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BMJ (Clinical Research Ed.) Jan 2024To evaluate the comparative efficacy and safety of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on glycaemic control, body weight, and lipid profile in adults... (Meta-Analysis)
Meta-Analysis
Comparative effectiveness of GLP-1 receptor agonists on glycaemic control, body weight, and lipid profile for type 2 diabetes: systematic review and network meta-analysis.
OBJECTIVE
To evaluate the comparative efficacy and safety of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on glycaemic control, body weight, and lipid profile in adults with type 2 diabetes.
DESIGN
Systematic review and network meta-analysis.
DATA SOURCES
PubMed, Web of Science, Cochrane Central Register of Controlled Trials (CENTRAL), and Embase from database inception to 19 August 2023.
ELIGIBILITY CRITERIA FOR SELECTING STUDIES
Eligible randomised controlled trials enrolled adults with type 2 diabetes who received GLP-1RA treatments and compared effects with placebo or any GLP-1RA drug, with a follow-up duration of at least 12 weeks. Trials with a crossover design, non-inferiority studies comparing GLP-1RA and other drug classes without a placebo group, using withdrawn drugs, and non-English studies were deemed ineligible.
RESULTS
76 eligible trials involving 15 GLP-1RA drugs and 39 246 participants were included in this network meta-analysis; all subsequent estimates refer to the comparison with placebo. All 15 GLP-1RAs effectively lowered haemoglobin A and fasting plasma glucose concentrations. Tirzepatide induced the largest reduction of haemoglobin A concentrations (mean difference -2.10% (95% confidence interval -2.47% to -1.74%), surface under the cumulative ranking curve 94.2%; high confidence of evidence), and fasting plasma glucose concentrations (-3.12 mmol/L (-3.59 to -2.66), 97.2%; high confidence), and proved the most effective GLP-1RA drug for glycaemic control. Furthermore, GLP-1RAs were shown to have strong benefits to weight management for patients with type 2 diabetes. CagriSema (semaglutide with cagrilintide) resulted in the highest weight loss (mean difference -14.03 kg (95% confidence interval -17.05 to -11.00); high confidence of evidence), followed by tirzepatide (-8.47 kg (-9.68 to -7.26); high confidence). Semaglutide was effective in lowering the concentration of low density lipoprotein (-0.16 mmol/L (-0.30 to -0.02)) and total cholesterol (-0.48 mmol/L (-0.84 to -0.11)). Moreover, this study also raises awareness of gastrointestinal adverse events induced by GLP-1RAs, and concerns about safety are especially warranted for high dose administration.
CONCLUSIONS
GLP-1RAs are efficacious in treating adults with type 2 diabetes. Compared with the placebo, tirzepatide was the most effective GLP-1RA drug for glycaemic control by reducing haemoglobin A and fasting plasma glucose concentrations. GLP-1RAs also significantly improved weight management for type 2 diabetes, with CagriSema performing the best for weight loss. The results prompt safety concerns for GLP-1RAs, especially with high dose administration, regarding gastrointestinal adverse events.
SYSTEMATIC REVIEW REGISTRATION
PROSPERO CRD42022342845.
Topics: Adult; Humans; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptide-1 Receptor Agonists; Glycated Hemoglobin; Glycemic Control; Hypoglycemic Agents; Network Meta-Analysis; Weight Loss; Lipid Metabolism
PubMed: 38286487
DOI: 10.1136/bmj-2023-076410 -
Reviews in Endocrine & Metabolic... Aug 2023Emerging evidence suggests that treatment with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) could be an interesting treatment strategy to reduce neurological... (Review)
Review
Emerging evidence suggests that treatment with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) could be an interesting treatment strategy to reduce neurological complications such as stroke, cognitive impairment, and peripheral neuropathy. We performed a systematic review to examine the evidence concerning the effects of GLP-1 RAs on neurological complications of diabetes. The databases used were Pubmed, Scopus and Cochrane. We selected clinical trials which analysed the effect of GLP-1 RAs on stroke, cognitive impairment, and peripheral neuropathy. We found a total of 19 studies: 8 studies include stroke or major cardiovascular events, 7 involve cognitive impairment and 4 include peripheral neuropathy. Semaglutide subcutaneous and dulaglutide reduced stroke cases. Liraglutide, albiglutide, oral semaglutide and efpeglenatide, were not shown to reduce the number of strokes but did reduce major cardiovascular events. Exenatide, dulaglutide and liraglutide improved general cognition but no significant effect on diabetic peripheral neuropathy has been reported with GLP-1 RAs. GLP-1 RAs are promising drugs that seem to be useful in the reduction of some neurological complications of diabetes. However, more studies are needed.
