Dipeptidyl Peptidase-4

(DPP-4) Inhibitors

A potential role for intestinal peptides in the restoration of normal insulin secretion and regulation of postprandial glucose (PPG) control was identified based on the observation that insulin responses to an oral glucose load exceeded those after IV glucose administration measured at the same blood glucose concentration. This so-called incretin effect is attributed to the insulinotropic action of gut hormones, particularly:

• Glucose-dependent insulinotropic polypeptide (GIP)
• Glucagon-like peptide 1 (GLP-1).

One approach to utilizing the therapeutic potential of GLP-1 has been the development of incretin mimetics. Since incretin hormone actions are rapidly degraded through N-terminal cleavage by the enzyme DPP-4, the use of DPP-4 inhibitors offers another strategy for the treatment of patients with type 2 diabetes (T2D). Currently, four agents of this class of antihyperglycemic medications are approved in the United States. One of the advantages of these drugs is that they can be taken orally whereas the incretin mimetics are administered by subcutaneous injection.

DPP-4 inhibitors are often incorrectly perceived as weak antidiabetic agents, especially compared with sulfonylurea (SFUs). When SFUs were being studied and introduced decades ago, the average baseline glycosylated hemoglobin (A1C) of participants who volunteered in those early studies was ~9.6%. By the time DPP-4 inhibitors were being studied, the baseline A1C in most studies was in the low 8% range, so the observed reductions in A1C were less. However, there have been several head-to-head studies comparing DPP-4s and SFUs which have demonstrated the noninferiority of DPP-4 inhibitors when starting off at the same baseline A1C.

Meta-analysis of 12 randomized studies comparing the efficacy of DPP-4 inhibitors with SFUs in reducing A1C demonstrated that DPP-4 inhibitors have better overall efficacy than second-generation SFUs, and better efficacy than third-generation SFUs in patients with chronic renal insufficiency. In the overall population, DPP-4 inhibitor-treatment reduced A1C slightly less (0.11% less) than treatment with third-generation SFUs; regardless, in trials longer than 32 weeks in duration a similar proportion of patients reached the A1C target of <7%. DPP-4 inhibitors are also associated with reduced body weight and a lower risk of hypoglycemia, total adverse events and cardiovascular (CV) events compared with SFUs. This suggests that DPP-4 inhibitors may have advantages over SFUs in long-term treatment and in special populations.

Sitagliptin (Januvia)

Sitagliptin, a selective DPP-4 inhibitor, is indicated as an adjunct to diet and exercise to improve glycemic control in adults with T2D. Specifically, it is approved:

• For initial therapy, either as monotherapy or in combination with metformin (MET) or a thiazolidinediones (TZD)
• As add-on to MET, a TZD, or an SFU when the single agent alone does not provide adequate glycemic control
• In combination therapy with insulin
• As part of triple combination therapy with MET and a TZD when dual therapy does not provide adequate glycemic control.

Monotherapy Trials

The efficacy and tolerability of sitagliptin monotherapy in patients with T2D were demonstrated in several randomized, double-blind, placebo-controlled trials. In an 18-week trial, 521 patients were randomized in a 1:2:2 ratio to receive placebo, sitagliptin 100 mg, or sitagliptin 200 mg qd after an appropriate washout and a diet/exercise or single-blind placebo run-in period. At the end of the treatment period, both sitagliptin 100 mg qd and 200 mg qd significantly decreased A1C compared with placebo (placebo-subtracted A1C: -0.60% and -0.48%, respectively). Patients with higher baseline A1C (≥9%) experienced greater placebo-subtracted reductions with sitagliptin treatment (-1.20% for 100 mg and -1.04% for 200 mg) than those with a baseline A1C <8% (-0.44% and -0.33%, respectively) or 8% to 8.9% (-0.61% and -0.39%, respectively). After 18 weeks, both dosages of sitagliptin also significantly decreased fasting plasma glucose (FPG) (placebo subtracted FPG: -12.6 mg/dL and -10.6 mg/dL, with 100 mg and 200 mg, respectively). Two-hour postprandial glucose (PPG) also was significantly reduced with sitagliptin 100 mg and 200 mg compared with placebo (placebo subtracted PPG: -41.4 mg/dL and -48.6 mg/dL, respectively). The incidence of hypoglycemia or GI adverse events (AEs) was not significantly different with either dose of sitagliptin compared with placebo. There were similar reductions in mean body weight in the three treatment groups (sitagliptin 100 mg -0.6 kg; sitagliptin 200 mg -0.2 kg; and placebo -0.7 kg).

A 24-week study used a similar design and found similar results. After 24 weeks, both sitagliptin 100 mg and 200 mg produced significant placebo-subtracted reductions in A1C (-0.79% and -0.94%, respectively) and FPG (-17.1 mg/dL and -21.3 mg/dL, respectively). Both sitagliptin 100 mg and 200 mg significantly reduced 2-hour PPG from baseline (placebo-subtracted PPG: -46.7 and -54.1 mg/dL, respectively). There were no significant differences in the reductions in A1C, FPG, or PPG between the two sitagliptin doses. The incidence of hypoglycemia and gastrointestinal (GI) AEs was not higher with either dose of sitagliptin compared with placebo. There were minimal reductions from baseline in body weight with sitagliptin 100 mg (-0.2 kg) and 200 mg (-0.1 kg); however, body weight was significantly reduced from baseline with placebo (-1.1 kg).

Sitagliptin was compared with MET as monotherapy in treatment-naïve patients with T2D in a randomized, double-blind, noninferiority trial. Patients were treated either with sitagliptin 100 mg once daily (n = 528) or MET 1000 mg bid (n = 522) for 24 weeks. The criteria for noninferiority was if the upper boundary of the 95% CI for the between-group difference in A1C change from baseline was <0.40%. At week 24, A1C change from baseline was -0.43% with sitagliptin and -0.57% with MET. The between-group difference (95% CI) was 0.14%, thus confirming noninferiority.

Long-Term Efficacy of Sitagliptin Monotherapy

In order to look at the long-term efficacy of sitagliptin monotherapy, patients in the 24-week placebo-controlled trial entered an extension period lasting 54 weeks. Patients were given either 100 mg or 200 mg of sitagliptin once a day. The changes in A1C from baseline at week 54 were -0.6% (95% CI: -0.7, -0.4) with 100 mg and -0.6% (-0.8, -0.5) with 200 mg. Sitagliptin was well tolerated and there was no weight gain. The durability of sitagliptin efficacy was demonstrated over this 54-week study.

Combination or Add-On Therapy Trials

Sitagliptin was studied as combination or add-on treatment with MET, an SFU, or pioglitazone in randomized, parallel group, placebo-controlled studies of 18-weeks or 24-weeks duration. In these studies, patients were randomized after appropriate washout and placebo run-in periods.

The efficacy and tolerability of the initial combination of sitagliptin and MET in patients with T2D inadequately controlled on diet and exercise were evaluated in a 24-week, study in which total of 1,091 patients with A1C 7.5% to 11% were randomized to one of six daily treatments: sitagliptin 100 mg/MET 1,000 mg (S100/M1,000 group), sitagliptin 100 mg/MET 2,000 mg (S100/M2,000 group), MET 1,000 mg (M1,000 group), MET 2,000 mg (M2,000 group) (all as divided doses administered bid), sitagliptin 100 mg qd (S100 group), or placebo. The placebo-subtracted A1C changes from baseline were: -2.07% (S100/M2,000), -1.57% (S100/M1,000), -1.30% (M2,000), -0.99% (M1,000) and -0.83% (S100) (P <0.001 for comparisons vs placebo and for coadministration vs respective monotherapies).

The proportion of patients achieving an A1C <7% and <6.5% was 66% and 44%, respectively, in the S100/M2000 group (P <0.001 vs S100 or M2,000 monotherapies). The incidences of hypoglycemia ranged from 0.5% to 2.2% across active treatment groups and were significantly different from that in the placebo group (0.6%). There were significant reductions in body weight in treatment groups relative to baseline ranging from -0.6 kg to 1.3 kg, except in the sitagliptin monotherapy group in which there was no change from baseline.

A 24-week trial in 701 patients evaluated the efficacy and tolerability of sitagliptin in patients who had inadequate glycemic control on MET (≥1500 mg/day) monotherapy. Patients were randomized in a 1:2 ratio to receive adjunctive placebo or sitagliptin 100 mg qd for 24 weeks. Mean baseline A1C was 8.0% (Figure 10-1). After 24 weeks, sitagliptin/MET therapy resulted in a significant placebo-subtracted reduction in A1C (-0.65%) (Figure 10-1-A), FPG (-25.4 mg/dL), and 2-hour PPG (-50.6 mg/dL) (Figure 10-1-B). Overall, the incidences of hypoglycemia and GI AEs between the two groups were similar. Mean body weight changes from baseline were not significantly different between the sitagliptin group (-0.7 kg) and the placebo group (-0.6 kg).

