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The Journal of Clinical Endocrinology... Dec 2023Polycystic ovary syndrome (PCOS) is a complex genetic trait and the most common endocrine disorder of women, clinically evident in 5% to 15% of reproductive-aged women...
PURPOSE
Polycystic ovary syndrome (PCOS) is a complex genetic trait and the most common endocrine disorder of women, clinically evident in 5% to 15% of reproductive-aged women globally, with associated cardiometabolic dysfunction. Adipose tissue (AT) dysfunction appears to play an important role in the pathophysiology of PCOS even in patients who do not have excess adiposity.
METHODS
We undertook a systematic review concerning AT dysfunction in PCOS, and prioritized studies that assessed AT function directly. We also explored therapies that targeted AT dysfunction for the treatment of PCOS.
RESULTS
Various mechanisms of AT dysfunction in PCOS were identified including dysregulation in storage capacity, hypoxia, and hyperplasia; impaired adipogenesis; impaired insulin signaling and glucose transport; dysregulated lipolysis and nonesterified free fatty acids (NEFAs) kinetics; adipokine and cytokine dysregulation and subacute inflammation; epigenetic dysregulation; and mitochondrial dysfunction and endoplasmic reticulum and oxidative stress. Decreased glucose transporter-4 expression and content in adipocytes, leading to decreased insulin-mediated glucose transport in AT, was a consistent abnormality despite no alterations in insulin binding or in IRS/PI3K/Akt signaling. Adiponectin secretion in response to cytokines/chemokines is affected in PCOS compared to controls. Interestingly, epigenetic modulation via DNA methylation and microRNA regulation appears to be important mechanisms underlying AT dysfunction in PCOS.
CONCLUSION
AT dysfunction, more than AT distribution and excess adiposity, contributes to the metabolic and inflammation abnormalities of PCOS. Nonetheless, many studies provided contradictory, unclear, or limited data, highlighting the urgent need for additional research in this important field.
Topics: Humans; Female; Adult; Polycystic Ovary Syndrome; Insulin Resistance; Phosphatidylinositol 3-Kinases; Adipose Tissue; Insulin; Cytokines; Obesity; Inflammation; Glucose
PubMed: 37329216
DOI: 10.1210/clinem/dgad356 -
Frontiers in Endocrinology 2023Glucagon-like peptide 1 (GLP-1) agonists and sodium-glucose co-transporter-2 (SGLT2) inhibitors are novel drugs which have recently seen rapid uptake in the treatment of... (Review)
Review
AIMS/HYPOTHESIS
Glucagon-like peptide 1 (GLP-1) agonists and sodium-glucose co-transporter-2 (SGLT2) inhibitors are novel drugs which have recently seen rapid uptake in the treatment of type 2 diabetes and obesity. The paucity of data regarding their safety during pregnancy and lactation causes a dilemma for the physician. The aim of the present study was to systematically review all available data on the offspring effects of GLP-1 agonists and SGLT2 inhibitors during pregnancy and lactation.
METHODS
We systematically searched PubMed, clinicaltrials.gov, FDA and EMA product information on GLP-1 agonists and SGLT2 inhibitors in pregnancy and lactation from inception up to 19 April 2022 without language restrictions. We approached both the Netherlands Pharmacovigilance Centre Lareb on January 17 2023 and the Teratology Information Service (TIS) of Switzerland on February 6 2023. Eligible studies investigating the safety (including congenital anomalies, fetal growth, perinatal demise) in animals or humans, or reporting the degree of transfer of these drugs to the fetus, breast milk or breastfed neonate. Two reviewers independently assessed and selected studies for inclusion and subsequently resolved discrepancies by discussion.
