GLP-1 Analogs and DPP-4 Inhibitors in Type 2 Diabetes Therapy: Review of Head-to-Head Clinical Trials

Abstract

The incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are released from enteroendocrine cells in response to the presence of nutrients in the small intestines. These homones facilitate glucose regulation by stimulating insulin secretion in a glucose dependent manner while suppressing glucagon secretion. In patients with type 2 diabetes (T2DM), an impaired insulin response to GLP-1 and GIP contributes to hyperglycemia. Dipeptidyl peptidase-4 (DPP-4) inhibitors block the breakdown of GLP-1 and GIP to increase levels of the active hormones. In clinical trials, DPP-4 inhibitors have a modest impact on glycemic control. They are generally well-tolerated, weight neutral and do not increase the risk of hypoglycemia. GLP-1 receptor agonists (GLP-1 RA) are peptide derivatives of either exendin-4 or human GLP-1 designed to resist the activity of DPP-4 and therefore, have a prolonged half-life. In clinical trials, they have demonstrated superior efficacy to many oral antihyperglycemic drugs, improved weight loss and a low risk of hypoglycemia. However, GI adverse events, particularly nausea, vomiting, and diarrhea are seen. Both DPP-4 inhibitors and GLP-1 RAs have demonstrated safety in robust cardiovascular outcome trials, while several GLP-1 RAs have been shown to significantly reduce the risk of major adverse cardiovascular events in persons with T2DM with pre-existing cardiovascular disease (CVD). Several clinical trials have directly compared the efficacy and safety of DPP-4 inhibitors and GLP-1 RAs. These studies have generally demonstrated that the GLP-1 RA provided superior glycemic control and weight loss relative to the DPP-4 inhibitor. Both treatments were associated with a low and comparable incidence of hypoglycemia, but treatment with GLP-1 RAs were invariably associated with a higher incidence of GI adverse events. A few studies have evaluated switching patients from DPP-4 inhibitors to a GLP-1RA and, as expected, improved glycemic control and weight loss are seen following the switch. According to current clinical guidelines, GLP-1RA and DPP-4 inhibitors are both indicated for the glycemic management of patients with T2DM across the spectrum of disease. GLP-1RA may be preferred over DPP-4 inhibitors for many patients because of the greater reductions in hemoglobin A1c and weight loss observed in the clinical trials. Among patients with preexisting CVD, GLP-1 receptor agonists with a proven cardiovascular benefit are indicated as add-on to metformin therapy.

<p>Long-Acting Injectable GLP-1 Receptor Agonists for the Treatment of Adults with Type 2 Diabetes: Perspectives from Clinical Practice</p>

“…For instance, several phase III RCTs have compared the efficacy of GLP-1RAs with that of Dipeptidyl peptidase-4 inhibitor (DPP4i) on HbA1c and weight reduction, consistently showing better performance of GLP-1RAs, as reviewed elsewhere. 49 In this context, RWS, beyond confirming such results, highlighted how the effectiveness of GLP-1RAs, as compared to that of DPP4i, is more likely to be affected by adherence to treatment. 50 This is an aspect that requires careful evaluation in clinical practice in order to achieve the same clinical benefit described in RCTs.…”

Circulating GLP-1 Levels as a Potential Indicator of Metabolic Syndrome Risk in Adult Women

“…Moreover, the FGF21 molecules secreted by iNKT cells play an important role in activating the thermogenic process in brown adipose tissue [ 37 ]. Inhibitors of DPP-4 (the enzyme that deactivates GLP-1) and GLP-1 analogs that have functions similar to those of GLP-1 have been commercialized for the treatment of diabetes [ 12 , 38 ] and have also recently been used for the treatment of obesity [ 12 , 38 , 39 , 40 ]. In addition to the GLP-1R in the pancreas, GLP-1 can bind to its receptor in various other organs (e.g., brain, stomach, muscles, liver, and heart) to perform diverse functions [ 36 ].…”

“…Whereas most previous studies were focused on GLP-1 as a therapeutic agent for the treatment of diabetes and obesity [ 11 , 12 , 13 , 14 , 15 , 16 , 30 , 38 ], we measured the circulating GLP-1 levels in the body under the fasting state. As mentioned above, GLP-1 plays an important role in regulating glucose homeostasis [ 11 , 12 , 13 ].…”

Effects of liraglutide versus sitagliptin on circulating cardiovascular biomarkers, including circulating progenitor cells, in individuals with type 2 diabetes and obesity: Analyses from the LYDIA trial

“…Differences between liraglutide and sitagliptin may be mediated by their different mechanisms of action and resulting effects. For example, despite both targeting the incretin pathway, liraglutide therapy results in greater increases in circulating GLP‐1 than sitagliptin therapy 8 …”