Sitagliptin

Sitagliptin for Type 2 diabetes: a 2015 update

Maria Lee1 and Mary K Rhee*2
1Emory University School of Medicine, Medicine/Endocrinology,
1303 Woodruff Memorial Research Building,101 Woodruff Circle, Suite 1303, Atlanta, GA 30322, USA
2Medicine/Endocrinology,
Emory University School of Medicine, Atlanta VA Medical Center,

Sitagliptin, a dipeptidyl peptidase 4 inhibitor, was the first in its class to receive approval from the US FDA in 2006 for the treatment of Type 2 diabetes mellitus. It has been evaluated in numerous clinical trials and has several attractive features as an antidiabetic agent, including a low risk for hypoglycemia, a neutral effect on weight, and an ability to be used in chronic kidney disease and more. This article provides an up-to-date discussion of the pharmacokinetics/pharmacodynamics, clinical efficacy, safety and tolerability of sitagliptin.

KEYWORDS: diabetes mellitus . dipeptidyl peptidase 4 inhibitor . incretin-based therapy . sitagliptin . Type 2 diabetes

1670 Clairmont Road, Decatur, GA 30033, USA
*Author for correspondence: Tel.: +1 404 321 6111; ext 2080
[email protected]

Type 2 diabetes mellitus, a metabolic disorder in which patients develop hyperglycemia due to defects in insulin secretion or action and relative hyperglucagonemia [1], has become an unmitigated global epidemic. It affects 9.3% of the US population, of which 28% are undi- agnosed [2], leads to substantial morbidity and mortality, and incurs significant healthcare costs. Diabetes significantly increases the risk for vascular complications, both microvascular (neuropathy, nephropathy and retinopathy) and macrovascular (coronary artery disease, cerebrovascular disease and peripheral arterial disease), and is currently the seventh leading cause of death in the USA [2].
Landmark trials [3–6] have shown that inten- sive glycemic control in individuals newly diag- nosed with diabetes significantly reduces microvascular and macrovascular complications, compared with conventional glycemic control. Consequently, drug development for diabetes therapy has focused primarily on improving gly- cemic control, resulting in a surge of new dia- betic medications over the past 10 years, which promote glucose control and, more recently, weight loss as well. Despite the growing number of diabetes treatment options, the available
drugs have yet to demonstrate efficacy in delay- ing or arresting the progressive decline of b cell function (insulin secretory ability) associated
with the natural history of the disease.
Until recently, standard pharmacologic treatment options for diabetes had been lim- ited to those with associated adverse effects of weight gain and hypoglycemia risk, and

include insulin, sulfonylureas, thiazolidine- diones, and meglitinides. But in 2005, exena- tide, the first glucagon like peptide-1 (GLP-1) mimetic was introduced, followed 1 year later by sitagliptin, the first dipeptidyl peptidase-4 (DPP-4) inhibitor. Both of these incretin- based classes of therapies showed promising safety and efficacy profiles, while also provid- ing benefits of either weight loss (GLP-1 mim- etics) or weight neutrality (DPP-4 inhibitors). The introduction of these therapies launched a new era in diabetes drug development, which previously targeted glycemic control alone with the goal of reducing complication risk, to one which also includes improvement in – or at least not exacerbation of – obesity, a major diabetes risk factor.
GLP-1 mimetics and DPP-4 inhibitors belong to the incretin-based class of medica- tions. Incretins are peptides produced in the gut that lead to glucose-lowering. GLP-1 is generated by the cleavage of proglucagon by prohormone convertase 1 in the L-cells found in the distal ileum and colon, and is secreted in response to meals, dietary glucose and lipids and parasympathetic stimulation. The actions of GLP-1 are mediated by binding to the GLP-1 receptor, a G protein coupled receptor found in pancreatic islets [7], cardiac tissue, the hypothalamus, and the gastrointestinal tract [8]. In the pancreatic islets, GLP-1 directly stimu- lates both glucose-dependent insulin secretion
and synthesis in b cells [8,9] and secretion of somatostatin, which subsequently inhibits glu- cagon secretion from a cells; these

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complementary actions reduce circulating glucose levels in a glucose-dependent fashion. In the gastrointestinal system, GLP-1 inhibits gastric emptying and gastric acid secretion by direct mechanisms in the stomach and indirectly via the vagal nerve and the central nervous system. Through pathways, which have not yet been fully elucidated and which involve the activation of GLP-1 receptors in the brain, including the hypo- thalamus, GLP-1 has been shown to promote satiety and inhibit appetite. The resulting modification of eating behavior in conjunction with slowed gastric motility and consequent gas- tric distention have been associated with weight loss [8]. In the heart, GLP-1 has been shown to increase inotropy and glucose uptake [10] and appears to have myocardial protective effects [11].
GLP-1 has a very short plasma half-life of less than
2 min due to its rapid degradation by DPP-4, an enzyme expressed throughout the body [7]. Inhibitors of DPP-4 reduce metabolism of GLP-1, and lead to increased circulating endogenous GLP-1 levels. Sitagliptin, the first DPP-4 inhibitor on the market, was approved in 2006 for use in Type 2 diabetes, either alone or in combination with
metformin or a PPARg agonist [12]. The purpose of this review is to provide an up-to-date overview of sitagliptin’s
clinical profile, including trials on safety and efficacy, and its role in special populations.

Pharmacodynamics
The chemical structure of sitagliptin (sitagliptin phosphate mono- hydrate, MK-0431) is 7-[(3R)-3-amino-1-oxo-4-(2,4,5- trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-1,2, 4-triazolo[4,3-a]pyrazine phosphate (1:1) monohydrate or C16H15F6N5O.H3PO4.H2O.

F
F

involved in cancer biology, disease pathogenesis and immune responses [14].
In 70 healthy males randomized to eight different treatment doses of sitagliptin versus placebo for 10 days, a dose-related inhibition of plasma DPP-4 activity was observed over the dose range of 25–600 mg. Plasma DPP-4 activity was significantly inhibited at all doses compared with placebo. Doses of 50 mg or higher were associated with inhibition of DPP-4 activity over 24 h, which was 80% or greater than that of placebo, and GLP-1 concentrations increased by two- to threefold with all doses of sitagliptin compared with placebo. On day 10 of the study, glucose, insulin, C-peptide, and glucagon levels mea- sured 4, 10 and 24 h after study drug administration were unchanged, which confirms the glucose-dependent mechanism by which GLP-1 lowers glucose levels such that in the setting of normal circulating glucose levels, sitagliptin did not cause hypoglycemia [15].
Similarly, in patients with Type 2 diabetes not treated with antidiabetic agents and randomized to sitagliptin 25 mg, sita- gliptin 200 mg or placebo [16], sitagliptin dose-dependently inhibited plasma DPP-4 activity by 80% or greater over 24 h (25 mg: 80% 2 h post dose, 47% 24 h post dose; 200 mg:
96% 2 h post dose, 80% 24 h post dose), enhanced active GLP-1 levels by twofold or higher, increased insulin and C-peptide, decreased glucagon and decreased glycemic excur- sion after oral glucose tolerance test (200 mg, 18% reduction; 25 mg, 9% reduction) [16].