RESULTS
We included 39 records (n=9 theoretical; based on drug properties, n=7 human; n=23 animal, including 76 human offspring, and an unknown number of animal offspring as these numbers could not be retrieved from the FDA and EMA product information). In animal studies, GLP1-agonists were associated with reduced fetal weight and/or growth, delayed ossification and skeletal variants, usually associated with a reduction in maternal weight gain and decreased food consumption. Exendin-4 (GLP1-agonist) was not transported across the maternal-fetal placental interface. In human studies, exenatide (GLP1-agonist) showed a fetal-to-maternal peptide concentration ratio of ≤ 0.017 in ex vivo human placental perfusion in a single placenta. Liraglutide (GLP1-agonist) showed no significant maternal to fetal transfer at least 3.5 hours after maternal exposure in a human study with one subject. In animal studies, GLP-1 agonists were excreted in breast milk; human data on excretion were not available. In animal studies, SGLT2 inhibitors were generally safe during the first trimester but exposure during postnatal day 21 to 90 in juvenile rats, a period coinciding with the late second and third trimester of human renal development, caused dilatation of the renal pelvis and tubules. Human data consisted of a pharmaceutical database of inadvertent pregnancies during SGLT2 inhibitor use, which found an increase in miscarriages and congenital malformations. In animal studies SGLT2 inhibitors were excreted in breast milk and affected neonatal growth, but human data are not available.
CONCLUSION/INTERPRETATION
We found evidence for adverse offspring effects of GLP-1 agonists and SGLT2 inhibitors also in human studies. Our findings broadly support the advice to discontinue GLP-1 agonists and SGLT2 inhibitors during pregnancy and lactation, and also support the ongoing registration of pregnancy outcomes in pharmacological databases since the amount of available data is scarce and mostly limited to animal studies.
REGISTRATION
https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=219877.
Topics: Female; Humans; Pregnancy; Rats; Animals; Sodium-Glucose Transporter 2 Inhibitors; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Breast Feeding; Placenta; Exenatide; Liraglutide; Lactation
PubMed: 37881498
DOI: 10.3389/fendo.2023.1215356 -
Annals of Internal Medicine May 2024Newer diabetes medications may have beneficial effects on mortality, cardiovascular outcomes, and renal outcomes. (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Newer diabetes medications may have beneficial effects on mortality, cardiovascular outcomes, and renal outcomes.
PURPOSE
To evaluate the effectiveness, comparative effectiveness, and harms of sodium-glucose cotransporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP1) agonists, dipeptidyl peptidase-4 (DPP4) inhibitors, and long-acting insulins as monotherapy or combination therapy in adults with type 2 diabetes mellitus (T2DM).
DATA SOURCES
MEDLINE and EMBASE for randomized controlled trials (RCTs) published from 2010 through January 2023.
STUDY SELECTION
RCTs lasting at least 52 weeks that included at least 500 adults with T2DM receiving eligible medications and reported any outcomes of interest.
DATA EXTRACTION
Data were abstracted by 1 reviewer and verified by a second. Independent, dual assessments of risk of bias and certainty of evidence (CoE) were done.
DATA SYNTHESIS
A total of 130 publications from 84 RCTs were identified. CoE was appraised using GRADE (Grading of Recommendations Assessment, Development and Evaluation) criteria for direct, indirect, and network meta-analysis (NMA); the highest CoE was reported. Compared with usual care, SGLT2 inhibitors and GLP1 agonists reduce all-cause mortality (high CoE) and major adverse cardiovascular events (MACE) (moderate to high CoE), SGLT2 inhibitors reduce progression of chronic kidney disease (CKD) and heart failure hospitalizations and GLP1 agonists reduce stroke (high CoE), and SGLT2 inhibitors reduce serious adverse events and severe hypoglycemia (high CoE). The threshold for minimally important differences, which was predefined with the American College of Physicians Clinical Guidelines Committee, was not met for these outcomes. Compared with usual care, insulin, tirzepatide, and DPP4 inhibitors do not reduce all-cause mortality (low to high CoE). Compared with insulin, SGLT2 inhibitors and GLP1 agonists reduce all-cause mortality (low to moderate CoE). Compared with DPP4 inhibitors, GLP1 agonists reduce all-cause mortality (moderate CoE). Compared with DPP4 inhibitors and sulfonylurea (SU), SGLT2 inhibitors reduce MACE (moderate to high CoE). Compared with SU and insulin, SGLT2 inhibitors and GLP1 agonists reduce severe hypoglycemia (low to high CoE).
LIMITATIONS
Infrequent direct comparisons between drugs of interest; sparse data for NMA on most outcomes; possible incoherence due to differences in baseline patient characteristics and usual care; insufficient data on predefined subgroups, including demographic subgroups, patients with prior cardiovascular disease, and treatment-naive persons.
