Combinations of Oral Blood Glucose Lowering Drugs. [Sodium-glucose co-transporter 2 (SGLT2) + Dipeptidyl peptidase 4 (DPP-4) inhibitor].
Pharmacology: Mechanism of action: Dapagliflozin/sitagliptin combination: Dapagliflozin/sitagliptin (Sidapvia) combines the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin and the dipeptidyl peptidase 4 (DPP4) inhibitor sitagliptin with distinct and complementary mechanisms of action to improve glycaemic control. The combination of both agents delivers clinically meaningful reductions in haemoglobin A1c (HbA1c) for improved glycaemic control in patients with type 2 diabetes mellitus. While sitagliptin has a neutral effect on weight, urinary glucose excretion (glucuresis) induced by dapagliflozin is associated with weight loss.
Dapagliflozin: Dapagliflozin is a highly potent, selective, and reversible inhibitor of sodium-glucose cotransporter 2 (SGLT2) that improves glycaemic control in patients with diabetes mellitus and provides cardio-renal benefits.
Inhibition of SGLT2 by dapagliflozin reduces reabsorption of glucose from the glomerular filtrate in the proximal renal tubule with a concomitant reduction in sodium reabsorption leading to urinary excretion of glucose and osmotic diuresis. Dapagliflozin therefore increases the delivery of sodium to the distal tubule which increases tubuloglomerular feedback and reduces intraglomerular pressure. This combined with osmotic diuresis leads to a reduction in volume overload, reduced blood pressure, and lower preload and afterload, which may have beneficial effects on cardiac remodelling and diastolic function, and preserve renal function. Other effects include an increase in haematocrit and reduction in body weight.
The cardio-renal benefits of dapagliflozin go beyond the blood glucose-lowering effect. In addition to the osmotic diuretic and related hemodynamic actions of SGLT2 inhibition, potential secondary effects on myocardial metabolism, ion channels, fibrosis, adipokines and uric acid may be mechanisms underlying the cardio-renal beneficial effects of dapagliflozin.
Dapagliflozin improves both fasting and postprandial plasma glucose levels by reducing renal glucose reabsorption leading to urinary excretion of excess glucose. This glucose excretion (glucuretic effect) is observed after the first dose, is continuous over the 24-hour dosing interval, and is sustained for the duration of treatment. The amount of glucose removed by the kidney through this mechanism is dependent upon the blood glucose concentration and GFR. Thus, in subjects with normal blood glucose and/or low GFR, dapagliflozin has a low propensity to cause hypoglycaemia, as the amount of filtrated glucose is small and can be reabsorbed by SGLT1 and unblocked SGLT2 transporters. Dapagliflozin does not impair normal endogenous glucose production in response to hypoglycaemia. Dapagliflozin acts independently of insulin secretion and insulin action. Over time, improvement in beta-cell function (HOMA-2) has been observed in clinical studies with dapagliflozin.
The majority of weight reduction is body-fat loss, including visceral fat, rather than lean tissue, or fluid loss as demonstrated by dual energy x-ray absorptiometry (DXA) and magnetic resonance imaging (MRI).
SGLT2 is selectively expressed in the kidney. Dapagliflozin does not inhibit other glucose transporters important for glucose transport into peripheral tissues and is greater than 1,400 times more selective for SGLT2 versus SGLT1, the major transporter in the gut responsible for glucose absorption.
