Dipeptidyl Peptidase-4 Inhibitors: 3 Years of Experience

Abstract

According to the latest American Diabetes Association guidelines, 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 in macrovascular disease. Recently a new class of antidiabetes drugs has been developed, dipeptidyl peptidase-4 (DPP-4) inhibitors, which act by inhibiting DPP-4, the enzyme that inactivates glucagon-like peptide-1 (GLP-1). Through the inhibition of DPP-4, DPP-4 inhibitors enhance the effects of GLP-1 and glucose-dependent insulinotropic peptide, increasing glucose-mediated insulin secretion and suppressing glucagon secretion. We conducted a review analyzing clinical efficacy and safety of DPP-4 inhibitors, both alone and in combination with other antidiabetes drugs, including randomized controlled trials about sitagliptin, vildagliptin, saxagliptin, and linagliptin conducted in the latest 15 years. We concluded that, once metformin fails to maintain glycemic control, addition of DPP-4 inhibitors should be the logical choice: they seems to lower HbA_1c levels by 0.6–0.9 percentage points and to have a comparable effect on HbA_1c versus the addition of a sulfonylurea or glitazone. They also have positive effects on β-cell function, and they have neutral effects on body weight. Furthermore, DPP-4 inhibitors prevent the risk of hypoglycemia posed by sulfonylureas.

Introduction

A ccording to the latest American Diabetes Association guidelines, 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 in macrovascular disease.¹ Additional analyses from several randomized trials suggest a small, but incremental, benefit in microvascular outcomes with HbA_1c values closer to normal, so providers might reasonably suggest more stringent HbA_1c goals for patients with short duration of diabetes, long life expectancy, and no significant cardiovascular disease, if this can be achieved without significant hypoglycemia or other adverse effects of treatment.^2
–4 On the other hand, less stringent HbA_1c goals may be appropriate for patients with a history of severe hypoglycemia, limited life expectancy, advanced microvascular or macrovascular complications, extensive comorbid conditions, and those with longstanding diabetes.^5,6 The current consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes asserts an earlier intervention at the time of diagnosis with metformin in combination with lifestyle changes and continuing timely augmentation of therapy with additional agents as a way of achieving and maintaining recommended levels of glycemic control.⁷ The choice of metformin as first-line therapy is primarily due to metformin's glucose-lowering effects, absence of weight gain, generally low level of side effects, and relatively low cost.¹ Other than metformin, the actually available drugs are:

• Sulfonylureas. They lower glycemia by enhancing insulin secretion. The major adverse side effect is hypoglycemia, which can be prolonged and life threatening, but such episodes, characterized by a need for assistance, coma, or seizure, are infrequent.⁸

• Glinides. Like sulfonylureas, they enhance insulin secretion, although they bind to a different site within the sulfonylurea receptor.⁹ They have a shorter circulating half-life than sulfonylureas and must be administered more frequently. Like with sulfonylureas, their major adverse side effect is hypoglycemia.

• α-Glucosidase inhibitors. They reduce postprandial hyperglycemia, delaying the breakdown of carbohydrates in the intestine and consequently slowing down the absorption of sugars without increasing circulating insulin levels and without causing hypoglycemia. The most common adverse event is meteorism.¹⁰

• Pioglitazone. Pioglitazone is a peroxisome proliferator-activated receptor modulator. It increases the sensitivity of muscle, fat, and liver to endogenous and exogenous insulin.¹¹ The most common adverse effects with pioglitazone are weight gain and fluid retention; however, the weight gain can be reduced by a combination of pioglitazone and metformin.¹²

Recent breakthroughs in the understanding of incretin-based therapies have provided additional options for the treatment of type 2 diabetes mellitus. The most important incretin, glucagon-like peptide-1 (GLP-1), is secreted by intestinal L-cells, mainly in response to food intake; it has several actions, including stimulation of insulin secretion and reduction of glucagon secretion, both in a glucose-dependent manner, and resulting in a reduced hepatic glucose production. Furthermore, GLP-1 slows gastrointestinal motility and increases satiety, reducing the food intake. It also promotes β-cell proliferation and probably neogenesis, while reducing apoptosis in animal models.^13
–15 Because GLP-1 is rapidly degraded by dipeptidyl peptidase-4 (DPP-4),¹⁶ GLP-1 receptor agonists resistant to DPP-4 have been developed. Exenatide and liraglutide are the available incretin mimetics; they have structural similarity and bind to the receptor for GLP-1 and display a similar broad range of activities relevant to improving glycemic control, but they are resistant to DPP-4 cleavage.¹⁷ Based on the same rationale, another class of antidiabetes drugs has been developed—DPP-4 inhibitors, which delay endogenous degradation of GLP-1 inhibiting DPP-4.¹⁸ DPP-4 inhibitors include sitagliptin, vildagliptin, saxagliptin, linagliptin, and alogliptin; we have recently published several studies on incretins, two studies on exenatide,^19,20 two studies on DPP-4 inhibitors,^21,22 and a review about saxagliptin's effects in combination with metformin, proving that, because of its positive effect on β-cell function and its neutral effects on body weight, saxagliptin is particularly indicated in young patients, with a long life expectancy. Furthermore, saxagliptin also reduces insulin resistance, decreasing homeostasis model assessment (HOMA) of insulin resistance (HOMA-IR), and prevents the risk of hypoglycemia posed by the sulfonylurea.²³ This time we decided to conduct a review on the class of DPP-4 inhibitors. We chose to analyze only DPP-4 inhibitors currently approved for marketing by the U.S. Food and Drug Administration, analyzing their effects both in monotherapy and in combination with other antidiabetes drugs.

Methods

A systematic search strategy was developed to identify randomized controlled trials in both MEDLINE (National Library of Medicine, Bethesda, MD) for 1996 through July 2011 and the Cochrane Register of Controlled Trials (The Cochrane Collaboration, Oxford, UK). The terms “sitagliptin,” “vildagliptin,” “saxagliptin,” “linagliptin,” “DPP-4 inhibitors,” “incretins,” and “glycemic control” were incorporated into an electronic search strategy that included the Dickersin filter for randomized controlled trials.²⁴ The bibliographies of all identified randomized trials and review articles were reviewed to look for additional studies of interest. We reviewed all of the citations retrieved from the electronic search to identify potentially relevant articles for this review. We subsequently reviewed the potential trials to determine their eligibility. To qualify for inclusion, clinical trials were required to meet a series of predetermined criteria regarding study design, study population, interventions evaluated, and outcome measured. Studies were required to be randomized trials comparing sitagliptin, vildagliptin, saxagliptin, or linagliptin at any dosage with any other antidiabetes drug in type 2 diabetes patients. Eligible trials had to present results on glycemic control or adverse events. Two different outcomes related to glycemic control decrease were of primary interest: (1) the proportion of individuals within each treatment group achieving clinically significant HbA_1c reduction and (2) the mean amount decrease (in mg/dL or mmol/L) of postprandial glycemia (PPG) within each treatment group. Variations of fasting plasma glucose (FPG), HOMA index, lipid profile, insulin resistance, and inflammatory parameters that occurred during various trials were secondary outcomes of interest, as was the frequency of patients having one or more adverse events. The following data were abstracted onto standardized case report forms: authors; year of publication; country of study; source of funding; study goal; means of randomization and blinding; duration of treatment; treatment characteristics; sex; numbers of and reasons for study withdrawal; HbA_1c and age characteristics of the treatment and control groups; outcomes; and adverse event data. A validated, three-item scale was used to evaluate the overall reporting quality of the trials selected for inclusion in the present review. This scale provided scoring for randomization (0–2 points), double-blinding (0–2 points), and account for withdrawals (1 point). Scores ranged between 0 and 5, and scores of 3 indicated a study of high quality.²⁵ Study selection was restricted to randomized controlled trials to ensure the inclusion of only high-quality evidence.

