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The New England Journal of Medicine Sep 2022Data are lacking on the comparative effectiveness of commonly used glucose-lowering medications, when added to metformin, with respect to microvascular and... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
Data are lacking on the comparative effectiveness of commonly used glucose-lowering medications, when added to metformin, with respect to microvascular and cardiovascular disease outcomes in persons with type 2 diabetes.
METHODS
We assessed the comparative effectiveness of four commonly used glucose-lowering medications, added to metformin, in achieving and maintaining a glycated hemoglobin level of less than 7.0% in participants with type 2 diabetes. The randomly assigned therapies were insulin glargine U-100 (hereafter, glargine), glimepiride, liraglutide, and sitagliptin. Prespecified secondary outcomes with respect to microvascular and cardiovascular disease included hypertension and dyslipidemia, confirmed moderately or severely increased albuminuria or an estimated glomerular filtration rate of less than 60 ml per minute per 1.73 m of body-surface area, diabetic peripheral neuropathy assessed with the Michigan Neuropathy Screening Instrument, cardiovascular events (major adverse cardiovascular events [MACE], hospitalization for heart failure, or an aggregate outcome of any cardiovascular event), and death. Hazard ratios are presented with 95% confidence limits that are not adjusted for multiple comparisons.
RESULTS
During a mean 5.0 years of follow-up in 5047 participants, there were no material differences among the interventions with respect to the development of hypertension or dyslipidemia or with respect to microvascular outcomes; the mean overall rate (i.e., events per 100 participant-years) of moderately increased albuminuria levels was 2.6, of severely increased albuminuria levels 1.1, of renal impairment 2.9, and of diabetic peripheral neuropathy 16.7. The treatment groups did not differ with respect to MACE (overall rate, 1.0), hospitalization for heart failure (0.4), death from cardiovascular causes (0.3), or all deaths (0.6). There were small differences with respect to rates of any cardiovascular disease, with 1.9, 1.9, 1.4, and 2.0 in the glargine, glimepiride, liraglutide, and sitagliptin groups, respectively. When one treatment was compared with the combined results of the other three treatments, the hazard ratios for any cardiovascular disease were 1.1 (95% confidence interval [CI], 0.9 to 1.3) in the glargine group, 1.1 (95% CI, 0.9 to 1.4) in the glimepiride group, 0.7 (95% CI, 0.6 to 0.9) in the liraglutide group, and 1.2 (95% CI, 1.0 to 1.5) in the sitagliptin group.
CONCLUSIONS
In participants with type 2 diabetes, the incidences of microvascular complications and death were not materially different among the four treatment groups. The findings indicated possible differences among the groups in the incidence of any cardiovascular disease. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; GRADE ClinicalTrials.gov number, NCT01794143.).
Topics: Albuminuria; Blood Glucose; Cardiovascular Diseases; Comparative Effectiveness Research; Diabetes Complications; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Drug Therapy, Combination; Dyslipidemias; Glomerular Filtration Rate; Glycated Hemoglobin; Heart Failure; Humans; Hypertension; Hypoglycemic Agents; Insulin Glargine; Liraglutide; Metformin; Microvessels; Sitagliptin Phosphate; Sulfonylurea Compounds
PubMed: 36129997
DOI: 10.1056/NEJMoa2200436 -
The New England Journal of Medicine Sep 2022The comparative effectiveness of glucose-lowering medications for use with metformin to maintain target glycated hemoglobin levels in persons with type 2 diabetes is... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
The comparative effectiveness of glucose-lowering medications for use with metformin to maintain target glycated hemoglobin levels in persons with type 2 diabetes is uncertain.
METHODS
In this trial involving participants with type 2 diabetes of less than 10 years' duration who were receiving metformin and had glycated hemoglobin levels of 6.8 to 8.5%, we compared the effectiveness of four commonly used glucose-lowering medications. We randomly assigned participants to receive insulin glargine U-100 (hereafter, glargine), the sulfonylurea glimepiride, the glucagon-like peptide-1 receptor agonist liraglutide, or sitagliptin, a dipeptidyl peptidase 4 inhibitor. The primary metabolic outcome was a glycated hemoglobin level, measured quarterly, of 7.0% or higher that was subsequently confirmed, and the secondary metabolic outcome was a confirmed glycated hemoglobin level greater than 7.5%.
