Sitagliptin and Ertugliflozin interacts in the following cases:
In patients with an eGFR ≥45 to <60 mL/min/1.73 m², Steglujan should be initiated at 5 mg/100 mg and up-titrated to 15 mg/100 mg as needed for glycaemic control.
Because the glycaemic lowering efficacy of ertugliflozin is reduced in patients with moderate renal impairment, if further glycaemic control is needed, the addition of other anti-hyperglycaemic agents should be considered.
Ertugliflozin/sitagliptin has not been studied in patients with severe hepatic impairment and is not recommended for use in these patients.
There are no data from the use of ertugliflozin/sitagliptin in pregnant women. There are limited data from the use of ertugliflozin in pregnant women. Based on results from animal studies, ertugliflozin may affect renal development and maturation. Therefore, ertugliflozin/sitagliptin should not be used during pregnancy.
There is no information regarding the presence of ertugliflozin/sitagliptin or its individual components in human milk, the effects on the breast-fed infant, or the effects on milk production. No studies in lactating animals have been conducted with the combined components of ertugliflozin/sitagliptin. Ertugliflozin and sitagliptin are present in the milk of lactating rats. Ertugliflozin caused effects in the offspring of lactating rats.
Pharmacologically mediated effects were observed in juvenile rats treated with ertugliflozin. Since human kidney maturation occurs in utero and during the first 2 years of life when exposure from breast-feeding may occur, a risk to newborns/infants cannot be excluded. Ertugliflozin/sitagliptin should not be used during breast-feeding.
The effect of Steglujan on fertility in humans has not been studied. No effects of ertugliflozin or sitagliptin on fertility were observed in animal studies.
Ertugliflozin/sitagliptin combination has no or negligible influence on the ability to drive and use machines. However, when driving or using machines, it should be taken into account that dizziness and somnolence have been reported with sitagliptin. In addition, patients should be alerted to the risk of hypoglycaemia when ertugliflozin/sitagliptin is used in combination with insulin or an insulin secretagogue and to the elevated risk of adverse reactions related to volume depletion, such as postural dizziness.
The safety of concomitantly administered ertugliflozin and sitagliptin has been evaluated in 990 patients with type 2 diabetes mellitus treated for 26 weeks in three studies; a factorial study of ertugliflozin 5 mg or 15 mg in combination with sitagliptin 100 mg once daily compared to the individual components, a placebo-controlled study of ertugliflozin 5 mg or 15 mg as add-on therapy to sitagliptin 100 mg and metformin once daily, and a placebo-controlled study of initial therapy with ertugliflozin 5 mg or 15 mg once daily in combination with sitagliptin 100 mg once daily. The incidence and type of adverse reactions in these three studies were similar to the adverse reactions seen with the individual monotherapies ertugliflozin and sitagliptin as described below in Table 1.
The safety and tolerability of ertugliflozin were assessed in 7 placebo- or active comparator-controlled studies with a total of 3 409 patients with type 2 diabetes mellitus treated with ertugliflozin 5 mg or 15 mg. In addition, the safety and tolerability of ertugliflozin in patients with type 2 diabetes and established atherosclerotic cardiovascular disease were assessed in VERTIS CV with a total of 5 493 patients treated with ertugliflozin 5 mg or 15 mg and a mean duration of exposure of 2.9 years.
The primary assessment of safety was conducted in a pool of three 26-week, placebo-controlled trials. Ertugliflozin was used as monotherapy in one trial and as add-on therapy in two trials. These data reflect exposure of 1 029 patients to ertugliflozin with a mean exposure duration of approximately 25 weeks. Patients received ertugliflozin 5 mg (N=519), ertugliflozin 15 mg (N=510), or placebo (N=515) once daily.
The most commonly reported adverse reactions across the clinical program were urinary tract infections, vulvovaginal mycotic infection and other female genital mycotic infections. Serious DKA occurred rarely.
Serious adverse reactions including pancreatitis and hypersensitivity reactions have been reported. Hypoglycaemia has been reported in combination with sulphonylurea (4.7%-13.8%) and insulin (9.6%).