Mechanism of Action and Route of Elimination

DPP-4 is a cell surface serine protease that selectively removes the N-terminal dipeptide from peptides with proline or alanine in the second position. DPP-4 has a major role in the differential or total inactivation of the neuropeptides NPY, PYY, and endomorphin-1 (YPWF-NH) and −2 (YPFF-NH) and an additional role in the inactivation of substance P and bradykinin. NPY is involved in the control of feeding energy homeostasis and blood pressure, whereas PYY is produced by endocrine cells of the small intestine and the colon and released after a meal as a peptide hormone circulating in the blood that inhibits several gastrointestinal functions such as gastric acid release. The most important action of DPP-4, however, is on circulating peptide hormones such as the incretins GLP-1 and glucose-dependent insulinotropic peptide, released in response to a meal.^26,27

DPP-4 inhibitors work to competitively inhibit the enzyme DPP-4; the inhibition of the DPP-4 enzyme prolongs and enhances the activity of incretins. However, recently published data suggested a negative feedback regulation of GLP-1 and glucose-dependent insulinotropic peptide secretion by DPP-4 inhibitors, involving sensing of intact, biologically active GLP-1: it seems that higher concentrations of intact, biologically active GLP-1 suppress L-cell secretion triggered by nutrients like oral glucose ingestion.²⁸

By preventing GLP-1 and glucose-dependent insulinotropic peptide inactivation, DPP-4 inhibitors are able to potentiate the secretion of insulin and suppress the release of glucagon by the pancreas. This drives blood glucose levels towards normal. As the blood glucose level approaches normal, the amounts of insulin released and glucagon suppressed diminish, thus tending to prevent an overshoot and subsequent low blood glucose (hypoglycemia), which is seen with some other oral hypoglycemic agents.

Elimination of sitagliptin and saxagliptin occurs primarily via renal excretion and involves active tubular secretion, whereas vildagliptin is mainly eliminated by liver metabolism, although a small proportion is eliminated unchanged by the kidney. With linagliptin, no dose adjustment is recommended for patients with kidney or liver impairment.

Clinical Recommendations

Sitagliptin is licensed at the recommended dose of 100 mg once daily either as monotherapy or in combination. As monotherapy, it is indicated in the United States as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus, whereas in the European Union, sitagliptin is indicated as monotherapy in patients who have inadequate glycemic control with diet and exercise and in whom metformin is inappropriate because of contraindications or intolerance. Sitagliptin is also indicated, both in the United States and in the European Union, in combination therapy with metformin, a sulfonylurea, or pioglitazone in patients who have inadequate control with these agents used as single agents plus diet and exercise. Recently, sitagliptin was also approved to be used in combination with insulin. 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 (Table 1).¹⁸ Vildagliptin, instead, is licensed at the recommended dose of 50 mg twice daily in combination with either metformin or pioglitazone and at the recommended dose of 50 mg once daily in combination with sulfonylureas in patients poorly controlled on the maximum doses of these drugs (Table 1).¹⁸ Saxagliptin, the last addition to the family of DPP-4 inhibitors, is administered at the recommended dose of 5 mg once daily in combination with metformin, or sulfonylureas or pioglitazone (Table 1).²⁹

Table 1.

Clinical Recommendations for Dipeptidyl Peptidase-4 Inhibitors

DPP-4 inhibitor	Dosage	Clinical recommendations
Sitagliptin	100 mg once daily	As an add-on therapy to:
		• metformin
		• sulfonylurea
		• pioglitazone
		• sulfonylurea plus metformin
		• pioglitazone plus metformin
		• as an add-on therapy to insulin
		As monotherapy (in the United States); as monotherapy^* (in the European Union)
Vildagliptin	50 mg twice daily; if combined with a sulfonylurea 50 mg once daily	As an add-on therapy to:
		• metformin
		• sulfonylurea^*
		• pioglitazone
Saxagliptin	5 mg once daily	As an add-on therapy to:
		• metformin
		• sulfonylurea^*
		• pioglitazone
Linagliptin	5 mg once daily	As an add-on therapy to:
		• metformin
		• sulfonylurea
		• pioglitazone
		As monotherapy^*

DPP-4, dipeptidyl peptidase-4.

In patients in whom metformin is inappropriate due to contraindications or intolerance.

Recently, in May 2011, another DPP-4 inhibitor, linagliptin, has been approved by the Food and Drug Administration as a monotherapy or in combination with other commonly prescribed medications for type 2 diabetes, such as metformin, sulfonylurea, and pioglitazone, at one dosage strength of 5 mg, once daily.³⁰ In contrast, alogliptin failed to gain Food and Drug Administration regulatory approval in 2009 because of insufficient data on cardiovascular risks, and it is currently under Food and Drug Administration evaluation after that Takeda, the company producing alogliptin, submitted new interim results from the EXAMINE (EXamination of CArdiovascular OutcoMes: AlogliptIN vs. Standard of CarE in Patients with Type 2 Diabetes Mellitus and Acute Coronary Syndrome) trial regarding cardiovascular safety.³¹

Adverse Events

Long-term effects of DPP-4 inhibitors on mortality and morbidity are so far inconclusive, although adverse effects, including nasopharyngitis (the common cold), headache, nausea, hypersensitivity, and skin reactions, have been observed in clinical studies. Other possible adverse effects, including hypersensitivity reactions and pancreatitis, have been reported.³² Although one in vitro study found that DPP-4 inhibitors, together with glucagon-like peptide-2, increased proliferation and migration of colon cancer cells, which might encourage cancer cells to metastasize,³³ carcinogenicity has not been confirmed in long-term, preclinical studies of the major DPP-4 inhibitors. Regarding vildagliptin, hepatic dysfunction has been noted in rare cases. This has led the European Medicines Agency to recommend liver function tests prior to initiation of treatment to establish the patient's baseline value. This should be followed by regular monitoring at 3-month intervals during the first year of treatment and periodically thereafter.

Comparison on Efficacy and Safety with Other Drugs

For a summary of all the following studies, see Tables 2 –5.

Table 2.