Topics: Humans; Hypoglycemic Agents; Liraglutide; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptide 1; Cardiovascular Diseases; Stroke; Diabetes Complications
PubMed: 37231200
DOI: 10.1007/s11154-023-09807-3 -
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 -
Reproductive Sciences (Thousand Oaks,... Nov 2023The objective of this study is to determine whether dienogest therapy after endometriosis surgery reduces the risk of recurrence compared with placebo or alternative... (Meta-Analysis)
Meta-Analysis Review
The objective of this study is to determine whether dienogest therapy after endometriosis surgery reduces the risk of recurrence compared with placebo or alternative treatments (GnRH agonist, other progestins, and estro-progestins). The design used in this study is systematic review with meta-analysis. The data source includes PubMed and EMBASE searched up to March 2022. A systematic review and meta-analysis were performed in accordance with guidelines from the Cochrane Collaboration. Keywords such as "dienogest," "endometriosis surgery," "endometriosis treatment," and "endometriosis medical therapy" were used to identify relevant studies. The primary outcome was recurrence of endometriosis after surgery. The secondary outcome was pain recurrence. An additional analysis focused on comparing side effects between groups. Nine studies were eligible, including a total of 1668 patients. At primary analysis, dienogest significantly reduced the rate of cyst recurrence compared with placebo (p < 0.0001). In 191 patients, the rate of cyst recurrence comparing dienogest vs GnRHa was evaluated, but no statistically significant difference was reported. In the secondary analysis, a trend toward reduction of pain at 6 months was reported in patients treated with dienogest over placebo, with each study reporting a significantly higher reduction of pain after dienogest treatment. In terms of side effects, dienogest treatment compared with GnRHa significantly increased the rate of spotting (p = 0.0007) and weight gain (p = 0.03), but it was associated with a lower rate of hot flashes (p = 0.0006) and a trend to lower incidence of vaginal dryness. Dienogest is superior to placebo and similar to GnRHa in decreasing rate of recurrence after endometriosis surgery. A significantly higher reduction of pain after dienogest compared with placebo was reported in two separate studies, whereas a trend toward reduction of pain at 6 months was evident at meta-analysis. Dienogest treatment compared with GnRHa was associated with a lower rate of hot flashes and a trend to lower incidence of vaginal dryness.
Topics: Female; Humans; Endometriosis; Progestins; Pelvic Pain; Hot Flashes; Nandrolone; Cysts
PubMed: 37217824
DOI: 10.1007/s43032-023-01266-0 -
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 -
Molecular Psychiatry Aug 2023Antipsychotic drugs differ in their propensity to cause extrapyramidal side-effects (EPS), but their dose-effects are unclear. Therefore, we conducted a systematic... (Meta-Analysis)
Meta-Analysis
Antipsychotic drugs differ in their propensity to cause extrapyramidal side-effects (EPS), but their dose-effects are unclear. Therefore, we conducted a systematic review and dose-response meta-analysis. We searched multiple electronic databases up to 20.02.2023 for fixed-dose studies investigating 16 second-generation antipsychotics and haloperidol (all formulations and administration routes) in adults with acute exacerbations of schizophrenia. The primary outcome was the number of participants receiving antiparkinsonian medication, and if not available, the number of participants with extrapyramidal side-effects (EPS) and the mean scores of EPS rating scales were used as proxies. The effect-size was odds ratio (ORs) compared with placebo. One-stage random-effects dose-response meta-analyses with restricted cubic splines were conducted to estimate the dose-response curves. We also examined the relationship between dopamine D receptor (DR) occupancy and ORs by estimating occupancies from administrated doses. We included data from 110 studies with 382 dose arms (37193 participants). Most studies were short-term with median duration of 6 weeks (range 3-26 weeks). Almost all antipsychotics were associated with dose-dependent EPS with varied degrees and the maximum ORs ranged from OR = 1.57 95%CI [0.97, 2.56] for aripiprazole to OR = 7.56 95%CI [3.16, 18.08] for haloperidol at 30 mg/d. Exceptions were quetiapine and sertindole with negligible risks across all doses. There was very low quality of findings for cariprazine, iloperidone, and zotepine, and no data for clozapine. The DR occupancy curves showed that the risk increased substantially when DR occupancy exceeded 75-85%, except for DR partial agonists that had smaller ORs albeit high DR occupancies. In conclusion, we found that the risk of EPS increases with rising doses and differs substantially in magnitude among antipsychotics, yet exceptions were quetiapine and sertindole with negligible risks. Our data provided additional insights into the current DR therapeutic window for EPS.