Adverse reactions listed below are classified according to frequency and system organ class (SOC), within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness. Frequency categories are defined according to the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1 000 to <1/100), rare (≥1/10 000 to <1/1 000), very rare (<1/10 000), not known (cannot be estimated from the available data).
Adverse reactions from placebo- and active comparator-controlled clinical trials and post-marketing experience:
| System organ class Frequency | Adverse reaction |
|---|---|
| Infections and infestations | |
| Very common | Urinary tract infections†,1 Vulvovaginal mycotic infection and other female genital mycotic infections†,1 |
| Common | Balanitis candida and other male genital mycotic infections†,1 |
| Not known | Necrotising fasciitis of the perineum (Fournier’s gangrene) |
| Blood and lymphatic system disorders | |
| Rare | Thrombocytopenia2 |
| Immune system disorders | |
| Not known | Hypersensitivity reactions including anaphylactic responsesa,2 |
| Metabolism and nutrition disorders | |
| Common | Hypoglycaemia†,1,2 |
| Rare | DKA†,1 |
| Nervous system disorders | |
| Common | Headache2 |
| Uncommon | Dizziness2 |
| Respiratory, thoracic and mediastinal disorders | |
| Not known | Interstitial lung diseasea,2 |
| Gastrointestinal disorders | |
| Uncommon | Constipation2 |
| Not known | Fatal and non-fatal haemorrhagic and necrotising pancreatitisa,2 Acute pancreatitisa,b,2 Vomitinga,2 |
| Skin and subcutaneous tissue disorders | |
| Uncommon | Pruritusa,2 |
| Not known | Exfoliative skin conditions including Stevens-Johnson syndromea,2 Angioedemaa,2 Bullous pemphigoida,2 Cutaneous vasculitisa,2 Rasha,2 Urticariaa,2 |
| Musculoskeletal and connective tissue disorders | |
| Not known | Arthropathya,2 Back paina,2 Arthralgiaa,2 Myalgiaa,2 |
| Vascular disorders | |
| Common | Volume depletion†,1 |
| Renal and urinary disorders | |
| Common | Increased urination‡,1 |
| Uncommon | Dysuria1, Blood creatinine increased/Glomerular filtration rate decreased†,1 |
| Not known | Acute renal failurea,2 Impaired renal functiona,2 |
| Reproductive system and breast disorders | |
| Common | Vulvovaginal pruritus1 |
| General disorders and administration site conditions | |
| Common | Thirst§,1 |
| Investigations | |
| Common | Serum lipids changed¶,1, Haemoglobin increased**1, BUN increased¶¶,1 |
1 Adverse reaction with ertugliflozin.
2 Adverse reaction with sitagliptin.
† See subsections below for additional information.
‡ Includes: pollakiuria, micturition urgency, polyuria, urine output increased, and nocturia.
§ Includes: thirst and polydipsia.
¶ Mean percent changes from baseline for ertugliflozin 5 mg and 15 mg versus placebo, respectively, were low-density lipoprotein cholesterol (LDL-C) 5.8% and 8.4% versus 3.2%; total cholesterol 2.8% and 5.7% versus 1.1%; however, high-density lipoprotein cholesterol (HDL-C) 6.2% and 7.6% versus 1.9%. Median percent changes from baseline for ertugliflozin 5 mg and 15 mg versus placebo, respectively, were triglycerides -3.9% and -1.7% versus 4.5%.
** The proportion of subjects having at least 1 increase in haemoglobin >2.0 g/dL was higher in the ertugliflozin 5 mg and 15 mg groups (4.7% and 4.1%, respectively) compared to the placebo group (0.6%).
¶¶ The proportion of subjects having any occurrence of blood urea nitrogen (BUN) values ≥50% increase and value >upper limit of normal (ULN) was numerically higher in the ertugliflozin 5 mg group and higher in the 15 mg group (7.9% and 9.8%, respectively) relative to the placebo group (5.1%).
a Adverse reactions were identified through post-marketing surveillance.
b See Sitagliptin cardiovascular outcomes study (TECOS) below.