Summary of the Studies Involving Sitagliptin Cited in This Review

Study	Subjects (n)	Duration	Drugs involved	Aim	Results
Aschner et al.³⁴	1,050	6 months	Sitagliptin 100 mg once daily or metformin 1,000 mg twice daily	To compare the efficacy and safety of monotherapy with sitagliptin and metformin in treatment-naive patients with type 2 diabetes	Sitagliptin was noninferior to metformin in improving HbA_1c in treatment-naive patients with type 2 diabetes. Although both treatments were generally well tolerated, a lower incidence of gastrointestinal-related adverse experiences was observed with sitagliptin.
Reasner et al.³⁵	1,250	3.5 months	Sitagliptin/metformin 50/1,000 mg twice daily or metformin 1,000 mg twice daily	To compare the glycemic efficacy and safety of initial combination with the fixed-dose of sitagliptin and metformin versus metformin monotherapy in drug-naive patients with type 2 diabetes	Initial treatment with sitagliptin/metformin provided superior glycemic improvement with a similar degree of weight loss and lower incidences of abdominal pain and diarrhea.
Yoon et al.³⁶	520	6 months	Sitagliptin/pioglitazone 100/30 mg once daily versus pioglitazone 30 mg once daily	To assess the safety and efficacy of initial combination therapy with sitagliptin and pioglitazone compared with pioglitazone monotherapy in drug-naive patients with type 2 diabetes	Sitagliptin plus pioglitazone substantially improved glycemic control and was generally well tolerated compared with pioglitazone monotherapy.
Derosa et al.²¹	151	12 months	Sitagliptin/pioglitazone 100/30 mg once daily versus metformin/pioglitazone 850/15 mg twice daily.	To compare the effects of the addition of sitagliptin or metformin to pioglitazone monotherapy in poorly controlled type 2 diabetes mellitus patients	Both sitagliptin and metformin added to pioglitazone gave a similar improvement of HbA_1c, FPG, and PPG, but metformin led to a decrease of body weight and to a faster and better improvement of insulin resistance and inflammatory state parameters, even if sitagliptin produced a better protection of β-cell function.
Arechavaleta et al.³⁷	1,305	7.5 months	Sitagliptin 100 mg once daily versus glimepiride (starting dose 1 mg/day and up-titrated to a maximum dose of up to 6 mg/day) added to previously taken metformin	To evaluate the efficacy and safety of adding sitagliptin or glimepiride to the treatment regimen of patients with type 2 diabetes mellitus and inadequate glycemic control on metformin monotherapy	Addition of sitagliptin or glimepiride led to similar improvement in glycemic control after 30 weeks. Compared with glimepiride, sitagliptin was associated with a lower risk of hypoglycemia and with weight loss.
Seck et al.³⁸	1,172	24 months	Sitagliptin 100 mg or glipizide 5 mg/day (up-titrated up to 20 mg/day) added to previously taken metformin	To evaluate the 2-year safety and efficacy of adding sitagliptin or glipizide to ongoing metformin in patients with type 2 diabetes	Adding sitagliptin to metformin monotherapy improved glycemic control over 2 years, similar to the glucose-lowering efficacy observed with adding glipizide, but with greater durability and generally better maintenance of β-cell function.
Vilsbøll et al.³⁹	641	6 months	Sitagliptin 100 mg once daily or placebo added to previously taken insulin±metformin	To evaluate the efficacy and tolerability of sitagliptin when added to insulin therapy alone or in combination with metformin in patients with type 2 diabetes	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.
Pratley et al.⁴⁰	665	6.5 months	Liraglutide 1.2 mg or 1.8 mg once daily versus sitagliptin 100 mg once daily added to previously taken metformin	To assess the efficacy and safety of liraglutide versus sitagliptin, as adjunct treatments to metformin, in individuals with type 2 diabetes who did not achieve adequate glycemic control with metformin alone	Liraglutide was superior to sitagliptin for reduction of HbA_1c and was well tolerated with minimum risk of hypoglycemia.

FPG, fasting plasma glucose; HbA_1c, glycated hemoglobin; PPG, postprandial glycemia.

Table 3.

Summary of the Studies Involving Vildagliptin Cited in This Review

Study	Subjects (n)	Duration	Drugs involved	Aim	Results
Kikuchi et al.⁴¹	202	3 months	Vildagliptin 50 mg twice daily versus placebo added to a stable dose of glimepiride (≥1 mg/day)	To investigate the efficacy and tolerability of vildagliptin as add-on to glimepiride in patients with type 2 diabetes mellitus who were inadequately controlled	Vildagliptin is effective and well tolerated as an add-on to glimepiride in patients with type 2 diabetes mellitus.
Matthews et al.⁴²	3,118	24 months	Vildagliptin 50 mg twice daily versus glimepiride up to 6 mg/day added to previously taken metformin	To show that vildagliptin added to metformin is noninferior to glimepiride in reducing HbA_1c levels	Vildagliptin add-on has similar efficacy to glimepiride after 2 years of treatment, with markedly reduced hypoglycemia risk and no weight gain.
Derosa et al.²²	168	12 months	Pioglitazone 30 mg once a day plus vildagliptin 50 mg twice daily versus glimepiride 2 mg three times daily plus vildagliptin 50 mg twice daily	To compare the effects of vildagliptin added to pioglitazone or glimepiride on metabolic- and insulin resistance–related indices in poorly controlled type 2 diabetes patients.	Pioglitazone plus vildagliptin was found to be more effective in preserving β-cell function and in reducing insulin resistance and inflammatory state parameters.
Ferranini et al.⁴³	2,789	13 months	Vildagliptin 50 mg twice daily or glimepiride titrated up to 6 mg/day added to previously taken metformin	To examine the efficacy and safety of vildagliptin versus glimepiride as add-on therapy to metformin in patients with type 2 diabetes mellitus	Addition of vildagliptin provides comparable efficacy to that of glimepiride and displays a favorable adverse events profile, with no weight gain and a significant reduction in hypoglycemia compared with glimepiride.
Foley et al.⁴⁴	1,092	24 months	Vildagliptin 50 mg twice daily and gliclazide up to 320 mg/day	To evaluate the safety and efficacy of vildagliptin in the treatment of type 2 diabetes	The reductions in HbA_1c were similar over a 2-year period between vildagliptin and gliclazide, but vildagliptin had significant benefits in terms of less weight gain and less hypoglycemia.
Filozof et al.⁴⁵	1,007	13 months	Vildagliptin 50 mg twice daily or gliclazide up to 320 mg/day added to previously taken metformin	To demonstrate noninferiority of vildagliptin compared with gliclazide, as an add-on therapy, in patients with type 2 diabetes inadequately controlled with metformin	Addition of vildagliptin provided similar HbA_1c-lowering efficacy compared with gliclazide after 52 weeks of treatment. Vildagliptin-treated patients had fewer hypoglycemic events and did not gain weight.
Filozof et al.⁴⁶	914	6 months	Vildagliptin 100 mg or metformin (500 mg twice daily added to metformin 500 mg twice daily	To evaluate the efficacy and safety of the addition of vildagliptin to low-dose metformin and compare it with an up-titration of metformin in type 2 diabetes mellitus patients	Addition of vildagliptin 100 mg daily achieved larger HbA_1c reduction with fewer gastrointestinal events than with increasing the metformin dose.
Blonde et al.⁴⁷	2478	3 months	Vildagliptin 100 mg versus thiazolidinediones added on a stable dose of metformin (≥1,000 mg/day)	To assess the efficacy and tolerability of vildagliptin compared with thiazolidinediones as an add-on to metformin treatment in a primary care patient population with type 2 diabetes	Vildagliptin is as effective as thiazolidinediones after 3 months of treatment as an add-on to metformin in a primary care population that included diverse patient subgroups.
Rosenstock et al.⁴⁸	786	6 months	Vildagliptin 100 mg daily given as equally divided doses versus rosiglitazone 8 mg in a once daily dose	To compare the efficacy and tolerability of vildagliptin and rosiglitazone	Vildagliptin is an effective and well-tolerated treatment option in patients with type 2 diabetes, demonstrating similar glycemic reductions as rosiglitazone but without weight gain.

HbA_1c, glycated hemoglobin.

Table 4.

Summary of the Studies Involving Saxagliptin Cited in This Review

Study	Subjects (n)	Duration	Drugs involved	Aim	Results
Pfützner at al.⁴⁹ and Jadzinsky et al.⁵⁰	1,306	19 months	Saxagliptin/metformin 5/500 mg versus saxagliptin/metformin 10/500 mg versus saxagliptin 10 mg/placebo versus metformin 500 mg/placebo	To assess the efficacy and safety of saxagliptin + metformin initial combination therapy compared with saxagliptin or metformin alone in treatment-naive type 2 diabetes mellitus patients with inadequate glycemic control	Saxagliptin + metformin initial combination therapy was well tolerated and produced sustained glycemic control for up to 76 weeks, with greater improvements in glycemic parameters compared with either drug alone.
De Fronzo et al.⁵¹	743	6 months	Saxagliptin 2.5 mg once daily versus saxagliptin 5 mg once daily versus saxagliptin 10 mg once daily versus placebo all added to previously taken metformin	To assess the efficacy and safety of saxagliptin as add-on therapy in patients with type 2 diabetes with inadequate glycemic control with metformin alone	Saxagliptin once daily added to metformin therapy was generally well tolerated and led to statistically significant improvements in glycemic indexes versus placebo added to metformin in patients with type 2 diabetes inadequately controlled with metformin alone.
Goke et al.⁵²	858	13 months	Saxagliptin 5 mg once daily versus glipizide up-titrated as needed from 5 to 20 mg/day as add-on therapy to previously taken metformin	To assess the efficacy and safety of saxagliptin versus glipizide as add-on therapy to metformin in patients with type 2 diabetes mellitus and inadequate glycemic control on metformin alone	Saxagliptin plus metformin was well tolerated, provided a sustained HbA_1c reduction over 52 weeks, and was noninferior to glipizide plus metformin, with reduced body weight and a significantly lower risk of hypoglycemia.