Another 24-week study assessed the efficacy and safety of the addition of sitagliptin in 353 patients treated with pioglitazone monotherapy. Patients were randomized (1:1) to receive placebo or sitagliptin 100 qd in addition to ongoing pioglitazone (Figure 10-2). After 24 weeks, sitagliptin/pioglitazone treatment resulted in significant placebo-subtracted reductions in A1C (-0.70%) (Figure 10-2-A) and FPG (-17.7 mg/dL). The effects on glycemic control were maintained over the 24-week treatment period. The percentage of patients achieving target A1C <7% was 45% and 23% in the sitagliptin/pioglitazone and placebo/pioglitazone groups, respectively (Figure 10-2-B). There was no between-group difference in mean body weight change. The overall incidence of AEs and hypoglycemia was similar in the two groups, although the incidence of abdominal pain was slightly higher in patients who received sitagliptin.

A 52-week, noninferiority trial compared the efficacy and tolerability of sitagliptin and glipizide in patients who had inadequate glycemic control with MET monotherapy. A total of 1,172 patients were randomized to sitagliptin 100 mg qd or glipizide up to 20 mg daily (maximum titrated dose). There were significant similar mean reductions in A1C (0.67%) vs baseline in each treatment group in these patients with mildly elevated baseline A1C levels (mean 7.5%), and similar proportions of patients achieved A1C goal (<7%) in each group (63% with sitagliptin vs 59% with glipizide). At 52 weeks, the prespecified bounds for noninferiority of sitagliptin vs glipizide were achieved. Patients in the sitagliptin group experienced significant weight loss (mean, -1.5 kg) from baseline at 52 weeks, while those in the glipizide group experienced significant weight gain (mean, +1.1 kg). The between-group difference was statistically significant (P <0.001). Additionally, there was a significantly higher rate of hypoglycemia in glipizide-treated patients than in sitagliptin-treated patients (patients experiencing at least one hypoglycemic episode regardless of severity: 32.0% vs 4.9%, respectively).

The efficacy and tolerability of adding sitagliptin 100 mg once daily to ongoing treatment with glimepiride alone or glimepiride in combination with MET was assessed in a 24-week, randomized, placebo-controlled trial in 441 patients. Of these patients, 212 (48%) were on glimepiride (≥4 mg/day) monotherapy and 229 (52%) were on glimepiride (≥4 mg/day) plus MET (≥1,500 mg/day) combination therapy. After 24 weeks, sitagliptin significantly reduced A1C by 0.74% relative to placebo. In the subset of patients on glimepiride plus MET, sitagliptin reduced A1C by 0.89% relative to placebo, compared with a reduction of 0.57% in the subset of patients on glimepiride alone. The addition of sitagliptin reduced FPG by 20.1 mg/dL and increased homeostasis model assessment-β, a marker of β-cell function, by 12% compared with placebo. The addition of sitagliptin was generally well tolerated, with a modest increase in the incidence of hypoglycemia (12% vs 2% with placebo) and body weight (+0.8 kg vs -0.4 kg with placebo), consistent with glimepiride therapy and the observed degree of glycemic improvement.

A 24-week, randomized, double-blind, placebo-controlled study assessed the efficacy and safety of adding sitagliptin 100 mg in 641 patients who were inadequately controlled on stable doses of insulin (long-acting, intermediate-acting, or premixed) with or without concomitant MET. The addition of sitagliptin significantly reduced A1C by 0.6% compared with placebo (0.0%). A greater proportion of patients achieved an A1C level <7% with sitagliptin compared with placebo (13% vs 5%, respectively). The incidence of adverse experiences was higher with sitagliptin (52%) compared with placebo (43%), due mainly to the increased incidence of hypoglycemia (sitagliptin 16% vs placebo 8%). However, the number of hypoglycemic events meeting the protocol-specified criteria for severity was low with sitagliptin (n = 2) and placebo (n = 1).

A 54-week study in 1,091 patients observed significant and comparable reductions from baseline in A1C levels with initial treatment with monotherapy with sitagliptin 100 mg (-0.8%), MET 1,000 mg (-1.0%), MET 2,000 mg (-1.3%) or the combination of sitagliptin 100 mg plus and MET 1,000 mg (-1.4%) or sitagliptin 100 mg plus MET 2,000 mg (-1.8%). Glycemic response was generally durable over time across treatments. Mean body weight decreased from baseline in the combination and MET monotherapy groups and was unchanged in the sitagliptin monotherapy group. The incidence of hypoglycemia was low (1% to 3%) across treatment groups. The incidence of GI adverse experiences with the combination of sitagliptin and MET was similar to that observed with MET alone.

Cardiovascular Outcomes

The long-term safety of adding sitagliptin to usual care was assessed in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), an international, randomized, placebo-controlled, double-blind study. The 14,671 enrolled patients had T2D with established cardiovascular disease (CVD), were at least 50 years of age, and had an A1C of between 6.5% to 8.0% when treated with stable doses of one or two oral antihyperglycemic agents or insulin. Antihyperglycemic therapy was encouraged throughout the study, with the goal of meeting individualized glycemic targets. Patients were randomized in a 1:1 ratio to receive either daily sitagliptin (100 mg, or 50 mg if baseline estimated glomerular filtration rate (eGFR) was ≥30 and <50 mL per minute per 1.73 m²) or placebo in addition to their existing therapy. The primary composite CV outcome was the first confirmed event of cardiovascular (CV) death, nonfatal myocardial infarction (MI), nonfatal stroke, or hospitalization for unstable angina.

Patients receiving sitagliptin in addition to standard care had lower A1C (0.4% lower at 4 months), received fewer additional antihyperglycemic agents (HR 0.72; 95% confidence interval (CI), 0.68 to 0.77; P <0.001), and were less likely to initiate long-term insulin therapy (HR, 0.70; 95% CI, 0.63 to 0.79; P <0.001) compared with patients receiving placebo. After a mean follow-up period of 3 years, 11.4% (839) of patients in the sitagliptin group experienced a primary composite CV outcome compared with 11.6% (851) in the placebo group, a nonsignificant difference (HR 0.98; 95% CI, 0.88 to 1.09; P <0.001 for noninferiority). Noninferiority was also met for the secondary composite CV outcome of first confirmed event of CV death, nonfatal MI, or nonfatal stroke (HR 0.99; 95% CI, 0.89 to 1.11; P <0.001).

No difference was observed in the rate of hospitalization for heart failure between treatment groups (HR 1.00; 95% CI, 0.83 to 1.20; P = 0.98). Overall, TECOS demonstrated that in patients with T2D and established CVD, the addition of sitagliptin to usual care did not significantly affect rates of death from any cause, CV death, or nonCV death, and did not affect rates of hospitalization for heart failure.

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Use in Patients With Renal Disease

Since sitagliptin is primarily renally excreted and its area under the curve (AUC0-∞) is increased approximately 2- to 4-fold compared with healthy subjects in patients with moderate to severe renal insufficiency and end-stage renal disease (ESRD), respectively, a randomized, placebo-controlled study assessed the safety of sitagliptin in T2D patients with a CrCl <50 mL/minute. After diet/exercise and an antihyperglycemic drug washout period (except in patients on prior insulin therapy who remained on insulin), 91 patients (A1C 6.2% to 10.3%, mean 7.7%) were randomized (2:1) to sitagliptin or placebo for 12 weeks. Patients with moderate renal insufficiency (creatinine clearance (CrCl) 30 to <50 mL/min) who were randomized to sitagliptin were treated with 50 mg qd and those with severe renal insufficiency (CrCl <30 mL/min) or ESRD received 25 mg qd in order to achieve drug exposure similar to that observed with 100 mg qd in patients with normal to mildly impaired renal function. At baseline, 10% were on insulin therapy and 43% had CrCl <30 mL/minute. The overall incidence of adverse event (AEs) was similar in the two groups. The incidences of drug-related AEs, serious AEs and discontinuations due to AEs were modestly, but not meaningfully, higher in sitagliptin-treated patients. Furthermore, there were no differences in the percentage of patients who experienced hypoglycemia or GI AEs between groups. Body weight was unchanged in sitagliptin-treated patients. Although this was a safety study, after 12 weeks, mean A1C and FPG decreased by 0.59% and 25.5 mg/dL, respectively, in the sitagliptin groups (doses pooled) and by 0.18% and 3.0 mg/dL in the placebo group.

Adverse Events With Sitagliptin

Adverse reactions reported in ≥5% of patients treated with sitagliptin and more commonly than in patients treated with placebo are:

• Upper respiratory tract infection
• Nasopharyngitis
• Headache.

Hypoglycemia was also reported more commonly in patients treated with the combination of sitagliptin and an SFU, with or without MET, vs placebo. Sitagliptin is contraindicated in patient with a history of a serious hypersensitivity reaction to sitagliptin, including anaphylaxis and angioedema. There have been post marketing reports of acute pancreatitis, including fatal and nonfatal hemorrhagic or necrotizing pancreatitis, in patients taking sitagliptin. If pancreatitis is suspected, sitagliptin should be discontinued promptly. It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using sitagliptin.