Topics: Adult; Humans; Antipsychotic Agents; Quetiapine Fumarate; Haloperidol; Clozapine; Receptors, Dopamine D2; Drug-Related Side Effects and Adverse Reactions
PubMed: 37537284
DOI: 10.1038/s41380-023-02203-y -
Frontiers in Endocrinology 2023A systematic review and meta-analysis was conducted to synthesize the available data from clinical trials and assess the safety issues of tirzepatide (pancreatitis and... (Meta-Analysis)
Meta-Analysis
PURPOSE
A systematic review and meta-analysis was conducted to synthesize the available data from clinical trials and assess the safety issues of tirzepatide (pancreatitis and gallbladder or biliary disease) in type 2 diabetes (T2D) and obesity.
METHODS
A systematic search was conducted in three electronic databases, namely Embase, PubMed, and the Cochrane Library, up until March 1, 2023, to identify randomized controlled trials (RCTs) comparing tirzepatide to either placebo or active hypoglycemic drugs in individuals with T2D and obesity. Heterogeneity was assessed using the I2 value and Cochran's Q test, and a fixed effects model was employed to estimate the safety profile of tirzepatide. The safety outcomes of interest, including pancreatitis, the composite of gallbladder or biliary diseases, cholecystitis, and cholelithiasis and biliary diseases, were evaluated. (The composite of gallbladder or biliary diseases incorporated cholelithiasis, cholecystitis, other gallbladder disorders, and biliary diseases.).
RESULTS
A total of nine trials with 9871 participants (6828 in the tirzepatide group and 3043 in the control group) that met the pre-specified criteria were included. When compared to all control groups consisting of basal insulin (glargine or degludec), selective GLP1-RA (dulaglutide or semaglutide once weekly), and placebo, an increased risk of pancreatitis was not found to be significantly associated with tirzepatide (RR 1.46, [95% CI] 0.59 to 3.61; I2 = 0.0%, p = 0.436). For gallbladder or biliary disease, the composite of gallbladder or biliary disease was significantly associated with tirzepatide compared with placebo or basal insulin (RR 1.97, [95% CI] 1.14 to 3.42; I2 = 0.0%, p = 0.558), but not with the risk of cholelithiasis, cholecystitis or biliary diseases.
CONCLUSION
Based on the currently available data, tirzepatide appears to be safe regarding the risk of pancreatitis. However, the increased risk of the composite outcome of gallbladder or biliary diseases observed in RCTs warrants further attention from physicians in clinical practice.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/PROSPERO, identifier CRD42023412400.
Topics: Humans; Cholecystitis; Diabetes Mellitus, Type 2; Insulin Glargine; Obesity; Pancreatitis; Cholelithiasis
PubMed: 37908750
DOI: 10.3389/fendo.2023.1214334 -
The American Journal of Geriatric... Jan 2024Emerging evidence suggests that glucagon-like peptide-1 receptor agonists (GLP-1RAs) may exert positive effects in patients with depression. Our aim was to conduct a... (Meta-Analysis)
Meta-Analysis Review
AIM/HYPOTHESIS
Emerging evidence suggests that glucagon-like peptide-1 receptor agonists (GLP-1RAs) may exert positive effects in patients with depression. Our aim was to conduct a systematic review and meta-analysis to examine the antidepressant effects of GLP-1RAs.
