Cardiovascular benefit in the limelight: shifting type 2 diabetes treatment paradigm towards early combination therapy in patients with overt cardiovascular disease

Shehadeh, Naim; Nakhleh, Afif

doi:10.1186/s12933-018-0760-6

Cited by 8 publications

(11 citation statements)

References 15 publications

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“…T2DM is often associated with cardiovascular complications, and the two often coexist as comorbidity. Patients with T2DM often have elevated levels of inflammatory cytokines, while hyperglycemia and high concentration of glycation end products can also cause vascular endothelial cell damage and calcification [70], which have important effects on the onset and progression of atherosclerosis [61,71], leading to related cardiovascular diseases. Metformin activates AMPK phosphorylation, which reduces oxidative stress, reduces the production of inflammatory cytokines, and increases eNOS (endothelial nitric oxide synthase) activity, which may be an important mechanism for metformin cardiovascular protection.…”

Section: Discussionmentioning

confidence: 99%

Effect of metformin on all-cause and cardiovascular mortality in patients with coronary artery diseases: a systematic review and an updated meta-analysis

Han

Xie

Liu

et al. 2019

Cardiovasc Diabetol

234

150

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Background Metformin is the most widely prescribed drug to lower glucose and has a definitive effect on the cardiovascular system. The goal of this systematic review and meta-analysis is to assess the effects of metformin on mortality and cardiac function among patients with coronary artery disease (CAD). Methods Relevant studies reported before October 2018 was retrieved from databases including PubMed, EMBASE, Cochrane Library and Web of Science. Hazard ratio (HR) was calculated to evaluate the all-cause mortality, cardiovascular mortality and incidence of cardiovascular events (CV events), to figure out the level of left ventricular ejection fraction (LVEF), creatine kinase MB (CK-MB), type B natriuretic peptide (BNP) and to compare the average level of low density lipoprotein (LDL). Results In this meta-analysis were included 40 studies comprising 1,066,408 patients. The cardiovascular mortality, all-cause mortality and incidence of CV events were lowered to adjusted HR (aHR) = 0.81, aHR = 0.67 and aHR = 0. 83 respectively after the patients with CAD were given metformin. Subgroup analysis showed that metformin reduced all-cause mortality in myocardial infarction (MI) (aHR = 0.79) and heart failure (HF) patients (aHR = 0.84), the incidence of CV events in HF (aHR = 0.83) and type II diabetes mellitus (T2DM) patients (aHR = 0.83), but had no significant effect on MI (aHR = 0.87) and non-T2DM patients (aHR = 0.92). Metformin is superior to sulphonylurea (aHR = 0.81) in effects on lowering the incidence of CV events and in effects on patients who don’t use medication. The CK-MB level in the metformin group was lower than that in the control group standard mean difference (SMD) = − 0.11). There was no significant evidence that metformin altered LVEF (MD = 2.91), BNP (MD = − 0.02) and LDL (MD = − 0.08). Conclusion Metformin reduces cardiovascular mortality, all-cause mortality and CV events in CAD patients. For MI patients and CAD patients without T2DM, metformin has no significant effect of reducing the incidence of CV events. Metformin has a better effect of reducing the incidence of CV events than sulfonylureas.

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Section: Discussionmentioning

confidence: 99%

Effect of metformin on all-cause and cardiovascular mortality in patients with coronary artery diseases: a systematic review and an updated meta-analysis

Han

Xie

Liu

et al. 2019

Cardiovasc Diabetol

234

150

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“…Prescribing information in the United States has some differences; ertugliflozin is not recommended in patients with an eGFR below 60 ml/min/1.73 m 2 , while canagliflozin, dapagliflozin and empagliflozin may be initiated below 60 ml/min/1.73 m 2 , but should be discontinued if persistently below 45 ml/min/1.73 m 2 (with the exception of dapagliflozin in patients with HFrEF, with or without T2D, where use is supported for eGFR ≥ 30 ml/min/1.73 m 2 ). If SGLT2i cannot be used, a GLP-1 RA with proven benefit should be considered to improve renal outcomes for patients with CKD or CKD is a factor [32], it may be that poorly controlled cardiorenal disease is being missed. For this reason, we believe that treatment algorithms should very clearly encourage such patients to be switched as a matter of urgency to SGLT2i or GLP-1 RA.…”

Section: Advocate For Post-cvot Treatment Pathways That Separate Hba1mentioning

confidence: 99%

“…More people with T2D die from CVD than any other cause [ 32 ], and the risk of CV death is particularly pronounced for those with renal comorbidities [ 25 , 33 , 34 ]. As death is the ultimate endpoint, mitigating cardiorenal risk is a priority in the management of patients with T2D who are at high CV and/or renal risk [ 35 , 36 ].…”

Section: Out Of Step With the Evidence: The Cvot-shaped Hole In Diabementioning

confidence: 99%

Worldwide inertia to the use of cardiorenal protective glucose-lowering drugs (SGLT2i and GLP-1 RA) in high-risk patients with type 2 diabetes