RESULTS
A total of 5047 participants (19.8% Black and 18.6% Hispanic or Latinx) who had received metformin for type 2 diabetes were followed for a mean of 5.0 years. The cumulative incidence of a glycated hemoglobin level of 7.0% or higher (the primary metabolic outcome) differed significantly among the four groups (P<0.001 for a global test of differences across groups); the rates with glargine (26.5 per 100 participant-years) and liraglutide (26.1) were similar and lower than those with glimepiride (30.4) and sitagliptin (38.1). The differences among the groups with respect to a glycated hemoglobin level greater than 7.5% (the secondary outcome) paralleled those of the primary outcome. There were no material differences with respect to the primary outcome across prespecified subgroups defined according to sex, age, or race or ethnic group; however, among participants with higher baseline glycated hemoglobin levels there appeared to be an even greater benefit with glargine, liraglutide, and glimepiride than with sitagliptin. Severe hypoglycemia was rare but significantly more frequent with glimepiride (in 2.2% of the participants) than with glargine (1.3%), liraglutide (1.0%), or sitagliptin (0.7%). Participants who received liraglutide reported more frequent gastrointestinal side effects and lost more weight than those in the other treatment groups.
CONCLUSIONS
All four medications, when added to metformin, decreased glycated hemoglobin levels. However, glargine and liraglutide were significantly, albeit modestly, more effective in achieving and maintaining target glycated hemoglobin levels. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; GRADE ClinicalTrials.gov number, NCT01794143.).
Topics: Blood Glucose; Comparative Effectiveness Research; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin Glargine; Liraglutide; Metformin; Sitagliptin Phosphate; Sulfonylurea Compounds; Treatment Outcome
PubMed: 36129996
DOI: 10.1056/NEJMoa2200433 -
Diabetes, Obesity & Metabolism Feb 2021To evaluate the efficacy and safety of once-weekly subcutaneous semaglutide, a glucagon-like peptide-1 (GLP-1) analogue, versus once-daily sitagliptin as add-on to... (Randomized Controlled Trial)
Randomized Controlled Trial
Efficacy and safety of once-weekly semaglutide versus once-daily sitagliptin as add-on to metformin in patients with type 2 diabetes in SUSTAIN China: A 30-week, double-blind, phase 3a, randomized trial.
AIM
To evaluate the efficacy and safety of once-weekly subcutaneous semaglutide, a glucagon-like peptide-1 (GLP-1) analogue, versus once-daily sitagliptin as add-on to metformin in patients with type 2 diabetes (T2D) in a multiregional clinical trial.
MATERIALS AND METHODS
In the 30-week, randomized, double-blind, double-dummy, active comparator SUSTAIN China trial, 868 adults with T2D inadequately controlled on metformin (HbA1c 7.0%-10.5%) were randomized to receive once-weekly semaglutide 0.5 mg (n = 288), semaglutide 1.0 mg (n = 290) or once-daily sitagliptin 100 mg (n = 290). The primary and confirmatory secondary endpoints were change from baseline to week 30 in HbA and body weight, respectively.
RESULTS
The trial enrolled ~70% (605/868) of the patients in China, and the remaining patients from four other countries, including the Republic of Korea. Both doses of semaglutide were superior to sitagliptin in reducing HbA and body weight after 30 weeks of treatment. The odds of achieving target HbA of less than 7.0% (53 mmol/mol), weight loss of 5% or higher, or 10% or higher, and the composite endpoint of HbA less than 7.0% (53 mmol/mol) without severe or blood glucose-confirmed symptomatic hypoglycaemia no weight gain, were all significantly higher with both semaglutide doses compared with sitagliptin. The safety profile for semaglutide was consistent with the known class effects of GLP-1 receptor agonists (RAs). Consistent efficacy and safety findings were seen in the Chinese subpopulation.
CONCLUSIONS
Once-weekly semaglutide was superior to sitagliptin in improving glycaemic control and reducing body weight in patients with T2D inadequately controlled on metformin. The safety and tolerability profiles were consistent with those of semaglutide and other GLP-1 RAs. Semaglutide is an effective once-weekly treatment option for the Chinese population.
Topics: Adult; China; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Metformin; Republic of Korea; Sitagliptin Phosphate; Treatment Outcome
PubMed: 33074557
DOI: 10.1111/dom.14232 -
Cell Death & Disease Oct 2021Acute lung injury (ALI) is a complication of severe acute pancreatitis (SAP). Sitagliptin (SIT) is a DPP4 inhibitor that exerts anti-inflammatory and antioxidant...