METHODS
Randomized controlled trials and prospective cohort studies investigating the effects of GLP-1RAs versus placebo or other antidiabetic therapies on depressive symptoms were searched for using multiple electronic sources (CENTRAL, PubMed, EMBASE, PsycINFO, World Health Organization International Clinical Trials Registry Platform, ClinicalTrials.gov, China Network Knowledge Infrastructure, China Biomedical Database, Wan Fang data, and Chinese Scientific Journals Database) from inception to February 16, 2023. We utilized a random effects model to analyze standardized mean differences for the change in depression rating scales comparing GLP-1RA treated groups with control treated groups.
RESULTS
The meta-analysis comprising 2,071 participants included 5 randomized controlled trials and 1 prospective cohort study. The meta-analysis indicated that the change from baseline in depression rating scale scores decreased significantly when patients received treatment with GLP-1RAs compared to control treatments (SMD = -0.12, 95% CI [-0.21, -0.03], p <0.01, I = 0%, p = 0.52). The subgroup analysis showed that the effects of GLP-1RAs on depressive symptoms were consistent in patients with Type 2 diabetes mellitus (SMD = -0.12, 95% CI [-0.21, -0.03], p <0.01, I = 2%, p = 0.40).
CONCLUSIONS
Adults treated with GLP-1RAs showed significant reductions in the depression rating scale scores compared to those treated with control substances. Our findings suggest that GLP-1RAs may be a potential treatment for alleviating depressive symptoms in humans.
Topics: Humans; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor Agonists; Prospective Studies; Hypoglycemic Agents; Antidepressive Agents
PubMed: 37684186
DOI: 10.1016/j.jagp.2023.08.010 -
EClinicalMedicine Aug 2023Refractory chronic cough (RCC) has a significant impact on patient's health-related quality of life and represents a challenge in clinical management. However, the...
BACKGROUND
Refractory chronic cough (RCC) has a significant impact on patient's health-related quality of life and represents a challenge in clinical management. However, the optimal treatment for RCC remains controversial. This study aimed to investigate and compare the efficacy and safety of the current pharmacological therapeutic options for RCC.
METHODS
A systematic review was performed by searching PubMed, Web of Science, Embase, and Ovid databases from January 1, 2008 to March 1, 2023. All randomised control trials (RCTs) reporting outcomes of efficacy or/and safety were included in the Bayesian network meta-analysis. Here, we compared the effects on Leicester Cough Questionnaire (LCQ), Visual Analogue Scale (VAS), and objective cough frequency of patients with RCC. Besides, we also compared the incidence of adverse events (AEs) for analysis of safety. PROSPERO registration: CRD42022345940.
FINDINGS
19 eligible RCTs included 3326 patients and 7 medication categories: P2X3 antagonist, GABA modulator, Transient Receptor Potential (TRP) modulator, NK-1 agonist, opioid analgesic, macrolide, and sodium cromoglicate. Compared with placebo, mean difference (MD) of LCQ and 24 h cough frequency for P2X3 antagonist relief were 1.637 (95% CI: 0.887-2.387) and -11.042 (P = 0.035). Compared with placebo, effect sizes (MD for LCQ and cough severity VAS) for GABA modulator were 1.347 (P = 0.003) and -7.843 (P = 0.003). In the network meta-analysis, gefapixant is the most effective treatment for patients with RCC (The Surface Under the Cumulative Ranking Curves (SUCRA) is 0.711 in LCQ, 0.983 in 24 h cough frequency, and 0.786 in cough severity VAS). Lesogaberan had better efficacy than placebo (SUCRA: 0.632 vs. 0.472) in 24 h cough frequency. Eliapixant and lesogaberan had better efficacy than placebo in cough severity VAS. However, TRP modulator had worse efficacy than placebo. In the meta-analysis of AEs, the present study found P2X3 antagonist had a significant correlation to AEs (RR: 1.129, 95% CI: 1.012-1.259), especially taste-related AEs (RR: 6.216, P < 0.05).