Prescribing Sitagliptin

In patients with T2D, the recommended dose of sitagliptin is 100 mg qd as monotherapy or combination therapy. Sitagliptin can be taken with or without food. Sitagliptin should not be used in patients with type 1 diabetes or for the treatment diabetic ketoacidosis (DKA) since it would not be effective in these settings. Dosage adjustment is recommended in patients with moderate (CrCl ≥30 to <50 mL/min) or severe (CrCl <30 mL/min) renal insufficiency and in patients with ESRD requiring hemodialysis or peritoneal dialysis. Since dosage adjustment based on renal function is needed, assessment of renal function is recommended prior to initiation of sitagliptin and periodically thereafter. Mean (SE) increases in serum creatinine were observed in patients treated with sitagliptin (0.12 mg/dL [0.04]) and in patients treated with placebo (0.07 mg/dL [0.07]). The clinical significance of this added increase in serum creatinine relative to placebo is not known.

Sitagliptin Fixed-Dose Combinations With Metformin (Janumet and Janumet XR)

Sitagliptin is also available in a fixed-dose, single-tablet formulation containing sitagliptin and MET (Janumet). Another fixed-dose, single-tablet formulation containing sitagliptin and MET is also available as an extended-release formulation (Janumet XR).

These combination formulations are indicated as an adjunct to diet and exercise to improve glycemic control in adult patients with T2D who are not adequately controlled on MET or sitagliptin alone or in patients already being treated with the combination of sitagliptin and MET. Although neither of these fixed-dose, single-tablet combination of sitagliptin and MET have been studied specifically in patients with an inadequate response to insulin, the combination of sitagliptin with/without MET administered separately was shown to be effective in patients with an inadequate response to insulin.

Prescribing Janumet

The dosage of Janumet should be individualized on the basis of the patient’s current regimen, effectiveness, and tolerability and should not exceed the maximum recommended daily dose of 100 mg sitagliptin and 2,000 mg MET (Table 8-1).

Janumet should generally be given twice daily with meals, with gradual dose escalation, to reduce the GI side effects due to MET.

The starting dose of Janumet should be based on the patient’s current regimen and should be given twice daily with meals. The following doses are available:

• 50 mg sitagliptin/500 mg MET
• 50 mg sitagliptin/1000 mg MET.

Prescribing Janumet XR

The dosage of Janumet XR should be individualized on the basis of the patient’s current regimen, effectiveness, and tolerability and should not exceed the maximum recommended daily dose of 100 mg sitagliptin and 2,000 mg MET XR.

Janumet XR should be administered once daily with food preferably in the evening, with gradual dose escalation, to reduce the GI side effects due to MET.

The starting dose of Janumet XR should be based on the patient’s current regimen and should be given twice daily with meals. The following dosages are available:

• 50 mg sitagliptin/500 mg MET XR
• 50 mg sitagliptin/1,000 mg MET XR
• 100 mg sitagliptin/1,000 mg/1000 mg MET XR.

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Sitagliptin Fixed-Dose Combination With Ertugliflozin (Steglujan)

Sitagliptin is also available with an SGLT2 inhibitor, ertugliflozin, as a once-daily fixed-dose combination tablet. Steglujan is indicated as an adjunct to diet and exercise to improve glycemic control in adults with T2D when treatment with both ertugliflozin and sitagliptin is appropriate. Steglujan is contraindicated in patients with severe renal impairment, end-stage renal disease, dialysis, a history of a serious hypersensitivity reaction to sitagliptin, such as anaphylaxis or angioedema, or a history of a serious hypersensitivity reaction to ertugliflozin.

The safety and efficacy of Steglujan were assessed in three randomized clinical trials involving 1985 patients with T2D: VERTIS SITA, VERTIS SITA2, and VERTIS FACTORIAL.

Prescribing Steglujan

The recommended dose of Steglujan is 5 mg ertugliflozin/100 mg sitagliptin once daily, taken in the morning, with or without food. In patients tolerating treatment, the dose may be increased to a maximum recommended dose of 15 mg ertugliflozin/100 mg sitagliptin, once daily, if additional glycemic control is needed.

Saxagliptin (Onglyza)

Saxagliptin is approved for monotherapy and combination therapy as an adjunct to diet and exercise to improve glycemic control in adults with T2D.

Saxagliptin is 10 times more potent than sitagliptin. The M2 metabolite is 2-fold less potent than saxagliptin. In healthy volunteers, mean C_max was 24 ng/mL for saxagliptin and 47 ng/mL for the M2 metabolite. Mean T_max was 2 hours for saxagliptin and 4 hours for M2. After an oral glucose load or a meal, there were 2- to 3-fold increases in circulating levels of active GLP-1 and GIP, decreased glucagon concentrations and increased glucose-dependent insulin secretion from pancreatic β cells. The increase in insulin and decrease in glucagon were associated with lower fasting glucose concentrations and reduced glucose excursions following an oral glucose load or a meal.

Monotherapy Trials

A 24-week, trial randomized 401 treatment-naïve patients to once-daily treatment with saxagliptin 2.5 mg, 5.0 mg, 10 mg, or placebo (main treatment cohort [MTC]). A separate open-label cohort (OLC) with 66 patients with baseline A1C >10% to <12% received saxagliptin 10 mg for 24 weeks. In the MTC, all three doses of saxagliptin demonstrated statistically significant decreases in mean A1C changes (all P <0.0001 vs placebo). Mean changes from baseline in FPG with saxagliptin also were significantly greater than with placebo. Mean changes from baseline in PPG at the 120-minutes time point were significantly lower with all three doses of saxagliptin compared with placebo. A greater proportion of saxagliptin-treated patients achieved A1C <7% at week 24 (35% [P = NS], 38% [P = 0.0443], 41% = 0.0443], 41% [P = 0.0133]) for saxagliptin 2.5, 5 and 10 mg, respectively, than placebo (24%). As in the MTC, clinically meaningful reductions in A1C, FPG and PPG were observed in the OLC. Consistent with the higher baseline A1C (10.7%) in these patients, the mean decrease in A1C of 1.9% was greater than those observed in the MTC, as were changes in FPG (-33 mg/dL) and PPG at 120 min (-66 mg/dL). By week 24, an A1C <7% was achieved in 14% of patients.

Combination Trials

The efficacy of saxagliptin at doses of 2.5 mg or 5 mg once daily in combination with MET, an SFU (glyburide), or a TZD (pioglitazone or rosiglitazone) was studied in four large, 24-week, randomized, double-blind, placebo-controlled trials.

Saxagliptin With Metformin as Initial Therapy

The efficacy of initial combination therapy with saxagliptin plus MET vs saxagliptin or MET monotherapy was evaluated in 1306 treatment-naïve patients with T2D and inadequate glycemic control. Patients were initially randomized to receive saxagliptin 5 mg plus MET 500 mg, saxagliptin 10 mg plus MET 500 mg, saxagliptin 10 mg plus placebo, or MET 500 mg plus placebo. From weeks 1 through 5, MET was uptitrated in 500-mg/day increments to 2,000 mg/day maximum in the saxagliptin 5 mg plus MET, saxagliptin 10 mg plus MET, and MET plus placebo treatment groups.

At 24 weeks, saxagliptin 5 mg plus MET and saxagliptin 10 mg plus MET demonstrated statistically significantly greater decreases vs saxagliptin 10 mg and MET monotherapies in A1C and FPG (Figure 10-3). The proportion of patients achieving an A1C <7% was 60.3% and 59.7%, respectively, for saxagliptin 5 mg plus MET and saxagliptin 10 mg plus MET compared with 32.2% with saxagliptin monotherapy and 41.1% with MET monotherapy (all P <0.0001 vs both monotherapies).

Saxagliptin Added to Metformin

Saxagliptin 2.5, 5.0, or 10 mg once daily as add-on therapy was evaluated in 743 patients with T2D with inadequate glycemic control with MET alone (1500-2500 mg/day). By week 24, all three doses of saxagliptin added to stable MET doses demonstrated statistically significant mean decreases from baseline vs placebo in A1C, FPG, and PPG (Table 10-1). More than twice as many patients achieved A1C <7.0% with 2.5, 5, and 10 mg saxagliptin compared with placebo. As in other clinical trials, β-cell function and postprandial C-peptide, insulin, and glucagon AUCs improved in all saxagliptin treatment groups. Reductions in body weight with saxagliptin were similar to that with placebo.

