Updated Guidelines for Management of Hyperglycemia in Type 2 Diabetes

Charlie Sieberg, Pharm.D., New Ulm Medical Center

Background: The American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) have issued a consensus report outlining the management of hyperglycemia in type 2 diabetes mellitus (T2DM). Although the ADA 2018 Standards of Medical Care in Diabetes guidelines recommended empagliflozin and liraglutide in patients with T2DM and established cardiovascular disease (CVD), the ADA/EASD consensus report goes further by providing a new approach to diabetes care in the context of comprehensive cardiovascular risk management.  

Evidence: The ADA/EASD consensus report was issued after a systematic evaluation of literature published from January 1, 2014 to February 28, 2018. A comprehensive search was conducted on PubMed for randomized clinical trials, systematic reviews, and meta-analyses that examined the effectiveness or safety of pharmacological or nonpharmacological interventions in adults with T2DM.

Discussion: This report outlines an approach to glucose lowering in T2DM that takes into consideration patient specific factors and new evidence for the benefit of specific medications to reduce mortality, heart failure (HF), and progression of renal disease in the setting of established CVD. Patient centered care, diabetes self-management and education support, and metformin as first-line therapy are recommended for all patients with T2DM.

For patients with T2DM and established CVD, sodium-glucose cotransporter-2 inhibitors (SGLT2i) or glucagon-like peptide-1 receptor agonists (GLP-1 RA) with proven CVD benefit are recommended. If HF or chronic kidney disease (CKD) predominates then an SGLT2i with evidence of reducing HF and/or CKD progression is preferred over a GLP-1 RA with CVD benefit. Evidence of CVD benefit is liraglutide > semaglutide > exenatide extended release for GLP-1 RA, and empagliflozin > canagliflozin for SGLT2i.  Liraglutide and empagliflozin are FDA approved for the reduction of cardiovascular events in patients with diabetes and CVD. Both empagliflozin and canagliflozin have shown reductions in HF and CKD progression.

For patients with T2DM and without established CVD or CKD, treatment decisions are guided by other patient specific factors. For those concerned with weight loss, a GLP-1 RA or SGLT2i is recommended. Evidence for weight loss among GLP-1 RA is semaglutide > liraglutide > dulaglutide > exenatide > lixisenatide. For those concerned with minimizing hypoglycemia, medication options include GLP-1 RA, SGLT-2i, dipeptidyl peptidase 4 inhibitors (DPP-4i), or thiazolidinediones (TZD). For those concerned with cost, a sulfonylurea or TZD is recommended.

Clinical trials within each drug class have been heterogenous and it is not clear whether benefits in CVD, HF, CKD, and weight loss are drug-class effects. Clinical trials may have different findings for individual medications due to differences in trial design and conduct, or there may be real differences between medications within a drug class due to properties of the individual compounds.

In patients who need an injectable medication, GLP-1 RA are the preferred choice to insulin. GLP-1 RA have a lower risk of hypoglycemia, are associated with weight loss, and some are available as once weekly injections. Insulin requires at least daily injections, is associated with weight gain, and has a greater risk of hypoglycemia. Trials comparing GLP-1 RA and insulin (basal, premixed, or basal-bolus) show similar or even better efficacy in HbA1c reduction. However, Insulin is still recommended for patients with extreme and symptomatic hyperglycemia.

Clinical Impact: CVD is the leading cause of death in patients with T2DM. Diabetes confers substantial independent CVD risk, and most patients with T2DM have additional risk factors such as hypertension, dyslipidemia, obesity, physical inactivity, CKD, and smoking. The T2DM treatment algorithm outlined in this guideline incorporates new evidence that specific SGLT2i and GLP-1 RA improve CVD, HF, and CKD outcomes in patients with established CVD or CKD.

References: 

  1. Davies MJ, D’Alessio DA, Fradkin J, et al. Management of Hyperglycemia in Type 2 Diabetes, 2018. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) [published online October 4, 2018]. Diabetes Care.doi.org/10.2337/dci18-0033.

  2. Riddle MC, Bakris G, Blonde L, et al. American Diabetes Association Standards of Medical Care in Diabetes – 2018. Diabetes Care. 2018;41(Suppl. 1):S73–S85.https://doi.org/10.2337/dc18-S008.