HbA_1c, glycated hemoglobin.

Table 5.

Summary of the Studies Involving Linagliptin Cited in This Review

Study	Subjects (n)	Duration	Drugs involved	Aim	Results
Taskinen et al.⁵³	701	8 months	Linagliptin 5 mg once daily versus placebo added to previously taken metformin	To evaluate the efficacy and safety of linagliptin as add-on therapy to metformin in patients with type 2 diabetes with inadequate glycemic control	Addition of linagliptin resulted in a significant and clinically meaningful improvement in glycemic control without weight gain or increased risk of hypoglycemia.
Del Prato et al.⁵⁴	503	8 months	Linagliptin 5 mg versus placebo	To assess the safety and efficacy of linagliptin in patients with type 2 diabetes	Monotherapy with linagliptin produced a significant improvement in glycemic control, accompanied by enhanced parameters of β-cell function, with a safety profile comparable with placebo.
Gomis et al.⁵⁵	389	8 months	Pioglitazone 30 mg plus linagliptin 5 mg vs pioglitazone plus placebo once daily	To compare the efficacy, safety, and tolerability of linagliptin administered in combination with pioglitazone in patients with type 2 diabetes mellitus exhibiting insufficient glycemic control	Linagliptin plus pioglitazone was well tolerated and produced significant and clinically meaningful improvements in glycemic control.
Owens et al.⁵⁶	1,058	8 months	Linagliptin 5 mg once daily versus placebo added to previously taken metformin plus sulfonylurea	To examine the efficacy and safety of linagliptin in patients with type 2 diabetes mellitus inadequately controlled by metformin and sulfonylurea combination treatment	Adding linagliptin to metformin in combination with a sulfonylurea significantly improved glycemic control in patients with type 2 diabetes and was well tolerated.

Sitagliptin

Aschner et al.³⁴ administered sitagliptin 100 mg once daily or metformin 1,000 mg twice daily for 24 weeks. Metformin was up-titrated from 500 to 2,000 mg/day (or maximum tolerated daily dose ≥1,000 mg) over a period of 5 weeks. The mean HbA_1c change from baseline at week 24 was −0.43% in the sitagliptin group and −0.57% in the metformin group, with an estimated difference of 0.14%. FPG decrease from baseline was greater with metformin (−19.4 mg/dL) compared with sitagliptin (−11.5 mg/dL). Reductions in fasting insulin, fasting proinsulin, and the proinsulin/insulin ratio were observed in both groups, even if the reduction was larger in the metformin group. Both treatments produced similar increases in HOMA for β-cell function (HOMA-β) and reductions in HOMA-IR over 24 weeks. High-density lipoprotein cholesterol (HDL-C) was similarly improved with both treatments. Triglycerides (TGs) were slightly reduced from baseline with sitagliptin. Small increases in total cholesterol (TC) were observed for each group, with a slightly greater increase for sitagliptin; modest increases in low-density lipoprotein cholesterol (LDL-C) and non–HDL-C were also observed with sitagliptin, but not metformin, over 24 weeks. Both treatments were generally well tolerated over 24 weeks.

Reasner et al.³⁵ randomized patients to sitagliptin/metformin 50/500 mg twice daily or metformin 500 mg twice daily (up-titrated over 4 weeks to achieve maximum doses of sitagliptin/metformin of 50/1,000 mg twice daily or metformin 1,000 mg twice daily) for 18 weeks. At week 18, the mean HbA_1c change from baseline was −2.4% for sitagliptin/metformin and −1.8% for metformin monotherapy, with a significant between-group difference of −0.6% (P<0.001). At week 18, a significantly greater proportion of patients in the sitagliptin/metformin group had HbA_1c values <7.0% relative to the metformin monotherapy group (49.2% vs. 34.2%, respectively; P<0.001) or <6.5% (31.8% vs. 16.0%, respectively; P<0.001). At week 18, treatment with sitagliptin/metformin led to a significantly larger decrease from baseline in FPG (−3.8 mmol/L) compared with metformin monotherapy (−3.0 mmol/L), resulting in a significant between-group difference of 0.9 mmol/L (P<0.001). Significant improvements in measures of β-cell function were observed following treatment with sitagliptin/metformin compared with metformin monotherapy at week 18. Both treatments led to small reductions from baseline in insulin resistance as measured by HOMA-IR. At week 18, body weight change from baseline was −1.6 kg in both the sitagliptin/metformin and metformin monotherapy groups. The mean percentage changes from baseline in TC, HDL-C, TGs, and non–HDL-C were generally similar between the two groups, with the exception of a significantly greater between-group reduction in TGs seen with sitagliptin/metformin compared with metformin monotherapy (P=0.049). Both treatments were well tolerated.

Yoon at al.³⁶ evaluated initial combination therapy with sitagliptin 100 mg once daily and pioglitazone 30 mg once daily versus pioglitazone 30 mg once daily in monotherapy for 24 weeks. Initial combination therapy with sitagliptin and pioglitazone led to a reduction from baseline in HbA_1c at week 24 of −2.4% compared with −1.5% with initial pioglitazone monotherapy (between-group difference, P<0.001). The mean reduction from baseline in FPG at week 24 was significantly (P<0.001) greater in the combination therapy group compared with the pioglitazone monotherapy group, with meaningful FPG reductions observed in both treatment groups of −63.0 mg/dL (−3.5 mmol) and −40.2 mg/dL (−2.2 mmol), respectively. The fasting proinsulin/insulin ratio decreased in the combination therapy group; this decrease was numerically greater than that observed in the pioglitazone monotherapy group (P=0.056). A greater numerical increase of HOMA-β was observed in the combination therapy group, whereas HOMA-IR and the Quantitative Insulin Sensitivity Check Index (QUICKI) showed similar improvements in both treatment groups. The insulinogenic index also increased significantly in the combination therapy group compared with the pioglitazone monotherapy group (P≤0.001).

Derosa et al.²¹ conducted a study about sitagliptin where they compared sitagliptin/pioglitazone 100/30 mg once daily and metformin/pioglitazone 850/15 mg twice daily. After 12 months of treatment the addition of both sitagliptin or metformin to pioglitazone gave a similar improvement of HbA_1c, FPG, and PPG, but metformin led also to a greater decrease of body weight (P<0.05 vs. sitagliptin) and to a faster and better improvement of HOMA-IR, adiponectin, resistin, and inflammatory state parameters such as tumor necrosis factor-α (P<0.05 vs. sitagliptin for all), even if sitagliptin produced a faster improvement of HOMA-β.