Acute lung injury (ALI) is a complication of severe acute pancreatitis (SAP). Sitagliptin (SIT) is a DPP4 inhibitor that exerts anti-inflammatory and antioxidant effects; however, its mechanism of action in SAP-ALI remains unclear. In this study, we investigated the effects of SIT on SAP-ALI and the specific pathways involved in SAP-induced lung inflammation, including oxidative stress, autophagy, and p62-Kelch-like ECH-associated protein 1 (Keap1)-NF-E2-related factor 2 (Nrf2) signalling pathways. Nrf2 knockout (Nrf2) and wild-type (WT) mice were pre-treated with SIT (100 mg/kg), followed by caerulein and lipopolysaccharide (LPS) administration to induce pancreatic and lung injury. BEAS-2B cells were transfected with siRNA-Nrf2 and treated with LPS, and the changes in inflammation, reactive oxygen species (ROS) levels, and autophagy were measured. SIT reduced histological damage, oedema, and myeloperoxidase activity in the lung, decreased the expression of pro-inflammatory cytokines, and inhibited excessive autophagy and ROS production via the activation of the p62-Keap1-Nrf2 signalling pathway and promotion of the nuclear translocation of Nrf2. In Nrf2-knockout mice, the anti-inflammatory effect of SIT was reduced, resulting in ROS accumulation and excessive autophagy. In BEAS-2B cells, LPS induced ROS production and activated autophagy, further enhanced by Nrf2 knockdown. This study demonstrates that SIT reduces SAP-ALI-associated oxidative stress and excessive autophagy through the p62-Keap1-Nrf2 signalling pathway and nuclear translocation of Nrf2, suggesting its therapeutic potential in SAP-ALI.
Topics: Acute Disease; Acute Lung Injury; Aldehydes; Animals; Autophagy; Autophagy-Related Protein 5; Beclin-1; Down-Regulation; Inflammation; Kelch-Like ECH-Associated Protein 1; Lung; Mice, Inbred C57BL; Mice, Knockout; NF-E2-Related Factor 2; Oxidative Stress; Pancreatitis; Protective Agents; Reactive Oxygen Species; Sequestosome-1 Protein; Signal Transduction; Sitagliptin Phosphate; Mice
PubMed: 34635643
DOI: 10.1038/s41419-021-04227-0 -
Scientific Reports Jan 2023Sitagliptin has been suggested as a treatment option for older adults with type 2 diabetes (T2D). However, no randomized controlled trial has been performed to evaluate... (Randomized Controlled Trial)
Randomized Controlled Trial
Sitagliptin has been suggested as a treatment option for older adults with type 2 diabetes (T2D). However, no randomized controlled trial has been performed to evaluate the efficacy and safety of sitagliptin treatment in older Japanese patients with T2D. The STREAM study was a multicenter, open-label, randomized controlled trial. T2D outpatients aged 65-80 years with moderately controlled glycemic levels (HbA1c 7.4-10.4%) under lifestyle interventions without or with oral anti-diabetic drugs excluding DPP4 inhibitors or GLP-1 receptor agonists were recruited (n = 176). The participants were randomized into sitagliptin group (n = 88) who received sitagliptin as an initial or an additive anti-diabetic drug and control group (n = 88) who did not. The treatment goal was HbA1c level < 7.4%. Efficacy and safety during 12-month treatment period were investigated. The mean (± SD) ages were 70.6 ± 3.9 and 71.9 ± 4.4 years old in sitagliptin and control groups, respectively. According to a mixed-effects model analysis, average changes from baseline over the treatment period in fasting plasma glucose (FPG), HbA1c, and glycated albumin (GA) were - 27.2 mg/dL, - 0.61%, and - 2.39%, respectively, in sitagliptin group, and 0.50 mg/dL, - 0.29%, and - 0.93%, respectively, in control group. The reductions in FPG, HbA1c, and GA were significantly greater in sitagliptin group (P < 0.0001, P < 0.01, and P < 0.0001, respectively). There were no differences in the incidence of adverse effects, except for cystatin C elevation and platelet count reduction in sitagliptin group. Sitagliptin treatment effectively improved the glycemic profile without any serious adverse effects in older T2D patients.Trial registration number: UMIN000010376.
Topics: Aged; Humans; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Drug Therapy, Combination; Glycated Hemoglobin; Hypoglycemic Agents; Sitagliptin Phosphate; Treatment Outcome
PubMed: 36599895
DOI: 10.1038/s41598-022-27301-9 -
Journal of Diabetes Investigation Jun 2023Imeglimin is a new antidiabetic drug structurally related to metformin. Despite this structural similarity, only imeglimin augments glucose-stimulated insulin secretion...