Sitagliptin: Sitagliptin is a member of a class of oral anti-hyperglycaemic agents called dipeptidyl peptidase 4 (DPP4) inhibitors. The improvement in glycaemic control observed with this medicinal product may be mediated by enhancing the levels of active incretin hormones. Incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. The incretins are part of an endogenous system involved in the physiologic regulation of glucose homeostasis. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signalling pathways involving cyclic AMP. Treatment with GLP-1 or with DPP4 inhibitors in animal models of type 2 diabetes mellitus has been demonstrated to improve beta cell responsiveness to glucose and stimulate insulin biosynthesis and release. With higher insulin levels, tissue glucose uptake is enhanced. In addition, GLP-1 lowers glucagon secretion from pancreatic alpha cells. Decreased glucagon concentrations, along with higher insulin levels, lead to reduced hepatic glucose production, resulting in a decrease in blood glucose levels. The effects of GLP-1 and GIP are glucose-dependent such that when blood glucose concentrations are low, stimulation of insulin release and suppression of glucagon secretion by GLP-1 are not observed. For both GLP-1 and GIP, stimulation of insulin release is enhanced as glucose rises above normal concentrations. Further, GLP-1 does not impair the normal glucagon response to hypoglycaemia. The activity of GLP-1 and GIP is limited by the DPP4 enzyme, which rapidly hydrolyses the incretin hormones to produce inactive products. Sitagliptin prevents the hydrolysis of incretin hormones by DPP4, thereby increasing plasma concentrations of the active forms of GLP-1 and GIP. By enhancing active incretin levels, sitagliptin increases insulin release and decreases glucagon levels in a glucose-dependent manner. In patients with type 2 diabetes mellitus with hyperglycaemia, these changes in insulin and glucagon levels lead to lower HbA1c and lower fasting and postprandial glucose concentrations. The glucose-dependent mechanism of sitagliptin is distinct from the mechanism of sulphonylureas, which increase insulin secretion even when glucose levels are low and can lead to hypoglycaemia in patients with type 2 diabetes mellitus and in normal subjects. Sitagliptin is a potent and highly selective inhibitor of the enzyme DPP4 and does not inhibit the closely-related enzymes DPP8 or DPP9 at therapeutic concentrations.
Pharmacodynamics: General: Dapagliflozin: Increases in the amount of glucose excreted in the urine were observed in healthy subjects and in patients with type 2 diabetes mellitus following the administration of dapagliflozin. Approximately 70 g of glucose was excreted in the urine per day (corresponding to 280 kcal/day) at a dapagliflozin dose of 10 mg/day in patients with type 2 diabetes mellitus for 12 weeks. This glucose elimination rate approached the maximum glucose excretion observed at 20 mg/day of dapagliflozin. Evidence of sustained glucose excretion was seen in patients with type 2 diabetes mellitus given dapagliflozin 10 mg/day for up to 2 years.
This urinary glucose excretion with dapagliflozin also results in osmotic diuresis and increases in urinary volume. Urinary volume increases in patients with type 2 diabetes mellitus treated with dapagliflozin 10 mg were sustained at 12 weeks and amounted to approximately 375 mL/day. The increase in urinary volume was associated with a small and transient increase in urinary sodium excretion that was not associated with changes in serum sodium concentrations.
Urinary uric acid excretion was also increased transiently (for 3-7 days) and accompanied by a reduction in serum uric acid concentration. At 24 weeks, reductions in serum uric acid concentrations ranged from 0.33 mg/dL to 0.87 mg/dL.
Sitagliptin: In a two-day study in healthy subjects, sitagliptin alone increased active GLP-1 concentrations, whereas metformin alone increased active and total GLP-1 concentrations to similar extents. Co-administration of sitagliptin and metformin had an additive effect on active GLP-1 concentrations. Sitagliptin, but not metformin, increased active GIP concentrations.
Clinical trial information: Clinical efficacy: Treatment with dapagliflozin added-on to sitagliptin (with or without metformin), in type 2 diabetes mellitus patients, produced clinically relevant and statistically significant improvements in mean change from baseline at Week 24 in HbA1c and fasting plasma glucose (FPG) compared to control. Additionally, a clinically relevant and statistically significant reduction in mean change from baseline in body weight was seen at Week 24. In a dedicated clinical study of dapagliflozin to evaluate body composition, decrease in weight was mainly attributable to a reduction in body-fat mass as measured by DXA.
In two studies of dapagliflozin 10 mg in type 2 diabetes mellitus patients with hypertension, statistically significant reductions in mean seated systolic blood pressure (SBP) were seen in patients treated with dapagliflozin 10 mg combined with other oral antidiabetic and antihypertensive treatments (an angiotensin-converting enzyme inhibitor [ACEi] or angiotensin receptor blocker [ARB] in one study and an ACEi or ARB plus one additional antihypertensive treatment in another study) compared to those treated with placebo at Week 12.
