Comparison of GLP-1 Receptor Agonists, SGLT-2 Inhibitors, and DPP-4 Inhibitors as an Add-On Drug to Insulin Combined With Oral Hypoglycemic Drugs: Umbrella Review.

Background: The objective was to evaluate the efficacy of the combination of Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), dipeptidyl peptidase-4 inhibitors (DPP-4i), and sodium-glucose cotransporter 2 inhibitor (SGLT-2i) in the treatment of Type 2 diabetes with poor efficacy of basic insulin and metformin/sulfonylurea by umbrella review. Materials and Methods: Forming the data of publication of each database through 13 September 2022, PubMed, EMBASE, and Cochrane Library were surveyed. Results: A total of seven meta-analyses were included in the umbrella review. The combination of GLP-1 RA (WMD -3.41 [-5.61, -1.21], p = 0.002), SGLT-2i (WMD -5.34 [-9.56, -1.13], p = 0.013), and DPP-4i (WMD -5.56 [-7.39, -3.73], p ≤ 0.001) can significantly reduce HbA1c levels, respectively. The combination of GLP-1 RA (WMD -1.55 [-2.92, -0.18], p = 0.027), SGLT-2i (WMD -2.96 [-6.68, 0.77], p = 0.12), and DPP-4i (WMD -2.05 [-2.82, -1.28], p ≤ 0.001) can significantly reduce fasting plasma glucose (FPG) levels, respectively. The combination of GLP-1 RA (WMD -3.24 [-5.14, -1.34], p < 0.001) can significantly reduce body weight of Type 2 diabetes mellitus (T2DM). The dose of basic insulin in diabetes patients after combined use of GLP-1 RA (WMD -2.74 [-4.26, -1.22], p ≤ 0.001) was significantly reduced. The combination use of GLP-1 RAs (OR 1.28 [1.05, 1.56], p = 0.017) increases the risk of hypoglycemia. Conclusions: The combination of GLP-1 RAs, DPP-4i, and SGLT-2i can effectively lower HbA1c and FPG in T2DM patients who have poor therapeutic effects on basic insulin combined with metformin/sulfonylureas, respectively. Compared to placebo, GLP-1 RAs can significantly reduce body weight and basic insulin dosage, while DPP-4i and SGLT-2i have a lower risk of hypoglycemia. Trial Registration: CRD42023410345.

Chai S ，Niu Y ，Liu F ，Wu S ，Yang Z ，Sun F ... -  《-》

The placebo response of injectable GLP-1 receptor agonists vs. oral DPP-4 inhibitors and SGLT-2 inhibitors: a systematic review and meta-analysis.

The size of the placebo response in type 2 diabetes (T2DM) treatment and its relation to the route of drug administration have not been systematically reviewed. We aimed to determine weight loss, change in HbA1c and incidence of adverse events after treatment with injectable placebo GLP-1 receptor agonist (GLP-1ra), compared with oral placebo DPP-4 inhibitor (DPP-4i) and placebo SGLT-2 inhibitor (SGLT-2i). PubMed, EMBASE and Central were searched up to September 2014 for randomized placebo controlled trials investigating GLP-1ra, DPP-4i or SGLT2-i. Data on placebo groups were extracted and pooled using a generic inverse variance random effects model. Sixty-seven trials were included, involving 2522, 5290 and 2028 patients randomized to placebo GLP-1ra, placebo DPP-4i and placebo SGLT-2i, respectively. Body weight decreased by -0.67 kg (95% CI -1.03, -0.31) after treatment with placebo GLP-1ra (-0.76 kg [95% CI -1.10, -0.43] with placebo short acting GLP-1ra and -0.32 kg [95% CI -1.75, 1.10] with placebo long acting GLP-1ra) and by -0.31 kg (95% CI -0.64, 0.01) with placebo DPP-4i (P = 0.06 for difference with placebo short acting GLP-1ra). Placebo SGLT-2i resulted in an intermediate -0.48 kg (95% CI -0.81, -0.15) weight loss. Weight loss with placebo showed a strong correlation with the active comparator drug (r(2)  = 0.40-0.78). HbA1c changed little with placebo treatment (-0.23%, 0.10% and -0.13% for placebo GLP-1ra, DPP-4i and SGLT-2i). Adverse events occurred frequently with placebo, were often similar to the active comparator drug and led to drop-out in 2.0-2.7% of cases. The response to placebo treatment was related to its active comparator, with injectable placebo GLP-1ra showing a relevant response on weight, whereas oral placebo DPP4i showed no significant response. These findings may suggest that subjective expectations influence T2DM treatment efficacy, which can possibly be employed therapeutically.

de Wit HM ，Te Groen M ，Rovers MM ，Tack CJ ... -  《-》

Risk of bone fracture by using dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists, or sodium-glucose cotransporter-2 inhibitors in patients with type 2 diabetes mellitus: a network meta-analysis of population-based cohort studies

