Assessing the risk of ketoacidosis due to sodium-glucose cotransporter (SGLT)-2 inhibitors in patients with type 1 diabetes: A meta-analysis and meta-regression
Sodium-glucose cotransporter-2 (SGLT2) inhibitors (SGLT2i) showed benefits in type 1 diabetes mellitus (T1DM), but the risk of diabetic ketoacidosis (DKA) limits their use. Ability to predict DKA risk and therapeutic responses would enable appropriate patient selection for SGLT2i. We conducted a met...
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| Veröffentlicht in: | PLoS medicine 2020-12, Vol.17 (12), p.e1003461 |
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| description | Sodium-glucose cotransporter-2 (SGLT2) inhibitors (SGLT2i) showed benefits in type 1 diabetes mellitus (T1DM), but the risk of diabetic ketoacidosis (DKA) limits their use. Ability to predict DKA risk and therapeutic responses would enable appropriate patient selection for SGLT2i. We conducted a meta-analysis and meta-regression of randomized controlled trials (RCTs) evaluating SGLT2i in T1DM to assess moderators of the relative risk (RR) of DKA, of glycemic (HbA1c, fasting plasma glucose, continuous glucose monitoring parameters, insulin dose, and insulin sensitivity indices) and non-glycemic (body mass index (BMI), systolic BP, renal function, albuminuria, and diabetic eye disorders) efficacy, and of other safety outcomes (including hypoglycemia, infections, major adverse cardiovascular events, and death).
We searched MEDLINE, Cochrane Library, EMBASE, ClinicalTrials.gov, Cochrane CENTRAL Register of Controlled Trials, and other electronic sources through August 30, 2020, for RCTs comparing SGLT2i with active comparators or placebo in adult patients with T1DM. Reviewers extracted data for relevant outcomes, performed random effects meta-analyses, subgroup analyses, and multivariable meta-regression. The strength of evidence was summarized with the GRADE approach. Among 9,914 records identified, 18 placebo-controlled RCTs (7,396 participants, 50% males, mean age 42 y (range 23 to 55 y), 5 different SGLT2i evaluated), were included. Main outcome measures were effect sizes and moderators of glycemic and non-glycemic efficacy and of safety outcomes. In a multivariable meta-regression model, baseline BMI (β = 0.439 [95% CI: 0.211, 0.666], p < 0.001) and estimated glucose disposal rate (eGDR) (β = -0.766 [-1.276, -0.256], p = 0.001) were associated with the RR of DKA (RR: 2.81; 95% CI:1.97, 4.01; p < 0.001, R2 = 61%). A model including also treatment-related parameters (insulin dose change-to-baseline insulin sensitivity ratio and volume depletion) explained 86% of variance across studies in the risk of DKA (R2 = 86%). The association of DKA with a BMI >27 kg/m2 and with an eGDR |
| doi_str_mv | 10.1371/journal.pmed.1003461 |
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We searched MEDLINE, Cochrane Library, EMBASE, ClinicalTrials.gov, Cochrane CENTRAL Register of Controlled Trials, and other electronic sources through August 30, 2020, for RCTs comparing SGLT2i with active comparators or placebo in adult patients with T1DM. Reviewers extracted data for relevant outcomes, performed random effects meta-analyses, subgroup analyses, and multivariable meta-regression. The strength of evidence was summarized with the GRADE approach. Among 9,914 records identified, 18 placebo-controlled RCTs (7,396 participants, 50% males, mean age 42 y (range 23 to 55 y), 5 different SGLT2i evaluated), were included. Main outcome measures were effect sizes and moderators of glycemic and non-glycemic efficacy and of safety outcomes. In a multivariable meta-regression model, baseline BMI (β = 0.439 [95% CI: 0.211, 0.666], p < 0.001) and estimated glucose disposal rate (eGDR) (β = -0.766 [-1.276, -0.256], p = 0.001) were associated with the RR of DKA (RR: 2.81; 95% CI:1.97, 4.01; p < 0.001, R2 = 61%). A model including also treatment-related parameters (insulin dose change-to-baseline insulin sensitivity ratio and volume depletion) explained 86% of variance across studies in the risk of DKA (R2 = 86%). The association of DKA with a BMI >27 kg/m2 and with an eGDR <8.3 mg/kg/min was confirmed also in subgroup analyses. Among efficacy outcomes, the novel findings were a reduction in albuminuria (WMD: -9.91, 95% CI: -16.26, -3.55 mg/g, p = 0.002), and in RR of diabetic eye disorders (RR: 0.27[0.11, 0.67], p = 0.005) associated with SGLT2i. A SGLT2i dose-response gradient was consistently observed for main efficacy outcomes, but not for adverse events (AEs). Overall, predictors of DKA and of other AEs differed substantially from those of glycemic and non-glycemic efficacy. A limitation of our analysis was the relatively short (≤52 weeks) duration of included RCTs. The potential relevance for clinical practice needs also to be confirmed by real-world prospective studies.