Glycaemic control: Add-on of dapagliflozin to sitagliptin alone or in combination with metformin: A total of 452 patients with type 2 diabetes mellitus who were drug naive, or who were treated at entry with metformin or a DPP4 inhibitor alone or in combination, and had inadequate glycaemic control (HbA1c ≥7.0% and ≤10.0% at randomization), participated in a 24-week, placebo-controlled study with a 24-week extension period to evaluate dapagliflozin in combination with sitagliptin with or without metformin.
Eligible patients were stratified based on the presence or absence of background metformin (≥1,500 mg/day) and within each stratum were randomized to either dapagliflozin 10 mg plus sitagliptin 100 mg once daily or placebo plus sitagliptin 100 mg once daily. Endpoints were tested for dapagliflozin 10 mg versus placebo for the total study group (sitagliptin with or without metformin) and for each stratum (sitagliptin alone or sitagliptin with metformin).
Thirty-seven percent (37%) of patients were drug naive, 32% were on metformin alone, 13% were on a DPP4 inhibitor alone, and 18% were on a DPP4 inhibitor plus metformin. Dose titration of dapagliflozin, sitagliptin or metformin was not permitted during the study.
The mean age of the total study population was 54.9 years (18% ≥65 years of age), mean body mass index (BMI) was 32.40 kg/m
2 and 54.8% were male. The mean duration of type 2 diabetes mellitus was 5.67 years and the mean baseline HbA1c was 7.93% (HbA1c was slightly lower in patients using metformin [7.83%] than in patients not using metformin [8.03%]).
In combination with sitagliptin (with or without metformin), dapagliflozin 10 mg provided significant improvements in HbA1c, HbA1c in patients with baseline HbA1c ≥8%, FPG, and significant reduction in body weight compared with the placebo plus sitagliptin (with or without metformin) group at Week 24. These improvements were also seen in the stratum of patients who received dapagliflozin 10 mg plus sitagliptin alone (n=110) compared with placebo plus sitagliptin alone (n=111), and in the stratum of patients who received dapagliflozin 10 mg plus sitagliptin with metformin (n=113) compared with placebo plus sitagliptin with metformin (n=113). Results on primary and key secondary endpoints are displayed in Table 1.
The proportion of patients achieving HbA1c <7% was higher in the dapagliflozin plus sitagliptin (with or without metformin) group (28.3%) compared to the placebo plus sitagliptin (with or without metformin) group (19.4%) at Week 24, using last observation carried forward (LOCF) analysis excluding data after rescue. Nominal p<0.05, for the difference between treatment groups.
The adjusted mean change from baseline in seated SBP in the full study population was -1.8 mmHg in the dapagliflozin plus sitagliptin (with or without metformin) group and 0.8 mmHg in the placebo plus sitagliptin (with or without metformin) group at Week 24, using last observation carried forward (LOCF) analysis including data after rescue. Nominal p<0.05, for the difference between treatment groups.
At Week 48, based on the longitudinal repeated measures analysis excluding data after rescue, adjusted mean change from baseline in HbA1c, HbA1c in patients with HbA1c ≥8% at baseline, FPG, 2-hour postprandial glucose (PPG), and body weight were -0.30%, -0.72%, -19.7 mg/dL, -43.0 mg/dL, and -2.03 kg, respectively, for patients treated with dapagliflozin 10 mg plus sitagliptin with or without metformin, and 0.38%, 0.26%, 13.5 mg/dL, -12.1 mg/dL, and 0.18 kg for patients treated with placebo plus sitagliptin with or without metformin. The mean reduction from baseline in HbA1c for patients treated with dapagliflozin 10 mg plus sitagliptin, compared with patients treated with placebo plus sitagliptin was 0.68% (nominal p<0.0001) at Week 48. For the stratum of patients without metformin, adjusted mean change from baseline in HbA1c for patients treated with dapagliflozin 10 mg plus sitagliptin was 0.00% and placebo plus sitagliptin was 0.85%; and for the stratum of patients with metformin, adjusted mean change from baseline in HbA1c for patients treated with dapagliflozin 10 mg plus sitagliptin was -0.44% and placebo plus sitagliptin was 0.15%.