Arechavaleta et al.³⁷ randomized patients to receive either sitagliptin 100 mg daily or glimepiride (starting dose of 1 mg/day and up-titrated, based upon each patient's self-monitoring of blood glucose results, to a maximum dose of up to 6 mg/day) as add-on therapy to a stable dose of metformin (≥1,500 mg/day) for 30 weeks. The mean change from baseline in HbA_1c at week 30 was −0.47% in the sitagliptin group and −0.54% in the glimepiride group, with a between group difference of 0.07%. Mean change from baseline in FPG at week 30 was −0.8 mmol/L in the sitagliptin group and −1.0 mmol/L in the glimepiride group, resulting in a between-group difference of 0.2. The mean percentage change from baseline for HDL-C was 4.4% in the sitagliptin group and 0.9% in the glimepiride group, resulting in a between-group difference of 3.5%. The median percentage change from baseline in TGs was −5.3% in the sitagliptin group and 2.1% in the glimepiride group, resulting in a between-group difference of −6.1%, also favoring sitagliptin. No meaningful between-group differences in TC, LDL-C, or non–HDL-C were observed. Glimepiride treatment was associated with a higher incidence of overall adverse experiences and drug-related adverse experiences compared with sitagliptin.

Seck et al.³⁸ enrolled patients who were taking a stable dose of metformin (≥1,500 mg/day) for at least 8 weeks in a double-blind manner and randomized them to receive either sitagliptin 100 mg once daily or glipizide 5 mg/day (up-titrated up to 20 mg/day based upon prespecified glycemic criteria) for 104 weeks. HbA_1c decreased by −0.33% in the sitagliptin group and −0.35% in the glipizide group. The FPG change from baseline at the end of the second year was similar between groups. Fasting insulin increased from baseline in the glipizide group, with no change observed in the sitagliptin group, resulting in a modest difference between groups. A decrease from baseline in fasting proinsulin and the proinsulin/insulin ratio at the end of the second year was observed in the sitagliptin group relative to the glipizide group. Improvements in HOMA-IR and QUICKI were observed with sitagliptin relative to glipizide at the end of the second year, suggesting a small decrease in insulin resistance associated with sitagliptin treatment. Measures of β-cell responsiveness postmeal remained stable relative to baseline in patients who had been treated with sitagliptin, whereas a reduction in responsiveness was observed in patients who had received glipizide.

Vilsbøll et al.³⁹ evaluated the efficacy and tolerability of sitagliptin 100 mg or placebo when added to insulin therapy alone or in combination with metformin in patients with type 2 diabetes. At week 24, the addition of sitagliptin to ongoing stable dose insulin therapy (±metformin) significantly (P<0.001) reduced HbA_1c by 0.6% from a baseline of 8.7% compared with no change from a baseline of 8.6% in the placebo group. The reduction from baseline in FPG at week 24 was significantly larger with sitagliptin compared with placebo.

Pratley et al.⁴⁰ treated participants already taking metformin (≥1,500 mg daily for ≥3 months) with 1.2 mg or 1.8 mg of subcutaneous liraglutide once daily or 100 mg of oral sitagliptin once daily. After 26 weeks, mean decreases in HbA_1c from baseline were −1.50% for 1.8 mg of liraglutide, −1.24% for 1.2 mg of liraglutide, and −0.90% for sitagliptin. After 26 weeks, mean decreases in FPG were −2.14 mmol/L for 1.8 mg of liraglutide, −1.87 mmol/L for 1.2 mg of liraglutide, and −0.83 mmol/L for sitagliptin. Also, mean weight loss was significantly greater with liraglutide: −3.38 kg for 1.8 mg of liraglutide, −2.86 kg for 1.2 mg of liraglutide, and −0.96 kg for sitagliptin. In assessment of β-cell function, both liraglutide doses were associated with significant improvements in HOMA-β, C-peptide concentration, and proinsulin/insulin ratio compared with sitagliptin, but no treatment-related differences were recorded for HOMA-IR or fasting insulin concentration.

Vildagliptin

Kikuchi et al.⁴¹ added vildagliptin 50 mg twice daily or placebo to a stable dose of glimepiride (≥1 mg/day). The mean change for HbA_1c was −1.0±0.06% in the vildagliptin group and −0.06±0.06% in patients receiving placebo. The between-treatment difference for HbA_1c was −0.95±0.08% (P<0.001). A significantly higher proportion of patients in the vildagliptin treatment group met the responder criteria of ≥0.5% reduction in HbA_1c (86.3% vs. 20.0%, respectively; P<0.001), and ≥1.0% reduction in HbA_1c (54.9% vs. 5.0%, respectively; P<0.001) compared with placebo. Target HbA_1c ≤6.5% was achieved by 45% of the patients in the vildagliptin treatment group and by 3.0% in the placebo group (P<0.001). FPG decreased rapidly in patients receiving vildagliptin (−20.9±2.8 mg/dL) with the maximum benefit achieved within the first 4 weeks after randomization, whereas it increased in the placebo group (+6.3±2.8 mg/dL, P<0.001 between treatments). During the treatment period, a small but statistically significant increase in weight with vildagliptin (+0.97±0.12 kg) compared with the placebo group (+0.06±0.12 kg) was noted (P<0.001). HOMA-β increased from baseline in the vildagliptin group (11.11±2.18), whereas it decreased in the placebo group (−1.30±2.18); the difference between the groups was significant (P<0.001). HOMA-IR decreased (−0.20±0.18) in the vildagliptin group, whereas it increased in the placebo group (0.22±0.18) without significant difference between the two treatments. The overall incidence of adverse events was similar across both treatment groups.

Matthews et al.⁴² randomized patients to receive vildagliptin (50 mg twice daily) or glimepiride (starting dose 2 mg/day titrated until a maximum of 6 mg/day) added to metformin. After week 24, pioglitazone could be prescribed if patients had reached the highest tolerated glimepiride dose and had an HbA_1c level >8.0%. Despite a similar decrease of HbA_1c by −0.1±0.0% and similar proportions of patients meeting an HbA_1c of <7% and ≤6.5% in both groups, significantly more patients reached the HbA_1c target of <7% without hypoglycemia in the vildagliptin group (36.0%) than in the glimepiride group (28.8%; P=0.004). FPG levels decreased to a similar extent by week 104 in both treatment groups (−0.5±0.1 mmol/L with vildagliptin and −0.7±0.1 mmol/L with glimepiride, respectively). Body weight decreased slightly with vildagliptin (−0.3±0.1 kg) but increased with glimepiride (+1.2±0.1 kg), with a between-group difference of 1.5±0.2 kg (P<0.001). Vildagliptin also had a modest beneficial effect on fasting lipid parameters, with significant between-group differences for TGs (P=0.039), non–HDL-C (P<0.001), and TC (P<0.001) levels. The fasting proinsulin/insulin ratio decreased from baseline to week 104 significantly more with vildagliptin than with glimepiride (−0.1±0.0 and −0.0±0.0, respectively; P=0.001), showing improved β-cell processing with vildagliptin. Insulin resistance, assessed using HOMA-IR, increased from baseline to week 104 significantly more with glimepiride (0.6±0.1) than with vildagliptin (0.1±0.1; P=0.01).

Ferranini et al.⁴³ enrolled patients receiving a stable dose of metformin (mean dose, 1,898 mg/day) and randomized them to receive vildagliptin 50 mg twice daily or glimepiride titrated up to 6 mg/day. At week 52, change in HbA_1c from baseline was −0.44±0.02% with vildagliptin and −0.53±0.02% with glimepiride, establishing noninferiority of vildagliptin. FPG decreased by a similar extent in both groups (−1.01±0.06 mmol/L with vildagliptin and −1.14±0.06 mmol/L with glimepiride). The overall incidence of confirmed hypoglycemia was nearly 10-fold lower in patients receiving vildagliptin. Body weight did not change during 52 weeks of treatment with vildagliptin (−0.23±0.11 kg) but increased with glimepiride (+1.56±0.12 kg); the mean between-group difference was statistically significant (P<0.001). All fasting lipid parameters—TGs, TC, non–HDL-C, and very LDL-C—improved with vildagliptin compared with glimepiride (P<0.01 for all).

