Efficacy and safety of sodium‐glucose co‐transporter‐2 inhibitors in type 2 diabetes mellitus: systematic review and network meta‐analysis

Zaccardi, Francesco; Webb, David R.; Htike, Zin Zin; Youssef, Dina Ahmed Hosney; Khunti, Kamlesh; Davies, Melanie J.

doi:10.1111/dom.12670

Cited by 417 publications

(420 citation statements)

References 73 publications

(80 reference statements)

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“…This effect has been confirmed with all SGLT2 inhibitors [29,40] : canagliflozin [41,42], dapagliflozin [43][44][45], empagliflozin [46], ertugliflozin [47] (Table 1). Generally, the reduction in systolic BP was greater (at least twofold) than the reduction in diastolic BP.…”

Section: ) Blood Pressure Lowering Effects Of Sglt2 Inhibitorsmentioning

confidence: 61%

Effects of reducing blood pressure on cardiovascular outcomes and mortality in patients with type 2 diabetes: Focus on SGLT2 inhibitors and EMPA-REG OUTCOME

Scheen

2016

Diabetes Research and Clinical Practice

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Please cite this article as: A.J. Scheen, Effects of reducing blood pressure on cardiovascular outcomes and mortality in patients with type 2 diabetes: focus on SGLT2 inhibitors and EMPA-REG OUTCOME, Diabetes Research and Clinical Practice (2016), doi: http://dx.doi.org/10.1016/j.diabres. 2016.09.016 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. SummaryEmpagliflozin, a sodium-glucose cotransporter type 2 (SGLT2) inhibitor, has shown a remarkable reduction in cardiovascular and all-cause mortality in patients with type 2 diabetes (T2D) and antecedents of cardiovascular disease in the EMPA-REG OUTCOME trial. This effect has been attributed to a hemodynamic rather than a metabolic effect, partly due to the osmotic/diuretic effect of empagliflozin and to the reduction in arterial blood pressure. The present review will : 1) summarize the results of specific studies having tested the blood pressure lowering effects of SGLT2 inhibitors; 2) describe the results of meta-analyses of trials having evaluated the effects on mortality and cardiovascular outcomes of lowering blood pressure in patients with T2D, with a special focus on baseline and target blood pressures; 3) compare the cardiovascular outcome results in EMPA-REG OUTCOME versus other major trials with antihypertensive agents in patients with T2D; and 4) evaluate post-hoc analyses from EMPA-REG OUTCOME, especially subgroups of patients of special interest regarding the blood pressure lowering hypothesis. Although BP reduction associated to empagliflozin therapy may partly contribute to the benefits reported in EMPA-REG OUTCOME, other mechanisms most probably play a greater role in the overall CV protection and reduction in mortality observed in this trial.

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Section: ) Blood Pressure Lowering Effects Of Sglt2 Inhibitorsmentioning

confidence: 61%

Effects of reducing blood pressure on cardiovascular outcomes and mortality in patients with type 2 diabetes: Focus on SGLT2 inhibitors and EMPA-REG OUTCOME

Scheen

2016

Diabetes Research and Clinical Practice

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“…These observations, along with acknowledgement of the high cost of measures aimed at reducing hypoglycaemia (i.e. structured education, psychological support, glucose self-monitoring, expensive glucoselowering drugs associated with a lower risk of hypoglycaemia compared with sulfonylureas and insulin) [27][28][29][30], would point to the opposite hypothesis, underlying the relevance of socioeconomic status as a determinant of country differences.…”

Section: Discussionmentioning

confidence: 99%

Global burden of hypoglycaemia-related mortality in 109 countries, from 2000 to 2014: an analysis of death certificates

et al. 2018

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Aims/hypothesis In the context of increasing prevalence of diabetes in elderly people with multimorbidity, intensive glucose control may increase the risk of severe hypoglycaemia, potentially leading to death. While rising trends of severe hypoglycaemia rates have been reported in some European, North American and Asian countries, the global burden of hypoglycaemia-related mortality is unknown. We aimed to investigate global differences and trends of hypoglycaemia-related mortality. Methods We used the WHO mortality database to extract information on death certificates reporting hypoglycaemia or diabetes as the underlying cause of death, and the United Nations demographic database to obtain data on mid-year population estimates from 2000 to 2014. We calculated crude and age-standardised proportions (defined as number of hypoglycaemia-related deaths divided by total number of deaths from diabetes [i.e. the sum of hypoglycaemia-and diabetes-related deaths]) and rates (hypoglycaemia-related deaths divided by mid-year population) of hypoglycaemia-related mortality and compared estimates across countries and over time.Results Data for proportions were extracted from 109 countries (31 had data from all years analysed [2000][2001][2002][2003][2004][2005][2006][2007][2008][2009][2010][2011][2012][2013][2014] available). Combining all countries, the age-standardised proportion of hypoglycaemia-related deaths was 4.49 (95% CI 4.44, 4.55) per 1000 total diabetes deaths. Compared with the overall mean, most Central American, South American and (mainly) Caribbean countries reported higher proportions (five more age-standardised hypoglycaemia-related deaths per 1000 total diabetes deaths in Chile, six in Uruguay, 11 in Belize and 22 in Aruba), as well as Japan (11 more age-standardised hypoglycaemia-related deaths per 1000 total diabetes deaths). In comparison, lower proportions were noted in most European countries, the USA, Canada, New Zealand and Australia. For countries with data available for all years analysed, trend analysis showed a 60% increase in hypoglycaemia-related deaths until 2010 and stable trends onwards. Rising trends were most evident for Argentina, Brazil, Chile, the USA and Japan. Data for rates were available for 105 countries (30 had data for all years analysed [2000][2001][2002][2003][2004][2005][2006][2007][2008][2009][2010][2011][2012][2013][2014] available). Combining all countries, the age-standardised hypoglycaemia-related death rate was 0.79 (95% CI 0.77, 0.80) per 1 million person-years. Most Central American, South American and Caribbean countries similarly reported higher rates of hypoglycaemia-related death, whilst virtually all European countries, the USA, Canada, Japan, New Zealand and Australia reported lower rates compared with the overall mean. Age-standardised rates were very low for most countries (lower than five per 1 million person-years in 89.5% of countries), resulting in small absolute differences among countries. As noted with the proportions analysis, trend analysis sho...