The proportion of patients at Week 24 and Week 48 who were rescued or discontinued for lack of glycaemic control (adjusted for baseline HbA1c) was higher for sitagliptin with or without metformin (40.5% and 56.5%, respectively) than for dapagliflozin plus sitagliptin with or without metformin (19.5% and 32.6%, respectively). (See Table 1.)
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Glycaemic control in special populations: Use in patients with type 2 diabetes mellitus and hypertension: Dapagliflozin: In two 12-week, placebo-controlled studies, a total of 1,062 patients with inadequately controlled type 2 diabetes mellitus and hypertension were treated with dapagliflozin 10 mg or placebo. Patients with inadequately controlled hypertension (seated systolic blood pressure ≥140 and <165 mmHg, seated diastolic blood pressure ≥85 and <105 mmHg, and a 24-hour mean blood pressure of ≥130/80 mmHg) despite pre-existing stable treatment with an ACEi or ARB (alone [Study 1] or in combination with an additional antihypertensive [Study 2]) as well as inadequate glycaemic control (HbA1c ≥7.0% and ≤10.5%) despite pre-existing stable treatment with oral antidiabetic therapies (OADs) or insulin (alone or in combination) prior to entry, were eligible for these studies. During the studies, no adjustments in antidiabetic and antihypertensive medications were allowed. Across the 2 studies, 527 patients were treated with dapagliflozin 10 mg and 535 with placebo. Patients treated with dapagliflozin 10 mg or placebo also received the following medications for blood pressure control, which were balanced between treatment groups: ACEis (64%), ARBs (36%), thiazide diuretics (16%), calcium channel blockers (9%), and beta-blockers (6%).
At Week 12 for both studies, dapagliflozin 10 mg plus usual treatment provided significant improvement in HbA1c and significant reduction in seated SBP compared with placebo plus usual treatment (see Table 2). Consistent reductions were seen in mean 24-hour ambulatory SBP in patients treated with dapagliflozin 10 mg compared with placebo. There was a small reduction in mean seated diastolic blood pressure in patients treated with dapagliflozin 10 mg that was not statistically significant compared with placebo. (See Table 2.)
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Use in patients with type 2 diabetes mellitus and renal impairment: Dapagliflozin: The glycaemic efficacy and safety of dapagliflozin was evaluated in a dedicated study of patients with eGFR ≥45 to <60 mL/min/1.73 m
2.
In this randomized, double blind, placebo-controlled trial a total of 321 adult patients with type 2 diabetes mellitus and eGFR ≥45 to <60 mL/min/1.73 m
2 (moderate renal impairment subgroup CKD 3A), with inadequate glycaemic control on current treatment regimen, were treated with dapagliflozin 10 mg or placebo. At Week 24, dapagliflozin 10 mg (n=159) provided significant improvements in HbA1c, FPG, body weight and SBP compared with placebo (n=161) (Table 3). The mean change from baseline in HbA1c and the placebo-corrected mean HbA1c change was -0.37% and -0.34%, respectively. The mean change from baseline in FPG and the placebo-corrected mean FPG was -21.46 mg/dL and -16.59 mg/dL, respectively. The mean body weight reduction (percentage) and the placebo-corrected mean body weight reduction was -3.42% and -1.43%, respectively. The mean reduction in seated SBP and the placebo-corrected mean reduction in seated SBP was -4.8 mmHg and -3.1 mmHg, respectively. (See Table 3.)
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The safety profile of dapagliflozin in the study was consistent with that in the general population of patients with type 2 diabetes mellitus. Mean eGFR decreased initially during the treatment period in the dapagliflozin group and subsequently remained stable during the 24-week treatment period (dapagliflozin: -3.39 mL/min/1.73 m
2 and placebo: -0.90 mL/min/1.73 m
2). At 3 weeks after termination of dapagliflozin, the mean change from baseline in eGFR in the dapagliflozin group was similar to the mean change in the placebo group (dapagliflozin: 0.57 mL/min/1.73 m
2 and placebo: -0.04 mL/min/1.73 m
2).