CONCLUSION
In adults with T2DM, SGLT2 inhibitors and GLP1 agonists (but not DPP4 inhibitors, insulin, or tirzepatide) reduce all-cause mortality and MACE compared with usual care. SGLT2 inhibitors reduce CKD progression and heart failure hospitalization and GLP1 agonists reduce stroke compared with usual care. Serious adverse events and severe hypoglycemia are less frequent with SGLT2 inhibitors and GLP1 agonists than with insulin or SU.
PRIMARY FUNDING SOURCE
American College of Physicians. (PROSPERO: CRD42022322129).
Topics: Humans; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Sodium-Glucose Transporter 2 Inhibitors; Hypoglycemic Agents; Network Meta-Analysis; Insulin; Adult; Cardiovascular Diseases; Glucagon-Like Peptide 1; Hypoglycemia; Drug Therapy, Combination
PubMed: 38639549
DOI: 10.7326/M23-1490 -
PloS One 2023Diabetic kidney disease (DKD) is a health burden of rising importance. Slowing progression to end stage kidney disease is the main goal of drug treatment. The aim of... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Diabetic kidney disease (DKD) is a health burden of rising importance. Slowing progression to end stage kidney disease is the main goal of drug treatment. The aim of this analysis is to compare drug treatments of DKD by means of a systemic review and a network meta-analysis.
METHODS
We searched Medline, CENTRAL and clinicaltrials.gov for randomized, controlled studies including adults with DKD treated with the following drugs of interest: single angiotensin-converting-enzyme-inhibitor or angiotensin-receptor-blocker (single ACEi/ARB), angiotensin-converting-enzyme-inhibitor and angiotensin-receptor-blocker combination (ACEi+ARB combination), aldosterone antagonists, direct renin inhibitors, non-steroidal mineralocorticoid-receptor-antagonists (nsMRA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i). As primary endpoints, we defined: overall mortality and end-stage kidney disease, as secondary endpoints: renal composite outcome and albuminuria and as safety endpoints: acute kidney injury, hyperkalemia and hypotension. Under the use of a random effects model, we computed the overall effect estimates using the statistic program R4.1 and the corresponding package "netmeta". Risk of bias was assessed using the RoB 2 tool and the quality of evidence of each pairwise comparison was rated according to GRADE (Grading of Recommendations Assessment, Development and Evaluation).
RESULTS
Of initial 3489 publications, 38 clinical trials were found eligible, in total including 42346 patients. Concerning the primary endpoints overall mortality and end stage kidney disease, SGLT2i on top of single ACEi/ARB compared to single ACEi/ARB was the only intervention significantly reducing the odds of mortality (OR 0.81, 95%CI 0.70-0.95) and end-stage kidney disease (OR 0.69, 95%CI 0.54-0.88). The indirect comparison of nsMRA vs SGLT2i in our composite endpoint suggests a superiority of SGLT2i (OR 0.60, 95%CI 0.47-0.76). Concerning safety endpoints, nsMRA and SGLT2i showed benefits compared to the others.
CONCLUSIONS
As the only drug class, SGLT2i showed in our analysis beneficial effects on top of ACEi/ARB treatment regarding mortality and end stage kidney disease and by that reconfirmed its position as treatment option for diabetic kidney disease. nsMRA reduced the odds for a combined renal endpoint and did not raise any safety concerns, justifying its application.
Topics: Adult; Humans; Angiotensin-Converting Enzyme Inhibitors; Diabetic Nephropathies; Angiotensin Receptor Antagonists; Network Meta-Analysis; Sodium-Glucose Transporter 2 Inhibitors; Kidney Failure, Chronic; Angiotensins; Diabetes Mellitus
PubMed: 37917640
DOI: 10.1371/journal.pone.0293183 -
Journal of the Royal Society of Medicine Sep 2023The cardiorenal protective effects of sodium-glucose co-transporter 2 inhibitors (SGLT2-Is) and glucagon-like peptide 1 receptor agonists (GLP1-RAs) across racial and...
