Sitagliptin: results from clinical practice

Keywords::

• DPP-4 inhibitors
• Glycemic control
• Metformin
• Sitagliptin

According to the latest American Diabetes Association (ADA) guidelines1, lowering glycated hemoglobin (HbA_1c) to below or around 7% has been shown to reduce microvascular and neuropathic complications of diabetes and, if implemented soon after the diagnosis of diabetes, is associated with long-term reduction of macrovascular disease. To help in achieving this goal, in recent years the new class of incretins has been developed as an additional option for the treatment of type 2 diabetes mellitus. Incretins are secreted by intestinal L-cells, mainly in response to food intake; the most important incretin, glucagon-like peptide-1 (GLP-1), has several actions including stimulation of insulin secretion and reduction of glucagon secretion, both in a glucose-dependent manner, resulting in reduced hepatic glucose production, delayed gastric emptying, and increased sense of satiety2–4. GLP-1 is rapidly degraded by dipeptidyl peptidase-4 (DPP-4), that limits GLP-1 time of action in the blood5.

Actually two classes of drugs based on the incretin system are available: GLP-1 receptor agonists such as exenatide and liraglutide, resistant to DPP-4 cleavage6, and DPP-4 inhibitors that delay endogenous degradation of GLP-17. The first DPP-4 inhibitor released for use in clinical practice was sitagliptin, followed by vildagliptin, saxagliptin and linagliptin. Sitagliptin can be used either as monotherapy or in combination. As monotherapy, sitagliptin is indicated in the USA as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus, whereas in Europe, it is indicated as monotherapy in patients who have inadequate glycemic control with diet and exercise and in whom metformin is inappropriate due to contraindications or intolerance.

Sitagliptin is also indicated, both in the USA and in Europe, in combination with metformin, sulfonylureas or pioglitazone in patients who have inadequate control with these agents used as monotherapy in addition to diet and exercise. Sitagliptin is also indicated as triple therapy in combination with metformin plus a sulfonylurea or metformin plus pioglitazone in patients who have inadequate glycemic control with the two agents. Recently, sitagliptin was also approved to be used in combination with insulin8,9.

Sitagliptin has been licensed at the recommended dose of 100 mg once daily; in patients with mild renal insufficiency (creatinine clearance [CrCl] ≥50 ml/min) no dosage adjustment is required. In patients with moderate renal insufficiency (CrCl ≥ 30 to <50 ml/min), instead, the dose of sitagliptin should be reduced to 50 mg once daily, while in patients with severe renal insufficiency (CrCl <30 ml/min) or with end-stage renal disease requiring hemodialysis or peritoneal dialysis, the dose of sitagliptin should be further reduced to 25 mg once daily8,9.

In the literature there are several studies about sitagliptin, used both alone and in combination with other anti-diabetic drugs, showing it to be safe and effective7. Sitagliptin administered in monotherapy proved to be non-inferior to metformin in improving HbA_1c in treatment-naïve patients with type 2 diabetes. Although both treatments were generally well tolerated, a lower incidence of gastrointestinal-related adverse experiences was observed with sitagliptin10. Moreover, a 24 week study conducted by Vilsbøll et al.11 showed that the addition of sitagliptin to ongoing, stable-dose insulin therapy, with or without concomitant metformin, improved glycemic control and was generally well tolerated in patients with type 2 diabetes mellitus. Sitagliptin also proved to be safe and effective when added to pioglitazone: sitagliptin plus pioglitazone gave an improvement in HbA_1c, fasting and post-prandial glucose similar to metformin plus pioglitazone. Metformin plus pioglitazone also led to a decrease in body weight and to faster and better improvement in insulin resistance and inflammatory state parameters, even if sitagliptin gave better protection for β-cell function12.

The effect of sitagliptin on β-cell function was better investigated in another study where the authors used a combined euglycemic hyperinsulinemic and hyperglycemic clamp, with subsequent arginine stimulation: when added to metformin, sitagliptin improved glycemic control, glucagon and homeostasis model assessment of insulin resistance (HOMA-IR). Sitagliptin plus metformin gave also an increase in HOMA-β, M-value, and C-peptide response to arginine and disposition index compared to placebo plus metformin13.