In T1DM, the risk of DKA and main therapeutic responses to SGLT2i are modified by baseline BMI and insulin resistance, by total insulin dose reduction-to-baseline insulin sensitivity ratio, and by volume depletion, which may enable the targeted use of these drugs in patients with the greatest benefit and the lowest risk of DKA.</description><identifier>ISSN: 1549-1676</identifier><identifier>ISSN: 1549-1277</identifier><identifier>EISSN: 1549-1676</identifier><identifier>DOI: 10.1371/journal.pmed.1003461</identifier><identifier>PMID: 33373368</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adult ; Bias ; Biology and Life Sciences ; Body mass index ; Care and treatment ; Comparative analysis ; Complications and side effects ; Diabetes ; Diabetes mellitus (insulin dependent) ; Diabetes Mellitus, Type 1 - complications ; Diabetes Mellitus, Type 1 - diagnosis ; Diabetes Mellitus, Type 1 - drug therapy ; Diabetic acidosis ; Diabetic Ketoacidosis - chemically induced ; Diabetic Ketoacidosis - diagnosis ; Diabetics ; Diagnosis ; Distribution ; Dosage and administration ; Drug development ; Drug dosages ; Epidermal growth factor receptors ; Eye disorders ; Fasting ; Female ; Genital tract ; Glucose ; Handbooks ; Hemoglobin ; Humans ; Hypoglycemia ; Hypoglycemic agents ; Insulin ; Insulin resistance ; Intervention ; Ketoacidosis ; Laboratory testing ; Male ; Medicine and Health Sciences ; Meta-analysis ; Middle Aged ; Na+/glucose cotransporter ; Optimization ; Patients ; Physical Sciences ; Randomized Controlled Trials as Topic ; Regulatory agencies ; Renal function ; Research and Analysis Methods ; Risk Assessment ; Risk Factors ; Sodium-Glucose Transporter 2 Inhibitors - adverse effects ; Treatment Outcome ; Type 1 diabetes ; Urinary tract ; Young Adult</subject><ispartof>PLoS medicine, 2020-12, Vol.17 (12), p.e1003461</ispartof><rights>COPYRIGHT 2020 Public Library of Science</rights><rights>2020 Musso et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2020 Musso et al 2020 Musso et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c631t-46d2d37d02cb934c9ac1a79ee5e278d4244539a3ed0788ac587d020f8fa2b75b3</citedby><cites>FETCH-LOGICAL-c631t-46d2d37d02cb934c9ac1a79ee5e278d4244539a3ed0788ac587d020f8fa2b75b3</cites><orcidid>0000-0002-8569-2872</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771708/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771708/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,2928,23866,27924,27925,53791,53793,79600,79601</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33373368$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Jia, Weiping</contributor><creatorcontrib>Musso, Giovanni</creatorcontrib><creatorcontrib>Sircana, Antonio</creatorcontrib><creatorcontrib>Saba, Francesca</creatorcontrib><creatorcontrib>Cassader, Maurizio</creatorcontrib><creatorcontrib>Gambino, Roberto</creatorcontrib><title>Assessing the risk of ketoacidosis due to sodium-glucose cotransporter (SGLT)-2 inhibitors in patients with type 1 diabetes: A meta-analysis and meta-regression</title><title>PLoS medicine</title><addtitle>PLoS Med</addtitle><description>Sodium-glucose cotransporter-2 (SGLT2) inhibitors (SGLT2i) showed benefits in type 1 diabetes mellitus (T1DM), but the risk of diabetic ketoacidosis (DKA) limits their use. Ability to predict DKA risk and therapeutic responses would enable appropriate patient selection for SGLT2i. We conducted a meta-analysis and meta-regression of randomized controlled trials (RCTs) evaluating SGLT2i in T1DM to assess moderators of the relative risk (RR) of DKA, of glycemic (HbA1c, fasting plasma glucose, continuous glucose monitoring parameters, insulin dose, and insulin sensitivity indices) and non-glycemic (body mass index (BMI), systolic BP, renal function, albuminuria, and diabetic eye disorders) efficacy, and of other safety outcomes (including hypoglycemia, infections, major adverse cardiovascular events, and death).