Pharmacokinetics
Sitagliptin has a relatively high bioavailability of 87% after oral ingestion, and 38% circulates bound to proteins. Its half-life is
12.4 h allowing for once daily dosing. Sitagliptin does not undergo extensive metabolism (79% excreted unchanged), and is primarily excreted renally (87%) via active tubular secretion and glomerular filtration with the remainder excreted fecally. Its pharmacokinetics is not affected by food, age, sex or obe- sity [17]. Sitagliptin does not inhibit CYP isozymes CYP3A4,

N • H PO

• H O

2C8, 2C9, 2D6, 1A2, 2C19, or 2B6 and does not induce

CF3

3 4 2

[13]

CYP3A4; therefore, it is unlikely to interact with other drugs that utilize these pathways. (See TABLE 1 for a summary of its pharmacokinetic properties.)

As a DPP-4 inhibitor, sitagliptin prevents the metabolism of GLP-1, allowing prolongation of its half-life and elevation of its plasma levels, leading to sustained effects of endoge- nous GLP-1 – increased insulin levels, decreased glucagon secretion, and overall enhanced tissue glucose uptake and decreased hepatic glucose production. Because GLP-1 action occurs in a glucose-dependent manner, sitagliptin carries a low risk for hypoglycemia in contrast to agents like sulfony- lureas, meglitinides and insulin. Sitagliptin is selective for DPP-4 and in vitro does not inhibit the activity of related peptidases, DPP-8 or DPP-9, at concentrations close to ther- apeutic doses. While the clinical importance of this selectivity is not known, evidence suggests that DDP-8 and DPP-9 are