AIMS/INTRODUCTION
Imeglimin is a new antidiabetic drug structurally related to metformin. Despite this structural similarity, only imeglimin augments glucose-stimulated insulin secretion (GSIS), with the mechanism underlying this effect remaining unclear. Given that glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) also enhance GSIS, we examined whether these incretin hormones might contribute to the pharmacological actions of imeglimin.
MATERIALS AND METHODS
Blood glucose and plasma insulin, GIP, and GLP-1 concentrations were measured during an oral glucose tolerance test (OGTT) performed in C57BL/6JJcl (C57BL/6) or KK-Ay/TaJcl (KK-Ay) mice after administration of a single dose of imeglimin with or without the dipeptidyl peptidase-4 inhibitor sitagliptin or the GLP-1 receptor antagonist exendin-9. The effects of imeglimin, with or without GIP or GLP-1, on GSIS were examined in C57BL/6 mouse islets.
RESULTS
Imeglimin lowered blood glucose and increased plasma insulin levels during an OGTT in both C57BL/6 and KK-Ay mice, whereas it also increased the plasma levels of GIP and GLP-1 in KK-Ay mice and the GLP-1 levels in C57BL/6 mice. The combination of imeglimin and sitagliptin increased plasma insulin and GLP-1 levels during the OGTT in KK-Ay mice to a markedly greater extent than did either drug alone. Imeglimin enhanced GSIS in an additive manner with GLP-1, but not with GIP, in mouse islets. Exendin-9 had only a minor inhibitory effect on the glucose-lowering action of imeglimin during the OGTT in KK-Ay mice.
CONCLUSIONS
Our data suggest that the imeglimin-induced increase in plasma GLP-1 levels likely contributes at least in part to its stimulatory effect on insulin secretion.
Topics: Animals; Mice; Incretins; Blood Glucose; Insulin; Mice, Inbred C57BL; Sitagliptin Phosphate; Hypoglycemic Agents; Glucose; Glucagon-Like Peptide 1; Gastric Inhibitory Polypeptide
PubMed: 36977210
DOI: 10.1111/jdi.14001 -
JAMA Internal Medicine Jul 2023Type 2 diabetes (T2D) is the leading cause of kidney disease in the US. It is not known whether glucose-lowering medications differentially affect kidney function. (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Type 2 diabetes (T2D) is the leading cause of kidney disease in the US. It is not known whether glucose-lowering medications differentially affect kidney function.
OBJECTIVE
To evaluate kidney outcomes in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness (GRADE) trial comparing 4 classes of glucose-lowering medications added to metformin for glycemic management in individuals with T2D.
DESIGN, SETTING, AND PARTICIPANTS
A randomized clinical trial was conducted at 36 sites across the US. Participants included adults with T2D for less than 10 years, a hemoglobin A1c level between 6.8% and 8.5%, and estimated glomerular filtration rate (eGFR) greater than or equal to 60 mL/min/1.73 m2 who were receiving metformin treatment. A total of 5047 participants were enrolled between July 8, 2013, and August 11, 2017, and followed up for a mean of 5.0 years (range, 0-7.6 years). Data were analyzed from February 21, 2022, to March 27, 2023.
INTERVENTIONS
Addition of insulin glargine, glimepiride, liraglutide, or sitagliptin to metformin, with the medication combination continued until the HbA1c was greater than 7.5%; thereafter, insulin was added to maintain glycemic control.
MAIN OUTCOMES AND MEASURES
Chronic eGFR slope (change in eGFR between year 1 and trial end) and a composite kidney disease progression outcome (albuminuria, dialysis, transplant, or death due to kidney disease). Secondary outcomes included incident eGFR less than 60 mL/min/1.73 m2, 40% decrease in eGFR to less than 60 mL/min/1.73 m2, doubling of urine albumin-to-creatinine ratio (UACR) to 30 mg/g or greater, and progression of Kidney Disease Improving Global Outcomes stage. Analyses were intention-to-treat.