Racial, ethnic and regional differences in the effect of sodium-glucose co-transporter 2 inhibitors and glucagon-like peptide 1 receptor agonists on cardiovascular and renal outcomes: a systematic review and meta-analysis of cardiovascular outcome trials.
OBJECTIVES
The cardiorenal protective effects of sodium-glucose co-transporter 2 inhibitors (SGLT2-Is) and glucagon-like peptide 1 receptor agonists (GLP1-RAs) across racial and ethnic groups are not well defined. By conducting a systematic review and meta-analysis of all randomised, placebo-controlled, cardiovascular disease (CVD) outcomes trials (CVOTs), we aimed to compare racial/ethnic as well as regional patterns in the effects of SGLT2-Is and GLP1-RAs on cardiovascular and renal outcomes in patients with type 2 diabetes (T2D).
DESIGN
Trials were identified from MEDLINE, Embase, the Cochrane Library, and search of bibliographies to 7 July 2023. Setting North America, South/Central America, Europe (Eastern and Western), Asia, Australia-New Zealand (Pacific), Asia/Pacific, and Africa.
SETTING
North America, South/Central America, Europe (Eastern and Western), Asia, Australia-New Zealand (Pacific), Asia/Pacific, and Africa.
PARTICIPANTS
people with type 2 diabetes enrolled in cardiovascular outcome trials of SGLT2-Is and GLP1-RAs.
MAIN OUTCOME MEASURES
Outcomes were (i) major adverse cardiovascular events (MACE), (ii) composite CVD death/heart failure (HF) hospitalization; (iii) composite renal outcome; and (iv) their components. Study-specific hazard ratios (HRs) with 95% confidence intervals (CIs) were pooled.
RESULTS
In total, 14 unique CVOTs (7 comparing SGLT2-Is vs placebo and 7 comparing GLP1-RAs vs placebo) were eligible. The proportion of participants enrolled in the trials ranged from 66.6-93.2% for White populations, 1.2-21.6% for Asian populations, 2.4-8.3% for Black populations and 0.9-23.1% for Other populations. The HR (95% CI) for MACE comparing SGLT2-Is vs placebo was 0.92 (0.86-0.98), 0.69 (0.53-0.92) and 0.70 (0.54-0.91) for White, Asian and Hispanic/Latino populations, respectively. Comparing GLP1-RAs vs placebo, the corresponding HR (95% CI) was 0.88 (0.80-0.97), 0.76 (0.63-0.93) and 0.82 (0.70-0.95), respectively. SGLT2-Is reduced the risk of all other cardiorenal outcomes in White and Asian populations, except for HF hospitalizations in Asians. No effects were observed in Black populations except for a reduced risk of HF hospitalizations by SGLT2-I. SGLT1-Is reduced the risk of composite CVD death/HF hospitalization in North America and Europe, whereas GLP1-RAs reduced the risk of MACE in Europe. GRADE certainty of evidence ranged from moderate to high.
CONCLUSIONS
There appears to be substantial racial/ethnic differences in the cardiorenal effects of SGLT2-Is and GLP1-RAs in patients with T2D, with consistent benefits observed among White and Asian populations and consistent lack of benefits in Black populations. Whether the differences are due to issues with under-representation of Black populations and low statistical power or racial/ethnic variations in the pharmacokinetics, pharmacodynamics and safety of SGLT2-Is and GLP1-RAs need further investigation.PROSPERO Registration: CRD42023401734.
PubMed: 37734450
DOI: 10.1177/01410768231198442 -
Advances in Therapy Oct 2023Evidence from cardiovascular outcome trials (CVOTs) for newer antidiabetic drugs is increasingly influencing revised recommendations for second-line therapy in type 2... (Review)
Review
INTRODUCTION
Evidence from cardiovascular outcome trials (CVOTs) for newer antidiabetic drugs is increasingly influencing revised recommendations for second-line therapy in type 2 diabetes (T2D). This systematic review aimed to compare the cost-effectiveness of newer antidiabetic drugs specified as sodium-glucose cotransporter 2 inhibitor (SGLT2i), glucagon-like peptide 1 receptor agonist (GLP-1RA), and dipeptidyl peptidase 4 inhibitor (DPP-4i) for T2D in a second-line setting.