Clinical efficacy
Since its approval by the US FDA in 2006, numerous clinical trials have been conducted to examine the efficacy and safety of sitagliptin, either as monotherapy or add-on therapy, compared with placebo or active comparator. Study subjects included adults aged 18–75 years with Type 2 diabetes and baseline A1c ranging from approximately 6.5–10%. Outcomes included reduction in A1c, fasting plasma glucose, 2 h postprandial glu- cose, proportion of patients achieving A1c <6.5 or 7.0%, and insulin resistance measured by homeostatic model assessment (HOMA). The trials discussed below include Phase III studies as well as more recent post-marketing trials conducted within the past few years. Sitagliptin versus placebo Sitagliptin monotherapy versus placebo Two large Phase III, multinational, randomized, double-blind placebo-controlled studies examined the efficacy and safety of sitagliptin (100 and 200 mg) versus placebo in uncontrolled Type 2 diabetes with mean baseline A1c levels of approxi- mately 8% (TABLE 2). Both doses of sitagliptin led to significant placebo-subtracted A1c reductions (0.79 and 0.94% for 100 and 200 mg, respectively, after 24 weeks [18], and 0.60 and 0.48% for 100 and 200 mg, respectively, after 18 weeks [19]). Similarly, in the sitagliptin groups, both fasting and 2 h postprandial glucose levels fell significantly compared with placebo – a greater fall in fasting glucose levels by 18.0– 19.8 mg/dl with sitagliptin 100 mg and by 16.2–21.6 mg/dl with sitagliptin 200 mg [18,19] compared with placebo; and greater fall in postprandial glucose levels by 46.8 mg/dl with sitagliptin 100 mg and by 52.3 mg/dl with sitagliptin 200 mg compared with placebo. Sitagliptin versus placebo as add-on therapy Two randomized, double-blind, placebo-controlled trials (Phase III, multinational, n = 701; and postmarketing, Japa- nese, n = 149) compared sitagliptin (up to 100 mg daily) with placebo as add-on therapy to metformin in patients with mean baseline A1c 8.0–8.3% [20,21] (TABLE 3). Sitagliptin significantly reduced A1c levels, compared with placebo, by 0.65% after 24 weeks and by 0.7% after 12 weeks, which was associated with significant reductions in fasting plasma glucose (—25.2 mg/dl [20] and —18.0 mg/dl [21]) and 2 h postprandial glucose —50.4 mg/dl [20] and —46.8 mg/dl [21]). The 12-week study was followed by a 40-week open label period during which all patients received sitagliptin. At 52 weeks, 36.2% of patients who started on placebo and switched to sitagliptin achieved A1c <6.9%, similar to the 37.5% of patients who took sitagliptin throughout the study period [21]. Sitagliptin as add-on therapy to pioglitazone was evaluated in another Phase III, multinational, randomized, double-blind, placebo-controlled study in which 353 patients with mean baseline A1c 8.0–8.1% were randomized to sitagliptin 100 mg daily or placebo for 24 weeks (TABLE 3). Compared with placebo, the sitagliptin group had a significantly greater A1c reduction by 0.70% and fasting plasma glucose reduction by 17.7 mg/dl, and was more likely to achieve A1c <7.0% (45.5% sitagliptin vs 23.0% placebo) [22]. To determine the benefit of sitagliptin 100 mg when added to insulin, a 24-week, postmarketing, multinational, random- ized, double-blind, placebo-controlled study was conducted in 641 patients treated with insulin alone or in combination with metformin (TABLE 3). The patients had baseline A1c of approxi- mately 8.7%, and had been receiving ongoing long-acting, intermediate-acting, or premixed insulin; 71 and 73% of the sitagliptin and placebo groups, respectively, were also treated with metformin. The sitagliptin group had a significantly greater A1c reduction of 0.6% relative to placebo and a larger percentage of patients reaching A1c <7% (13 vs 5% in placebo). They also had significantly greater reductions in fast- ing plasma glucose (—15.0 mg/dl) and 2 h postprandial glucose (—36.1 mg/dl) relative to placebo [23]. Sitagliptin versus oral active comparators A summary of randomized studies investigating the efficacy of sitagliptin versus active comparators is shown in TABLE 4. In 1772 patients already treated with metformin, comparison between the addition of sitagliptin 100 mg daily versus glipi- zide 5–20 mg daily (a sulfonylurea), on glycemic control was performed in a multinational, randomized, double-blind, active-controlled, non-inferiority study. The patients had a mean A1c of 7.5% at baseline. After 52 weeks, A1c fell by 0.67% in both groups, and similar proportions in each group achieved A1c <7% (sitagliptin 63%, glipizide 59%; difference of 3.9%; 95% CI: —2.8 to 10.7) [24], confirming non- inferiority of sitagliptin compared with glipizide. A similar comparative effectiveness study was conducted to evaluate the efficacy of sitagliptin 100 mg daily versus pioglita- zone 30 mg daily (a thiazolidinedione) as add-on therapy to metformin and sulfonylurea. In this 24-week randomized study in 119 Taiwanese patients with mean baseline A1c of approxi- mately 8.4%, A1c reduction was similar in both intervention groups (pioglitazone, —0.94%; sitagliptin, —0.71%; p = 0.16), as was the proportion of patients achieving A1c <7%. Table 2. Efficacy of sitagliptin as monotherapy versus placebo in adults with uncontrolled Type 2 diabetes mellitus. Study (year) (duration) Treatment (mg) [# of patients] A1c levels (%) Change from baseline Fasting plasma glucose (mg/dl) Change from baseline Patients achieving A1c <7% (%) Ref. Aschner et al. (2006) Sita 100 [238] –0.61 [8.01] –12.6 [171.2] 41 [18] (24 weeks) Sita 200 [250] –0.76 [8.08] –16.2 [174.8] 45 Placebo [253] 0.18 [8.03] 5.4 [176.6] 17 Raz et al. (2006) Sita 100 [205] –0.48 [8.04] –12.6 [180.2] 35.8 [19] (18 weeks) Sita 200 [206] –0.36 [8.14] –10.8 [183.8] 28.6 Placebo [110] 0.12 [8.05] 7.2 [183.8] 15.5 Mohan et al. (2009) Sita 100 [352] –0.7 [8.7] –25.2 [189.2] 20.6 [67] (18 weeks) Placebo [178] 0.3 [8.7] 5.4 [189.2] 5.3 Nonaka et al. (2008) Sita 100 [75] –0.65 [7.54] –22.5 [164.0] 58.1 [68] (12 weeks) Placebo [76] 0.41 [7.69] 9.4 [164.0] 14.5 Least squares mean change from baseline are presented. mg/dl × 0.0555 = mmol/l Sita: Sitagliptin. However, pioglitazone treatment led to a greater decrease in fasting plasma glucose than sitagliptin (—35.7 and —22.8 mg/ dl, respectively; p 0.02), as well as a significant reduction in insulin resistance, as measured by HOMA, which was not observed with sitagliptin (—1.56 vs 0.00; p = 0.002) [25]. The addition of sitagliptin versus canagliflozin (a sodium- glucose co-transporter 2 inhibitor, the newest class of diabetes medications added to the market) to metformin alone or met- formin plus sulfonylurea was examined in two large Phase III, multinational, randomized, double-blind studies. In the first study, 1284 patients with mean baseline A1c of approximately 8.0% were randomized to canagliflozin 100 or 300 mg, sita- gliptin 100 mg or placebo daily for 26 weeks, followed by a 26-week period in which the placebo group was switched to sitagliptin. At week 26, both doses of canagliflozin significantly reduced A1c relative to placebo (0.62 and 0.77%); sitagliptin reduced A1c by 0.66% (no statistical analysis was performed). By week 52, the effect of canagliflozin 300 mg was superior to Table 3. Efficacy of sitagliptin versus placebo as add-on therapy in adults with uncontrolled Type 2 diabetes mellitus. Study (year) (duration) Treatment (mg) [# of patients] A1c levels (%) Change from baseline Fasting plasma glucose (mg/dl) Change from baseline Patients achieving A1c <7% (%) Ref. Charbonnel et al. Sita 100 + Metf [453] –0.67 [7.96] –16.2 [169.4] 47 [20] (2006) Placebo + Metf [224] –0.02 [8.03] 9.0 [173.0] 18.3 (24 weeks) Kadowaki et al. Sita 50 + Metf [76] –0.4 [8.1] –10.8 [149.6] 17.1 [21] (2013) Placebo + Metf [71] 0.3 [8.3] 7.2 [160.4] 4.4 (12 weeks blind S/S + Metf [64] –0.8 [8.0] –10.8 [142.3] 37.5 period) P/S + Metf [58] –0.9 [8.1] –18.0 [151.4] 36.2 (52 week open label) Rosenstock et al. Sita 100 + Pio [175] –0.85 [8.05] –16.8 [168.3] 45.4 [22] (2006) Placebo + Pio [178] –0.15 [8.0] 1.1 [165.6] 23.0 (24 weeks) Vilsboll et al. Sita 100 + Insulin ± Metf 305 –0.6 [8.7] –18.6 [175.9] 13 [23] (2010) Placebo + Insulin ± Metf 312 0.0 [8.6] –3.4 [179.1] 5 (24 weeks) Least squares mean change from baseline are presented. mg/dl × 0.0555 = mmol/l Metf: Metformin; P/S: Patients initially on placebo who switched to sitagliptin after 12 weeks; Pio: Pioglitazone; S/S: Patients initially on sitagliptin who continued on sitagliptin; Sita: Sitagliptin. Table 4. Efficacy of sitagliptin versus oral active comparators as add-on therapy in adults with uncontrolled Type 2 diabetes mellitus. Study (duration) Treatment (mg) [# of patients] A1c levels (%) Change from baseline Fasting plasma glucose (mg/dl) Change from baseline Patients achieving A1c <7% (%) Ref. Nauck et al. (2007) Sita 100 + Metf [588] –0.67 [7.5] – 10.1 [157.7] 63 [24] (52 weeks) Glip + Metf [584] –0.67 [7.5] – 7.6 [159.3] 59 Lavalle- Sita 100 + Metf [354] –0.73 [7.9] –18.0 [169.4] 50.6 [26] Gonzalez et al. Cana 100 + Metf [368] –0.73 [7.9] –27.0 [169.4] 41.4 (2013) Cana 300 + Metf [367] –0.88 [8.0] –36.0 [173.0] 54.7 (52 weeks) Schernthaner et al. Sita 100 + Metf + Sulf –0.66 [8.1] –5.4 [164.0] 47.6 [27] (2013) [378] –1.03 [8.1] –30.6 [169.4] 35.3 (52 weeks) Cana 300 + Metf + Sulf [377] Liu et al. (2013) Sita 100 + –0.71 [8.27] –22.9 [176.6] 28.3 [25] (24 weeks) Metf + Sulf [60] –0.94 [8.54] –35.7 [182.0] 28.8 Pio + Metf + Sulf [59] Ferrannini et al. Sita 100 + Metf [56] –0.40 [8.03] –16.0 [178.4] 36.8 [28] (2013) Empa +/- Metf [547] –0.34 to –0.63 –21.1 to -32.1 27.0–44.6 (78 weeks) Metf [56] [7.9–8.0] [176.6–182.0] 31.0 –0.56 [8.2] –25.9 [176.6] Li et al. (2014) Sita 100 + –1.1 [8.5] –27.0 [147.7] 59 [29] (24 weeks) Metf + oral [61] –1.2 [8.9] –32.4 [151.4] 59 Saxa + Metf + oral [66] –1.3 [8.8] –43.2 [158.6] 65 Vilda + Metf + oral [63] that of sitagliptin with a 0.15% (95% CI: —0.27 to —0.03) greater reduction in A1c [26]. The second trial [27], which included 755 patients with mean baseline A1c 8.1%, who were randomized to canagliflozin 300 mg or sitagliptin 100 mg daily for 52 weeks, confirmed the findings that canagliflozin led to a significantly greater improvement in A1c levels compared with sitagliptin (—1.03% canagliflozin vs —0.66% sitagliptin, respec- tively). Moreover, more patients achieved A1c <7.0% and <6.5% with canagliflozin compared with sitagliptin [27]. When compared with a different SGLT2 inhibitor, empagliflozin (10 and 25 mg daily), with or without metformin in a multi- national, Phase IIb, randomized, open-label extension study [28], the sitagliptin plus metformin group had a comparable reduc- tion in A1c levels as the empagliflozin groups (—0.34 to —0.63% empagliflozin vs —0.40% with sitagliptin) after 12 weeks. Since sitagliptin became available for use in diabetes, several other DPP-4 inhibitors have received FDA approval. To evalu- ate for potential differences in efficacy between these related drugs, a randomized, open-label clinical study in 207 patients in China compared sitagliptin, saxagliptin and vildagliptin as add-on therapy to metformin plus a second oral antidiabetic agent (glimepiride, acarbose, or pioglitazone). After 24 weeks of treatment, all groups saw significant reductions in A1c (—1.2% saxagliptin, —1.3% vildagliptin and —1.1% sitagliptin, respectively) from mean baseline A1c of 8.72%, in fasting blood glucose (—32.4 mg/dl saxagliptin, —43.2 mg/dl vilda- gliptin, —27.0 mg/dl sitagliptin) and in 2 h post-prandial glu- cose (—61.3 mg/dl saxagliptin, —66.7 mg/dl vildagliptin, —57.7 mg/dl sitagliptin). Reductions in A1c and 2 h post- prandial glucose levels were similar among the groups, but fast- ing plasma glucose decreased the most with vildagliptin and the least with sitagliptin (difference of 17.1 mg/dl (95% CI: 11.5, 22.7) [29]. Sitagliptin versus injectable active comparators, including insulin While both GLP-1 mimetics and DPP4 inhibitors are incretin- based therapies, their mechanisms of action are distinct, which has prompted evaluation for differences in efficacy in glycemic control. Two randomized studies compared sitagliptin versus liraglutide, a GLP-1 agonist, as add-on therapy to sulfonyl- urea [30] or to metformin [31] (TABLE 5). When added to a sulfo- nylurea in a cohort of 99 Japanese patients with mean baseline A1c of approximately 7.8%, liraglutide (0.9 mg daily) was asso- ciated with a significantly greater reduction in A1c levels Table 5. Efficacy of sitagliptin versus injectable comparator; as add-on to insulin in adults with uncontrolled Type 2 diabetes mellitus. Study (year) (duration) Treatment (mg) [# of patients] A1c levels (%) Change from baseline Fasting plasma glucose (mg/dl) Change from baseline Patients achieving A1c <7% (%) Ref. Yokoyama et al. (2014) Sita 50–100 + Sulf [49] –0.24 [7.9] 0.5 [145.9] 26.3 [30] (24 weeks) Lira + Sulf [50] –0.59 [7.7] –21.1 [142.3] 39.5 Charbonnel et al. Sita 100 + Metf [269] –1.3 [8.2] –34.2 [174.8] 62.8 [31] (2013) Lira + Metf [253] –1.4 [8.1] –39.6 [173.0] 72.3 (26 weeks) Aschner et al. (2012) Sita 100 + Metf [265] –1.13% [8.5] Not specified 42% [32] (24 weeks) Insulin glargine + Metf [250] –1.72% [8.5] 68% Katsuno et al. (2013) Sita 50 + premix insulin –0.51 [8.1] Not specified [33] (12 weeks) BID [45] –0.28 [8.2] Sita 50 + multiple –0.83 [8.0] insulin [15] Sita 50 + basal insulin + orals [11] Least squares mean change from baseline are presented. mg/dl x 0.0555 = mmol/l. Basal insulin + orals: Basal daily insulin + orals (sulfonylureas, a-glucosidase inhibitors, and/or metformin); Cana: Canagliflozin; Glip: Glipizide; Insulin: Insulin; Lira: Liraglutide; Metf: Metformin; Multiple insulin: Multiple daily insulin; Pio: Pioglitazone; Premix insulin BID: Premixed insulin twice a day; Sita: Sitagliptin; SU: Sulfonylurea. throughout the 24-week intervention period, compared with sitagliptin (50 mg titrated to 100 mg daily as needed per pro- tocol; week 12, —0.78% liraglutide vs —0.24% sitagliptin; p < 0.0001) with some attenuation of effect by week 24 (—0.59% liraglutide vs —0.24% sitagliptin; p = 0.0525). Fasting plasma glucose also decreased significantly in the lira- glutide group but not in the sitagliptin group [30]. In contrast, in a 26-week multinational study [31] comparing liraglutide (0.6–1.2 mg daily) and sitagliptin (100 mg daily) as add-on therapy to metformin in 653 patients with mean baseline A1c 8.2%, a similar A1c reduction was found (A1c change —1.3% liraglutide vs —1.4% sitagliptin; difference: 0.1%; 95% CI: —0.1 to 0.2), suggesting that sitagliptin was non-inferior to liraglutide [31]. The general approach to diabetes treatment after patients have sequentially failed additional oral agents is to add or switch to insulin therapy, with the underlying principle that the natural history of Type 2 diabetes is a gradual and progres- sive decline in b cell function, with a consequent decline in the ability to adequately secrete insulin in response to hyperglyce- mia. However, evidence suggests that in the early stages, the decline in insulin secretion with diabetes progression may be primarily due to a loss of glucose-stimulated insulin secretion, whereas the b cell response to other stimuli, such as GLP-1, may remain intact. Studies that have investigated the efficacy of sitagliptin in patients with a moderate duration of diabetes and who are failing oral therapies or already taking insulin may provide an indirect method of addressing this issue. In a ran- domized, open-label trial [32], 515 patients already treated with metformin and with baseline A1c 7–11% were randomized to either insulin glargine or sitagliptin 100 mg daily. A1c reduc- tion was greater for patients on insulin glargine (—1.72%) compared with sitagliptin (—1.13%) with a mean difference of 0.59% (p < 0.0001), suggesting that sitagliptin may not be sufficient once significant loss of b cell function has occurred. A prospective non-randomized clinical study in Japan evaluated sitagliptin as add-on therapy in 71 patients taking insulin alone or insulin combined with oral hypoglycemic agents for 12 weeks [33] (TABLE 5). The patients, who had an average diabetes duration of 18.1 years, were divided into three groups – premixed insu- lin twice a day, multiple daily insulin injections or basal insulin plus oral hypoglycemic medications, which mostly included sul- fonylureas, a-glucosidase inhibitors and metformin. With pre- intervention A1c levels averaging 8.1%, the A1c change after adding sitagliptin in patients on multiple daily insulin injec- tions was —0.28%, twice daily insulin injections —0.51%, and basal insulin plus oral agents —0.83%. These findings show a lower magnitude of improvement in patients with long- standing diabetes who are already requiring more intensive insulin treatment, an indicator of greater progression in the natural history of diabetes, which support the results of the pre- vious study suggesting that the efficacy of sitagliptin may wane as b cell function fails. Safety & tolerability The safety and tolerability of sitagliptin are discussed below and summarized in TABLE 6. Hypoglycemia Because DPP-4 inhibitors, such as sitagliptin generally stimu- late insulin secretion in a glucose-dependent manner, hypogly- cemia poses a minor risk when sitagliptin is used as monotherapy or in combination with other agents that are not known to cause hypoglycemia. When given as monotherapy or Table 6. Safety/tolerability of sitagliptin in patients with Type 2 diabetes mellitus. Study (year) (duration) Treatment (mg) [# of patients] Hypoglycemia incidence (%) Weight change (kg) GI side effects incidence (%) Ref. Aschner et al. (2006) Sita 100 [238] 1.3 –0.2 16.4 [18] (24 weeks) Sita 200 [250] 0.8 –0.1 16.4 Placebo [253] 0.8 –1.1 11.5 Charbonnel et al. (2006) Sita 100 + Metf [453] 1.3 –0.6 to –0.7 11.9 [20] (24 weeks) Placebo + Metf [224] 2.1 –0.6 to –0.7 10.5 Rosenstock et al. (2006) Sita 100 + Pio [175] 1.1 +1.8 13.7 [22] (24 weeks) Placebo + Pio [178] 0.0 +1.5 6.2 Vilsboll et al. (2010) Sita 100 + Insulin ± Metf [305] 16†8† +0.1 [23] (24 weeks) Placebo + Insulin ± Metf [312] +0.1 Nauck et al. (2007) Sita 100 + Metf [588] 4.9 –1.5 20.4 [24] (52 weeks) Glip + Metf [584] 32.0 +1.1 19.3 Schernthaner et al. (2013) Sita 100 + Metf + Sulf [378] 40.7 +0.1 None reported [27] (52 weeks) Cana 300 + Metf + Sulf [377] 43.2 –2.3 None reported Yokoyama et al. (2014) (24 weeks) Sita 50–100 + Sulf [49] Lira + Sulf [50] 10.2‡ 18.0‡ +0.29 –0.60 None reported None reported [30] as add-on to metformin [20,21] or pioglitazone [22], sitagliptin