We searched MEDLINE, Cochrane Library, EMBASE, ClinicalTrials.gov, Cochrane CENTRAL Register of Controlled Trials, and other electronic sources through August 30, 2020, for RCTs comparing SGLT2i with active comparators or placebo in adult patients with T1DM. Reviewers extracted data for relevant outcomes, performed random effects meta-analyses, subgroup analyses, and multivariable meta-regression. The strength of evidence was summarized with the GRADE approach. Among 9,914 records identified, 18 placebo-controlled RCTs (7,396 participants, 50% males, mean age 42 y (range 23 to 55 y), 5 different SGLT2i evaluated), were included. Main outcome measures were effect sizes and moderators of glycemic and non-glycemic efficacy and of safety outcomes. In a multivariable meta-regression model, baseline BMI (β = 0.439 [95% CI: 0.211, 0.666], p < 0.001) and estimated glucose disposal rate (eGDR) (β = -0.766 [-1.276, -0.256], p = 0.001) were associated with the RR of DKA (RR: 2.81; 95% CI:1.97, 4.01; p < 0.001, R2 = 61%). A model including also treatment-related parameters (insulin dose change-to-baseline insulin sensitivity ratio and volume depletion) explained 86% of variance across studies in the risk of DKA (R2 = 86%). The association of DKA with a BMI >27 kg/m2 and with an eGDR <8.3 mg/kg/min was confirmed also in subgroup analyses. Among efficacy outcomes, the novel findings were a reduction in albuminuria (WMD: -9.91, 95% CI: -16.26, -3.55 mg/g, p = 0.002), and in RR of diabetic eye disorders (RR: 0.27[0.11, 0.67], p = 0.005) associated with SGLT2i. A SGLT2i dose-response gradient was consistently observed for main efficacy outcomes, but not for adverse events (AEs). Overall, predictors of DKA and of other AEs differed substantially from those of glycemic and non-glycemic efficacy. A limitation of our analysis was the relatively short (≤52 weeks) duration of included RCTs. The potential relevance for clinical practice needs also to be confirmed by real-world prospective studies.
In T1DM, the risk of DKA and main therapeutic responses to SGLT2i are modified by baseline BMI and insulin resistance, by total insulin dose reduction-to-baseline insulin sensitivity ratio, and by volume depletion, which may enable the targeted use of these drugs in patients with the greatest benefit and the lowest risk of DKA.</description><subject>Adult</subject><subject>Bias</subject><subject>Biology and Life Sciences</subject><subject>Body mass index</subject><subject>Care and treatment</subject><subject>Comparative analysis</subject><subject>Complications and side effects</subject><subject>Diabetes</subject><subject>Diabetes mellitus (insulin dependent)</subject><subject>Diabetes Mellitus, Type 1 - complications</subject><subject>Diabetes Mellitus, Type 1 - diagnosis</subject><subject>Diabetes Mellitus, Type 1 - drug therapy</subject><subject>Diabetic acidosis</subject><subject>Diabetic Ketoacidosis - chemically induced</subject><subject>Diabetic Ketoacidosis - diagnosis</subject><subject>Diabetics</subject><subject>Diagnosis</subject><subject>Distribution</subject><subject>Dosage and administration</subject><subject>Drug development</subject><subject>Drug dosages</subject><subject>Epidermal growth factor receptors</subject><subject>Eye disorders</subject><subject>Fasting</subject><subject>Female</subject><subject>Genital tract</subject><subject>Glucose</subject><subject>Handbooks</subject><subject>Hemoglobin</subject><subject>Humans</subject><subject>Hypoglycemia</subject><subject>Hypoglycemic agents</subject><subject>Insulin</subject><subject>Insulin resistance</subject><subject>Intervention</subject><subject>Ketoacidosis</subject><subject>Laboratory testing</subject><subject>Male</subject><subject>Medicine and Health Sciences</subject><subject>Meta-analysis</subject><subject>Middle Aged</subject><subject>Na+/glucose