METHODS
A systematic review was conducted following the Preferred Reporting Items for Systematic Reviews (PRISMA) guidelines, and all relevant published studies were searched comprehensively in electronic databases, including PubMed, Embase, Web of Science, and International Health Technology Assessment database published from April 2023. The quality of the included studies was evaluated using Consolidated Health Economic Evaluation Reporting Standards (CHEERS) 2022 reporting checklists.
RESULTS
We included 28 studies that met the inclusion criteria. Overall reporting of the identified studies largely met CHEERS 2022 recommendations. The CORE and Cardiff models were the most frequently utilized for pharmacoeconomic evaluation in T2D. Four studies consistently discovered that SGLT2i was more cost-effective than GLP-1RA in T2D who were not adequately controlled by metformin monotherapy. Four studies compared GLP-1RA with DPP-4i, sufonylurea (SU), or insulin. Except for one that demonstrated SU was cost-effective, all were GLP-1RA. Five studies revealed that SGLT2i was more cost-effective than DPP-4i or SU. Eleven studies indicated that DPP-4i was more cost-effective than traditional antidiabetic drugs. Four additional studies explored the cost-effectiveness of various antidiabetic drugs as second-line options, indicating that SU, SGLT2i, or meglitinides were more economically advantageous. The most common driven factors were the cost of new antidiabetic drugs.
CONCLUSION
Newer antidiabetic drugs as second line are the cost-effective option for T2D from the cost-effectiveness perspective, especially SGLT2i.
Topics: Humans; Hypoglycemic Agents; Diabetes Mellitus, Type 2; Cost-Benefit Analysis; Dipeptidyl-Peptidase IV Inhibitors; Metformin; Glucagon-Like Peptide-1 Receptor
PubMed: 37515713
DOI: 10.1007/s12325-023-02612-z -
Journal of Diabetes Research 2024Beyond glycemic control, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2is) have been proposed to reduce the... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Beyond glycemic control, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2is) have been proposed to reduce the risk of cardiovascular events. The aim of the present systematic review and meta-analysis is to demonstrate the effects of GLP-1 RA and SGLT2is on intima-media thickness (IMT).
METHODS
PubMed, EMBASE, Web of Science, SCOPUS, and Google Scholar databases were searched from inception to September 9, 2023. All interventional and observational studies that provided data on the effects of GLP-1 RAs or SGLT2is on IMT were included. Critical appraisal was performed using the Joanna Briggs Institute checklists. IMT changes (preintervention and postintervention) were pooled and meta-analyzed using a random-effects model. Subgroup analyses were based on type of medication (GLP-1 RA: liraglutide and exenatide; SGLT2i: empagliflozin, ipragliflozin, tofogliflozin, and dapagliflozin), randomized clinical trials (RCTs), and diabetic patients.
RESULTS
The literature search yielded 708 related articles after duplicates were removed. Eighteen studies examined the effects of GLP-1 RA, and eleven examined the effects of SGLT2i. GLP-1 RA and SGLT2i significantly decreased IMT (MD = -0.123, 95% CI (-0.170, -0.076), < 0.0001, = 98% and MD = -0.048, 95% CI (-0.092, -0.004), = 0.031, = 95%, respectively). Metaregression showed that IMT change correlated with baseline IMT, whereas it did not correlate with gender, duration of diabetes, and duration of treatment.
CONCLUSIONS
Treatment with GLP-1 RA and SGLT2i can lower IMT in diabetic patients, and GLP-1 RA may be more effective than SGLT2i.
Topics: Humans; Carotid Intima-Media Thickness; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptide-1 Receptor Agonists; Hypoglycemic Agents; Sodium-Glucose Transporter 2 Inhibitors; Cardiovascular Diseases
PubMed: 38529046
DOI: 10.1155/2024/3212795 -
Cardiovascular Diabetology Jan 2024Numerous clinical studies have explored sodium-glucose cotransporter 2 inhibitor (SGLT2i) in patients with chronic heart failure (CHF), with or without type 2 diabetes... (Meta-Analysis)
Meta-Analysis
PURPOSE
Numerous clinical studies have explored sodium-glucose cotransporter 2 inhibitor (SGLT2i) in patients with chronic heart failure (CHF), with or without type 2 diabetes mellitus (T2DM), and SGLT2i were proved to significantly reduce CHF hospitalization, cardiovascular death, cardiovascular mortality, all-cause mortality and myocardial infarction in patients with or without T2DM. However, only a limited few have investigated the effects of SGLT-2i on HF disease-specific health status and cardiac function. This meta-analysis aims to assess the effects of SGLT2i on disease-specific health status and cardiac function in CHF patients.