was associated with a low incidence of hypoglycemia (~1.0%), which was similar to that observed with placebo. In two active comparator trials, fewer patients on sitagliptin experienced hypoglycemia compared with glipizide (5 vs 32%) [24] or cana- gliflozin (4.1 vs 6.8%) [26] when each were evaluated as add-on therapy to metformin. When comparing sitagliptin and canagli- flozin as add-on therapy to metformin and sulfonylurea, no sig- nificant difference in hypoglycemia was noted [27]; similar findings were observed when comparing pioglitazone and sita- gliptin as add-on therapies [25]. However, when sitagliptin is taken in conjunction with hypoglycemic agents, such as insulin, sulfonylureas [34], or meglitinides, higher rates of hypoglycemic episodes were observed when compared with sitagliptin monotherapy or as add-on to metformin. Patients taking sitagliptin as add-on to insulin, with or without metformin had higher rates of hypo- glycemia (16%) compared with placebo as add-on (8%) [23]. Interestingly, when sitagliptin was evaluated as add-on therapy to various insulin regimens in a different study, there were no episodes of severe hypoglycemia; however, mild or moderate hypoglycemia was not addressed [33]. One active comparator trial in which sitagliptin did have significantly higher rates of symptomatic hypoglycemia was in comparison with liraglutide as add-on to metformin (12.0 vs 4.0%, respec- tively) [31]. Weight gain Unlike metformin and GLP-1 mimetics, both of which can promote mild weight loss, and pioglitazone, insulin, megliti- nides, and sulfonylureas, which can produce weight gain, DPP-4 inhibitors generally have a weight neutral effect. Body weight did not change significantly in patients taking sitagliptin monotherapy versus placebo [18,19] or in sitagliptin versus pla- cebo as add-on to insulin ± metformin [23]. On background metformin, sitagliptin showed a similar weight reduction as placebo (0.6–0.7 kg) [20,21]. On background pioglitazone, sita- gliptin showed a similar weight increase as placebo (1.8 kg sita- gliptin versus 1.5 kg placebo, difference of 0.2 kg; 95% CI: —0.5 to 1.0) [22]. When used as add-on therapy to metformin, sitagliptin patients lost 1.5 kg, whereas glipizide patients gained 1.1 kg [24]. Canagliflozin produced greater weight reductions than sitagliptin in two studies (canagliflozin 100 mg, —3.3 kg; canagliflozin 300 mg, —3.7 kg; sitagliptin —1.2 kg; p < 0.001 for both doses of canagliflozin compared with sita- gliptin [26]; and canagliflozin 300 mg, —2.3 kg vs sitagliptin, +0.1 kg; p < 0.001 [27]). On background metformin and sulfo- nylurea, patients randomized to pioglitazone gained 1.6 kg more on average than those in the sitagliptin group [25]. Changes in body weight in patients on sitagliptin versus liraglu- tide on background sulfonylurea were not significant compared with baseline and not significantly different from each other either [30]. Gastrointestinal side effects Overall incidence of any gastrointestinal side effects, including abdominal pain, nausea, vomiting, and diarrhea, ranged from 1.3 to 20.4%, and was similar in those on sitagliptin compared with placebo [19–21,24]. Gastrointestinal events were more com- mon in sitagliptin compared with pioglitazone (20.0% sitaglip- tin vs 6.8%) [25] but less common compared with liraglutide (10.7% sitagliptin vs 32.7%) [31]. In a pooled analysis of 10,246 patients, there was no significant difference between the sitagliptin group and non-exposed group in rates of diarrhea (after removing confounding effects of metformin), nausea or vomiting, or abdominal pain, but the incidence of constipation was higher with sitagliptin (2.6 vs 1.9%) [34], although not clin- ically significant. Pancreatitis/pancreatic cancer As a result of 88 reported post-marketing cases of acute pancre- atitis in patients on sitagliptin [35], the FDA announced in Sep- tember 2009 that they would insert information regarding acute pancreatitis into the prescribing information for sitaglip- tin and sitagliptin/metformin. A case–control study of 1269 hospitalized acute pancreatitis cases compared with con- trols found that use of GLP-1-based therapies (exenatide or sitagliptin) within 30 days had an odds ratio for pancreatitis of 2.24, while use for 30 days to 2 years had an odds ratio of 2.01, both of which were significant increases [36]. However, there is risk of bias in the observational studies, including insufficient accounting of confounding variables, methodologi- cal shortcomings, and limited power [37]. A systematic review and meta-analysis of 55 randomized studies and five observational studies evaluated pancreatitis in patients with Type 2 diabetes treated with GLP-1 mimetics or DPP-4 inhibitors compared with placebo, lifestyle modifica- tion, or other antidiabetic agents. Pooled analysis showed that pancreatitis was not significantly increased with incretin therapy compared with control (odds ratio 1.11; 95% CI: 0.57–2.17) [37], even when subgrouped by GLP-1 agonist or DPP-4 inhibi- tor. In a retrospective cohort study of 5560 patients comparing sitagliptin to glargine, there were no reported episodes of pan- creatitis [38]. Another retrospective study evaluating exenatide or sitagliptin versus control demonstrated no increased risk (haz- ard ratio 1.0) for acute pancreatitis in the sitagliptin group [39]. In February 2014, the FDA released an article outlining their comprehensive evaluation of pancreatitis and pancreatic cancer and their relation to incretin-based therapies [40]. Included in their review were numerous studies of healthy ani- mals and diabetic rodents on incretin therapies that showed no findings of pancreatic toxic effects or pancreatic tumors. They also reviewed data from more than 200 trials, including more than 28,000 patients who had taken an incretin-based drug. A pooled analysis of data from 25 clinical trials in the sitaglip- tin database provided no compelling evidence of increased risk of pancreatitis or pancreatic cancer. Safety data was reviewed from two randomized cardiovascular outcome trials involving thousands of diabetic patients taking incretin-based therapy, the Saxagliptin Assessment of Vascular Outcomes Recorded (SAVOR) trial and the Examination of Cardiovascular Out- comes with Alogliptin versus Standard of Care (EXAMINE) trial. Both trials had few and similar numbers of cases of acute pancreatitis (SAVOR: 22 drug, 16 placebo; EXAMINE: 12 drug, 8 placebo) and few or zero cases of pancreatic cancer (SAVOR: 5 drug, 12 placebo; EXAMINE: 0 both groups). According to the FDA, “a causal association between incretin- based drugs and pancreatitis or pancreatic cancer [.. .] is incon- sistent with the current data” [40]. Allergic/hypersensitivity reactions Postmarketing reports of anaphylaxis, angioedema, and Steven– Johnson syndrome appear in prescribing information of most DPP-4 inhibitors, including that of sitagliptin. However, in a pooled analysis of about 10,200 patients, the incidence of angioedema while on an ACE inhibitor was similar in the sita- gliptin group versus the non-exposed group. The higher rates of skin-related disorders in the sitagliptin group were due to slightly increased rates of contact dermatitis (0.7 vs 0.3 events per 100 patient-years), macular rash (0.3 vs 0.1) and acne (0.2 vs 0.0) [34]. Infections The enzyme DPP-4 is known to regulate T cell activation; one in vitro study showed that inhibition of DPP-4 as well as ami- nopeptidase N resulted in suppression of inflammatory immune responses [41]. Consequently, there may be a theoreti- cal concern for increased infections with DPP-4 inhibitors used in the clinical setting. In a pooled analysis, bronchitis, cellulitis, gastroenteritis, influenza, nasopharyngitis, pharyngitis, sinusitis, upper respiratory infection, urinary tract infection and viral infection all occurred with similar frequency in the sitagliptin and non-exposed groups [34]. Sitagliptin & cardiovascular disease Given the increased risk for cardiovascular disease (CVD) in diabetes, it is particularly important that new therapies for dia- betes not only avoid further exacerbation of risk for cardiovas- cular disease but also provide benefit in reducing incident CVD events. The development of both Type 2 diabetes and CVD are associated with increased levels of inflammation, as indicated by elevated levels of inflammatory molecules, such as interleukin (IL)-1, IL-6, IL-18, C-reactive protein, fibrinogen, cell-adhesion molecules and tumor necrosis factor-a, and it is thought that reducing these inflammatory levels may be associ- ated with a reduction in CVD risk. Studies with sitagliptin have shown associated reductions in markers of inflammation, suggesting potential beneficial effects on CVD outcomes. In a small study of 36 subjects with Type 2 diabetes randomized to sitagliptin or placebo for 6 weeks, those in the sitagliptin group had significantly reduced levels of C-reactive protein (CRP; rel- ative reduction of 44.9%), IL-6 (24.7% relative reduction), IL-18 (7.3% relative reduction), secreted phospholipase- A2 (12.9% relative reduction), soluble intercellular adhesion molecule-1 (5.3% relative reduction), and E-selectin (5.9% rel- ative reduction), compared with placebo [42]. These findings were corroborated in a similar