0
selected
-
1.
Cardiovascular outcome trials of the newer anti-diabetic medications.
Acharya, T, Deedwania, P
Progress in cardiovascular diseases. 2019;(4):342-348
Abstract
Concerns of elevated cardiovascular disease (CVD) risk with some anti-diabetic medications warranted phase 4 clinical trials to demonstrate CVD safety of newly marketed anti-diabetic drugs. Although initially designed to evaluate safety, some of these CVD outcome trials (CVOTs) have in fact shown CVD benefits. New medication classes, like glucagon-like peptide 1 (GLP-1) analogues and sodium-glucose co-transporter 2 (SGLT2) inhibitors, have shown reductions in the risk of major adverse cardiovascular events (MACE) including, myocardial infarction, stroke, CV death, and heart failure (HF). Perhaps more importantly, SGLT2 inhibitors demonstrated reduction in the risk of HF hospitalizations, being the first class of anti-diabetic drugs to do so. Conversely, dipeptidyl peptidase 4 (DPP-4) inhibitors did not significantly affect atherosclerotic CVD end-points and some actually increased the risk of HF hospitalizations. Further, the adverse/beneficial CVD effects of these medications may not be class specific. This review focuses on the main results of these CVOTs while highlighting the heterogeneity of CVD end-points within each class and discusses important mechanistic insights and adverse effect profiles.
-
2.
[Application of new glucose lowering drugs: DPP-4 inhibitors, GLP-1 receptor agonists and SGLT-2 inhibitors].
Verburg, AFE, van den Donk, M, Wiersma, T
Nederlands tijdschrift voor geneeskunde. 2019
Abstract
A comprehensive review of the literature on DPP-4 inhibitors, GLP-1 receptor agonists and SGLT-2 inhibitors has resulted in small changes to the medication roadmap of the type 2 diabetes mellitus standard of the Dutch College of General Practitioners. SGLT-2 inhibitors and GLP-1 receptor agonists may have benefits related to cardiovascular outcomes in patients with high cardiovascular risk, especially in those who have experienced a cardiovascular event. However, ascribing effectiveness related to cardiovascular outcomes on the basis of a single cardiovascular safety trial is premature. Metformin, sulfonylurea derivatives and insulin are still the cornerstone of type 2 diabetes mellitus treatment in primary care.
-
3.
A Review of Cardiovascular Outcomes Trials of Glucose-Lowering Therapies and Their Effects on Heart Failure Outcomes.
Nassif, ME, Kosiborod, M
The American journal of cardiology. 2019;:S12-S19
Abstract
Type 2 diabetes mellitus has long been recognized as a major risk factor for adverse atherosclerotic cardiovascular disease events; however, recent data indicate that heart failure is now emerging as the most common and morbid cardiovascular complication of type 2 diabetes mellitus. When heart failure develops in patients with type 2 diabetes, prognosis is ominous, highlighting the need for glucose-lowering therapies that can prevent heart failure, improve outcomes, or both. Prior to 2008, there was a paucity of randomized controlled trials evaluating long-term cardiovascular outcomes with glucose-lowering therapies. This changed after guidance on the assessment of novel glucose-lowering agents was issued by both the US Food and Drug Administration and the European Medicines Agency. Since then, significant progress has been made as a result of large cardiovascular outcomes trials. Though randomized controlled trials on insulin, sulfonylureas, and metformin are still limited, cardiovascular outcomes trials on newer glucose-lowering agents have included hundreds of thousands of patients with multiple years of follow-up. The increased risk of thiazolidinediones on heart failure had been well theorized and is now established; however, the increase in heart failure hospitalization with certain dipeptidyl peptidase-4 inhibitors was unexpected. The reasons for discrepancies with regard to heart failure risk with different dipeptidyl peptidase-4 inhibitors remain unclear, and further mechanistic studies are ongoing. The role of glucagon-like peptide-1 receptor agonists among patients with heart failure also remains unclear, and their effects may differ in patients with and without established heart failure, particularly those with decompensated heart failure with reduced ejection fraction.
-
4.
Mechanism by which dipeptidyl peptidase-4 inhibitors increase the risk of heart failure and possible differences in heart failure risk.