METHODS
A comprehensive search was conducted of trials by searching in PubMed, EMBASE, CENTRAL, Scopus, and Web of Science, and two Chinese databases (CNKI and Wanfang), Clinical Trials ( http://www.
CLINICALTRIALS
gov ) were also searched.
RESULTS
A total of 18 randomized controlled trials (RCTs) involving 23,953 participants were included in the meta-analysis. The effects of SGLT2 inhibitors were compared with control or placebo groups in CHF with or without T2DM. The SGLT2 inhibitors group exhibited a significant reduction in pro b-type natriuretic peptide (NT-proBNP) levels by 136.03 pg/ml (95% confidence interval [CI]: -253.36, - 18.70; P = 0.02). Additionally, a greater proportion of patients in the SGLT2 inhibitors group showed a ≥ 20% decrease in NT-proBNP (RR = 1.45, 95% CI [0.92, 2.29], p = 0.072). However, no statistically significant difference was observed for the effects on B-type natriuretic peptide (BNP). The use of SGLT-2 inhibitors led to a noteworthy improvement in LVEF by 2.79% (95% CI [0.18, 5.39];P = 0.036). In terms of health status, as assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ) and 6-minute walk distance, SGLT2 inhibitors led to a significant improvement in KCCQ clinical summary (KCCQ-CS) score (WMD = 1.7, 95% CI [1.67, 1.73], P < 0.00001), KCCQ overall summary (KCCQ-OS) score (WMD = 1.73, 95% CI [0.94, 2.52], P < 0.00001), and KCCQ total symptom (KCCQ-TS) score (WMD = 2.88, 95% CI [1.7, 4.06], P < 0.00001). Furthermore, the occurrence of KCCQ-CS and KCCQ-OS score increases ≥ 5 points had relative risks (RR) of 1.25 (95% CI [1.11, 1.42], P < 0.00001) and 1.15 (95% CI [1.09, 1.22], P < 0.00001), respectively. Overall, SGLT2 inhibitors increased the 6-minute walk distance by 23.98 m (95% CI [8.34, 39.62]; P = 0.003) compared to control/placebo from baseline.
CONCLUSIONS
The SGLT2 inhibitors treatment offers an effective strategy for improving NT-proBNP levels, Kansas City Cardiomyopathy Questionnaire scores and 6-minute walk distance in CHF with or without T2DM. These findings indicate that SGLT2i improve cardiac function and health status in CHF with or without T2DM, and provide valuable guidance for clinicians making treatment decisions for patients with CHF.
Topics: Humans; Sodium-Glucose Transporter 2 Inhibitors; Natriuretic Peptide, Brain; Heart Failure; Health Status; Diabetes Mellitus, Type 2; Chronic Disease; Cardiomyopathies; Randomized Controlled Trials as Topic
PubMed: 38172861
DOI: 10.1186/s12933-023-02042-9 -
Cardiovascular Diabetology Feb 2024The 2022 Canadian Cardiovascular Society (CCS) cardiorenal guideline provided clinical recommendations on sodium-glucose co-transport 2 inhibitors (SGLT2i) and... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The 2022 Canadian Cardiovascular Society (CCS) cardiorenal guideline provided clinical recommendations on sodium-glucose co-transport 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) use. Since then, additional trials of relevance for SGLT2i have been published. This update re-evaluates the clinical recommendations for using SGLTi and their indirect comparison with existing evidence on GLP-1RA as compared to the standard of care to reduce cardiorenal morbidity and mortality.
METHODS
We updated our existing search and screening of the literature from September 2021 to April 2023 for randomized controlled trials of SGLT2i and GLP-1RA with placebo control. We conducted risk of bias assessment, data extraction and updated our meta-analysis of studies with similar interventions and components. The certainty of the evidence was determined using GRADE.