RESULTS
Of the 5047 participants, 3210 (63.6%) were men. Baseline characteristics were mean (SD) age 57.2 (10.0) years; HbA1c 7.5% (0.5%); diabetes duration, 4.2 (2.7) years; body mass index, 34.3 (6.8); blood pressure 128.3/77.3 (14.7/9.9) mm Hg; eGFR 94.9 (16.8) mL/min/1.73 m2; and median UACR, 6.4 (IQR 3.1-16.9) mg/g; 2933 (58.1%) were treated with renin-angiotensin-aldosterone inhibitors. Mean chronic eGFR slope was -2.03 (95% CI, -2.20 to -1.86) mL/min/1.73 m2 per year for patients receiving sitagliptin; glimepiride, -1.92 (95% CI, -2.08 to -1.75) mL/min/1.73 m2 per year; liraglutide, -2.08 (95% CI, -2.26 to -1.90) mL/min/1.73 m2 per year; and insulin glargine, -2.02 (95% CI, -2.19 to -1.84) mL/min/1.73 m2 per year (P = .61). Mean composite kidney disease progression occurred in 135 (10.6%) patients receiving sitagliptin; glimepiride, 155 (12.4%); liraglutide, 152 (12.0%); and insulin glargine, 150 (11.9%) (P = .56). Most of the composite outcome was attributable to albuminuria progression (98.4%). There were no significant differences by treatment assignment in secondary outcomes. There were no adverse kidney events attributable to medication assignment.
CONCLUSIONS AND RELEVANCE
In this randomized clinical trial, among people with T2D and predominantly free of kidney disease at baseline, no significant differences in kidney outcomes were observed during 5 years of follow-up when a dipeptidyl peptidase 4 inhibitor, sulfonylurea, glucagonlike peptide 1 receptor agonist, or basal insulin was added to metformin for glycemic control.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT01794143.
Topics: Male; Adult; Humans; Middle Aged; Female; Diabetes Mellitus, Type 2; Insulin Glargine; Glycated Hemoglobin; Glucose; Liraglutide; Albuminuria; Hypoglycemic Agents; Kidney; Sitagliptin Phosphate; Metformin; Kidney Diseases; Disease Progression; Glomerular Filtration Rate
PubMed: 37213109
DOI: 10.1001/jamainternmed.2023.1487 -
Diabetes, Obesity & Metabolism Aug 2023To investigate the hypothesis that weight loss with the glucagon-like peptide-1 receptor agonist (GLP-1RA) liraglutide alone would lead to a greater reduction in the... (Randomized Controlled Trial)
Randomized Controlled Trial
Effect of the glucagon-like peptide-1 receptor agonist liraglutide, compared to caloric restriction, on appetite, dietary intake, body fat distribution and cardiometabolic biomarkers: A randomized trial in adults with obesity and prediabetes.
AIMS
To investigate the hypothesis that weight loss with the glucagon-like peptide-1 receptor agonist (GLP-1RA) liraglutide alone would lead to a greater reduction in the proportion of fat to lean tissue mass when compared to caloric restriction (CR) alone, as well as when compared to treatment with sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, that also enhances GLP-1 activity - to determine the independent effects of each treatment.
METHODS
A total of 88 adults with obesity and prediabetes were randomized to 14 weeks of intervention with CR (-390 kcal/d), liraglutide (1.8 mg/d), or the dipeptidyl peptidase-4 inhibitor sitagliptin (100 mg/d) as a weight-neutral comparator. Changes between groups in appetite and hunger ratings measured via visual analogue scales, dietary intakes, body weight, body composition via dual energy x-ray absorptiometry, and resting energy expenditure via indirect calorimetry were assessed using the Kruskal-Wallis test or Pearson's chi-squared test.
RESULTS
Weight loss ≥5% of baseline body weight occurred in 44% of participants in the CR group, 22% of the liraglutide group and 5% of the sitagliptin group (p = 0.02). The ratio of fat to lean mass decreased by 6.5% in the CR group, 2.2% in the liraglutide group, and 0% in the sitagliptin group (p = 0.02). Visceral fat reduced by 9.5% in the CR group, 4.8% in the liraglutide group, and 0% in the sitagliptin group (p = 0.04). A spontaneous reduction in dietary simple carbohydrates in the CR group was associated with improved homeostatic model assessment of insulin resistance score (HOMA-IR).
CONCLUSIONS
Although both liraglutide and CR are valuable strategies for cardiometabolic risk reduction, CR was associated with greater weight loss and more favourable improvements in body composition than treatment with liraglutide alone. Differences in the response to each of these interventions enables patients to be stratified to the most optimal intervention for their personal risk factors.