Derosa et al.²² evaluated the effects of pioglitazone 30 mg once daily plus vildagliptin 50 mg twice daily compared with glimepiride 2 mg three times daily plus vildagliptin 50 mg twice daily. Both treatments gave a similar improvement of HbA_1c, FPG, and PPG without statistically significant differences between the two groups. Fasting plasma insulin and HOMA-IR after pioglitazone plus vildagliptin were significantly lower (P<0.05 for both), and the HOMA-β value was significantly higher (P<0.01) than the values obtained in the group treated with glimepiride plus vildagliptin after 12 months.

Foley et al.⁴⁴ compared the efficacy and safety of vildagliptin 50 mg twice daily with gliclazide in doses of up to 320 mg daily. Vildagliptin decreased HbA_1c from 8.6% to 7.3% within 12 weeks, and the result was maintained for another 52 weeks; by 104 weeks, HbA_1c had increased to 7.7%. In the gliclazide group, HbA_1c decreased to 7.1% from a baseline of 8.7% within 16 weeks and was more or less maintained for another 24 weeks; by 104 weeks, HbA_1c had increased to 7.7%. These changes from baseline to week 104 were significant for both groups. The FPG levels decreased by 0.2±0.2 mmol/L in the vildagliptin group and by 0.7±0.2 mmol/L in the gliclazide group, with a statistically significant between-group difference of 0.5 mmol/L (P<0.025). Fasting proinsulin decreased in the vildagliptin group (−2.6±1.3 pmol/L) and increased in the gliclazide group (6.0±1.3 pmol/L); the between-group difference was statistically significant (P<0.001). The fasting insulin tended to increase by 3.9±3.3 pmol/L in the vildagliptin group and by 15.8±3.3 pmol/L in the gliclazide group (P<0.001). The fasting proinsulin/insulin ratio decreased by 0.10±0.02 in the vildagliptin group and by 0.04±0.02 in the gliclazide group (P<0.01). HOMA-IR remained unchanged (0.0±0.3) in the vildagliptin group and increased in the gliclazide group by 0.7±0.3 (P<0.01). In the vildagliptin group, weight increased by 0.8±0.2 kg compared with 1.6±0.2 kg in the gliclazide group (P<0.01). Mild hypoglycemia was recorded in four patients (0.7%) in the vildagliptin group and 14 (1.7%) in the gliclazide group.

Similar results were obtained by Filozof and Gautier,⁴⁵ who demonstrated the noninferiority of vildagliptin, 50 mg twice daily, compared with gliclazide, up to 320 mg/day, as an add-on therapy to metformin ≥1,500 mg. They obtained a mean change of HbA_1c of −0.81±0.06% with vildagliptin and −0.85±0.06% with gliclazide. The difference of mean reduction in fasting proinsulin levels between the two treatment groups was statistically significant (P<0.001), with a slight decrease from baseline to end point in the vildagliptin group (−5.98 pmol/L) and an increase in the gliclazide group (2.03 pmol/L). The proinsulin/insulin ratio decreased in both treatment groups, but the decrease was greater with vildagliptin (P<0.001). Vildagliptin gave a small decrease in mean fasting insulin (−2.08 pmol/L) compared with gliclazide (+10.2 pmol/L) (P<0.001). Mean HOMA-IR decreased in both treatment groups, with larger changes with vildagliptin (−0.67 vs. −0.11; P=0.016). Body weight was maintained in the vildagliptin group, whereas an increase was observed in the gliclazide group (+0.08 vs. +1.36; P<0.001). Except for nasopharyngitis, frequency of common adverse events (headache, pain in extremity, asthenia, bronchitis, fatigue, tremor, and hyperhidrosis) was higher in the gliclazide group compared with the vildagliptin group. The total number of hypoglycemic events was nearly twice as high in the gliclazide group compared with the vildagliptin group.

In a study conducted by the same research group,⁴⁶ patients were randomized to receive vildagliptin 100 mg once daily and metformin 500 mg twice daily or metformin monotherapy up to 1,000 mg twice daily. In the vildagliptin/metformin group HbA_1c was consistently lower than in the metformin group at all study visits. The mean reductions in HbA_1c was −0.65±0.13% and −0.51±0.12% in the combination and monotherapy groups in patients with HbA_1c >8% at baseline and −0.46±0.03% and −0.31±0.03%, respectively, in patients with HbA_1c ≤8%. The proportion of patients achieving HbA_1c ≤6.5% was significantly higher in the combination group compared with the metformin monotherapy group (53.8% vs. 41.2%, respectively). The adjusted mean change from baseline in FPG was numerically higher in the vildagliptin/metformin group than in the metformin group (−0.77 mmol/L and −0.59 mmol/L, respectively). A reduction in body weight was observed in both treatment groups, but the change was significantly higher in the metformin group than in the combination group (−1.35 kg vs. −0.62 kg; P<0.001). The overall adverse events rate was comparable in patients receiving vildagliptin/metformin and metformin, even if fewer gastrointestinal events were recorded in the combination group.

The GALIANT study⁴⁷ compared vildagliptin 100 mg and thiazolidinediones (agent and dose at the investigators' discretion) as add-on therapy in patients inadequately controlled on a stable dose of metformin (≥1,000 mg/day). Change in HbA_1c was −0.68±0.02% with vildagliptin and −0.57±0.03% with thiazolidinediones; thus noninferiority for vildagliptin was established. In addition, statistical superiority of vildagliptin over thiazolidinediones as add-on therapy to metformin after a 3-month treatment was shown (P=0.001). Change in FPG was −1.01 mmol/L (−18.2 mg/dL) in the vildagliptin group and −1.37 mmol/L (−24.7 mg/dL) in thiazolidinediones group, and this difference was significant (P<0.001). Vildagliptin treatment was associated with a decrease in weight of −0.58 kg, whereas thiazolidinediones were associated with an increase of +0.33 kg (P<0.001 for the difference).

Similar results regarding the comparison between rosiglitazone and vildagliptin were recorded by Rosenstock et al.⁴⁸ In this study patients were randomized to vildagliptin 100 mg daily, given as equally divided doses, or rosiglitazone 8 mg daily, given as an once-daily dose. The adjusted mean change in HbA_1c was −1.1±0.1% (P<0.001) in patients receiving vildagliptin and −1.3±0.1% (P<0.001) in patients receiving rosiglitazone, proving the noninferiority of vildagliptin. The FPG reduction was −1.3±0.1 mmol/L (P<0.001) in patients receiving vildagliptin and −2.3±0.2 mmol/L (P<0.001) in patients receiving rosiglitazone (P<0.001 vs vildagliptin). Body weight did not change with vildagliptin but increased significantly during rosiglitazone monotherapy; the between-treatment difference was −1.9±0.3 kg (P<0.001). Compared with rosiglitazone, vildagliptin produced significant decreases in TGs (−9%, P=0.010), TC (−14%, P<0.001), LDL-C (−16%, P<0.001), and non-HDL-C (−16%, P<0.001) but less improvement in HDL-C (+4 vs. +9% from baseline, P=0.003 for between-group difference). Relative to rosiglitazone, vildagliptin decreased the TC to HDL-C ratio by 9.1±1.9% (P<0.0001). In patients receiving vildagliptin, the most frequent specific adverse events (≥4% in either group) were nasopharyngitis (6.8%), dizziness (6.0%), headache (5.0%), and upper respiratory tract infection (4.5%); in rosiglitazone-treated patients, the most common adverse events were nasopharyngitis (7.5%), headache (5.2%), dizziness (4.1%), and peripheral edema (4.1%).

