: a randomized, 24‐week, double‐blind, placebo‐controlled trial , 2011, Diabetes, obesity & metabolism.

[62]  Douglas G Altman,et al.  Small study effects in meta-analyses of osteoarthritis trials: meta-epidemiological study , 2010, BMJ : British Medical Journal.

[63]  C. Bailey,et al.  Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trial , 2010, The Lancet.

[64]  E. Ferrannini,et al.  Dapagliflozin Monotherapy in Type 2 Diabetic Patients With Inadequate Glycemic Control by Diet and Exercise , 2010, Diabetes Care.

[65]  D. Moher,et al.  Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. , 2010, International journal of surgery.

[66]  Enrique Morales,et al.  Sodium-Glucose Cotransport Inhibition With Dapagliflozin in Type 2 Diabetes , 2008, Diabetes Care.

[67]  O. Pedersen,et al.  Effect of a multifactorial intervention on mortality in type 2 diabetes. , 2008, The New England journal of medicine.

[68]  S. Grundy,et al.  Primary Prevention of Cardiovascular Diseases in People With Diabetes Mellitus , 2006, Diabetes Care.

[69]  Tania B. Huedo-Medina,et al.  Assessing heterogeneity in meta-analysis: Q statistic or I2 index? , 2006, Psychological methods.

[70]  I. Hozo,et al.  Estimating the mean and variance from the median, range, and the size of a sample , 2005, BMC medical research methodology.

[71]  F. J. del Cañizo-Gómez,et al.  Cardiovascular risk factors in patients with type 2 diabetes. Do we follow the guidelines? , 2004, Diabetes research and clinical practice.

[72]  N J Wald,et al.  A strategy to reduce cardiovascular disease by more than 80% , 2003, BMJ : British Medical Journal.

[73]  J. Sterne,et al.  Publication and related bias in meta-analysis: power of statistical tests and prevalence in the literature. , 2000, Journal of clinical epidemiology.

[74]  S Duval,et al.  Trim and Fill: A Simple Funnel‐Plot–Based Method of Testing and Adjusting for Publication Bias in Meta‐Analysis , 2000, Biometrics.

[75]  C. Agardh,et al.  Urinary excretion rate of NC1 and Tamm-Horsfall protein in the microalbuminuric type I diabetic patient. , 1994, Journal of diabetes and its complications.