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“…The question that thus arises is which of the two pharmacological agents should be added first, either SGLT2i or DPP-4i, in T2D patients who do not reach individual HbA1c targets with metformin [55]. According to the results of a recent systematic review and network meta-analysis of clinical trials and compared to DPP-4i, almost similar reductions in HbA1c were reported with dapagliflozin and empagliflozin but a greater reduction in HbA1c was observed with canagliflozin, especially at the dosage of 300 mg [10]. Superiority of canagliflozin versus DPP-4i was confirmed in a recent real-world study [56].…”

Section: Expert Opinionmentioning

confidence: 99%

“…SGLT2i, which target the kidney and promote glucosuria, belong to the newest pharmacological class of glucose-lowering agents [8]. Both their efficacy and safety have been recently reviewed [9,10]. The demonstration of a remarkable reduction in cardiovascular and all-cause mortality with empagliflozin in T2D patients with history of cardiovascular disease in the EMPA-REG OUTCOME trial [11] raised considerable interest among diabetologists and cardiologists, although the underlying mechanisms of protection remain largely unknown [12].…”

Section: Introductionmentioning

confidence: 99%

DPP-4 inhibitor plus SGLT-2 inhibitor as combination therapy for type 2 diabetes: from rationale to clinical aspects

Scheen

2016

Expert Opinion on Drug Metabolism & Toxicology

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SUMMARYIntroduction : Type 2 diabetes (T2D) is a complex disease with multiple defects, which generally require a combination of several pharmacological approaches to control hyperglycemia. Combining a dipeptidyl peptidase-4 inhibitor (DPP-4i) and a sodium-glucose cotransporter type 2 inhibitor (SGT2i) appears to be an attractive approach.Area covered: An extensive literature search was performed to analyze the pharmacokinetics, pharmacodynamics and clinical experience of different gliptin-gliflozin combinations.Expert opinion: There is a strong rationale for combining a DPP-4i and a SGLT2i in patients with T2D because the two drugs exert different and complementary glucose-lowering effects.Dual therapy (initial combination or stepwise approach) is more potent than either monotherapy in patients treated with diet and exercise or already treated with metformin.Combining the two pharmacological options is safe and does not induce hypoglycemia. The additional glucose-lowering effect is more marked when a gliflozin is added to a gliptin than when a gliptin is added to a gliflozin. Two fixed-dose combinations (FDCs) are already available (saxagliptin-dapagliflozin and linagliptin-empagliflozin) and others are in current development. Bioequivalence of the two compounds given as FDC tablets was demonstrated when compared with coadministration of the individual tablets. FDCs could simplify the antihyperglycaemic therapy and improve drug compliance. Article highlights box -Type 2 diabetes (T2D) often requires the combination of several medications with complementary actions to reach glucose control targets while limiting side effects -The combination of a dipeptidyl peptidase-4 inhibitor (DPP-4i) and a sodium-glucose cotransporter type 2 inhibitor (SGLT2i) is an attractive approach for the management of T2D. Keywords-Both saxagliptin plus dapagliflozin and linagliptin plus empagliflozin combined therapies have been tested as separate tablets (no clinically relevant pharmacokinetic drug-drug interactions) and as fixed-dose combination (FDC : bioequivalence studies).-DPP-4i -SGLT2i combined therapies are more efficacious than either monotherapy to control blood glucose, without worsening of the safety profile.-Initial DPP-4i -SGLT2i combination may be considered or one compound may the added to the other. However, which one should be used in first place remains an open question.

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Efficacy and safety of sodium‐glucose co‐transporter‐2 inhibitors in type 2 diabetes mellitus: systematic review and network meta‐analysis

Cited by 417 publications

References 73 publications

Effects of reducing blood pressure on cardiovascular outcomes and mortality in patients with type 2 diabetes: Focus on SGLT2 inhibitors and EMPA-REG OUTCOME

Effects of reducing blood pressure on cardiovascular outcomes and mortality in patients with type 2 diabetes: Focus on SGLT2 inhibitors and EMPA-REG OUTCOME

Global burden of hypoglycaemia-related mortality in 109 countries, from 2000 to 2014: an analysis of death certificates

DPP-4 inhibitor plus SGLT-2 inhibitor as combination therapy for type 2 diabetes: from rationale to clinical aspects

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