Cardiovascular Outcomes Trials in Type 2 Diabetes Mellitus

Cardiology ◽  
2016 ◽  
Vol 135 (2) ◽  
pp. 108-126
Author(s):  
Karan Kapoor ◽  
Praveen George ◽  
Michael Miller
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Disease Risk ◽  
Macrovascular Disease ◽  
Cardiovascular Outcomes ◽  
Significant Shift ◽  
Glucose Lowering ◽  
Dipeptidyl Peptidase 4 Inhibitors

Objectives: To review the spectrum of contemporary cardiovascular outcomes trials (CVOTS) in type 2 diabetes mellitus (T2DM), spanning both the pre- and post-ACCORD eras. Methods: We reviewed a total of 12 CVOTs and delineated the two eras in accordance with the 2008 US Food and Drug Administration (FDA) mandate requiring completion of CVOTs prior the licensing of new glucose-lowering agents. The salient implications regarding macrovascular disease complications were summarized. Results: Five trials in the pre-ACCORD and 7 in the post-ACCORD era were identified. Heterogeneous results pertaining to the degree of glycemic control associated with optimal macrovascular disease risk reduction, as well as the safest pharmacologic means to do so, were observed. Conclusions: The post-ACCORD era is representative of a significant shift in the landscape of CVOTs in T2DM, with an emphasis on safety of glucose-lowering agents. Recently completed and ongoing trials of dipeptidyl peptidase-4 inhibitors and sodium-glucose cotransporter 2 inhibitors will continue to inform clinical practice on safe and effective ways to reduce CV risk in T2DM.

scholarly journals P1028EFFECTS OF CANAGLIFLOZIN ON MAJOR ADVERSE CARDIOVASCULAR OUTCOMES IN PATIENTS WITH DIFFERENT BASELINE LEVELS OF TYPE 2 DIABETES MELLITUS DISEASE SEVERITY: RESULTS FROM THE CANVAS PROGRAM

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Tamara Young ◽  
Jing-wei Li ◽  
Amy Kang ◽  
Hiddo Heerspink ◽  
Carinna Hockham ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Disease Severity ◽  
Cardiovascular Outcomes ◽  
Oral Glucose ◽  
Glucose Lowering ◽  
Duration Of Diabetes ◽  
Event Rates

Abstract Background and Aims Patient with type 2 diabetes mellitus (T2DM) included in trials of sodium-glucose cotransporter 2 inhibitors are heterogeneous in terms of disease severity. We assessed the effects of canagliflozin compared to placebo on cardiovascular and renal outcomes in the CANVAS program according to severity of T2DM as indicated by intensity of treatment, duration of diabetes and glycaemic control. Method We compared effects on major adverse cardiovascular events ([MACE], defined as cardiovascular death, non-fatal myocardial infarction or non-fatal stroke) according to three indicators of T2DM severity at study baseline: number of oral glucose lowering treatments or insulin therapy (0-1, 2, 3+, insulin), duration of diabetes (<10, 10-16, >16 years) and HbA1c (<7.0, 7.0-7.5, 7.5-8.0, 8.0-8.5, 8.5-9, >9.0%). We also assessed effects on other pre-specified cardiovascular outcomes, and an adjudicated composite of end-stage kidney disease, renal death or sustained 40% decline in estimated glomerular filtration rate. We assessed for constancy of hazard ratios across subgroups by fitting an interaction term that tested for linear trend. Results Of 10,142 participants in the CANVAS Program, 1011 experienced a MACE during a mean follow-up of 3.6 years. Event rates for MACE were higher in those with longer duration of diabetes and higher HbA1c at baseline. The effect of canagliflozin on MACE in the overall population (HR 0.86, 95 % CI 0.75-0.97) was consistent irrespective of the number of glucose lowering treatments (p=0.509), duration of diabetes (p=0.174) and baseline HbA1c (p =0.314). Effects were also consistent across different levels of T2DM disease severity for all other outcomes studied. Conclusion Higher event rates were observed in those with longer disease duration and higher HbA1c. The proportional risk reductions achieved with canagliflozin were comparable regardless of diabetes duration, number of therapies or HbA1C at baseline.

scholarly journals Pharmacological Management of Diabetes for Reducing Glucose Levels and Cardiovascular Disease Risk: What Evidence in South Asians?