study of 40 Japanese patients with known coronary artery disease (CAD) and uncontrolled diabetes who were assigned to either sitagliptin 50 mg daily or aggressive conventional control for 6 months, in which the sita- gliptin group had a significant decrease in CRP levels, com- pared with the control group [43]. The results of such studies suggest that sitagliptin likely would not increase the risk for CVD based on pathophysiological mechanisms involving inflammation, and may even be beneficial in lowering CVD risk. Studies that have focused on more clinically relevant endpoints in patients taking sitagliptin have shown no increased risk for car- diovascular outcomes overall. In a retrospective cohort study of 72,738 patients with Type 2 diabetes, 11% of whom had used sitagliptin at some point during the study, patients who had taken sitagliptin had similar risk as non-sitagliptin users for all-cause mortality, all-cause hospital admissions, and cardiovascular-related hospital admissions [44]. These findings were supported in a pooled analysis of data from 25 randomized studies with 14,611 patients randomized to sitagliptin or a com- parator, with focus on the incidence of major adverse cardiovas- cular events (MACE), including ischemic events and cardiovascular deaths [45]. There was no difference in rate of MACE between sitagliptin and non-sitagliptin exposed groups or between sitagliptin and placebo, indicating that sitagliptin is not associated with increased cardiovascular risk in patients with Type 2 diabetes [45]. While longer term prospective studies are needed, some observational findings suggest that sitagliptin might have pro- tective effects with regard to cardiovascular disease. A retrospective analysis of 445 diabetic patients hospitalized for acute coronary syndrome in Israel categorized patients into three groups according to antidiabetic agents taken before admission: sitagliptin (monotherapy or in combination with any other oral hypoglycemics); metformin (monotherapy or in combination with other orals, excluding sitagliptin); and other oral hypoglycemics. Patients in the sitagliptin group were found to have significantly lower in-hospital complication rate (e.g. post MI angina, re-infarction, pulmonary edema, etc.; 9.7% sitagliptin vs 24.4% metformin vs 45.5% other), lower rate of 30-day MACE (12.9% sitagliptin vs 31.6% metformin, 48.5% other), and shorter hospital stay compared with the other treat- ment groups (5.4 days sitagliptin vs 5.6 metformin vs 6.5 other) [46]. In a prospective randomized study in 76 Japanese patients with stable CAD and newly diagnosed impaired glucose toler- ance or mild Type 2 diabetes, the effect of sitagliptin 100 mg daily was compared with placebo on carotid IMT, as a measure of CVD [47]. While the sitagliptin group did not have signifi- cant regression in their IMT, they did have significantly less progression compared with controls. Incidence of cardiovascular events was similar between the two groups [47]. Additional information on the effect of sitagliptin on IMT is anticipated after the completion of the PROLOGUE trial, an ongoing randomized controlled study in Japan evaluating differences in carotid IMT between sitagliptin versus conventional treatment without DPP-4 inhibitors, GLP-1 analogs or insulin, after 12 and 24 months of treatment [48]. Despite these promising results, conflicting findings regard- ing sitagliptin on cardiovascular safety have been reported. A Taiwanese retrospective analysis of the cardiovascular safety and efficacy of sitagliptin in patients with Type 2 diabetes and chronic kidney disease after acute myocardial infarction (MI) found increased cardiovascular outcomes. In 205 subjects who took sitagliptin and 820 matched controls, the sitagliptin group had similar risks of ischemic stroke, all-cause mortality, or hos- pitalization for heart failure compared with the non-sitagliptin group, but a higher risk of recurrent MI (HR 1.73; p = 0.008) and percutaneous coronary revascularization (HR 1.43; p = 0.026) [49]. Moreover, in a retrospective analysis of 8288 matched pairs (sitagliptin vs never exposed to sitagliptin) of Taiwanese patients over 1.5 years, a greater number of patients treated with sitagliptin reached the outcome of a first hospitalization for heart failure compared with controls (339 vs 275, HR 1.21; p = 0.017), with no significant difference in all-cause mortality [50]. These findings may suggest a class effect given findings of increased hospitalization rate for heart failure with saxagliptin, another DPP-4 inhibitor [51]. Currently, a multinational randomized trial, Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), is under- way to evaluate the effect of sitagliptin versus placebo as add-on therapy to existing antidiabetic agents on cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina [52]. The study investigators plan to enroll approximately 14,000 patients, ages 50 years or older, with known Type 2 diabetes, cardiovascular disease, and A1c 6.5– 8.0%. TECOS is expected to be completed this year, when defin- itive data about sitagliptin and its effect on cardiovascular disease is anticipated. In addition, the TRUST study will be performed in six centers of Japan, with plans to recruit stable coronary artery disease patients with Type 2 diabetes, who have undergone suc- cessful percutaneous coronary intervention. They will be ran- domized to sitagliptin or control for 48 weeks to compare the primary endpoint of percentage change in plaque volume mea- sured by intravascular ultrasound [53]. Sitagliptin in special populations The use of sitagliptin in special scenarios is discussed in this section, with focus on patients with chronic kidney disease or end stage renal disease (ESRD) on dialysis, patients with non- alcoholic fatty liver disease (NAFLD), and the elderly. Also dis- cussed is the inpatient use of sitagliptin in hospitalized medical or surgical patients. Sitagliptin in chronic kidney disease There were two large 54-week randomized studies comparing sitagliptin to glipizide in patients with uncontrolled Type 2 diabetes, chronic renal dysfunction, and mean baseline A1c of approximately 7.9%. In 426 patients with moderate–severe chronic kidney disease, who were randomized to renally dosed sitagliptin or glipizide, sitagliptin was noninfe- rior to glipizide with an A1c reduction of 0.8 versus 0.6%, respectively (difference of 0.11%; 95% CI: —0.29 to 0.06). Both drugs were generally well tolerated, but sitagliptin had sig- nificantly lower symptomatic hypoglycemia (6.2% sitagliptin vs 17.0% glipizide; p = 0.001) and was associated with a decrease in body weight compared with an increase seen with glipizide (—0.6 kg sitagliptin vs 1.2 kg glipizide; p < 0.001) [54]. In another trial that enrolled 129 patients with ESRD, random- ized to sitagliptin 25 mg daily or glipizide, A1c again improved to a comparable degree between the two groups (—0.72% sita- gliptin vs —0.87% glipizide; a difference of 0.15%; 95% CI: 0.18–0.49%). While the incidence of symptomatic hypoglyce- mia was similar (6.3% sitagliptin vs 10.8% glipizide; difference of —4.8%; 95% CI: —15.7 to 5.6%), the incidence of severe hypoglycemia was significantly lower with sitagliptin than with glipizide (0 vs 7.7%, respectively; difference of —7.8%; 95% CI: —17.1 to —1.9). Both medications were otherwise generally well tolerated in these patients with ESRD [55]. Sitagliptin in NAFLD A case–control study retrospectively evaluated patients with both Type 2 diabetes and NAFLD, comparing those who were treated with sitagliptin 50 mg daily (cases, n = 20) versus those treated with diet and exercise alone (controls, n = 20) for 48 weeks. Fasting plasma glucose, A1c, AST and ALT levels were measured at baseline and every 12 months after initiation of treatment. The sitagliptin group had a decrease in their A1c levels by 0.7%, which was significantly greater than that observed in the controls. All patients treated with sitagliptin tolerated the drug; there were no sitagliptin-related adverse effects that required dose reduction or drug cessation and no significant changes in AST or ALT. These findings are sup- ported by the liver’s limited role in the metabolism of sitaglip- tin, as opposed to most oral hypoglycemic agents. Moreover, sitagliptin appears to be low risk in exacerbating the chronic liver damage seen in NAFLD [56]. Sitagliptin in the inpatient setting A pilot, multicenter, open-label, randomized study investigated the safety and efficacy of sitagliptin for the inpatient manage- ment of 90 general medicine and surgery patients with Type 2 diabetes. These patients had baseline A1c levels of 7.8–8.4% and were randomized to sitagliptin, sitagliptin plus glargine, or to basal-bolus insulin (glargine and lispro) during their hospitalization. All groups also received supplemental lis- pro before meals and at bedtime as needed for elevated glu- cose levels per protocol. After the first day of treatment, improvement in blood glucose levels was similar in all three groups and included no significant differences in mean daily blood glucose, number of glucose readings in the 70–140 mg/ dl range, number of glucose readings >200 mg/dl, or number of treatment failures, length of stay, or incidence of hypoglycemia [57].