cotransporter</subject><subject>Optimization</subject><subject>Patients</subject><subject>Physical Sciences</subject><subject>Randomized Controlled Trials as Topic</subject><subject>Regulatory agencies</subject><subject>Renal function</subject><subject>Research and Analysis Methods</subject><subject>Risk Assessment</subject><subject>Risk Factors</subject><subject>Sodium-Glucose Transporter 2 Inhibitors - 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complications</topic><topic>Diabetes Mellitus, Type 1 - diagnosis</topic><topic>Diabetes Mellitus, Type 1 - drug therapy</topic><topic>Diabetic acidosis</topic><topic>Diabetic Ketoacidosis - chemically induced</topic><topic>Diabetic Ketoacidosis - diagnosis</topic><topic>Diabetics</topic><topic>Diagnosis</topic><topic>Distribution</topic><topic>Dosage and administration</topic><topic>Drug development</topic><topic>Drug dosages</topic><topic>Epidermal growth factor receptors</topic><topic>Eye disorders</topic><topic>Fasting</topic><topic>Female</topic><topic>Genital tract</topic><topic>Glucose</topic><topic>Handbooks</topic><topic>Hemoglobin</topic><topic>Humans</topic><topic>Hypoglycemia</topic><topic>Hypoglycemic agents</topic><topic>Insulin</topic><topic>Insulin resistance</topic><topic>Intervention</topic><topic>Ketoacidosis</topic><topic>Laboratory testing</topic><topic>Male</topic><topic>Medicine and Health Sciences</topic><topic>Meta-analysis</topic><topic>Middle Aged</topic><topic>Na+/glucose cotransporter</topic><topic>Optimization</topic><topic>Patients</topic><topic>Physical Sciences</topic><topic>Randomized Controlled Trials as Topic</topic><topic>Regulatory agencies</topic><topic>Renal function</topic><topic>Research and Analysis Methods</topic><topic>Risk Assessment</topic><topic>Risk Factors</topic><topic>Sodium-Glucose Transporter 2 Inhibitors - adverse effects</topic><topic>Treatment Outcome</topic><topic>Type 1 diabetes</topic><topic>Urinary tract</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Musso, Giovanni</creatorcontrib><creatorcontrib>Sircana, Antonio</creatorcontrib><creatorcontrib>Saba, Francesca</creatorcontrib><creatorcontrib>Cassader, Maurizio</creatorcontrib><creatorcontrib>Gambino, Roberto</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Neurosciences Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><collection>PLoS Medicine</collection><jtitle>PLoS medicine</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Musso, Giovanni</au><au>Sircana, Antonio</au><au>Saba, Francesca</au><au>Cassader, Maurizio</au><au>Gambino, Roberto</au><au>Jia, Weiping</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Assessing the risk of ketoacidosis due to sodium-glucose cotransporter (SGLT)-2 inhibitors in patients with type 1 diabetes: A meta-analysis and meta-regression</atitle><jtitle>PLoS medicine</jtitle><addtitle>PLoS Med</addtitle><date>2020-12-01</date><risdate>2020</risdate><volume>17</volume><issue>12</issue><spage>e1003461</spage><pages>e1003461-</pages><issn>1549-1676</issn><issn>1549-1277</issn><eissn>1549-1676</eissn><abstract>Sodium-glucose cotransporter-2 (SGLT2) inhibitors (SGLT2i) showed benefits in type 1 diabetes mellitus (T1DM), but the risk of diabetic ketoacidosis (DKA) limits their use. Ability to predict DKA risk and therapeutic responses would enable appropriate patient selection for SGLT2i. We conducted a meta-analysis and meta-regression of randomized controlled trials (RCTs) evaluating SGLT2i in T1DM to assess moderators of the relative risk (RR) of DKA, of glycemic (HbA1c, fasting plasma glucose, continuous glucose monitoring parameters, insulin dose, and insulin sensitivity indices) and non-glycemic (body mass index (BMI), systolic BP, renal function, albuminuria, and diabetic eye disorders) efficacy, and of other safety outcomes (including hypoglycemia, infections, major adverse cardiovascular events, and death).