Sano, M
Journal of cardiology. 2019;(1):28-32
Abstract
Dipeptidyl peptidase-4 (DPP-4) inhibitors are oral antidiabetic drugs that safely reduce the blood glucose level over the long term. In Japan, DPP-4 inhibitors have become the oral antidiabetic drugs most frequently prescribed for patients with type 2 diabetes. However, the results of several cardiovascular outcomes studies have suggested that some DPP-4 inhibitors may increase the risk of hospitalization for heart failure. In patients with diabetes, heart failure is the most frequent cardiovascular condition, and it has a negative impact on the quality of life as well as being a potentially fatal complication. Therefore, it is important to determine whether an increased risk of heart failure is associated with certain DPP-4 inhibitors or is a class effect of these drugs. This review explores the mechanism by which DPP-4 inhibitors may increase the risk of heart failure and possible differences among these drugs. The available research suggests that DPP-4 inhibitors cause sympathetic activation as a class effect and this may increase the risk of heart failure. Unlike other DPP-4 inhibitors, sitagliptin and alogliptin are mainly excreted in the urine and suppress renal sodium-hydrogen exchanger 3 activity. These two drugs did not increase the risk of hospitalization for heart failure in large-scale cardiovascular outcomes studies.
-
5.
Meta-analyses of the effects of DPP-4 inhibitors, SGLT2 inhibitors and GLP1 receptor analogues on cardiovascular death, myocardial infarction, stroke and hospitalization for heart failure.
Sinha, B, Ghosal, S
Diabetes research and clinical practice. 2019;:8-16
Abstract
AIM: To assess the effects DPP-4i; SGLT2-i & GLP1-RA on CV death, MI, stroke and hHF. This is probably the first meta-analysis to assess the effects of these drugs on MI and stroke in totality, including non-fatal & fatal MI and stroke. METHODS Scientific databases were searched for RCTs with pre-specified inclusion criteria and each end-point from the selected 13 studies was reported as an effect size (M H odds ratio) with a 95% confidence interval P value. RESULTS The pooled analysis of all the 5 available CVOT with DPP-4i resulted in a neutral effect on MI, stroke, the combined end points of MI & Stroke, CV death and hHF. The pooled analysis of all the 5 available CVOTs with GLP1-RA resulted in a neutral effect on MI. However, there was a statistically significant 12% reduction in CV death (P = 0.01), 13% reduction in stroke (P = 0.02) and 11% reduction the combined end points of MI & Stroke (P = 0.001). The impact of GLP1-RA inhibitors on hHF was neutral. The pooled analysis of all the 3 available CVOTs with SGLT2-i resulted in a neutral effect on MI, stroke, the combined end points of MI & Stroke and CV death. There was however a statistically significant 28% reduction in hHF (P < 0.001). CONCLUSION DPP-4i & SGLT-2i are neutral as far as all aspects of CV outcomes are concerned except for hHF which is significantly reduced by the latter. GLP1-RA as a class reduce risk of ASCVD showing a significant reduction in MI and stroke.
-
6.
Effect of DPP-IV Inhibitors on Glycemic Variability in Patients with T2DM: A Systematic Review and Meta-Analysis.
Lee, S, Lee, H, Kim, Y, Kim, E
Scientific reports. 2019;(1):13296
Abstract
Glycemic variability (GV) has been an emerging target for preventing complications related to type 2 diabetes. For reducing GV, DPP-IV inhibitors have shown effectiveness compared to other oral anti-hyperglycemic drugs (OADs), but systematic evaluation has yet to be existed. A systematic review and meta-analysis of randomized controlled trials (RCTs) were performed to evaluate the effect of DPP-IV inhibitors compared with other OADs, on GV as measured by mean amplitude of glycemic excursions (MAGE). Searches were conducted using Pubmed, EMBASE, and the Cochrane Library, from which eligible studies were retrieved; seven RCTs were included in the analysis. DPP-IV inhibitors were found to significantly reduce MAGE compared to other OADs (mean difference = -14.61; 95% CI = -19.00 to -10.21; p < 0.0001) without significant heterogeneity among sulfonylureas (mean difference = -14.93; 95% CI = -21.60 to -8.26; p < 0.0001). Initial combination therapy with DPP-IV inhibitors more effectively reduced MAGE than stepwise add-on therapies (p = 0.006), although no differences in MAGE were found based on HbA1c values. These findings indicate that DPP-IV inhibitors are promising alternatives for reducing GV in type 2 diabetes patients. However, further studies utilizing larger numbers of patients and longer-term follow-ups are needed.