Schernthaner

Shehadeh

Аметов

et al. 2020

Cardiovasc Diabetol

Self Cite

108

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The disclosure of proven cardiorenal benefits with certain antidiabetic agents was supposed to herald a new era in the management of type 2 diabetes (T2D), especially for the many patients with T2D who are at high risk for cardiovascular and renal events. However, as the evidence in favour of various sodium–glucose transporter-2 inhibitor (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA) accumulates, prescriptions of these agents continue to stagnate, even among eligible, at-risk patients. By contrast, dipeptidyl peptidase-4 inhibitors (DPP-4i) DPP-4i remain more widely used than SGLT2i and GLP-1 RA in these patients, despite a similar cost to SGLT2i and a large body of evidence showing no clear benefit on cardiorenal outcomes. We are a group of diabetologists united by a shared concern that clinical inertia is preventing these patients from receiving life-saving treatments, as well as placing them at greater risk of hospitalisation for heart failure and progression of renal disease. We propose a manifesto for change, in order to increase uptake of SGLT2i and GLP-1 RA in appropriate patients as a matter of urgency, especially those who could be readily switched from an agent without proven cardiorenal benefit. Central to our manifesto is a shift from linear treatment algorithms based on HbA1c target setting to parallel, independent considerations of atherosclerotic cardiovascular disease, heart failure and renal risks, in accordance with newly updated guidelines. Finally, we call upon all colleagues to play their part in implementing our manifesto at a local level, ensuring that patients do not pay a heavy price for continued clinical inertia in T2D.

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“…The goal of durable glycemic control is to reduce the long-term risk of diabetes-related cardiovascular morbidity and mortality 57 . Recent studies showed that SGLT2Is have been shown to decrease cardiovascular events in treating high-risk patients with T2DM 34 . Likewise, the addition of empagliflozin to metformin therapy improves in patients with established CVD or heart failure 78 .…”

Section: Discussionmentioning

confidence: 99%

Cardiovascular safety and efficacy of metformin-SGLT2i versus metformin-sulfonylureas in type 2 diabetes: systematic review and meta-analysis of randomized controlled trials

Gebrie

Getnet

Manyazewal

2021

Sci Rep

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Diabetes is a serious threat to global health and among the top 10 causes of death, with nearly half a billion people living with it worldwide. Treating patients with diabetes tend to become more challenging due to the progressive nature of the disease. The role and benefits of combination therapies for the management of type 2 diabetes are well-documented, while the comparative safety and efficacy among the different combination options have not been elucidated. We aimed to systematically synthesize the evidence on the comparative cardiovascular safety and efficacy of combination therapy with metformin-sodium-glucose cotransporter-2 inhibitors versus metformin-sulfonylureas in patients with type 2 diabetes. We searched MEDLINE-PubMed, Embase, Cochrane Library, and ClinicalTrials.gov up to 15 August 2019 without restriction in the year of publication. We included randomized controlled trials of patients with type 2 diabetes who were on metformin-sodium-glucose cotransporter-2 inhibitors or metformin-sulphonylureas combination therapy at least for a year. The primary endpoints were all-cause mortality and serious adverse events, and the secondary endpoints were cardiovascular mortality, non-fatal myocardial infarction, non-fatal stroke, hypoglycemia, and changes in glycated hemoglobin A1c (HbA1c), body weight, fasting plasma glucose, blood pressure, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol. We used a random-effects meta-analysis model to estimate mean differences for continuous outcomes and risk ratio for dichotomous outcomes. We followed PICOS description model for defining eligibility and the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) 2015 guidelines for reporting results. Of 3,190 citations, we included nine trials involving 10,974 participants. The pooled analysis showed no significant difference in all-cause mortality (risk ration [RR] = 0.93, 95% CI [0.52, 1.67]), serious adverse events (RR = 0.96, 95% CI [0.79, 1.17]) and adverse events (RR = 1.00, 95% CI [0.99, 1.02]) between the two, but in hypoglycemia (RR = 0.13, 95% CI [0.10, 0.17], P < 0.001). Participants taking metformin-sodium glucose cotransporter-2 inhibitors showed a significantly greater reduction in HbA1c (mean difference [MD] = − 0.10%, 95% CI [− 0.17, − 0.03], body weight (MD = − 4.57 kg, 95% CI [− 4.74, − 4.39], systolic blood pressure (MD = − 4.77 mmHg, 95% CI [− 5.39, − 4.16]), diastolic blood pressure (MD = − 2.07 mmHg, 95% CI [− 2.74, − 1.40], and fasting plasma glucose (MD = − 0.55 mmol/L, 95% CI [− 0.69, − 0.41]), p < 0.001. Combination therapy of metformin and sodium-glucose cotransporter-2 inhibitors is a safe and efficacious alternative to combination therapy of metformin and sulphonylureas for patients with type 2 diabetes who are at risk of cardiovascular comorbidity. However, there remains a need for additional long-term randomized controlled trials as available studies are very limited and heterogeneous.

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Cardiovascular benefit in the limelight: shifting type 2 diabetes treatment paradigm towards early combination therapy in patients with overt cardiovascular disease

Cited by 8 publications

References 15 publications

Effect of metformin on all-cause and cardiovascular mortality in patients with coronary artery diseases: a systematic review and an updated meta-analysis

Effect of metformin on all-cause and cardiovascular mortality in patients with coronary artery diseases: a systematic review and an updated meta-analysis

Worldwide inertia to the use of cardiorenal protective glucose-lowering drugs (SGLT2i and GLP-1 RA) in high-risk patients with type 2 diabetes

Cardiovascular safety and efficacy of metformin-SGLT2i versus metformin-sulfonylureas in type 2 diabetes: systematic review and meta-analysis of randomized controlled trials

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