Saxagliptin Added to Glyburide

The addition of saxagliptin 2.5 mg or 5 mg once daily to a stable dose of glyburide (7.5 mg once daily) compared with uptitrated glyburide in 768 patients who had inadequate glycemic control on suboptimal dose of an SFU alone for ≥2 months (defined as less than the maximum approved dose for each SFU). During a single-blind, 4-week dietary and exercise run-in period, previous SFU therapy was discontinued and replaced with glyburide 7.5 mg once daily. Following the run-in period, patients were randomized to receive 2.5 mg or 5 mg of saxagliptin added to 7.5 mg glyburide or to placebo plus a 10-mg total daily dose of glyburide. Patients who received placebo were eligible for blinded glyburide uptitration to a total daily dose of 15 mg. At week 24, 92% of glyburide-only patients had been uptitrated to a total glyburide dose of 15 mg/day. Both doses of saxagliptin in combination with glyburide were associated with significant decreases from baseline in A1C, FPG and 2-hour PPG. More than twice as many patients in both saxagliptin plus glyburide groups achieved A1C <7%. Mean body weight increased in all treatment groups and were significantly greater in each saxagliptin treatment group vs uptitrated glyburide (+0.7 kg [P = 0.0381] and +0.8 kg [P = 0.0120] for saxagliptin 2.5 and 5 mg, respectively, vs +0.3 kg for uptitrated glyburide].

Saxagliptin Added to Thiazolidinedione

A total of 565 patients with inadequate glycemic control despite at least 12 weeks of treatment with TZD monotherapy (pioglitazone 30 or 45 mg or rosiglitazone 4 or 8 mg) were treated with saxagliptin (2.5 or 5 mg once daily) or placebo, all in addition to a stable dose of TZD. The primary outcome measure was change in A1C from baseline to week 24. Secondary outcomes included change from baseline in FPG and proportion of patients achieving A1C <7. At week 24, there were significant reductions from baseline in A1C and FPG in both saxagliptin groups compared with placebo (Figure 10-4). A significantly greater proportion of patients in the saxagliptin 2.5 mg and 5 mg groups achieved an A1C <7% (42.2% and 41.8% respectively; both P <0.05 vs 25.6% with placebo). In addition, there were statistically significant reductions from baseline in PPG-AUC in both saxagliptin groups compared with the placebo group (both P <0.0001). A small increase from baseline in body weight occurred in all treatment groups (1.3, 1.4, and 0.9 kg for saxagliptin 2.5 and 5 mg and placebo, respectively).

Long-Term Use

The long-term efficacy of saxagliptin added to MET was demonstrated by the preliminary results of an extension of the 24-week study discussed above. After 102 weeks, the placebo-subtracted changes from baseline in A1C levels in patients who received saxagliptin 2.5 or 5 mg once-daily add-on therapy vs MET alone were 0.62% and 0.72%, respectively. During this period, 58% and 52% of patients treated with 2.5 or 5 mg of saxagliptin in combination with MET compared with 72% of those treated with MET monotherapy discontinued treatment or received rescue therapy for insufficient glycemic control.

Cardiovascular Outcomes

The safety and efficacy of saxagliptin with respect to CV outcomes in patients with T2D who are at risk for CV events was evaluated in the SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus–Thrombolysis in Myocardial Infarction 53) trial. This phase 4 trial enrolled 16,492 patients with a history of documented T2D, a glycated hemoglobin level of 6.5% to 12.0%, and either a history of established CV disease or multiple risk factors for vascular disease. Eligible patients were randomized 1:1 to receive 5 mg saxagliptin daily (2.5 mg daily in patients with an eGFR rate of ≤50 mL/min/1.73m²) or placebo. The primary efficacy and safety endpoint was a composite of CV death, nonfatal MI, or nonfatal ischemic stroke. The secondary endpoint was the primary composite endpoint plus hospitalization for heart failure, coronary revascularization, or unstable angina.

Saxagliptin neither reduced nor increased the risk of the primary composite endpoint (7.3% vs 7.2% for placebo; HR 1.00, 95% CI 0.89-1.12; P <0.001), thus meeting the criterion for noninferiority to placebo but not providing any cardioprotective benefit (P = 0.99 for superiority). The major secondary composite endpoint occurred in 12.8% of patients in the saxagliptin group, compared with 12.4% of patients in the placebo group (HR 1.02, 95% CI 0.94-1.11; P = 0.66). Saxagliptin was associated with significantly improved glycemic control and reduced the development and progression of microalbuminuria. Individual analysis of the components of these composite endpoints revealed that more patients in the saxagliptin group were hospitalized for heart failure than in the placebo group (3.5% vs. 2.8% for placebo; HR 1.27, CI 1.07-1.51; P = 0.007).

Overall, saxagliptin did not reduce or increase the risk of the primary composite endpoint of CV death, nonfatal MI, or nonfatal ischemic stroke when added to the standard of care in patients at high risk for CV events. However, an increase in the risk for hospitalization for heart failure was observed.

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Adverse Events With Saxagliptin

Saxagliptin as monotherapy or in combination with other OADs was generally well tolerated, with most adverse reactions being of mild or moderate intensity. In the above clinical trials, the incidence of treatment-emergent AEs was generally similar to that in patients who received other OADs or placebo. The most common AEs reported in ≥5% of patients treated with saxagliptin and more commonly than in patients treated with placebo were:

• Upper respiratory tract infection
• Urinary tract infection
• Nasopharyngitis
• Headache.

The incidence of hypoglycemic events in patients treated with saxagliptin was generally similar to that in patients receiving placebo or other OADs. In patients treated with saxagliptin 2.5 or 5 mg as monotherapy, the incidence of hypoglycemic events was 4% and 6%, respectively (vs 4% of placebo recipients). When used as add-on therapy, the incidence was 9% and 8% with saxagliptin 2.5 or 5 mg, respectively (vs 7% of patients who received MET, glyburide, or a TZD).

Prescribing Saxagliptin

In patients with T2D, the recommended dose of saxagliptin is 2.5 mg or 5 mg once daily taken regardless of meals. Saxagliptin should not be used in patients with type 1 diabetes or for the treatment DKA since it would not be effective in these settings. Saxagliptin has not been studied in combination with insulin.

No dosage adjustment for saxagliptin is recommended for patients with mild renal impairment (CrCl >50 mL/min). However, the recommended dose of saxagliptin is 2.5 mg qd for patients with moderate or severe renal impairment (CrCl ≤50 mL/min) or with ESRD requiring hemodialysis. Saxagliptin should be administered following hemodialysis. Because the dose of saxagliptin should be limited to 2.5 mg based upon renal function, assessment of renal function is recommended prior to initiation of saxagliptin and periodically thereafter. When coadministered with strong cytochrome P450 3A4/5 (CYP3A4/5) inhibitors (eg, ketoconazole, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir and telithromycin), the recommended dose of saxagliptin is 2.5 mg qd.

Saxagliptin Fixed-Dose Combination With Metformin XR (Kombiglyze XR)

Saxagliptin is also available in a fixed-dose, single-tablet formulation containing saxagliptin and MET XR (Kombiglyze XR). This combination formulation is indicated as an adjunct to diet and exercise to improve glycemic control in adults with T2D when treatment with both saxagliptin and MET is appropriate. This fixed-dose, single-tablet combination of saxagliptin and MET XR has not been studied specifically in patients with an inadequate response to insulin. However, the combination of alogliptin with/without MET administered separately was shown to be effective in patients with an inadequate response to insulin.

Prescribing Kombiglyze XR

The dosage of Kombiglyze XR should be individualized on the basis of the patient’s current regimen, effectiveness and tolerability. It should generally be administered once daily with the evening meal, with gradual dose titration to reduce the GI side effects associated with MET. The following dosage forms are available:

• 5 mg saxagliptin and 500 mg MET XR
• 5 mg saxagliptin and 1000 mg MET XR
• 2.5 mg saxagliptin and 1000 mg MET XR.

The recommended starting dose of Kombiglyze XR in patients who need 5 mg of saxagliptin and who are not currently treated with MET is 5 mg saxagliptin/500 mg MET XR once daily with gradual dose escalation to reduce the GI side effects due to MET. The maximum daily recommended dose is 5 mg saxagliptin and 2,000 mg MET XR.

Saxagliptin Fixed-Dose Combination With Dapagliflozin (Qtern)

Qtern is a fixed dose combination of 5 mg or 10 mg of the SGLT2 inhibitor dapagliflozin and 5 mg of saxagliptin. Qtern is indicated as an adjunct to diet and exercise to improve glycemic control in adults with T2D. Qtern is contraindicated in patients with an eGFR of ≤ 45 mL/min/1.73 m², ESRD, or patients on dialysis.