Ertugliflozin causes an osmotic diuresis, which may lead to intravascular volume contraction and adverse reactions related to volume depletion. In the pool of placebo-controlled studies, the incidence of adverse events related to volume depletion (dehydration, dizziness postural, presyncope, syncope, hypotension and orthostatic hypotension) was low (<2%) and not notably different across the ertugliflozin and placebo groups. In the subgroup analyses in the broader pool of phase 3 studies, subjects with eGFR <60 mL/min/1.73 m², subjects ≥65 years of age and subjects on diuretics had a higher incidence of volume depletion in the ertugliflozin groups relative to the comparator group. In subjects with eGFR <60 mL/min/1.73 m², the incidence was 5.1%, 2.6% and 0.5% for ertugliflozin 5 mg, ertugliflozin 15 mg and the comparator group and for subjects with eGFR 45 to <60 mL/min/1.73 m², the incidence was 6.4%, 3.7% and 0% respectively.
In the pool of placebo-controlled studies, the incidence of documented hypoglycaemia was increased for ertugliflozin 5 mg and 15 mg (5% and 4.5%) compared to placebo (2.9%). In this population, the incidence of severe hypoglycaemia was 0.4% in each group. When ertugliflozin was used as monotherapy, the incidence of hypoglycaemic events in the ertugliflozin groups was 2.6% in both groups and 0.7% in the placebo group. When used as add-on to metformin, the incidence of hypoglycaemic events was 7.2% in the ertugliflozin 5 mg group, 7.8% in the ertugliflozin 15 mg group and 4.3% in the placebo group.
When ertugliflozin was added to metformin and compared to sulphonylurea, the incidence of hypoglycaemia was higher for the sulphonylurea (27%) compared to ertugliflozin (5.6% and 8.2% for ertugliflozin 5 mg and 15 mg, respectively).
In the VERTIS CV sub-studies, when ertugliflozin was added to insulin with or without metformin, the incidences of documented hypoglycaemia were 39.4%, 38.9% and 37.5% for ertugliflozin 5 mg, ertugliflozin 15 mg and placebo, respectively. When ertugliflozin was added to a sulphonylurea, the incidences of hypoglycaemia were 7.3%, 9.3% and 4.2% for ertugliflozin 5 mg, ertugliflozin 15 mg and placebo, respectively. When ertugliflozin was added to metformin and a sulphonylurea, the incidences of hypoglycaemia were 20%, 26.5% and 14.5% for ertugliflozin 5 mg, ertugliflozin 15 mg and placebo, respectively.
In patients with moderate renal impairment taking insulins, sulphonylurea, or meglitinides as background medicinal products, documented hypoglycaemia was 36%, 27% and 36% for ertugliflozin 5 mg, ertugliflozin 15 mg, and placebo, respectively.
In VERTIS CV, ketoacidosis was identified in 19 (0.3%) ertugliflozin-treated patients and in 2 (0.1%) placebo-treated patients. Across 7 other phase 3 clinical trials in the ertugliflozin development program, ketoacidosis was identified in 3 (0.1%) ertugliflozin-treated patients and 0 (0%) of comparator-treated patients.
Initial increases in mean creatinine and decreases in mean eGFR in patients treated with ertugliflozin were generally transient during continuous treatment. Patients with moderate renal impairment at baseline had larger mean changes that did not return to baseline at Week 26; these changes reversed after treatment discontinuation.
In VERTIS CV, treatment with ertugliflozin was associated with an initial decrease in mean eGFR (at Week 6, -2.7, -3.8 and -0.4 mL/min/1.73 m² in the ertugliflozin 5 mg, ertugliflozin 15 mg and placebo groups, respectively) followed by a return toward baseline. Long-term, continued treatment with ertugliflozin was associated with a slower decline in eGFR compared to placebo (up to week 260).
In VERTIS CV, the incidences of renal-related adverse reactions (e.g., acute kidney injury, renal impairment, acute prerenal failure) were 4.2%, 4.3% and 4.7% in patients treated with ertugliflozin 5 mg, ertugliflozin 15 mg and placebo respectively in the overall population and were 9.7%, 10% and 10.2% in patients treated with ertugliflozin 5 mg, ertugliflozin 15 mg and placebo respectively in patients with an eGFR from 30 to less than 60 mL/min/1.73 m².