-
7.
Predictors of the Therapeutic Efficacy and Consideration of the Best Combination Therapy of Sodium-Glucose Co-transporter 2 Inhibitors.
Lee, JY, Cho, Y, Lee, M, Kim, YJ, Lee, YH, Lee, BW, Cha, BS, Kang, ES
Diabetes & metabolism journal. 2019;(2):158-173
Abstract
BACKGROUND We investigated the predictive markers for the therapeutic efficacy and the best combination of sodium-glucose co-transporter 2 (SGLT2) inhibitors (empagliflozin, dapagliflozin, and ipragliflozin) therapy in patients with type 2 diabetes mellitus (T2DM). METHODS A total of 804 patients with T2DM who had taken SGLT2 inhibitor as monotherapy or an add-on therapy were analyzed. Multivariate regression analyses were performed to identify the predictors of SGLT2 inhibitor response including the classes of baseline anti-diabetic medications. RESULTS After adjusting for age, sex, baseline body mass index (BMI), diabetes duration, duration of SGLT2 inhibitor use, initial glycosylated hemoglobin (HbA1c) level, estimated glomerular filtration rate (eGFR), and other anti-diabetic agent usage, multivariate analysis revealed that shorter diabetes duration, higher initial HbA1c and eGFR were associated with better glycemic response. However, baseline BMI was inversely correlated with glycemic status; lean subjects with well-controlled diabetes and obese subjects with inadequately controlled diabetes received more benefit from SGLT2 inhibitor treatment. In addition, dipeptidyl peptidase 4 (DPP4) inhibitor use was related to a greater reduction in HbA1c in patients with higher baseline HbA1c ≥7%. Sulfonylurea users experienced a larger change from baseline HbA1c but the significance was lost after adjustment for covariates and metformin and thiazolidinedione use did not affect the glycemic outcome. CONCLUSION A better response to SGLT2 inhibitors is expected in Korean T2DM patients who have higher baseline HbA1c and eGFR with a shorter diabetes duration. Moreover, the add-on of an SGLT2 inhibitor to a DPP4 inhibitor is likely to show the greatest glycemic response.
-
8.
Heart failure in patients with type 2 diabetes mellitus: assessment with echocardiography and effects of antihyperglycemic treatments.
Iwakura, K
Journal of echocardiography. 2019;(4):177-186
Abstract
Heart failure is one of the major cardiovascular complications in patients with type 2 diabetes mellitus (T2DM) and increases the risk of morbidity and mortality. Although active management for heart failure is needed in patients with T2DM, traditional treatment and some new class of antihyperglycemic drugs, such as glucagon-like peptide-1 receptor agonists or dipeptidyl peptidase-4 inhibitors, could not reduce the risk of heart failure. Recent major trials demonstrated sodium-glucose co-transporter-2 (SGLT2) inhibitors improve prognosis of T2DM patients through prevention of heart failure. Both heart failure with reduced ejection fraction and that with preserved ejection fraction (HFpEF) is observed in T2DM patients, and HFpEF is often overlooked and misdiagnosed in these population. Left ventricular hypertrophy, left atrial dilatation, diastolic dysfunction, and subclinical systolic dysfunction indicated as reduced global longitudinal strain are major abnormalities on echocardiography in patients with diabetic cardiomyopathy. These structural and functional changes are also prevalent in the general patients with T2DM, and those with these abnormalities have higher incidence of heart failure than those without them. Glycemic control might improve some of these abnormalities on echocardiography, but it is still unclear whether their improvement could be associated with risk reduction for heart failure. At now, there are only limited data on the effects of DPP-4 inhibitors or SGLT2 inhibitors on echocardiography in T2DM patients. Large-scale trials are needed to clarify how antihyperglycemic drugs affect echocardiographic parameters.
-
9.
Efficacy of DPP-4 inhibitors, GLP-1 analogues, and SGLT2 inhibitors as add-ons to metformin monotherapy in T2DM patients: a model-based meta-analysis.