2020 ◽  
Vol 17 ◽  
Author(s):  
Nazim Ghouri ◽  
Hareem Javed ◽  
Naveed Sattar
Keyword(s):  
Type 2 Diabetes ◽  
South Asian ◽  
Disease Risk ◽  
South Asians ◽  
Cardiovascular Disease Risk ◽  
Cardiovascular Outcomes ◽  
Renal Outcome ◽  
Glucose Lowering ◽  
Dipeptidyl Peptidase 4 Inhibitors

Introduction/Aims: South Asians experience more type 2 diabetes, which is earlier in onset and with more rapid glycaemic deterioration, although average body mass indices are lower than in whites. Cardiovascular outcomes from diabetes drug trials are now reported as standard, with data from newer therapies influencing patient management. However, less is known of the effect of such therapies in South Asians. The aim of this narrative review was to extract, wherever possible, the glucose-lowering efficacy and cardiovascular and renal outcome data for these therapies in South Asians. Discussion/Conclusions: Despite the higher prevalence and global burden of type 2 diabetes and adverse outcomes in South Asians, they remain underrepresented in global trials. Even when recruited, the current method of classifying ethnicity does not commonly allow South Asian data to be extracted and reported separately from all Asians. Interrogation of available trial data suggests broadly comparable effects on glycaemia and weight in Asians to other ethnicities with use of glucagon-like peptide 1 receptor agonists (GLP-1RA), but a potentially early, albeit marginally, greater glycaemia benefit with Dipeptidyl peptidase-4 inhibitors (DPP4i) which may not be sustained. Furthermore, there appears a potentially greater glycaemia benefit with use of sodium-glucose transport protein 2 inhibitors (SGLT2i) in Asians compared to whites. Whether such findings are true in all Asians subgroups requires further direct study. For cardiovascular outcomes, available data suggest at least comparable and potentially greater outcome benefits in Asians; point estimates were more favourable for Asians in the vast majority of GLP-1RA and SGLT2i outcome trials. It was, however, impossible to determine whether the effects were similar across all Asian subgroups. We conclude that trialists should be encouraged to record ethnicity with better granularity to allow differing ethnic groups data to be better interrogated. In the meantime, doctors should, where possible, confidently follow newer guidelines for the use of newer glucose lowering agents for treating glycaemia and the prevention of cardiovascular and cardiorenal complications in South Asian people with type 2 diabetes.

scholarly journals Mortality and other adverse outcomes in patients with type 2 diabetes mellitus admitted for COVID-19 in association with glucose-lowering drugs: a nationwide cohort study

BMC Medicine ◽  
2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Luis M. Pérez-Belmonte ◽  
◽  
José David Torres-Peña ◽  
María D. López-Carmona ◽  
M. Mar. Ayala-Gutiérrez ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Adverse Outcomes ◽  
Hospital Death ◽  
Glucose Lowering ◽  
Dipeptidyl Peptidase 4 ◽  
Dipeptidyl Peptidase 4 Inhibitors ◽  
At Home