RESULTS
Evidence from three new trials and additional results from an updated existing trial on SGLT2i met our inclusion criteria after an updated search. Across all the included studies, the total sample size was 151,023 adults, with 90,943 in SGLT2i trials and 60,080 in GLP-1 RA trials. The mean age ranged from 59.9 to 68.4 years. Compared with standard care, the use of SGLT2i and GLP-1 RA showed significant reductions in the outcomes of cardiovascular (CV) mortality (14% & 13%), any-cause mortality (12% & 12%), major adverse CV events (MACE) (11% & 14%), heart failure (HF) hospitalization (30% & 9%), CV death or HF hospitalization (23% & 11%), and kidney composite outcome (32% & 22%). In participants with T2D, both classes demonstrated significant cardiorenal protection. But, only GLP-1RA showed a reduction in non-fatal stroke (16%) and only SGLT2i showed a reduction in HF hospitalization (30%) in this population of people living with T2D.
CONCLUSIONS
This updated and comprehensive meta-analysis substantiates and strengthens the clinical recommendations of the CCS cardiorenal guidelines.
Topics: Adult; Aged; Humans; Middle Aged; Canada; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Heart Failure; Hypoglycemic Agents; Sodium-Glucose Transporter 2 Inhibitors
PubMed: 38360604
DOI: 10.1186/s12933-024-02154-w -
Cardiovascular Diabetology Mar 2024Randomized controlled trials and real-world studies suggest that combination therapy with sodium-glucose transport protein 2 inhibitors (SGLT2is) and glucagon-like... (Meta-Analysis)
Meta-Analysis
Effectiveness and safety of the combination of sodium-glucose transport protein 2 inhibitors and glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes mellitus: a systematic review and meta-analysis of observational studies.
BACKGROUND
Randomized controlled trials and real-world studies suggest that combination therapy with sodium-glucose transport protein 2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) is associated with improvement in fasting plasma glucose (FPG), glycated hemoglobin (HbA1c), systolic blood pressure (SBP), body mass index (BMI), and total cholesterol levels. However, a systematic review of available real-world evidence may facilitate clinical decision-making in the real-world scenario. This meta-analysis assessed the safety and effectiveness of combinations of SGLT2is + GLP-1RAs with a focus on their cardioprotective effects along with glucose-lowering ability in patients with type 2 diabetes mellitus (T2DM) in a real-world setting.
METHODS
Electronic searches were performed in the PubMed/MEDLINE, PROQuest, Scopus, CINAHL, and Google Scholar databases. Qualitative analyses and meta-analyses were performed using the Joanna Briggs Institute SUMARI software package and Review Manager v5.4, respectively.
RESULTS
The initial database search yielded 1445 articles; of these, 13 were included in this study. The analyses indicated that SGLT2is + GLP-1RAs combinations were associated with significantly lower all-cause mortality when compared with individual therapies (odds ratio [95% confidence interval [CI] 0.49 [0.41, 0.60]; p < 0.00001). Significant reductions in BMI (- 1.71 [- 2.74, - 0.67]; p = 0.001), SBP (- 6.35 [- 10.17, - 2.53]; p = 0.001), HbA1c levels (- 1.48 [- 1.75, - 1.21]; p < 0.00001), and FPG (- 2.27 [- 2.78, - 1.76]; p < 0.00001) were associated with the simultaneous administration of the combination. Changes in total cholesterol levels and differences between simultaneous and sequential combination therapies for this outcome were not significant.
CONCLUSION
This systematic review and meta-analysis based on real-world data suggests that the combination of SGLT2is + GLP-1RAs is associated with lower all-cause mortality and favorable improvements in cardiovascular, renal, and glycemic measurements. The findings drive a call-to-action to incorporate this combination early and simultaneously in managing T2DM patients and achieve potential cardiovascular benefits and renal protection.
Topics: Humans; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Glucagon-Like Peptide-1 Receptor Agonists; Glycated Hemoglobin; Blood Glucose; Cholesterol; Glucagon-Like Peptide-1 Receptor
PubMed: 38500154
DOI: 10.1186/s12933-024-02192-4