Safety, tolerability, and nonglycemic effects of incretin-based therapies

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  • The glucagon-like peptide (GLP)-1 agonists promote a 1 kg to 4 kg weight loss and satiety, while the dipeptidyl peptidase (DPP)-4 inhibitors are usually weight neutral
  • The GLP-1 agonists and DPP-4 inhibitors have a favorable safety profile, including rare occurrence of severe hypoglycemia and a low incidence of mild to moderate hypoglycemia
  • Mild to moderate nausea associated with GLP-1 agonists generally resolves over 4 to 8 weeks and can be minimized by dose escalation strategies
  • Hypersensitivity reactions occur infrequently with DPP-4 inhibitors
  • Active surveillance and investigation are ongoing regarding the possible association of GLP-1 agonists and/or DPP-4 inhibitors with acute pancreatitis; thyroid medullary cancer; and with cardiovascular disease

The authors received editorial assistance from the Primary Care Education Consortium and WriteHealth, LLC in the development of this activity and honoraria from the Primary Care Education Consortium. They have disclosed that Dr Campbell is on the advisory board for Daiichi-Sankyo and the speakers bureau for Eli Lilly and Co; Dr Cobble is on the advisory board for Abbott Laboratories, AstraZeneca, and Eli Lilly and Co and speakers bureau for Abbott Laboratories, AstraZeneca/Bristol Myers Squibb, Eli Lilly and Co, GlaxoSmithKline, and Novo Nordisk Inc; Dr Reid is on the advisory board and speakers bureau for Amylin Pharmaceuticals, Medtronic, Novo Nordisk Inc, and sanofi-aventis; and Dr Shomali is on the advisory board for Novo Nordisk Inc and speakers bureau for Amylin Pharmaceuticals, Eli Lilly and Co, sanofi-aventis, and Takeda Pharmaceuticals.


The GLP-1 agonists and DPP-4 inhibitors have important benefits beyond lowering glycosylated hemoglobin, fasting plasma glucose, and postprandial glucose. Although an important treatment goal for type 2 diabetes mellitus (T2DM) is to reduce the risk of other diabetes-related diseases, eg, cardiovascular disease, many glucose-lowering agents cause weight gain, thereby adding to the burgeoning problem of obesity and related long-term consequences, as shown in our 3 case studies. In addition, cardiovascular risks associated with thiazolidinediones have become a major concern.

Side effects and their impact on patient tolerability are also important considerations when selecting and titrating therapy. Concerns about hypoglycemia can affect patient adherence to a medication regimen and a patient’s willingness to continue and intensify therapy, especially with insulin and sulfonylureas.1-3 As seen in Cases 1 (metformin-related diarrhea) and 2 (pioglitazone-related edema), patient adherence and willingness to continue therapy can be jeopardized by medication-related side effects.

Given these issues, the use of glucose-lowering medications that reduce related risk factors and have a favorable safety profile is advantageous. The GLP-1 agonists and DPP-4 inhibitors are desirable options, based on these considerations.

Reducing risk

The importance of weight

It is well recognized that weight gain is a major risk factor for T2DM and other disorders. It is also clear that concerns about weight gain adversely affect a patient’s willingness to begin treatment with glucose-lowering medications such as thiazolidinediones (TZDs), insulin, and sulfonylureas.1-3 The other side of the story is probably less appreciated—that is, weight loss can be a significant motivating factor for patients with T2DM that, in our experience, can improve adherence to lifestyle intervention and a medication regimen. In fact, improved quality of life, as assessed by physical and emotional domains, has been reported as a result of liraglutide-associated weight loss.4 In addition, multidimensional assessment of patient satisfaction generally has shown similar improvement with liraglutide 1.2 mg once daily and sitagliptin 100 mg once daily, and significantly greater improvement with liraglutide 1.8 mg once daily.5 Consequently, the ability of GLP-1 agonists to promote weight loss in most patients and of DPP-4 inhibitors to be weight neutral offers important benefits. Weight is an issue in all 3 of our patient cases, especially in Cases 1 and 2, where the patients’ body mass indices (BMIs) are ≥30 kg/m2.

Either as monotherapy or when added to glucose-lowering therapy, twice-daily exenatide or once-daily liraglutide generally promotes a 1 kg to 4 kg weight loss.4,6-11 The addition of exenatide or liraglutide to metformin, a sulfonylurea, or both resulted in a mean 2.9 kg weight loss with exenatide and a 3.2 kg loss with liraglutide after 26 weeks.12 Patients who continued liraglutide for an additional 14 weeks lost an additional 0.4 kg, while patients switched from exenatide to liraglutide lost an additional 0.9 kg.13 The amount of weight lost is greater with a higher baseline BMI.14,15 It is important to note, however, that 16% of patients did not experience any weight loss,14 possibly because no specific caloric restriction was required.14,16 Slight increases to slight decreases in weight have been observed in clinical trials with sitagliptin and saxagliptin.17-23 Comparison of liraglutide with sitagliptin showed a mean weight loss of 2.9 kg and 3.4 kg for liraglutide 1.2 mg and 1.8 mg once daily, respectively, over 26 weeks and a 1.0 kg weight loss with sitagliptin 100 mg once daily.5 Analysis of a large cohort database that followed patients for up to 1 year showed that patients treated with exenatide lost a mean of 3.0 kg, while patients treated with sitagliptin lost 1.1 kg and those treated with insulin gained 0.6 kg.24 Accordingly, the DPP-4 inhibitors are considered weight neutral.


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