The effects of sitagliptin seem to be maintained after 2 years of therapy when it is added to previously taken anti-diabetic drugs in patients not adequately controlled14. As well as being effective for glycemic control, sitagliptin improved body weight by −4.3% and it also showed a positive effect on lipid profile; in particular, sitagliptin decreased total cholesterol by −13.3%, low density cholesterol by −20.4%, and triglycerides by −32.3%, and also increased high density cholesterol by +13.6%14. Moreover, it has been largely demonstrated that in type 2 diabetic patients there is an increase in biomarkers of systemic low-grade inflammation and endothelial dysfunction such as high sensitivity C-reactive protein, interleukin-6, tumor necrosis factor-α (TNF-α), soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble E-selectin, matrix metalloproteinase-2 and -9 compared to healthy subjects, both in a fasting state and after an oral glucose tolerance test15,16.

An effect of sitagliptin on inflammation has been suggested, with a reduction of retinol binding protein-4, (RBP-4), visfatin, chemerin, resistin, and vaspin levels17,18. In this context, the meta-analysis written by Qiang et al.19 compared the therapeutic efficacy of sitagliptin and metformin in the treatment of type 2 diabetes mellitus. They identified 21 studies, seven of which were included in the meta-analysis. They observed that sitagliptin and metformin have a comparable effect in reducing HbA_1c, in decreasing BMI, and in improving HOMA-β, but sitagliptin was inferior to metformin in improving HOMA-IR. This partially confirms what was previously reported; however, we think that the best choice in clinical practice is to use metformin and sitagliptin together, if there are no contraindications.

Sitagliptin, in fact, is effective in reducing HbA_1c with a comparable effect to a sulfonylurea or pioglitazone. Other than improving glycemic control, sitagliptin seems to have other positive effects: it improves the lipid profile14, and has a positive effect on β-cell function13,17,18. In contrast to thiazolidinediones and sulfonylureas, that usually give a little weight gain, sitagliptin seems to be neutral or to reduce body weight14. Other than that, it seems to be well tolerated, in contrast to metformin which is frequently associated with gastrointestinal-related adverse events. Hypoglycemia has been reported only when sitagliptin was used in combination with a sulfonylurea in 4.7–13.8% of patients and with insulin in 9.6% of patients. Sitagliptin adverse effects include nasopharyngitis, headache, nausea, hypersensitivity, and skin reactions. Serious side effects reported with sitagliptin include pancreatitis and hypersensitivity, even if these events are rare8.

Regarding the role sitagliptin should have in clinical practice, we think that in patients with newly diagnosed type 2 diabetes mellitus, metformin should be the first choice, followed by the addition of pioglitazone because of its positive effect in enhancing the action of insulin in insulin-sensitive tissue by increasing glucose uptake in skeletal muscle and adipose tissue, and decreasing hepatic glucose production20. Metformin plus pioglitazone combination, in fact, proved to be effective and well tolerated in patients with type 2 diabetes mellitus; the small weight gained proved to be less than previously reported and to be considerably less than what might have been expected given the large improvement in glycemic control21.

Regarding concern about pioglitazone use and the increased risk of bladder cancer22, after a review of several studies, the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) concluded that, even if there is a small risk of bladder cancer with pioglitazone, the benefits of pioglitazone continue to outweigh its risk in patients responding adequately to treatment. The CHMP recommended carefully choosing patients who will receive pioglitazone therapy, excluding those who have or have had bladder cancer or those with blood in the urine that has not yet been investigated23.

When metformin and pioglitazone combination is not enough to maintain adequate glycemic control, sitagliptin should be preferred to sulfonylureas as the third agent because of their positive effect on β-cells. This was also confirmed in the literature which demonstrated that sitagliptin should be preferred to glibenclamide as an addition to metformin plus pioglitazone combination for its better protection of β-cell secretion and its neutral effect on body weight24,25. Furthermore, sitagliptin prevents the risk of hypoglycemia posed by sulfonylureas.

Transparency

Declaration of funding

The authors received no payment in preparation of this manuscript.

Declaration of financial/other relationships

P.M. and G.D. have disclosed that they have no significant relationships with or financial interests in any commercial companies related to this study or article.

CMRO peer reviewers may have received honoraria for their review work. The peer reviewers on this manuscript have disclosed that they have no relevant financial relationships.