Sitagliptin in the elderly
Few studies have examined the use of sitagliptin in the elderly population. A post hoc pooled analysis was performed of 25 ran- domized, double blind studies that examined the incidence of adverse events in elderly diabetic patients (65 years or older),
who were randomized to sitagliptin 100 mg daily (n = 1261) or a comparator (n = 1185) for 12 weeks to 2 years. Overall adverse events were similar between the two groups, but death
and drug-related adverse events were more common in the ‘non-exposed’ group (comparator or placebo). Hypoglycemia was less frequent in the sitagliptin group compared with the non-exposed group (7.0 vs 14.3 per 100 patient-years), largely due to higher incidence of sulfonylurea use in the non-exposed group [58].

Sitagliptin in the real world
Sitagliptin has shown efficacy in randomized controlled trials, but is it effective in real life? A retrospective review of 3081 Taiwanese patients taking sitagliptin, with mean baseline A1c 9.0% and no history of insulin therapy [59] demonstrated reduction of A1c by 0.96% at 3 months, 0.96% at 6 months and sustained reduction at 12 months. It was even effective in reducing A1c in patients taking multiple oral antidiabetic drugs – when added to two drugs, A1c decreased by 1.10% at month 6; three drugs, by 0.78%; four drugs, by 0.91% [59]. Utilization data from the Italian Medicines Agency Monitoring Registry showed that sitagliptin produced an A1c reduction of 0.88% and decrease in body weight of 1.0%. The safety profile was similar to that seen in registration trials [60].
A systematic review and meta-analysis of 12 randomized tri- als ‡76 weeks long with 14,829 participants examined the gly- cemic durability of DPP-4 inhibitors. DPP-4 inhibitors
reduced A1c overall from baseline, but A1c increased by 0.22% at the end compared with the midpoint of the study [61]. Two of the included 104-week trials involved sitagliptin [62,63]. Sita- gliptin 100 mg daily as monotherapy produced an A1c reduc- tion from baseline of —0.8% at 54 weeks and —1.2% at 104 weeks, whereas sitagliptin 50 mg twice daily plus metfor- min 1000 mg twice daily decreased A1c by 1.8% at 52 weeks and by 1.7% at 104 weeks [63]. In a different study, sitagliptin 100 mg daily as add-on therapy to metformin resulted in an A1c change of —0.8% at 24 weeks and —0.54% at 104 weeks, with a difference of +0.26% between 24 and 104 weeks of intervention [62]. It is unclear which patient factors are associ- ated with the most durability in glycemic improvements with DPP-4 inhibitors [61]. Fixed dose combination tablets of sita- gliptin/metformin or Janumet are available in dosages of 50 mg/500 mg and 50 mg/1000 mg. Janumet has been shown to be bioequivalent to co-administration of corresponding doses
of sitagliptin and metformin as individual tablets [64].