INTERPRETATION
In this network meta-analysis, P2X3 antagonist showing advantages in terms of efficacy is currently the most promising medication for treatment of RCC. GABA modulator also showed potential efficacy for RCC but with AEs of the central system. Nevertheless, the role of TRP modulator needed to be revisited. Further research is needed to determine the potential beneficiary population for optimizing the pharmacological management of chronic cough.
FUNDING
National Natural Science Foundation of China (81870079), Guangdong Science and Technology Project (2021A050520012), Incubation Program of National Science Foundation for Distinguished Young Scholars (GMU2020-207).
PubMed: 37538538
DOI: 10.1016/j.eclinm.2023.102100 -
EClinicalMedicine Oct 2023Innovative GLP-1 receptor agonist (GLP-1RA)-based treatment strategies-such as tirzepatide, GLP-1RA plus basal insulin fixed-ratio combinations [FRC], GLP-1RA plus...
BACKGROUND
Innovative GLP-1 receptor agonist (GLP-1RA)-based treatment strategies-such as tirzepatide, GLP-1RA plus basal insulin fixed-ratio combinations [FRC], GLP-1RA plus sodium glucose cotransporter-2 inhibitors [SGLT-2i] combinations, and high-dose GLP-1RA-have been listed among the most efficacious options for type 2 diabetes management. However, differences in their glucometabolic effects have not been assessed in dedicated head-to-head trials. In the absence of such trials, we aimed to provide a useful comparison among these treatment strategies to guide clinical practice.
METHODS
In this network meta-analysis, we searched PubMed, MEDLINE, and Web of Science (from database inception to June 24, 2023) for randomised controlled studies, published in English, that enrolled individuals with type 2 diabetes treated with tirzepatide, iGlarLixi, iDegLira, GLP-1RA plus SGLT-2i combination, or high-dose GLP-1RA (dulaglutide 3 mg and 4.5 mg, semaglutide 2 mg) compared with placebo or active comparators. Eligible studies reported change from baseline in HbA1c as an outcome, which was the primary outcome of this analysis. Secondary outcomes were changes in fasting and post-prandial glucose, bodyweight, LDL-cholesterol, blood pressure and risk of hypoglycaemia. We assessed risk of bias through the Cochrane Collaboration's tool (RoB2 tool), publication bias through visual inspection of funnel plots and Egger's test, and heterogeneity by comparing the magnitude of the common between-study variance (τ) for each outcome with empirical distributions of heterogeneity variances. This network meta-analysis was registered in PROSPERO (CRD42022329878).
FINDINGS
40 trials were included. Tirzepatide 15 mg ranked first in terms of HbA1c reduction compared to other GLP-1RA-based strategies, even those including insulin (vs. iDegLira MD -0.40%, 95% CI [-0.66; -0.14], low certainty; vs. iGlarLixi MD -0.48%, 95% CI [-0.75; -0.21], low certainty), without increasing the risk of hypoglycaemia (vs. iDegLira OR 0.35, 95% CI [0.16; 0.79], high certainty; vs. iGlarLixi OR 0.31, 95% CI [0.20; 0.48], high certainty). Tirzepatide 15 mg was also the most efficacious on weight lowering, even compared to high-dose GLP-1RA (eg, semaglutide 2 mg MD -6.56 kg, 95% CI [-7.38; -5.73], low certainty) and GLP-1RA plus SGLT-2i combination (MD -4.61 kg, 95% CI [-5.29; -3.93], low certainty). Risk of bias and publication bias were generally low throughout studies, while high levels of heterogeneity were detected for most outcomes.
INTERPRETATION
Aiming to support clinicians in tailoring treatment to patients' needs, we suggest that a hierarchy among treatment strategies be devised considering the best options for type 2 diabetes. Tirzepatide, followed by GLP-1RA plus basal insulin FRC and GLP-1RA plus SGLT-2i combination, was associated with greater benefit on HbA1c than high-dose GLP-1RA.
FUNDING
Fondazione per la Ricerca Biomedica "Saverio e Isabella Cianciola" and Next Generation EU, in the context of the National Recovery and Resilience Plan, Investment PE8-Project Age-It: Ageing Well in an Ageing Society.
PubMed: 37719418
DOI: 10.1016/j.eclinm.2023.102181