FDA guidance on antihyperglyacemic therapies for type 2 diabetes: One decade later

Abstract

In 2008, the US Food and Drug Administration (FDA) issued a guidance to industry statement concerning evaluation of the cardiovascular (CV) safety of new antihyperglycaemic therapies for type 2 diabetes. Fifteen CV outcome trials assessing three novel classes of antihyperglycaemic therapies, DPP‐4 inhibitors, GLP‐1 receptor agonists and SGLT‐2 inhibitors, were completed by the end of 2018 and several others are ongoing. In addition, one comparative insulin trial also has been completed. None of these trials reported an increase in risk for major adverse CV events (MACE), and six agents have demonstrated CV benefits. This experience has led to the first FDA‐approved indications for antihyperglycaemic medications to reduce the risk of CV death (empagliflozin) and to reduce the risk of MACE (liraglutide, canagliflozin), both indications specific to patients with established atherosclerotic cardiovascular disease (ASCVD). Because of the aggregate results from dedicated CV outcomes trials conducted in response to the FDA guidance statement, the contemporary paradigm for treatment of patients with type 2 diabetes has evolved substantially. However, the guidance has substantially increased the cost of developing new medications to address this important disease that afflicts hundreds of millions of adults worldwide, with reduction in quality of life as well as in life expectancy. The cost burden of drug development of medications proven effective that may directly impact cost to patients and to their insurers might be alleviated by modifications to the present guidance statement. These include areas of trial design, aspects of trial operation, expansion of composite outcomes to include broader component CV outcomes and continued evolution of analytic methodology. The guidance statement will benefit from consideration of a number of modifications to support continued innovation and, of course, the safety of marketed medications for type 2 diabetes. However, the requirement to assess each new antihyperglycaemic medication in at least one large‐scale standard randomized clinical outcomes trial should remain, so that clinicians can be reassured about the favourable efficacy/safety profiles of the medications they prescribe.

Die Behandlung des Diabetes mellitus: Mythen und Evidenz

“…Am Körper tragbare Computersysteme (Wearables), wie etwa ein kontinuierlich messender Glu-kosesensor am Handgelenk (Zuckeruhr), erlauben den durch Empowerment versierten Patienten*innen eine sofortige Intervention [38]. Neben mittlerweile gesicherten Erkenntnissen zur Therapie bestimmter Formen des Diabetes mellitus, wie dem immunologisch verursachten Typ-1-Insulinmangeldiabetes, gibt es eine intensive und kontroverse Diskussion zur stadiengerechten und für die Betroffenen möglichst angemessenen Therapie der jeweiligen Diabeteserkrankung [39][40][41].…”

“…2008 forderte dann die USamerikanische Food and Drug Administration (FDA) von den Pharmafirmen substanzielle Veränderungen in ihren Forschungsstrategien und die Durchführung aussagekräftiger Endpunktstudien, insbesondere um die für antihyperglykämische Medikamente hochrelevante Sicherheit und Effizienz in der Wirkung auf das kardiovaskuläre System zu belegen [40]. Tatsächlich wurde so ein Paradigmenwechsel in der klinischen Diabetestherapieforschung ausgelöst; es ging jetzt in der Bewertung ganz wesentlich um die Auswirkung von Medikamenten auf die Mortalitätsrate, während die Diskussion um Surrogatparameter zunehmend irrelevant anmutete [41]. Große Interventionsstudien [45][46][47][48][49][50][51] wurden aufgelegt (.…”

“…Langzeitbeobachtungen zur Abschätzung der Nachhaltigkeit von Therapieeffekten wie in der UKPDS stehen noch aus, aber bei diesen Therapieansätzen werden nicht nur Blutzuckersenkungen, sondern weitere Zusatzeffekte antizipiert [36,49,53]. Aktuelle Studien, wie von der FDA im Jahr 2008 gefordert [40], zeigen tatsächlich bereits günstige Effekte auf die kardiovaskulären Endpunkte [39,41]. Die neuen, antihyperglykämischen Pharmaka finden bereits Eingang in die aktuellen Therapieempfehlungen der großen Fachgesellschaften [58].…”

Glucagon-Like Peptide-1 Receptor Agonists in Adult Patients With Type 2 Diabetes: Review of Cardiovascular Outcome Trials

“…Given the recognized importance for any increased risk that could contribute to cardiovascular (CV) dysfunction in T2D, regulatory bodies have been prudent in providing enhanced guidance around approval for new pharmacotherapies for T2D. They specify that novel antidiabetes pharmacotherapies seeking regulatory approval should demonstrate no excess risk compared with placebo for CV events, including CV mortality, stroke and myocardial infraction (MI) (2,3), at pre-or postmarketing regulatory stages. The introduction of these regulatory approval changes in 2008 expanded the scope and cost of research necessary for drug approval, notably via the initiation of several long-term cardiovascular outcome trials (CVOTs), primarily involving 3 novel antihyperglycemic drug classes, including dipeptidyl peptidase-4 (DPP4) inhibitors, sodiumglucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs).…”

FDA guidance on cardiovascular risk of antidiabetic therapies: One decade later

“…These have confirmed a non‐inferior MACE or beneficial effects on MACE compared to placebo when added to standard care. The FDA is now reconsidering the 2008 guidance, and McGuire et al provide a thoughtful and constructive evaluation of lessons learned and possible modifications to this guidance in their opinion article “FDA guidance on antihyperglycaemic therapies for type 2 diabetes: one decade later.”…”