The efficacy and safety of Qtern was established in three 24-week randomized, double-blind trials: two active-comparator-controlled and one placebo-controlled. In one trial of 870 patients, saxagliptin 5 mg daily in combination with dapagliflozin 5 mg daily was compared to either agent separately as an add-on to metformin; The average change from baseline in A1C levels was significantly greater in the combination group (-1.02% [95% CI: -1.13%, -0.90%]) compared to either saxagliptin (-0.69% [95% CI: -0.80%, -0.59%]; P <0.0001) or dapagliflozin alone (-0.62% [95% CI: -0.73%, -0.51%]; P <0.0001). The second active-comparator-controlled trial enrolled 534 patients and had a similar design, except that the dose of dapagliflozin was 10 mg instead of 5 mg. In the combination (saxagliptin 5 mg/dapagliflozin 10 mg) group, A1C change from baseline was significantly greater (-1.49% [95% CI: -1.64%, -1.34%) than in the saxagliptin 5 mg (−1.00% [95% CI: -1.15%, -0.85%]; P <0.0001) and dapagliflozin 10 mg (-1.23% [95% CI: -1.38%, -1.08%]; P = 0.0148) comparator groups. Finally, in a trial of 315 patients on a baseline therapy of dapagliflozin and metformin, A1C change from baseline was significantly greater in the saxagliptin 5 mg group (-0.5% [95% CI: -0.6%, -0.4%]) compared to the placebo group (-0.2% [-0.3%, -0.1%]; P <0.0001).

On the basis of the above trials, a triple combination (dapagliflozin/saxagliptin/metformin; marketed as Qternmet) also received FDA approval in 2019; however, Qternmet was voluntarily withdrawn from the market in April 2021.

The recommended starting dose of Qtern is 5 mg/5 mg dapagliflozin/saxagliptin; it may be increased to 10 mg/5 mg dapagliflozin/saxagliptin in patients who require additional glycemic control. Qtern tablets are taken once daily, in the morning, with or without food.

Linagliptin (Tradjenta)

Linagliptin is indicated as an adjunct to diet and exercise to improve glycemic control in adults with T2D. Linagliptin can be used as monotherapy or as add-on or combination therapy with other commonly prescribed OADs (e.g., MET, SFU, or pioglitazone). Linagliptin is the first DPP-4 inhibitor approved at one dosage strength; no dose adjustment is recommended for patients with T2D who have kidney or liver impairment.

Studies have shown that the pharmacokinetic parameters of linagliptin are similar in healthy subjects and in patients with T2D. The absolute bioavailability of linagliptin is approximately 30%. Administration with a high-fat meal has a small, but not clinically relevant, effect on C_max and AUC; therefore, linagliptin may be administered with or without food. After once-daily dosing, a steady-state plasma concentration of linagliptin 5 mg is reached by the third dose. Unlike other DPP-4 inhibitors so far characterized, linagliptin is excreted unchanged mainly via feces (~80%) rather than by the renal route (~5%). Studies in healthy subjects and patients with T2D with normal or various degrees of renal or hepatic function indicate that no dosage adjustment is necessary in patients with renal or hepatic impairment.

Monotherapy Trials

The efficacy and safety of linagliptin monotherapy were evaluated in two double-blind, placebo-controlled studies, one of 18-weeks duration and another of 24-weeks duration that enrolled 730 patients with T2D with inadequate glycemic control (A1C, 7% to 10%). Before randomization in both studies, patients previously treated with OADs underwent a washout period of 6 weeks, which included a placebo run-in period during the last 2 weeks. Patients previously untreated with OADs underwent a 2-week placebo run-in period. In the 18-week study, treatment with linagliptin 5 mg once daily provided statistically significant improvements from baseline in A1C and FPG compared with placebo. By 18 weeks, 28% of linagliptin-treated patients achieved an A1C <7% compared with 15% of patients in the placebo-group.

In the 24-week study, 336 patients received linagliptin 5 mg once daily and 167 patients received placebo. Overall, the adjusted mean difference in the change in A1C comparing linagliptin with placebo was -0.69% (P <0.0001). Changes in adjusted mean A1C increased over time (-0.46% at 6 weeks to -0.69% at 24 weeks, all P <0.0001) (Figure 10-5). Reductions from baseline were smaller in patients previously treated with OADs than the difference between linagliptin and placebo in OAD-naïve patients. Patients treated with linagliptin were more likely to achieve a reduction in A1C of ≥0.5% at 24 weeks than those in the placebo arm (47.1% and 19.0%, respectively; P <0.0001). Fasting plasma glucose improved by -1.3 mmol/L (P <0.0001) with linagliptin vs placebo, and linagliptin produced an adjusted mean reduction from baseline after 24 weeks in 2-hour postprandial glucose of -3.2 mmol/L (P <0.0001). Linagliptin monotherapy was well tolerated and exhibited a safety profile comparable with that of placebo, with a very low incidence of hypoglycemia (8.6% with linagliptin vs 22.8% with placebo in the 24-week study). There were no clinically significant changes in body weight between treatment groups.

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Combination or Add-On Treatment

Linagliptin has been studied as combination or add-on treatment with MET, an SFU, or pioglitazone in randomized, parallel group, placebo-controlled studies of 18-weeks or 24-weeks duration. In these studies, patients were randomized after appropriate washout and placebo run-in periods.

Linagliptin Added to Metformin

Linagliptin as an add-on to MET was evaluated in 701 patients previously treated with MET alone or MET and other OADs. Eligible patients were randomized in a 3:1 ratio to treatment with either placebo or linagliptin 5 mg once daily. All patients continued to take their usual dosage of MET throughout the trial. After 24 weeks of treatment, linagliptin reduced the mean A1C level by 0.49%, whereas in the placebo group, A1C increased by 0.15%; a treatment difference of -0.64% (P <0.0001). The significant difference between treatments in mean A1C change increased over time from 6 weeks (-0.43%) to 18 weeks (-0.65%), then remained stable until the end of the 24 weeks (-0.64%) (Figure 10-6). The placebo-corrected reduction in A1C from baseline at 24 weeks was greater in patients who had previously been treated with an OAD in addition to MET compared with those who had not previously received an OAD in addition to MET (-0.79 vs -0.60%, respectively; but not significant). Linagliptin treatment also resulted in significant reductions vs placebo in FPG (-0.59 vs 0.58 mmol/L) and 2-hour PPG (-2.7 vs 1.0 mmol/L; all P <0.0001). Overall, linagliptin was well tolerated. AEs occurred at a similar rate in both groups. Hypoglycemia was rare, occurring in three patients (0.6%) treated with linagliptin and five patients (2.8%) in the placebo group. Body weight did not change significantly from baseline in either group.

Linagliptin Added to a Sulfonylurea

An 18-week, placebo-controlled study in a total of 245 patients with T2D evaluated the efficacy of linagliptin added to an SFU. Patients on SFU monotherapy (n = 142) were randomized after completing a 2-week, single-blind, placebo run-in period. Patients on an SFU plus one additional OAD (n = 103) were randomized after a washout period of 4 weeks and a 2-week single-blind placebo run-in period. Patients were randomized to the addition of linagliptin 5 mg or to placebo, each administered once daily. After 18 weeks, linagliptin in combination with an SFU provided statistically significant improvement in A1C compared with placebo. Although FPG decreased by 8.2 mg/dL while it increased by 8.1 mg/dL, the difference compared with placebo was not significant. There was no significant difference between linagliptin and placebo in body weight.

Linagliptin Added to Metformin and a Sulfonylurea

The efficacy of linagliptin 5 mg added to a combination of MET and an SFU was assessed in 1058 patients with T2D in a 24-week placebo-controlled study. The most common SFUs used by patients in the study were glimepiride (31%), glibenclamide (26%), and gliclazide (26%, not available in the United States). Patients previously treated with an SFU and MET with inadequate glycemic control were randomized to receive linagliptin 5 mg or placebo, each administered once daily. In combination with an SFU and MET, linagliptin provided statistically significant improvements in A1C and FPG compared with placebo (Table 10-2). Change from baseline in body weight did not differ significantly between the groups.

Linagliptin Added to Pioglitazone as Initial Therapy

Linagliptin plus pioglitazone as initial combination treatment was evaluated in a 24-week, placebo-controlled study in drug-naïve or previously treated patients with T2D. After appropriate washout and placebo run-in periods, patients were randomized to receive pioglitazone 30 mg plus placebo or linagliptin 5 mg plus pioglitazone 30 mg, both once daily. After 24 weeks of treatment, the adjusted mean change in A1C from baseline for linagliptin plus pioglitazone was -1.1 compared with -0.6 for placebo plus pioglitazone. The difference in the adjusted mean A1C between the linagliptin and placebo groups was -0.5 (P <0.0001). Patients taking linagliptin plus pioglitazone compared with those receiving placebo plus pioglitazone were more likely to achieve an A1C of <7.0% (42.9% vs 30.5%, respectively; P = 0.0051) and reduction in A1C of ≥0.5% (75.0% vs 50.8%, respectively; P <0.0001). Reductions in FPG were significantly greater for linagliptin plus pioglitazone than with placebo plus pioglitazone.

Overall, the proportion of patients that experienced at least one AE was similar in both groups (52.5% and 53.1% in the linagliptin plus pioglitazone and placebo plus pioglitazone, respectively). Most AEs were of mild or moderate intensity. Weight increase, the most frequently reported drug-related AE, occurred in 2.3% and 0.8% of the linagliptin plus pioglitazone and placebo plus pioglitazone arms, respectively. Hypoglycemic events (mostly mild) occurred in 1.2% of the linagliptin plus pioglitazone group and in none of the patients receiving placebo plus pioglitazone.