Type 2 diabetes mellitus (T2DM) is linked to a heightened likelihood of experiencing fractures. It is crucial to ascertain whether medications used to lower blood sugar levels can elevate the risk of fractures. We aimed to investigate and compare the effects of glucagon-like peptide 1 receptor agonists (GLP-1RA), Dipeptidyl Peptidase-4 Inhibitors (DPP-4i), and Sodium-Glucose Cotransporter-2 Inhibitors (SGLT-2i) on the fracture risk in patients with T2D in the real world. A network meta-analysis conducted an inclusive literature search in PubMed, Scopus, Web of Science, and Cochrane Library to select appropriate population-based cohort studies that investigated the risk of bone fractures of (GLP-1RA), (DPP-4i) or (SGLT-2i) in the real world. A network meta-analysis (NMA) was performed using R software to investigate the risk of total fractures as a primary outcome among patients who used (GLP-1RAs), (SGLT-2i) or (DPP-4i) versus each other or other glucose-lowering medications (GLMs). The odds ratio (OR) and 95% confidence interval (CI) were summarized overall network and for each pairwise direct and indirect comparison. The surface under the cumulative ranking curve (SUCRA) with the P-scores was calculated for each treatment in the network meta-analysis to detect their cumulative ranking probabilities in lowering the risk of total fractures. In our NMA, we identified a set of 13 population-based cohort studies comprising a total of 1,064,952 patients. The risk of fracture was identified with the follow-up duration for each class. We found a significant decrease in the fracture risk by about 87% associated with patients who used SGLT2 inhibitors in combination with other glucose-lowering medications, followed by SGLT2 inhibitors alone by about 67%, then GLP-1 receptor agonists by about 60%, and at last DPP-4 inhibitors by about 55%. Our study's collective findings suggest a significant association of the low risk of fracture with the use of SGLT2i with other GLMs combination, SGLT2i alone, GLP-1RA, and DPP-4i, respectively. This population-based analysis offers the best available evidence and might be helpful for clinicians in the decision of the most suitable T2DM treatment strategies, especially for elderly type 2 diabetic patients, as they may be safe in terms of fracture. https://www.crd.york.ac.uk/prospero/, identifier CRD42023448720.

Mostafa MEA ，Alrasheed T 《Frontiers in Endocrinology》

Characteristics of new users of recent antidiabetic drugs in Canada and the United Kingdom.

Characteristics of patients using newer 2nd and 3rd line antidiabetic drugs in a real-world setting are poorly understood. We described the characteristics of new users of sodium-glucose co-transporter-2 inhibitors (SGLT-2i), dipeptidyl peptidase-4 inhibitors (DPP-4i), and glucagon-like peptide-1 receptor agonists (GLP-1 RA) in Canada and the United Kingdom (UK) between 2016 and 2018. We conducted a multi-database cohort study using administrative health databases from 7 Canadian provinces and the UK Clinical Practice Research Datalink. We assembled a base cohort of antidiabetic drug users between 2006 and 2018, from which we constructed 3 cohorts of new users of SGLT-2i, DPP-4i, and GLP-1 RA between 2016 and 2018. Our cohorts included 194,070 new users of DPP-4i, 166,722 new users of SGLT-2i, and 27,719 new users of GLP-1 RA. New users of GLP-1 RA were more likely to be younger (mean ± SD: 56.7 ± 12.2 years) than new users of DPP-4i (67.8 ± 12.3 years) or SGLT-2i (64.4 ± 11.1 years). In Canada, new users of DPP-4i were more likely to have a history of coronary artery disease (22%) than new users of SGLT-2i (20%) or GLP-1 RA (15%). Although SGLT-2i, DPP-4i, and GLP-1 RAs are recommended as 2nd or 3rd line therapy for type 2 diabetes, important differences exist in the characteristics of users of these drugs. Contrary to existing guidelines, new users of DPP-4i had a higher prevalence of cardiovascular disease at baseline than new users of SGLT2i or GLP-1RA.

Brunetti VC ，St-Jean A ，Dell'Aniello S ，Fisher A ，Yu OHY ，Bugden SC ，Daigle JM ，Hu N ，Alessi-Severini S ，Shah BR ，Ronksley PE ，Lix LM ，Ernst P ，Filion KB ，Canadian Network for Observational Drug Effect Studies (CNODES) Investigators ... -  《BMC Endocrine Disorders》

Incretin mimetics and sodium-glucose co-transporter 2 inhibitors as monotherapy or add-on to metformin for treatment of type 2 diabetes: a systematic review and network meta-analysis.

Jia S ，Wang Z ，Han R ，Zhang Z ，Li Y ，Qin X ，Zhao M ，Xiang R ，Yang J ... -  《-》