Abstract Background Limited evidence exists on the role of glucose-lowering drugs in patients with COVID-19. Our main objective was to examine the association between in-hospital death and each routine at-home glucose-lowering drug both individually and in combination with metformin in patients with type 2 diabetes mellitus admitted for COVID-19. We also evaluated their association with the composite outcome of the need for ICU admission, invasive and non-invasive mechanical ventilation, or in-hospital death as well as on the development of in-hospital complications and a long-time hospital stay. Methods We selected all patients with type 2 diabetes mellitus in the Spanish Society of Internal Medicine’s registry of COVID-19 patients (SEMI-COVID-19 Registry). It is an ongoing, observational, multicenter, nationwide cohort of patients admitted for COVID-19 in Spain from March 1, 2020. Each glucose-lowering drug user was matched with a user of other glucose-lowering drugs in a 1:1 manner by propensity scores. In order to assess the adequacy of propensity score matching, we used the standardized mean difference found in patient characteristics after matching. There was considered to be a significant imbalance in the group if a standardized mean difference > 10% was found. To evaluate the association between treatment and study outcomes, both conditional logit and mixed effect logistic regressions were used when the sample size was ≥ 100. Results A total of 2666 patients were found in the SEMI-COVID-19 Registry, 1297 on glucose-lowering drugs in monotherapy and 465 in combination with metformin. After propensity matching, 249 patients on metformin, 105 on dipeptidyl peptidase-4 inhibitors, 129 on insulin, 127 on metformin/dipeptidyl peptidase-4 inhibitors, 34 on metformin/sodium-glucose cotransporter 2 inhibitor, and 67 on metformin/insulin were selected. No at-home glucose-lowering drugs showed a significant association with in-hospital death; the composite outcome of the need of intensive care unit admission, mechanical ventilation, or in-hospital death; in-hospital complications; or long-time hospital stays. Conclusions In patients with type 2 diabetes mellitus admitted for COVID-19, at-home glucose-lowering drugs showed no significant association with mortality and adverse outcomes. Given the close relationship between diabetes and COVID-19 and the limited evidence on the role of glucose-lowering drugs, prospective studies are needed.

scholarly journals Impact of Regulatory Guidance on Evaluating Cardiovascular Risk of New Glucose-Lowering Therapies to Treat Type 2 Diabetes Mellitus

Circulation ◽  
2020 ◽  
Vol 141 (10) ◽  
pp. 843-862 ◽  
Author(s):  
Abhinav Sharma ◽  
Neha J. Pagidipati ◽  
Robert M. Califf ◽  
Darren K. McGuire ◽  
Jennifer B. Green ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Cardiovascular Outcomes ◽  
Regulatory Approval ◽  
Cardiovascular Outcome ◽  
Glucose Lowering ◽  
Cardiovascular Outcome Trials ◽  
Regulatory Guidance

Responding to concerns about the potential for increased risk of adverse cardiovascular outcomes, specifically myocardial infarction, associated with certain glucose-lowering therapies, the US Food and Drug Administration and the Committee for Medicinal Products for Human Use of the European Medicines Agency issued guidance to the pharmaceutical industry in 2008. Glucose-lowering therapies were granted regulatory approval primarily from smaller studies that have demonstrated reductions in glycated hemoglobin concentration. Such studies were overall underpowered and of insufficient duration to show any effect on cardiovascular outcomes. The 2008 guidance aimed to ensure the cardiovascular safety of new glucose-lowering therapies to treat patients with type 2 diabetes mellitus. This resulted in a plethora of new cardiovascular outcome trials, most designed primarily as placebo-controlled noninferiority trials, but with many also powered for superiority. Several of these outcome trials demonstrated cardiovascular benefits of the newer agents, resulting in the first-ever cardiovascular protection indications for glucose-lowering therapies. Determining whether the guidance continues to have value in its current form is critically important as we move forward after the first decade of implementation. In February 2018, a think tank comprising representatives from academia, industry, and regulatory agencies convened to consider the guidance in light of the findings of the completed cardiovascular outcome trials. The group made several recommendations for future regulatory guidance and for cardiovascular outcome trials of glucose-lowering therapies. These recommendations include requiring only the 1.3 noninferiority margin for regulatory approval, conducting trials for longer durations, considering studying glucose-lowering therapies as first-line management of type 2 diabetes mellitus, considering heart failure or kidney outcomes within the primary outcome, considering head-to-head active comparator trials, increasing the diversity of patients enrolled, evaluating strategies to streamline registries and the study of unselected populations, and identifying ways to improve translation of trial results to general practice.

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