Cardiovascular outcome trials of glucose-lowering medications: an update

Abstract

Three further cardiovascular (CV) outcome studies of glucose-lowering drugs (linagliptin, albiglutide and dapagliflozin) have recently been published, adding to the twelve earlier within-class studies. The linagliptin study (CARMELINA) recruited people with renal disease as well as prior CV events and confirms the overall CV safety (and other safety) of the dipeptidylpeptidase-4 (DPP4) inhibitors, with no heart failure risk associated with this agent. However, taken together with the findings from two previous studies of DPP4 inhibitors (sitagliptin and saxagliptin), the three DPP4 inhibitor CV outcome trials (CVOTs) have highlighted a safety signal regarding risk of pancreatitis. Like CARMELINA, the albiglutide study (Harmony Outcome) had a very high CV event rate. Despite being a short duration study, albiglutide showed strong superiority for reduction in the major adverse CV events (MACE) composite in people with extant cardiovascular disease (CVD), in line with the earlier studies on the GLP-1 receptor agonists (GLP-1RAs) liraglutide and semaglutide. Positive effects can be detected for all these medications from before 12 months and continue for the whole study duration. No new safety issues for albiglutide are identified and the lack of a pancreatitis or a pancreatic cancer signal for this class is now clear. For the sodiumglucose cotransporter-2 (SGLT2) inhibitor class, the DECLARE-TIMI 58 study (of dapagliflozin) clearly indicates strong protection for heart failure in those with CVD, and probably in those with no prior CVD. There is also strong protection against renal decline with dapagliflozin, with similar risk estimates in DECLARE as previously reported for empagliflozin and canagliflozin. However, findings for MACE outcomes with dapagliflozin are not concordant with the empagliflozin and canagliflozin studies, and are not convincingly superior across class and for the longer term. Care is required when prescribing the SGLT2 inhibitor class of medications to people with foot vascular issues or prior amputation, and to insulin users in regard of ketoacidosis. In summary, taking into account the findings from these new studies, it is suggested that a GLP-1RA should be offered to all people with CVD and type 2 diabetes, and SGLT2 inhibitors should be prescribed for those at high risk of heart failure or with progressive decline in eGFR. DPP4 inhibitors are a safe choice within the glucose-lowering stepped algorithm. Keywords Cardiovascular outcomes. Glucose-lowering medications. Review. Type 2 diabetes mellitus Abbreviations ACS Acute coronary syndrome CV Cardiovascular CVD Cardiovascular disease CVOT Cardiovascular outcome trial DPP4 Dipeptidylpeptidase-4 FDA US Food and Drugs Administration GLP-1RA GLP-1 receptor agonist MACE Major adverse cardiovascular events MI Myocardial infarction SGLT2 Sodium-glucose cotransporter-2

Advances in type 2 diabetes therapy: a focus on cardiovascular and renal outcomes

“…There have also been concerns regarding an increased risk of acute pancreatitis in post‐marketing studies, although a more recent meta‐analysis of randomised controlled trials did not find any association between GLP1 receptor agonist use and acute pancreatitis . The risk of pancreatitis is probably overstated at present, but the medication should be ceased permanently if pancreatitis develops, and GLP1 receptor agonists should be avoided in patients with a prior history of pancreatitis.…”

Increased Mortality Burden in Young Asian Subjects with Dysglycemia and Comorbidities

“…However, this risk increased to 3.7 or 3.8 if the subjects had diabetes and myocardial infarction or stroke simultaneously, suggesting increased mortality in patients with diabetes along with cardiometabolic multimorbidity. In addition, recent results from large cardiovascular outcome trials of novel anti-diabetic agents that control not only glucose but also multiple metabolic risk factors, reconfirms the importance of simultaneous intervention of multiple risk factors in patients with diabetes for the prevention of cardiovascular diseases [22]. Our study results showed that decreased renal function with eGFR <45 mL/min/1.73 m 2 resulted in a 3.4-fold increased mortality risk in patients with diabetes, which is the highest among the various comorbidities.…”

Pharmacoepidemiology: Using randomised control trials and observational studies in clinical decision‐making

“…However, no dipeptidyl peptidase‐4 inhibitor drugs appear to reduce the risk of CVD in CVOT (but do not increase the risk) despite reducing HbA1c. Conversely, all sodium‐glucose transporter 2 inhibitor agents appear to reduce CVD risk to some extent in CVOT . These disparate outcomes suggest that a reduction of HbA1c is not sufficient to predict whether a drug to treat diabetes will lead to a reduction in hard CVD clinical endpoints.…”

“…in CVOT. 77 These disparate outcomes suggest that a reduction of HbA1c is not sufficient to predict whether a drug to treat diabetes will lead to a reduction in hard CVD clinical endpoints. Thus, careful consideration of whether soft endpoints reported in clinical trials translate into clinically meaningful hard endpoints must always be given.…”