Inoue, H, Tamaki, Y, Kashihara, Y, Muraki, S, Kakara, M, Hirota, T, Ieiri, I
British journal of clinical pharmacology. 2019;(2):393-402
-
-
Free full text
-
Abstract
AIMS: The aim of the present study was to quantitate the hypoglycaemic effects of dipeptidyl peptidase-4 inhibitors (DPP-4i), glucagon-like peptide-1 receptor agonists (GLP-1r) and sodium glucose cotransporter 2 inhibitors (SGLT2i) as add-on treatments to metformin monotherapy in patients with type 2 diabetes mellitus (T2DM) using a model-based meta-analysis (MBMA). METHODS A systematic literature search of public databases was conducted to develop models that describe the time courses of the fasting plasma glucose (FPG)- and haemoglobin A1c (HbA1c)-lowering effects of three antidiabetic classes using NONMEM 7.3.0. RESULTS Seventy-six publications were eligible for this study, and 873 FPG and 1086 HbA1c values were collected. We developed a physiological indirect response model that described the time courses of FPG and HbA1c and simulated reductions in these values 90 days after the initiation of add-on treatments. FPG and HbA1c reductions with once weekly exenatide, liraglutide and dulaglutide were greater than those with other drugs. Mean changes from baseline FPG and HbA1c with these drugs were as follows: exenatide (-22.5 and -16.6%), liraglutide (-22.1 and -16.3%), and dulaglutide (-19.3 and -14.3%). The hypoglycaemic effects of DPP-4i and SGLT2i were similar. CONCLUSIONS Once weekly exenatide, liraglutide and dulaglutide provided better hypoglycaemic effects among the antidiabetic drugs analysed. Long-acting GLP-1r appears to be more useful for T2DM patients inadequately controlled with metformin monotherapy.
-
10.
Randomised clinical trial: the DPP-4 inhibitor, vildagliptin, inhibits gastric accommodation and increases glucagon-like peptide-1 plasma levels in healthy volunteers.
Rotondo, A, Masuy, I, Verbeure, W, Biesiekierski, JR, Deloose, E, Tack, J
Alimentary pharmacology & therapeutics. 2019;(8):997-1004
Abstract
BACKGROUND Dipeptidyl peptidase-4 (DPP-4) inactivates glucagon-like peptide-1 (GLP-1). Whether DPP-4 inhibition affects GLP-1 metabolism and/or food intake in humans remains unknown. AIMS To evaluate the effect of vildagliptin (DPP-4 inhibitor) on gastric accommodation and ad libitum food intake in healthy volunteers (HVs) METHODS The effects of acute oral vildagliptin administration (50 mg) were evaluated in two randomised, placebo-controlled, single-blinded trials. Protocol 1 (n = 10, 32.3 ± 3 years, 23.4 ± 0.7 kg/m2 ): 60 min after treatment, a nutrient drink (270 kcal) was infused intragastrically and intragastric pressure (IGP) was measured for 1 h. Protocol 2 (n = 10, 24.3 ± 0.8 years, 22.3 ± 0.9 kg/m2 ): 60 min after treatment, HVs consumed one nutrient drink (300 kcal). Thirty minutes thereafter, HVs ate ad libitum from a free-choice buffet for 30 min. Blood was collected at several time points to measure active GLP-1 plasma levels. RESULTS During the first 20 min after nutrient infusion, the drop in IGP was smaller after vildagliptin compared to placebo (treatment-by-time interaction effect: P = 0.008). No differences were seen on epigastric symptom scores. Planned contrast analysis showed that active GLP-1 levels were higher after vildagliptin compared to placebo (P = 0.018) only after nutrient ingestion. Total food intake (316.38 ± 58.89 g vs 399.58 ± 63.02 g, P = 0.359) and total caloric intake (594.77 ± 115.17 kcal vs 742.77 ± 107.10 kcal, P = 0.371) did not differ between treatments. CONCLUSIONS Vildagliptin inhibits gastric accommodation without affecting epigastric symptom scoring in HVs. Active GLP-1 plasma levels were increased after vildagliptin treatment, but the increase was not sufficient to affect ad libitum food intake. The study was registered at Clincialtrials.gov (NCT 03500900).