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Cardiovascular Outcomes Trial of Linagliptin

The CV outcomes of linagliptin were investigated in CAROLINA, a randomized, double-blind, active-controlled, noninferiority trial which compared the CV safety of linagliptin and glimepiride. CAROLINA enrolled 6042 patients with T2D and established atherosclerotic CV disease or CV risk factors. Patients were randomized (1:1) to receive 5 mg oral linagliptin once daily or glimepiride (1 mg escalated up to 4 mg) once daily. The primary endpoint was time to first occurrence of CV death, nonfatal myocardial infarction, or nonfatal stroke (3P-MACE). Secondary endpoints included 4P-MACE (time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina). The primary outcome (3P-MACE) occurred in 11.8% of the participants taking linagliptin and 12.0% of the participants taking glimepiride (HR 0.98; P <0.001 for non-inferiority). Because the criterion for superiority was not met (P=0.76), other outcomes were not statistically analyzed; however, 4P-MACE occurred with similar frequency in the linagliptin group (13.2%) compared to the glimepiride group (13.3%). In summary, linagliptin was non-inferior to glimepiride with respect to the risk of composite CV outcomes in adult patients with T2D and elevated CV risk.

Long-Term Treatment

The efficacy of linagliptin is being evaluated in a 104-week, double-blind, glimepiride-controlled, noninferiority trial in patients with T2D with insufficient glycemic control despite MET therapy. Patients being treated with MET only entered a run-in period of 2-weeks duration, whereas patients pretreated with MET and one additional OAD entered a run-in treatment period of 6-weeks duration with MET monotherapy (dose of ≥1500 mg/day) and washout of the other agent. After an additional 2-week placebo run-in period, patients were randomized 1:1 to the addition of linagliptin 5 mg once daily or glimepiride. Glimepiride was given as an initial dose of 1 mg/day, then electively titrated over the next 12 weeks to a maximum dose of 4 mg/day as needed to optimize glycemic control. Thereafter, the glimepiride dose was to be kept constant, except for down-titration to prevent hypoglycemia. After 52 weeks, linagliptin and glimepiride both had reductions from baseline in A1C (-0.4% for linagliptin, -0.6% for glimepiride) from a baseline mean of 7.7%. Patients treated with linagliptin exhibited a significant mean decrease from baseline body weight compared with a significant weight gain in patients administered glimepiride (-1.1 kg vs +1.4 kg, P <0.0001).

Adverse Events With Linagliptin

In placebo-controlled clinical trials, nasopharyngitis was the most common adverse reaction, occurring in ≥5% of patients (5.8% vs 5.5% with linagliptin and placebo, respectively). Adverse reactions reported in ≥2% of patients treated with linagliptin in combination with pioglitazone, SFU, or MET and at least 2-fold more commonly than in patients in the placebo groups were nasopharyngitis (4.3% vs 1.2% when combined with an SFU), hyperlipidemia (2.7% vs 0.8% when combined with pioglitazone), cough (2.4% vs 1.1% when combined with MET), hypertriglyceridemia (2.4% vs 0.0% when combined with an SFU) and weight gain (2.3% vs 0.8% in combination with pioglitazone).

Prescribing Linagliptin

The recommended dose of linagliptin, as monotherapy or combination or add-on therapy, is 5 mg once daily. Linagliptin can be taken with or without food. When linagliptin is used in combination with an insulin secretagogue (eg, SFU), a lower dose of the insulin secretagogue may be required to reduce the risk of hypoglycemia. No dose adjustment is recommended for patients who have impaired renal or liver function.

Linagliptin Fixed-Dose Combination With Metformin (Jentadueto)

Linagliptin is also available in a fixed-dose, single-tablet formulation containing saxagliptin and MET (Jentadueto). This combination formulation is indicated as an adjunct to diet and exercise to improve glycemic control in adults with T2D when treatment with both linagliptin and MET is appropriate. This fixed-dose, single-tablet combination of linagliptin and MET has not been studied specifically in patients with an inadequate response to insulin with MET. However, the addition of linagliptin in patients with inadequate glycemic control despite insulin with/without MET and with/with pioglitazone was shown in a 24-week clinical trial. As a result, Jentadueto was recently approved in Europe as add-on treatment in patients receiving insulin.

Prescribing Jentadueto

The starting dosage of Jentadueto should be individualized on the basis of the patient’s current regimen. Jentadueto should be given twice daily with meals, with gradual dose escalation to reduce the GI side effects due to MET. The maximum recommended dose is 2.5 mg linagliptin/1000 mg MET bid. The following dosage forms are available:

• 2.5 mg linagliptin/500 mg MET hydrochloride
• 2.5 mg linagliptin/850 mg MET hydrochloride
• 2.5 mg linagliptin/1000 mg MET hydrochloride.

Linagliptin Fixed-Dose Combination With Empagliflozin (Glyxambi)

Glyxambi is a once-daily tablet taken in the morning that combines 10 mg or 25 mg of empagliflozin, an SGLT2 inhibitor, with 5 mg of linagliptin, a DPP-4 inhibitor. It is indicated as an adjunct to diet and exercise to improve glycemic control in adults with T2D when treatment with both empagliflozin and linagliptin is appropriate. Glyxambi should not be used in patients with severe renal impairment, end-stage renal disease, or dialysis. Glyxambi was the first diabetes treatment to combine the dual mechanisms of action of an SGLT2 inhibitor and a DPP-4 inhibitor in a fixed-dose formulation.

The efficacy and safety of Glyxambi (10/5 mg and 25/5 mg) compared with empagliflozin (10 mg or 25 mg) or linagliptin (5 mg) individually was evaluated in 686 adults with T2D and A1C between 7.0 and 10.5%, who were also taking high-dose metformin (mean dose 1889 mg daily). The study examined the change from baseline in A1C at 24 weeks, and demonstrated superior A1C reduction with Glyxambi compared with the individual components of empagliflozin or linagliptin (Figure 10-7). Starting from a mean baseline of approximately 8.0%, those receiving empagliflozin/linagliptin achieved mean A1C levels of 6.9% with the 10/5-mg dose and 6.7% with the 25/5-mg dose at 24 weeks compared with 7.3% and 7.4% with empagliflozin 10 and 25 mg, respectively, and 7.3% with linagliptin 5 mg.

The recommended dose of Glyxambi is 10 mg empagliflozin/5 mg linagliptin once daily, taken in the morning, with or without food. In patients tolerating Glyxambi, the dose may be increased to 25 mg empagliflozin/5 mg linagliptin once daily.

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Linagliptin Fixed-Dose Combination With Empagliflozin and Metformin (Trijardy XR)

Trijardy XR is a fixed dose combination of the SGLT2 inhibitor empagliflozin, linagliptin, and metformin; it is available in four extended-release tablet formulations:

• 5 mg empagliflozin/2.5 mg linagliptin/1000 mg metformin
• 10 mg empagliflozin/5 mg linagliptin/1000 mg metformin
• 12.5 mg empagliflozin/2.5 mg linagliptin/1000 mg metformin
• 25 mg empagliflozin/5 mg linagliptin/1000 mg metformin.

Trijardy XR is indicated as an adjunct to diet and exercise to improve glycemic control in adults with T2D. Trijardy XR is contraindicated in patients with an eGFR of < 30 mL/min/1.73 m², ESRD, or patients on dialysis.

The safety and efficacy of Trijardy XR were established in a randomized, double-blind, active-controlled trial involving a total of 686 patients on a baseline therapy of metformin. Participants were randomized into one of five groups: 1) linagliptin 5 mg in combination with empagliflozin 25 mg; 2) linagliptin 5 mg in combination with empagliflozin 10 mg; 3) empagliflozin 25 mg; 4) empagliflozin 10 mg; and 5) linagliptin 5 mg. The combination treatment groups demonstrated superior glycemic control compared to their individual components. The change from baseline in A1C levels was significantly greater in the linagliptin 5 mg/empagliflozin 25 mg group (-1.2%) compared to either linagliptin 5 mg (-0.7%; treatment difference -0.5% [95% CI: -0.7%, -0.3%]; P <0.0001) or empagliflozin 25 mg (-0.6%; treatment difference -0.6% [95% CI: -0.7%, -0.4%]; P <0.0001) alone. Similarly, a significantly greater change from baseline in A1C was achieved in the linagliptin 5 mg/empagliflozin 10 mg group (-1.1%) than in the linagliptin 5 mg (-0.7%; treatment difference -0.4% [95% CI: -0.6%, -0.2%]; P <0.0001) group or empagliflozin 10 mg (-0.7%; treatment difference -0.4% [95% CI: -0.6%, -0.2%]; P <0.0001) group.