Topics: Humans; Adult; Liraglutide; Glucagon-Like Peptide-1 Receptor; Prediabetic State; Caloric Restriction; Appetite; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Sitagliptin Phosphate; Obesity; Dipeptidyl-Peptidase IV Inhibitors; Body Weight; Eating; Body Fat Distribution; Weight Loss; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Cardiovascular Diseases
PubMed: 37188932
DOI: 10.1111/dom.15113 -
Nature Communications Oct 2021Despite recent advances in understanding skin scarring, mechanisms triggering hypertrophic scar formation are still poorly understood. In the present study, we...
Despite recent advances in understanding skin scarring, mechanisms triggering hypertrophic scar formation are still poorly understood. In the present study, we investigate mature human hypertrophic scars and developing scars in mice at single cell resolution. Compared to normal skin, we find significant differences in gene expression in most cell types present in scar tissue. Fibroblasts show the most prominent alterations in gene expression, displaying a distinct fibrotic signature. By comparing genes upregulated in murine fibroblasts during scar development with genes highly expressed in mature human hypertrophic scars, we identify a group of serine proteases, tentatively involved in scar formation. Two of them, dipeptidyl-peptidase 4 (DPP4) and urokinase (PLAU), are further analyzed in functional assays, revealing a role in TGFβ1-mediated myofibroblast differentiation and over-production of components of the extracellular matrix in vitro. Topical treatment with inhibitors of DPP4 and PLAU during scar formation in vivo shows anti-fibrotic activity and improvement of scar quality, most prominently after application of the PLAU inhibitor BC-11. In this study, we delineate the genetic landscape of hypertrophic scars and present insights into mechanisms involved in hypertrophic scar formation. Our data suggest the use of serine protease inhibitors for the treatment of skin fibrosis.
Topics: Animals; Cell Differentiation; Cicatrix; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Female; Gene Expression; Humans; Membrane Proteins; Mice, Inbred BALB C; Myofibroblasts; Single-Cell Analysis; Sitagliptin Phosphate; Transforming Growth Factor beta1; Mice
PubMed: 34716325
DOI: 10.1038/s41467-021-26495-2 -
BMJ (Clinical Research Ed.) Oct 2022To emulate the GRADE (Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study) trial using real world data before its publication. GRADE directly... (Observational Study)
Observational Study
OBJECTIVE
To emulate the GRADE (Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study) trial using real world data before its publication. GRADE directly compared second line glucose lowering drugs for their ability to lower glycated hemoglobin A (HbA).
DESIGN
Observational study.
SETTING
OptumLabs® Data Warehouse (OLDW), a nationwide claims database in the US, 25 January 2010 to 30 June 2019.
PARTICIPANTS
Adults with type 2 diabetes and HbA 6.8-8.5% while using metformin monotherapy, identified according to the GRADE trial specifications, who also used glimepiride, liraglutide, sitagliptin, or insulin glargine.
MAIN OUTCOME MEASURES
The primary outcome was time to HbA ≥7.0%. Secondary outcomes were time to HbA >7.5%, incident microvascular complications, incident macrovascular complications, adverse events, all cause hospital admissions, and all cause mortality. Propensity scores were estimated using the gradient boosting machine method, and inverse propensity score weighting was used to emulate randomization of the treatment groups, which were then compared using Cox proportional hazards regression.
RESULTS
8252 people were identified (19.7% of adults starting the study drugs in OLDW) who met eligibility criteria for the GRADE trial (glimepiride arm=4318, liraglutide arm=690, sitagliptin arm=2993, glargine arm=251). The glargine arm was excluded from analyses owing to small sample size. Median times to HbA ≥7.0% were 442 days (95% confidence interval 394 to 480 days) for glimepiride, 764 (741 to not calculable) days for liraglutide, and 427 (380 to 483) days for sitagliptin. Liraglutide was associated with lower risk of reaching HbA ≥7.0% compared with glimepiride (hazard ratio 0.57, 95% confidence interval 0.43 to 0.75) and sitagliptin (0.55, 0.41 to 0.73). Results were consistent for the secondary outcome of time to HbA >7.5%. No significant differences were observed among treatment groups for the remaining secondary outcomes.
CONCLUSIONS
In this emulation of the GRADE trial, liraglutide was statistically significantly more effective at maintaining glycemic control than glimepiride or sitagliptin when added to metformin monotherapy. Generating timely evidence on medical treatments using real world data as a complement to prospective trials is of value.
Topics: Adult; Blood Glucose; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin Glargine; Liraglutide; Metformin; Prospective Studies; Randomized Controlled Trials as Topic; Retrospective Studies; Sitagliptin Phosphate; Sulfonylurea Compounds; Treatment Outcome
PubMed: 36191949
DOI: 10.1136/bmj-2022-070717