Beyond Metformin: Safety Considerations in the Decision-Making Process for Selecting a Second Medication for Type 2 Diabetes Management

Abstract

The trend toward personalized management of diabetes has focused attention on the differences among available pharmacological agents in terms of mechanisms of action, efficacy, and, most important, safety. Clinicians must select from these features to develop individualized therapy regimens. In June 2013, a nine-member Diabetes Care Editors’ Expert Forum convened to review safety evidence for six major diabetes drug classes: insulin, sulfonylureas (SUs), thiazolidinediones (TZDs), glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, and sodium glucose cotransporter 2 inhibitors. This article, an outgrowth of the forum, summarizes well-delineated and theoretical safety concerns related to these drug classes, as well as the panelists’ opinions regarding their best use in patients with type 2 diabetes. All of the options appear to have reasonably wide safety margins when used appropriately. Those about which we know the most—metformin, SUs, insulin, and perhaps now also TZDs—are efficacious in most patients and can be placed into a basic initial algorithm. However, these agents leave some clinical needs unmet. Selecting next steps is a more formidable process involving newer agents that are understood less well and for which there are unresolved questions regarding risk versus benefit in certain populations. Choosing a specific agent is not as important as implementing some form of early intervention and advancing rapidly to some form of combination therapy as needed. When all options are relatively safe given the benefits they confer, therapeutic decision making must rely on a personalized approach, taking into account patients’ clinical circumstances, phenotype, pathophysiological defects, preferences, abilities, and costs.

Tratamento do Diabetes Melito Tipo 2: Ainda Existe Lugar Para as Sulfonilureias?

“…4,7,8 Até o momento, os estudos clí-nicos randomizados foram incapazes de demonstrar efeito desfavorável das sulfonilureias sobre o risco cardiovascular. 8,9 A dificuldade desse tipo de estudo em mostrar dados potenciais de medicamentos é comum, uma vez que, para isso, é necessário grande número de pacientes e longo tempo de seguimento.…”

“…A disponibilidade dessas novas opções para o tratamento do diabetes em questão tornou a escolha de quais medicamentos usar em determinado paciente, tarefa cada vez mais complexa. 4 As principais diretrizes de tratamento do diabetes melito tipo 2 recomendam a metformina como monoterapia inicial em doentes que a tolerem, dada a sua eficácia em controlar a glicemia, ao seu baixo custo, à sua segurança e ao seu potencial de redução do risco cardiovascular. 1,5,6 Em razão da natureza progressiva da doença, é frequente, porém, a necessidade de adição de outros medicamentos para obtenção de controle glicêmico e, nessa etapa do tratamento, várias opções estão disponíveis, e a escolha é direcionada por características individuais do paciente e não há recomendação geral sobre a preferência de uma classe de medicamentos em relação a outra.…”

Treatment of Type 2 Diabetes: From “Guidelines” to “Position Statements” and Back

“…A large proportion of weight gain attributed to the initiation of insulin therapy can be avoided with simple lifestyle reinforcement measurements. In consideration of lifestyle modification or any other longterm treatment of type 2 diabetes, the importance of teamwork and patient empowerment cannot be underestimated (18,19). Teamwork includes a multidisciplinary team of nurses, dietitians, social workers, medical psychologists, and the treating physician.…”

“…First, individualization of the stringency by which glycemic control targets are set (1,(16)(17)(18)(19) has left many open questions regarding the best glycemic target for a given patient (20)(21)(22). While the ADA/EASD Position Statement (1,2) supports a target HbA 1c of ,7% for most patients, it recommends a more stringent target (HbA 1c 6.0-6.5%) for select patients, as long as it can be achieved without increased risk of hypoglycemia or other prominent side effects.…”

Should Sulfonylureas Remain an Acceptable First-Line Add-on to Metformin Therapy in Patients With Type 2 Diabetes? Yes, They Continue to Serve Us Well!

“…A similar conclusion was reported in a recent published consensus report from Diabetes Care that suggested that "the ideal antihyperglycemic agent would be easy to administer, unlikely to cause symptomatic side effects that pose barriers to adherence, inexpensive, reliably efficacious, and safe. By such standards, it can be argued that the remaining modern SUs do well (although they do leave some clinical needs unmet)" (25). …”