The recommended starting dose of Trijardy XR should be individualized depending on the patient’s current regimen: in patients on metformin but not empagliflozin (and regardless of linagliptin), the dose of Trijardy XR should contain a similar total daily dose of metformin and a total daily dose of empagliflozin 10 mg and linagliptin 5 mg; in patients on metformin and empagliflozin (regardless of linagliptin), the starting dose of Trijardy XR should contain a similar total daily dose of metformin and empagliflozin and linagliptin 5 mg. Trijardy XR tablets are taken once a day, during a morning meal.

Alogliptin (Nesina)

Alogliptin, the fourth selective DPP-4 inhibitor, was recently approved by the FDA as an adjunct to diet and exercise to improve glycemic control in adults with T2D.

The pharmacokinetic parameters of alogliptin are similar in healthy subjects and in patients with T2D. The absolute bioavailability of alogliptin is approximately 100%. Administration of alogliptin with a high-fat meal results in no significant change in total and peak exposure to alogliptin. Therefore, linagliptin may be administered with or without food. After administration of single oral doses up to 800 mg in healthy subjects, the peak plasma alogliptin concentration (median T_max) occurred 1 to 2 hours after dosing. At the maximum recommended clinical dose of 25 mg, alogliptin is eliminated with a mean terminal half-life of approximately 21 hours. Alogliptin does not undergo extensive metabolism and 60% to 71% of the dose is excreted as unchanged drug in the urine. Studies in healthy subjects and patients with T2D with normal or various degrees of renal function indicate that dosage adjustment is necessary in patients with moderate or severe renal impairment. In patients with moderate renal impairment (CrCl ≥30 to <60 mL/min) an approximate 2-fold increase in plasma AUC of alogliptin was observed, and in those with severe renal impairment (CrCl ≥15 to <30 mL/min) and end-stage renal disease (CrCl <15 mL/min or requiring dialysis), an approximate 3- and 4-fold increase in plasma AUC of alogliptin were observed, respectively.

Efficacy

The glycemic efficacy of alogliptin was assessed in nine randomized, double-blind, placebo- or active-controlled studies as monotherapy and in combination with MET, an SFU, a TZD (either alone or in combination with MET or an SFU), and insulin (either alone or in combination with MET) in a total of 8673 patients with T2D. Three trials were performed in patients with inadequate glycemic control with diet and exercise, while the patients in six trials had failed treatment with one or more antihyperglycemic agents. Overall, treatment with alogliptin resulted clinically meaningful and statistically significant improvements in A1C and FPG compared with placebo. The reductions in A1C and fasting plasma glucose appeared to be related to the degree of A1C elevation at baseline.

Patients with Inadequate Glycemic Control on Diet and Exercise

Three 26-week placebo- or active-controlled studies in a total of 1768 patients assessed the glycemic efficacy of alogliptin as monotherapy or in combination with MET or pioglitazone. All three studies had a 4-week, single-blind, placebo run-in period followed by a 26-week randomized treatment period. The mean changes from baseline in A1C, FPG, and proportion of patient achieving A1C ≤7% are summarized in Table 10-3.

Alogliptin Monotherapy

In one study, monotherapy with alogliptin 25 mg qd resulted in statistically significant placebo-subtracted reductions in A1C. A greater proportion of patients in the alogliptin group achieved the ≤7.0% A1C target. In addition, reductions in FPG were significantly greater with alogliptin compared with placebo (-16 mg/dL and +11, respectively; difference -28 mg/dL; P <0.01). Improvements in A1C were not affected by gender, age, or baseline BMI. The mean change in body weight with alogliptin was similar to placebo.

Alogliptin Add-On to Metformin

In the second 26-week trial, patients were randomized to one of seven treatment groups: placebo; alogliptin 12.5 mg bid, MET 500 mg or 1000 mg bid, alogliptin 12.5 mg bid in combination with MET 500 mg bid or MET 1000 mg bid. Both combination regimens resulted in statistically significant improvements in A1C compared with their respective individual alogliptin and MET component regimens. Significantly greater proportions of patients in both combination regimens achieved the ≤7.0% A1C target compared with the alogliptin or MET monotherapy groups. Compared with alogliptin monotherapy, the combinations of alogliptin 12.5 mg bid with either MET 500 or 1000 mg bid resulted in significantly greater comparator-subtracted reductions in FPG (-22 mg/dL and -36 mg/dL, P <0.05 for both).

Similarly, compared with either MET monotherapy regimen, both combinations of alogliptin and MET produced significantly greater net decreases in FPG (-20 mg/dL with alogliptin bid + MET 500 bid and -14 mg/dL with alogliptin bid + MET 1000 bid; P <0.05 for both). In a subgroup of 193 patients who underwent a standard meal challenge, there were significantly greater reductions in 2-hour PPG levels compared with alogliptin alone (-25 mg/dL and -43 mg/dL with 12,5 mg alogliptin with MET 500 mg or 1000 mg bid, respectively, compared with alogliptin 12.5 mg bid) or MET alone (-19 mg/dL and -32 mg/dL with 12.5 mg alogliptin with MET 500 mg or 1000 mg bid, respectively, compared with MET 500 mg or 1000 mg bid).

Alogliptin With or Without Pioglitazone

In the third 26-week, active-controlled study, patients with a mean baseline A1C of 8.8% were treated with alogliptin 25 mg qd alone, pioglitazone 30 mg qd alone, or alogliptin 25 mg qd in combination with pioglitazone 30 mg qd. Coadministration of alogliptin 25 mg with pioglitazone 30 mg resulted in statistically significant (P <0.01) improvements from baseline both in A1C and FPG compared with either of the components alone. Almost twice the number of patients treated with the combination regimen achieved the ≤7% A1C target goal compared with alogliptin or pioglitazone monotherapy (63% vs 24% and 34%, respectively).

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Patients With Inadequate Glycemic Control on One or More Agents

The efficacy of alogliptin in combination with MET, an SFU, a TZD (either alone or in combination with MET or an SFU) and insulin (either alone or in combination with MET) was assessed in six double-blind, placebo- and/or active-controlled studies. All patients entered a 4-week, single-blind, placebo run-in period prior to randomization. The mean changes from baseline in A1C are summarized in Table 10-4.

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Alogliptin Added to MET

Two 26-week studies were performed in patients inadequately controlled on MET at a dose of at least 1500 mg per day or at the maximum tolerated dose. Patients were maintained on a stable dose of MET (median dose = 1700 mg) during the treatment period.

In the first placebo-controlled trial, the addition of alogliptin 25 mg qd to MET resulted in statistically significant improvements from baseline in A1C (placebo-subtracted change -0.5). The placebo-subtracted decrease in FPG with alogliptin also was statistically significant (17 mg/dL; P <0.001). Significantly more patients who received the combination of alogliptin and MET achieved the ≤7% target goal compared with those who received MET and placebo (44% vs 18%; P <0.001).

Alogliptin With/Without Pioglitazone Added to MET

In the second 26-week double-blind, placebo- and active-controlled study, patients already on MET were treated with either placebo; alogliptin 25 mg alone; 15 mg, 30 mg, or 45 mg of pioglitazone alone; or 12.5 mg or 25 mg of alogliptin in combination with 15 mg, 30 mg, or 45 mg of pioglitazone. Patients were maintained on a stable dose of MET. All three combination regimens of alogliptin and pioglitazone provided statistically significant improvements in A1C and the proportions of patients achieving the ≤7% target goal compared with placebo, to alogliptin alone, or to pioglitazone alone when added to background MET. In addition, all three combinations produced significant reductions in FPG (-38 mg/dL, -42 mg/dL, and -53 mg/dL with alogliptin 25 mg combined with pioglitazone 15 mg, 30 mg, or 45 mg, respectively (all P <0.01 compared with placebo and the corresponding dosages of alogliptin or pioglitazone).

Alogliptin or Pioglitazone and MET

In a 52-week, active-comparator study, patients inadequately controlled on a current regimen of pioglitazone 30 mg and MET (at least 1500 mg/day at the maximum tolerated dose) were randomized to receive the addition of alogliptin 25 mg, pioglitazone 15 mg, 30, or 45 mg, or combinations of alogliptin 25 mg with either pioglitazone or MET. Patients were maintained on a stable dose of MET (median dose = 1,700 mg). When added to pioglitazone and MET, alogliptin 25 mg resulted in a statistically superior decrease in A1C (-0.4) and FPG (-15 mg/dL and -4 mg/dL; alogliptin add-on compared with pioglitazone/MET combination) at week 52.

Alogliptin Add-On to Pioglitazone and MET With/Without an SFU

In a 26-week, placebo-controlled study, patients inadequately controlled with a TZD alone or in combination with MET or an SFU (10 mg) were treated with alogliptin 25 mg qd or placebo. Patients were maintained on a stable dose of pioglitazone (median dose = 30 mg) during the treatment period; those who were also previously treated with MET (median dose = 2000 mg) or an SFU (median dose = 10 mg) prior to randomization were maintained on the combination therapy during the treatment period. The addition of alogliptin 25 mg qd to pioglitazone therapy resulted in statistically significant improvements from baseline in A1C and FPG compared with the addition of placebo to pioglitazone. A significantly greater proportion of patients achieved the ≤7% target goal.