We searched MEDLINE, Cochrane Library, EMBASE, ClinicalTrials.gov, Cochrane CENTRAL Register of Controlled Trials, and other electronic sources through August 30, 2020, for RCTs comparing SGLT2i with active comparators or placebo in adult patients with T1DM. Reviewers extracted data for relevant outcomes, performed random effects meta-analyses, subgroup analyses, and multivariable meta-regression. The strength of evidence was summarized with the GRADE approach. Among 9,914 records identified, 18 placebo-controlled RCTs (7,396 participants, 50% males, mean age 42 y (range 23 to 55 y), 5 different SGLT2i evaluated), were included. Main outcome measures were effect sizes and moderators of glycemic and non-glycemic efficacy and of safety outcomes. In a multivariable meta-regression model, baseline BMI (β = 0.439 [95% CI: 0.211, 0.666], p < 0.001) and estimated glucose disposal rate (eGDR) (β = -0.766 [-1.276, -0.256], p = 0.001) were associated with the RR of DKA (RR: 2.81; 95% CI:1.97, 4.01; p < 0.001, R2 = 61%). A model including also treatment-related parameters (insulin dose change-to-baseline insulin sensitivity ratio and volume depletion) explained 86% of variance across studies in the risk of DKA (R2 = 86%). The association of DKA with a BMI >27 kg/m2 and with an eGDR <8.3 mg/kg/min was confirmed also in subgroup analyses. Among efficacy outcomes, the novel findings were a reduction in albuminuria (WMD: -9.91, 95% CI: -16.26, -3.55 mg/g, p = 0.002), and in RR of diabetic eye disorders (RR: 0.27[0.11, 0.67], p = 0.005) associated with SGLT2i. A SGLT2i dose-response gradient was consistently observed for main efficacy outcomes, but not for adverse events (AEs). Overall, predictors of DKA and of other AEs differed substantially from those of glycemic and non-glycemic efficacy. A limitation of our analysis was the relatively short (≤52 weeks) duration of included RCTs. The potential relevance for clinical practice needs also to be confirmed by real-world prospective studies.
In T1DM, the risk of DKA and main therapeutic responses to SGLT2i are modified by baseline BMI and insulin resistance, by total insulin dose reduction-to-baseline insulin sensitivity ratio, and by volume depletion, which may enable the targeted use of these drugs in patients with the greatest benefit and the lowest risk of DKA.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>33373368</pmid><doi>10.1371/journal.pmed.1003461</doi><orcidid>https://orcid.org/0000-0002-8569-2872</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1549-1676 |
| ispartof | PLoS medicine, 2020-12, Vol.17 (12), p.e1003461 |
| issn | 1549-1676 1549-1277 1549-1676 |
| language | eng |
| recordid | cdi_plos_journals_2490315585 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Public Library of Science (PLoS) Journals Open Access; PubMed Central |
| subjects | Adult Bias Biology and Life Sciences Body mass index Care and treatment Comparative analysis Complications and side effects Diabetes Diabetes mellitus (insulin dependent) Diabetes Mellitus, Type 1 - complications Diabetes Mellitus, Type 1 - diagnosis Diabetes Mellitus, Type 1 - drug therapy Diabetic acidosis Diabetic Ketoacidosis - chemically induced Diabetic Ketoacidosis - diagnosis Diabetics Diagnosis Distribution Dosage and administration Drug development Drug dosages Epidermal growth factor receptors Eye disorders Fasting Female Genital tract Glucose Handbooks Hemoglobin Humans Hypoglycemia Hypoglycemic agents Insulin Insulin resistance Intervention Ketoacidosis Laboratory testing Male Medicine and Health Sciences Meta-analysis Middle Aged Na+/glucose cotransporter Optimization Patients Physical Sciences Randomized Controlled Trials as Topic Regulatory agencies Renal function Research and Analysis Methods Risk Assessment Risk Factors Sodium-Glucose Transporter 2 Inhibitors - adverse effects Treatment Outcome Type 1 diabetes Urinary tract Young Adult |
| title | Assessing the risk of ketoacidosis due to sodium-glucose cotransporter (SGLT)-2 inhibitors in patients with type 1 diabetes: A meta-analysis and meta-regression |
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