Regulatory affairs
Sitagliptin was approved by the FDA in October 2006 and by the European Medicines Agency in April 2007. As of 2010, it was approved in 85 countries for use as monotherapy and in

combination therapy. In the USA, it is indicated as monother- apy as an adjunct to diet and exercise in patients with Type 2 diabetes; in the EU. it is indicated as monotherapy for Type 2 diabetes uncontrolled with diet and exercise and in whom metformin is not an option due to contraindications/ intolerance. In both the USA and the EU, sitagliptin is indi- cated in combination therapy with metformin, a sulfonylurea, or a thiazolidinedione in patients whose diabetes has been uncontrolled on any of the above as single agents plus diet and exercise. It is also approved to be used with insulin, and as tri- ple therapy in combination with metformin plus a sulfonylurea or metformin plus a thiazolidinedione in cases of uncontrolled hyperglycemia on those two drugs [65].
Other GLP-1 mimetics have been developed and have received FDA approval – liraglutide, dulaglutide and albiglutide (lixisenatide approved in Europe but not in the USA at this time). Additional new DPP-4 inhibitors on the market include saxagliptin, linagliptin and alogliptin (vildagliptin, anagliptin and teneligliptin is approved in Japan, but not in the USA at this time).

Conclusion
Sitagliptin effectively reduces A1c levels by 0.6–1.0% when used as monotherapy or as add on to sulfonylurea, metformin, pioglitazone, or insulin. Overall, sitagliptin is generally compa- rable with other available oral agents for diabetes in its efficacy for glycemic control, with the exception of SGLT2 inhibitors and possible GLP-1 mimetics.
Aside from clinical efficacy, benefits of sitagliptin also include low risk of hypoglycemia, its neutral effect on weight, and tolerability and safety in special populations. It even shows promise in the inpatient management of diabetes and could possibly be used in lieu of bolus insulin in select patients [57]. Thus far, the risk for pancreatitis, pancreatic cancer [40], and cardiovascular events does not appear to be increased by sita- gliptin [44,45]. The effectiveness of sitagliptin in the ‘real world’ setting, outside of research studies, appears robust even when added to two or more oral antidiabetic agents [59,60].

Expert commentary
Intensive glycemic control has been shown to reduce both acute and chronic complications of diabetes. Over the past 20 years, the armamentarium of diabetes drugs has expanded significantly from those which primarily reduce glucose levels – but are also associated with the unwelcome side effect of weight gain – to newer drug classes which both effectively improve glycemia and promote weight neutrality and even weight loss. The incretin- based therapies were the first of these newer therapies to dem- onstrate glycemic benefit without concomitant weight gain, and include the GLP-1 mimetics and the DPP-4 inhibitors.

Sitagliptin was the first approved DPP-4 inhibitor in the USA. This group of drugs has demonstrated efficacy in lower- ing glucose levels by raising endogenous GLP-1 levels, which in turn leads to increased insulin secretion. DPP-4 inhibitors are unique in their action through an incretin mechanism which reduces glucose levels while maintaining weight neutrality, and have the advantage of being an oral formulation compared with their cousin GLP-1 mimetics. Moreover, while longer term studies are still needed, sitagliptin has been shown to be safe with lower risk for hypoglycemia, particularly when com- pared with other oral hypoglycemic drugs. Further studies are ongoing regarding its effect on cardiovascular disease, and there will be long-term monitoring for any association with pancrea- titis and pancreatic cancer, although rare.
Incretin-based therapies are relatively new agents in the his- tory of diabetes therapies; however, new drugs targeting other unique mechanisms for glucose lowering are in development. Sodium glucose transporter subtype 2 (SGLT-2) inhibitors are the newest agents to have been approved for treatment of dia- betes, and they function by inhibiting the SGLT-2 inhibitor in the renal proximal tubules, resulting in glucosuria and reduc- tion of circulating plasma glucose levels. Another potential new class of diabetes drugs is the glucagon receptor antagonists, which are currently in Phase II trials. This class of compounds holds promise as diabetes is associated with persistent elevations in glucagon levels despite concomitant hyperglycemia.
Although significant advances have been made in drug devel- opment, the remaining and critical challenge is to change the
natural history of diabetes by delaying or stopping the progres- sive loss of b cell mass and decline of b cell function. This continues to be an important focus of future research to pre-
vent the microvascular and macrovascular complications that lead to significant morbidity and mortality in diabetic patients.

Five-year view
Over the next 5 years, addition of new drug classes for the treatment of diabetes, including glucagon antagonists as well as those which specifically target underlying pathophysiologic pathways leading to disease, are expected to be seen on the market. New data on the safety as well as reduction of long- term complications with use of the GLP-1 mimetics and DDP-4 inhibitors should also be available.

Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial con- flict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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58. Round EM, Engel SS, Golm GT, et al. Safety of sitagliptin in elderly patients with type 2 diabetes: a pooled analysis of
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