In the pool of three placebo-controlled clinical trials, female genital mycotic infections (e.g., genital candidiasis, genital infection fungal, vaginal infection, vulvitis, vulvovaginal candidiasis, vulvovaginal mycotic infection, vulvovaginitis) occurred in 9.1%, 12%, and 3% of females treated with ertugliflozin 5 mg, ertugliflozin 15 mg, and placebo, respectively. In females, discontinuation due to genital mycotic infections occurred in 0.6% and 0% of patients treated with ertugliflozin and placebo, respectively.
In the same pool, male genital mycotic infections (e.g., balanitis candida, balanoposthitis, genital infection, genital infection fungal) occurred in 3.7%, 4.2%, and 0.4% of males treated with ertugliflozin 5 mg, ertugliflozin 15 mg, and placebo, respectively. Male genital mycotic infections occurred more commonly in uncircumcised males. In males, discontinuations due to genital mycotic infections occurred in 0.2% and 0% of patients treated with ertugliflozin and placebo, respectively. In rare instances, phimosis was reported and sometimes circumcision was performed.
In VERTIS CV, urinary tract infections occurred in 12.2%, 12% and 10.2% of patients treated with ertugliflozin 5 mg, ertugliflozin 15 mg and placebo, respectively. The incidences of serious urinary tract infections were 0.9%, 0.4%, and 0.8% with ertugliflozin 5 mg, ertugliflozin 15 mg and placebo, respectively.
Across 7 other phase 3 clinical trials in the ertugliflozin development program, the incidences of urinary tract infections were 4% and 4.1% for ertugliflozin 5 mg and 15 mg groups and 3.9% for placebo. Most of the events were mild or moderate, and no serious cases were reported.
In addition to the adverse reactions described in the table above, adverse experiences reported regardless of causal relationship to medication and occurring in at least 5% and more commonly in patients treated with sitagliptin included upper respiratory tract infection and nasopharyngitis. Additional adverse experiences reported regardless of causal relationship to medication that occurred more frequently in patients treated with sitagliptin (not reaching the 5% level, but occurring with an incidence of >0.5% higher with sitagliptin than that in the control group) included osteoarthritis and pain in extremity.
Some adverse reactions were observed more frequently in studies of combination use of sitagliptin with other anti-diabetic medicinal products than in studies of sitagliptin monotherapy. These included hypoglycaemia (frequency very common with the combination of sulphonylurea and metformin), influenza (common with insulin (with or without metformin)), nausea and vomiting (common with metformin), flatulence (common with metformin or pioglitazone), constipation (common with the combination of sulphonylurea and metformin), peripheral oedema (common with pioglitazone or the combination of pioglitazone and metformin), somnolence and diarrhoea (uncommon with metformin), and dry mouth (uncommon with insulin (with or without metformin)).
The cardiovascular safety study with sitagliptin (TECOS) included 7 332 patients treated with sitagliptin, 100 mg daily (or 50 mg daily if the baseline eGFR was ≥30 and <50 mL/min/1.73 m²), and 7 339 patients treated with placebo in the intention-to-treat population. Both treatments were added to usual care targeting regional standards for haemoglobin A1c (HbA1c) and cardiovascular (CV) risk factors. The overall incidence of serious adverse events in patients receiving sitagliptin was similar to that in patients receiving placebo.
In the intention-to-treat population, among patients who were using insulin and/or a sulphonylurea at baseline, the incidence of severe hypoglycaemia was 2.7% in sitagliptin-treated patients and 2.5% in placebo-treated patients; among patients who were not using insulin and/or a sulphonylurea at baseline, the incidence of severe hypoglycaemia was 1% in sitagliptin-treated patients and 0.7% in placebo-treated patients. The incidence of adjudication-confirmed pancreatitis events was 0.3% in sitagliptin-treated patients and 0.2% in placebo-treated patients.
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