Saxagliptin

Pfützner et al.⁴⁹ and Jadzinsky et al.⁵⁰ randomized patients to take saxagliptin/metformin 5/500 mg, saxagliptin/metformin 10/500 mg, 10 mg of saxagliptin/placebo, or 500 mg of metformin/placebo. Mean changes from baseline HbA_1c were −2.31% for saxagliptin/metformin 5/500 mg, −2.33% for saxagliptin/metformin 10/500 mg, −1.55% for saxagliptin 10 mg, and −1.79% for metformin 500 mg (P<0.0001 vs. metformin and saxagliptin monotherapies for saxagliptin/metformin 5/500 mg and saxagliptin/metformin 10/500 mg). A higher proportion of patients achieved an HbA_1c of <7% at week 76 with saxagliptin/metformin 5/500 mg and saxagliptin/metformin 10/500 mg than with either agent alone. Similarly, a higher proportion of patients achieved an HbA_1c of <6.5% at week 76 with saxagliptin/metformin 5/500 mg and saxagliptin/metformin 10/500 mg than with either agent alone. Regarding FPG, saxagliptin/metformin 5/500 mg and saxagliptin/metformin 10/500 mg groups had similar results (−54±2.6 and −55±2.6 mg/dL, respectively), whereas changes for the monotherapy groups were smaller (−24±3.0 mg/dL for saxagliptin 10 mg and −40±2.8 mg/dL for metformin 500 mg). Regarding PPG, mean decrease from baseline was −137±5.6 mg/dL with saxagliptin/metformin 5/500 mg, −129±5.9 mg/dL with saxagliptin/metformin 10/500 mg, −94±6.6 mg/dL with saxagliptin monotherapy, and −86±5.9 mg/dL with metformin/placebo. Changes with saxagliptin/metformin combination were greater than either monotherapy. Regarding body weight, small decreases were observed in all treatment groups, and also the safety profile was similar across treatment groups.

De Fronzo et al.⁵¹ added 2.5, 5, or 10 mg of saxagliptin or placebo to a stable dose of metformin (from 1,500 but not >2,550 mg/day). At week 24, treatment with saxagliptin led to clinically and statistically significant reductions in HbA_1c from baseline versus metformin/placebo. Differences from baseline versus placebo were −0.73% for the combination 2.5 mg of saxagliptin/metformin, −0.83% for the combination 5 mg of saxagliptin/metformin, and −0.72% for the combination 10 mg of saxagliptin/metformin, respectively (all P<0.0001). The percentage of patients achieving HbA_1c <7.0% was comparable for 5 and 10 mg of saxagliptin and higher than that for 2.5 mg of saxagliptin. A greater percentage of patients taking saxagliptin achieved HbA_1c <7.0% versus those taking metformin/placebo. The differences from metformin/placebo were 20.5% for the combination 2.5 mg of saxagliptin/metformin, 27.0% for the combination 5 mg of saxagliptin/metformin, and 27.9% for the combination 10 mg of saxagliptin/metformin, respectively (all P<0.0001). Statistically significant FPG reductions at week 24 were observed in all saxagliptin treatment groups versus the metformin/placebo group (P<0.0001). The early insulin response based on the insulinogenic index and the insulin sensitivity increased in all saxagliptin treatment groups at week 24. Regarding adverse events, the overall frequency of confirmed hypoglycemia during the 24-week treatment period was similar for saxagliptin-treated patients (0.5%) and metformin/placebo-treated patients (0.6%). No dose relationship was observed among the three saxagliptin groups.

Regarding the comparison between saxagliptin and sulfonylureas, Goke et al.⁵² compared saxagliptin 5 mg/day with glipizide up-titrated as needed from 5 to 20 mg/day as add-on therapy to metformin (≥1,500 mg/day). At 52 weeks, saxagliptin/metformin was noninferior to glipizide/metformin in lowering HbA_1c. The mean changes from baseline HbA_1c were −0.74% with saxagliptin/metformin and −0.80% glipizide/metformin, respectively; the between-group difference was 0.06%. The proportion of patients reporting one or more hypoglycemic event over 52 weeks was low in the saxagliptin/metformin group (3.0%) and was significantly lower compared with the glipizide/metformin group (36.3%) (difference vs. glipizide/metformin, P<0.0001). Regarding body weight, treatment with saxagliptin was associated with a mean change from baseline of −1.1 kg with saxagliptin and +1.1 kg with glipizide, respectively; the between-group difference was −2.2 kg (P<0.0001). There was a small rise per week in HbA_1c during weeks 24–52 in both treatment groups (mean changes per week, 0.001% for saxagliptin and 0.004% for glipizide). The rise per week was statistically significantly smaller with saxagliptin versus glipizide (−0.002% difference, P=0.04), indicating a more sustained effect on glycemic control beyond week 24. Numerical reductions in fasting proinsulin (mean difference vs. glipizide/metformin, −5.5±1.67) and numerically smaller increases in fasting glucagon (mean difference vs. glipizide/metformin, −4.9±1.88) were demonstrated for saxagliptin versus glipizide. Patients treated with glipizide/metformin had a greater mean increase in HOMA-2β (+21.7±2.56) versus saxagliptin/metformin (+7.4±2.54).

Linagliptin

Taskinen et al.⁵³ evaluated linagliptin 5 mg/day compared with placebo administered as add-on therapy to metformin ≥1,500 mg/day in patients with type 2 diabetes with inadequate glycemic control. Among patients with a baseline HbA_1c of ≥7.0%, 26% of individuals treated with linagliptin versus 9% of those in the placebo group achieved the HbA_1c target of <7.0% at 24 weeks (P=0.0001). A significant difference was also seen with regard to reaching a target of <6.5% for those with a baseline HbA_1c of ≥6.5% (10% with linagliptin vs. 2% with placebo; P=0.0016). Similarly, 50% of those treated with linagliptin compared with 22% of the placebo group achieved a reduction in HbA_1c of ≥0.5% at 24 weeks (P<0.0001). More than twice as many patients in the placebo group compared with those receiving linagliptin required rescue medication (19% vs. 8%, respectively; associated odds ratio 0.28; P=0.0001). Finally, neither group was associated with any significant change in mean body weight from baseline to week 24 (−0.5 kg for placebo vs. −0.4 kg for linagliptin). Linagliptin was well tolerated, and the safety assessment revealed no trends of clinical relevance.

A similar study was conducted by Del Prato et al.,⁵⁴ who administered linagliptin 5 mg/day or placebo to patients with type 2 diabetes who were either treatment-naive or who had received one oral antidiabetes drug. The geometric mean trough plasma concentrations of linagliptin remained constant over time: 6.4 and 6.5 nmol/L at weeks 12 and 24, respectively. Median DPP-4 inhibition at these time points was 84.2% and 82.8%, respectively. There was no difference in the mean linagliptin trough levels over time between patients with normal renal function and those with mild or moderate renal impairment: 8.0±7.3, 8.0±7.6, and 6.6±1.8 nmol/L, respectively. Adjusted mean differences of the changes in HbA_1c, FPG, and PPG between baseline and week 24 significantly favored linagliptin over placebo. The adjusted mean difference in the change in HbA_1c comparing linagliptin and placebo was −0.69% (P<0.0001). Linagliptin treatment resulted in a greater reduction of FPG (adjusted mean change, −1.3 mmol/L; P<0.0001) and PPG (adjusted mean change, −3.2 mmol/L; P<0.0001) compared with placebo after 24 weeks. The improvement in glycemic control achieved with linagliptin was associated with enhancement of markers of β-cell function, such as proinsulin/insulin ratio and HOMA-β. Twice as many patients in the placebo arm required rescue therapy than patients randomized to linagliptin (20.9% vs. 10.2%, respectively; P=0.0002). The percentage of patients with a baseline HbA_1c of ≥7.0% who achieved HbA1c <7.0% after 24 weeks of treatment with linagliptin was 25.2% (77/306) compared with 11.6% (17/147) in the placebo group (P=0.0006). Linagliptin monotherapy was well tolerated during the 24 weeks of treatment.