Alogliptin Add-On to Glyburide

The efficacy of alogliptin as an add-on to an SFU was evaluated in a 26-week, placebo-controlled study in which patients inadequately controlled on an SFU were treated with alogliptin 25 mg qd or placebo as added to an SFU. Patients were maintained on a stable dose of glyburide (median dose = 10 mg) during the treatment period. The addition of alogliptin 25 mg to glyburide therapy resulted in statistically significant improvements from baseline in A1C (-0.5) and FPG (-11 mg/dL) compared with placebo.

Add-On to Insulin With/Without MET

Alogliptin as add-on in patients inadequately controlled on insulin alone (42%) or in combination with MET (58%) (mean baseline A1C = 9.3%) were treated with alogliptin 25 mg qd or placebo. Patients were maintained on their insulin regimen (median dose = 55 IU) upon randomization and those previously treated with insulin in combination with MET (median dose = 1700 mg) prior to randomization continued on the combination regimen. Patients entered the trial on short-, intermediate-, or long-acting (basal) insulin or premixed insulin. Alogliptin 25 mg qd added on to insulin therapy resulted in statistically significant placebo-subtracted improvement from baseline in A1C (-0.6) and FPG (-18 mg/dL). Clinically meaningful reductions in A1C were observed with alogliptin compared with placebo regardless of whether subjects were receiving concomitant MET and insulin (-0.2% placebo vs -0.8% alogliptin therapy or insulin alone (-0.1% placebo vs -0.7% alogliptin). Improvements in A1C were not affected by baseline insulin dose.

Cardiovascular Outcomes

The long-term CV safety of alogliptin was examined in a randomized, placebo-controlled clinical study (EXAMINE) in approximately 5400 patients with a high-risk of CVD, followed over 4.5 years. Patients with T2D and either an acute MI or unstable angina requiring hospitalization within the previous 15 to 90 days were randomized to receive alogliptin or placebo in addition to existing antihyperglycemic and CV drug therapy. The primary objective was to demonstrate the noninferiority of alogliptin vs placebo on major CV events in these patients.

Results from EXAMINE indicated that rates of major adverse CV events were not increased with alogliptin compared with placebo. A composite of CV death, nonfatal MI, and nonfatal stroke was reported in 11.3% of patients assigned to alogliptin and in 11.8% of patients assigned to placebo (HR, 0.96; upper boundary of the one-sided repeated CI, 1.16; P <0.001 for noninferiority). Glycated hemoglobin levels were significantly lower with alogliptin than with placebo (mean difference, -0.36 percentage points; P <0.001).

In the SAVOR-TIMI 53 trial, treatment with saxagliptin did not significantly affect the rate of ischemic events compared with placebo; however, the rate of hospitalization for heart failure was increased. This concern about the CV safety of DPP-4 inhibitors led to the investigation of hospital admission rates for heart failure in patients receiving alogliptin in the EXAMINE trial. The prespecified exploratory MACE endpoint was a composite of all-cause mortality, nonfatal MI, nonfatal stroke, urgent revascularization due to unstable angina, and hospital admission for heart failure. This exploratory endpoint was observed in 16.0% of alogliptin-treated patients compared with 16.5% of patients in the placebo group (HR 0.98, 95% CI 0.86-1.12). The post-hoc analyses were of CV death and hospital admission for heart failure, assessed by history of heart failure and brain natriuretic peptide concentration at baseline. Alogliptin had no effect on this post-hoc composite (HR 1.00; 95% CI 0.82-1.21).

Adverse Events

Alogliptin as monotherapy or in combination with other OADs was generally well tolerated, with most adverse reactions being of mild or moderate intensity. In a pooled analysis of 14 controlled clinical trials, the overall incidence of AEs was 66% in patients treated with alogliptin 25 mg compared with 62% with placebo and 70% with an active comparator. The incidence of discontinuations due to AEs was 4.7% with alogliptin 25 mg compared with 4.5% with placebo or 6.2% with an active comparator. Adverse reactions reported in ≥4% of patients treated with alogliptin and more frequently than in patients who received placebo were:

• Nasopharyngitis
• Headache
• Upper respiratory tract infection.

The incidence of hypoglycemic events in patients treated with alogliptin in placebo- and active-controlled trials was generally low and the events were not considered to be severe except for one event in the add-on to insulin trial. The rate of hyperglycemia was highest when alogliptin was added to insulin with/without MET (27% vs 24% with placebo) and lowest when alogliptin was added to MET (0% vs 3% with placebo, respectively). The rates of hyperglycemia with alogliptin were lower than those with glipizide alone (5.4% vs 26%, respectively) and when alogliptin or glipizide was added to MET (1.4% vs 23.8%, respectively).

Prescribing Alogliptin

The recommended dose of alogliptin is 25 mg once daily in patients with normal renal function or mild renal impairment.

The dose should be adjusted in patients with moderate or severe renal impairment or ESRD:

• In moderate renal impairment (CrCl ≥30 to <60 mL/min) the recommended dose is 12.5 mg once daily.
• In severe/renal impairment/ESRD (CrCl <30 mL/min) the recommended dose is 6.25 mg once daily.

Alogliptin is available in three dosage strength tablets: 6.25 mg, 12.5 mg, and 25 mg.

Alogliptin Fixed-Dose Combination With Metformin (Kazano)

Alogliptin is also available in a fixed-dose, single-tablet formulation containing alogliptin and MET (Kazano).

This combination formulation is indicated as an adjunct to diet and exercise to improve glycemic control in adults with T2D. This fixed-dose, single-tablet combination of alogliptin and MET has not been studied specifically in patients with an inadequate response to insulin. However, the combination of alogliptin with/without MET administered separately was shown to be effective in patients with an inadequate response to insulin (Table 10-4).

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Prescribing Kazano

The starting dose of Kazano should be individualized on the basis of the patient’s current regimen. Kazano should be taken twice daily with food. The dosage may be adjusted based on effectiveness and tolerability, while not exceeding the maximum recommended daily dose of 25 mg alogliptin and 2,000 mg MET.

Kazano is available as tablets containing:

• 12.5 mg alogliptin and 500 mg MET
• 12.5 mg alogliptin and 1,000 mg MET.

Alogliptin Fixed-Dose Combination With Pioglitazone (Oseni)

Alogliptin is also available in a fixed-dose, single-tablet formulation containing alogliptin and pioglitazone. It is currently the only single-tablet combination formulation of a DPP-4 inhibitor and pioglitazone.

This combination formulation is indicated as an adjunct to diet and exercise to improve glycemic control in adults with T2D. The combination of alogliptin and pioglitazone administered separately or as a fixed-dose, single-tablet formulation has not been studied in patients with an inadequate response to insulin.

Prescribing Oseni

The starting dose of Oseni should be individualized on the basis of the patient’s current regimen and concurrent medical condition but not to exceed a daily dose of alogliptin 25 mg and pioglitazone 45 mg.

• In patients with NYHA Class I or II heart failure, the initial dose of pioglitazone should limited to 15 mg once daily. Oseni should not be used in patients with established NYHA Class III or IV heart failure.
• In patients with moderate renal impairment (CrCl ≥30 to <60 mL/min), the recommended dosages are 12.5 mg alogliptin/15 mg pioglitazone, 12.5 mg alogliptin/30 mg pioglitazone, and 2.5 mg alogliptin/45 mg pioglitazone. Oseni is not recommended for patients with severe renal impairment or ESRD requiring dialysis.
• The maximum recommended dose of pioglitazone is 15 mg once daily in patients taking strong CYP2C8 inhibitors (eg, gemfibrozil).

Oseni is available as tablets containing:

• 25 mg alogliptin and 15 mg pioglitazone
• 25 mg alogliptin and 30 mg pioglitazone
• 25 mg alogliptin and 45 mg pioglitazone
• 12.5 mg alogliptin and 15 mg pioglitazone
• 12.5 mg alogliptin and 30 mg pioglitazone
• 12.5 mg alogliptin and 45 mg pioglitazone.

Summary

The introduction of DPP-4 inhibitors over a decade ago represented a significant advance in the treatment of T2D, especially after the thiazolidinediones fell out of favor. Not only are they effective in improving overall glycemic control as indicated by the FBG and PPG values and A1C, but at the same time they are either weight neutral or lead to weight loss. These effects on weight are very important since weight gain associated with intensification of therapy in an effort to normalize or near normalize A1C is a significant challenge in clinical practice.The combination of DPP-4 inhibitors with MET appears to be not only effective in terms of metabolic outcomes but also safe in terms of a lower risk of hypoglycemia. It also appears that the weight gain seen with SFUs and TZDs is blunted when these agents are combined with this class of antidiabetic agents. The CV outcome trials for all of the DPP-4 inhibitors were neutral and the side effect profile for this class of agents is very tolerable. They have taken a back seat in the treatment armamentarium to SGLT2 inhibitors but still play an important therapeutic role around the US and around the world.