Gomis et al.⁵⁵ compared the initial combination of pioglitazone 30 mg plus linagliptin 5 mg or placebo. HbA_1c change from baseline was −1.06±0.06% for linagliptin plus pioglitazone compared with −0.56±0.09% for placebo plus pioglitazone; the difference was significant (P<0.0001). After 24 weeks of treatment, 42.9% of patients in the linagliptin plus pioglitazone group and 30.5% in the placebo plus pioglitazone group achieved HbA_1c <7.0% (P=0.0051). After 24 weeks of treatment, FPG change in the linagliptin plus pioglitazone group was −1.8±0.1 mmol/L compared with −1.0±0.2 mmol/L for placebo plus pioglitazone with a between-group difference of −0.8 mmol/L (P<0.0001). At week 24, the ratio of relative change in adjusted geometric mean HOMA-IR showed a difference for linagliptin plus pioglitazone versus placebo plus pioglitazone of 0.85 (P=0.0076). By week 24, mean weight had increased in both groups, but the adjusted mean change was greater with linagliptin plus pioglitazone (2.3 kg) than with placebo plus pioglitazone (1.2 kg) with a 1.1 kg difference (P=0.014). The proportion of patients who experienced at least one adverse event was similar in both groups.

Owens et al.⁵⁶ randomized patients to linagliptin 5 mg once daily or placebo added to metformin plus sulfonylurea. Linagliptin was superior to placebo in reducing HbA_1c and FPG (P<0.0001). The proportion of participants achieving a reduction in HbA_1c of ≥6 mmol/mol (≥0.5%) was 58.2% with linagliptin and 30.2% with placebo. After 24 weeks, HOMA-β decreased in the placebo group by 9.1±4.3 (mU/L)/(mmol/L) compared with an increase in the linagliptin group of 7.8±2.5 (mU/L)/(mmol/L) with a treatment difference between of 16.9 (mU/L)/(mmol/L) (P=0.0008). The adjusted mean change in HOMA-IR was −0.06 (mU/L)×(mmol/L) with linagliptin and −0.74 (mU/L)×(mmol/L) with placebo, with a treatment difference of 0.7 (mU/L)×(mmol/L) (P=0.018). Generally, treatment with linagliptin in combination with metformin and sulfonylurea was well tolerated, and no new safety concerns arose in this trial.

Sitagliptin versus vildagliptin

Marfella et al.⁵⁷ compared sitagliptin 100 mg once daily versus vildagliptin 50 mg twice daily on daily blood glucose fluctuations in patients with type 2 diabetes inadequately controlled by metformin. Decreases in HbA_1c, FPG, and PPG were almost similar in the two groups after 3 months of both sitagliptin and vildagliptin treatments, whereas the mean amplitude of glycemic excursions (MAGE) decreased significantly along with the vildagliptin group. Indeed, continuous subcutaneous glucose monitoring measurements provided evidence for large MAGE decrements in the vildagliptin group compared with the sitagliptin group (P<0.01). Focusing on hormone profiles during standard meal and interprandial periods, the increase in GLP-1 after food intake was substantially identical in the two groups, whereas a significant (P<0.05) and sustained increase during the interprandial period of active GLP-1 in the vildagliptin-treated group toward sitagliptin occurred. In addition, plasma glucagon levels were more suppressed during the interprandial period in subjects receiving vildagliptin compared with those receiving sitagliptin, but such differences did not reach statistical significance during the postprandial period. Finally, both postmeal and interprandial plasma insulin level reductions were similar in the two groups.

Sitagliptin versus saxagliptin

Scheen et al.⁵⁸ randomized 801 adult with type 2 diabetes mellitus on stable metformin doses (1,500–3,000 mg/day) to add-on 5 mg of saxagliptin or 100 mg of sitagliptin once daily for 18 weeks. The addition of saxagliptin or sitagliptin to metformin therapy produced similar decreases in mean HbA_1c from baseline to week 18: −0.52% with saxagliptin and −0.62% with sitagliptin. The proportion of patients achieving therapeutic HbA_1c ≤6.5% was similar between the two groups: 26.3% for saxagliptin plus metformin compared with 29.1% with sitagliptin plus metformin. Adding saxagliptin or sitagliptin to metformin therapy produced changes in FPG of −0.60 mmol/L (−10.8 mg/dL) and −0.90 mmol/L (−16.2 mg/dL), respectively, without any apparent differences between treatment groups for the changes from baseline in fasting insulin, glucagon, proinsulin, or C-peptide. Similarly, the small improvement in β-cell function, as measured by the change from baseline in HOMA-β, did not differ between the two treatments. The safety profile of the combination of saxagliptin plus metformin was similar to that of sitagliptin plus metformin.

Conclusions

According to a previously published review about DPP-4 inhibitors,⁵⁹ we observed that once metformin fails to maintain glycemic control, addition of DPP-4 inhibitors should be the logical choice because they seems to lower HbA_1c levels by 0.6–0.9 percentage points and to have a comparable effect on HbA_1c versus the addition of a sulfonylurea or glitazone. Other than giving an improvement of glycemic control, DPP-4 inhibitors seem to have other positive effects: they give an improvement of lipid profile^35,37,42,43 and have a positive effect on β-cell function, giving a greater durability of β-cells compared with sulfonylureas.³⁸ Unlike thiazolidinediones and sulfonylureas, which usually give a little weight gain, DPP-4 also seem to be neutral^42,43,45,48 or to reduce body weight.^35,37 Other than that, DPP-4 inhibitors seem to be well tolerated. Unlike metformin, they do not give gastrointestinal-related adverse events; the addition of vildagliptin to metformin proved to achieve larger HbA_1c reduction with fewer gastrointestinal events than with increasing the metformin dose.⁴⁶ Because of their positive effects on β-cell function, DPP-4 inhibitors are particularly indicated in relatively young patients, with a long life expectancy: whereas sulfonylureas increase HOMA-2β and proinsulin,⁵² DPP-4 inhibitors reduce them, granting a longer survival of β-cells.²² Furthermore, DPP-4 inhibitors prevent the risk of hypoglycemia posed by sulfonylureas.^37,42,43,45 Hypoglycemia is defined by a glucose level of ≤70 mg/dL (3.9 mmol/L), although in someone with diabetes, hypoglycemic symptoms can sometimes occur at higher glucose levels or may fail to occur at lower. Hypoglycemia can be mild, recognized easily by the patient, and reversed with a small amount of carbohydrates eaten or drunk, or it may be severe enough to cause unconsciousness requiring intravenous dextrose or an injection of glucagon. It is rare, but possible, for hypoglycemia to result in brain damage or death: an estimated 2–4% of deaths of people with type 1 diabetes mellitus have been attributed to hypoglycemia.^60,61 Individuals with type 2 diabetes mellitus who experienced severe hypoglycemia were more likely to have heart attacks, strokes, eye problems, and kidney damage and die than those who did not have an episode.⁶² From the evidence that DPP-4 inhibitors prevent the risk of hypoglycemia, they should be preferred to sulfonylureas, especially in older people where hypoglycemia is more frequent, as recently reported both about sitagliptin⁶³ and vildagliptin.⁶⁴ Regarding the differences among the various DPP-4 inhibitors, they share the same mechanism of action and the same effects on glycemic control: sitagliptin and vildagliptin gave a similar decrease in HbA_1c, FPG, and PPG,⁵⁷ and so do sitagliptin and saxagliptin.⁵⁸ Compared with sitagliptin, however, vildagliptin proved to give a larger decrement in MAGE.⁵⁸

From all the data reported, we can safely conclude that DPP-4 inhibitors seem to be safe and to have a comparable effect on HbA_1c compared with sulfonylurea or thiazolidinediones. They should be the logical choice when metformin fails to achieve glycemic control in both young and older patients.

Footnotes

Author Disclosure Statement

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the article. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was used in the production of this manuscript.

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