Supportive study: Dapagliflozin dual energy X-ray absorptiometry in patients with type 2 diabetes mellitus: Due to the mechanism of action of dapagliflozin, a study was done to evaluate body composition and bone mineral density in 182 patients with type 2 diabetes mellitus. Treatment with dapagliflozin 10 mg added on to metformin over a 24-week period provided significant improvements compared with placebo plus metformin, respectively, in body weight (mean change from baseline: -2.96 kg versus -0.88 kg); waist circumference (mean change from baseline: -2.51 cm versus -0.99 cm), and body-fat mass as measured by DXA (mean change from baseline: -2.22 kg versus −0.74 kg) rather than lean tissue or fluid loss. Dapagliflozin plus metformin treatment showed a numerical decrease in visceral adipose tissue compared with placebo plus metformin treatment (change from baseline: -322.6 cm
3 versus -8.7 cm
3) in an MRI substudy. Week 24 was analysed using last observation carried forward (LOCF) analysis including data after rescue.
The improvements in body weight, waist circumference, body-fat mass and visceral adipose tissue observed at Week 24 were sustained at Week 50 and Week 102. There was no change in bone mineral density in either treatment group up to Week 102 (mean decrease from baseline for all anatomical regions <1.0%).
Cardiovascular outcomes studies in patients with type 2 diabetes mellitus: Dapagliflozin: Dapagliflozin Effect on Cardiovascular Events (DECLARE) was an international, multicentre, randomized, double-blind, placebo-controlled clinical study conducted to determine the effect of dapagliflozin compared with placebo on CV and renal outcomes when added to current background therapy. All patients had type 2 diabetes mellitus and either at least two additional CV risk factors (age ≥55 years in men or ≥60 years in women and one or more of dyslipidaemia, hypertension or current tobacco use) without having had a CV event at baseline (primary prevention) or established CV disease (secondary prevention). DECLARE was designed to ensure inclusion of a broad population.
Of 17,160 randomized patients, 6,974 (40.6%) had established CV disease and 10,186 (59.4%) did not have established CV disease. 8,582 patients were randomized to dapagliflozin 10 mg and 8,578 to placebo and were followed for a median of 4.2 years.
The mean age of the study population was 63.9 years, 37.4% were female, 79.6% were White, 3.5% Black or African-American and 13.4% Asian. In total, 22.4% had had diabetes for ≤5 years, mean duration of diabetes was 11.9 years. Mean HbA1c was 8.3% and mean BMI was 32.1 kg/m
2.
At baseline, 10.0% of patients had a history of heart failure. Mean eGFR was 85.2 mL/min/1.73 m
2, 7.4% of patients had eGFR <60 mL/min/1.73 m
2 and 30.3% of patients had micro- or macroalbuminuria (urine albumin to creatinine ration [UACR] ≥30 to ≤300 mg/g or >300 mg/g, respectively).
Most patients (98.1%) used one or more diabetic medications at baseline, 82.0% of the patients were being treated with metformin, 40.9% with insulin, 42.7% with a sulfonylurea, 16.8% with a DPP4 inhibitor, and 4.4% with a GLP-1 agonist.
Approximately 81.3% of patients were treated with ACEi or ARB, 75.0% with statins, 61.1% with antiplatelet therapy, 55.5% with acetylsalicylic acid, 52.6% with beta-blockers, 34.9% with calcium channel blockers, 22.0% with thiazide diuretics and 10.5% with loop diuretics.
Results on primary and secondary endpoints are displayed in Figures 1 and 2. (See Figures 1 and 2.)
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Heart failure or cardiovascular death: Dapagliflozin 10 mg was superior to placebo in preventing the primary composite endpoint of hospitalization for heart failure or CV death (Hazard Ratio [HR] 0.83 [95% CI 0.73, 0.95]; p=0.005) (Figure 3).
Exploratory analyses of the single components suggest that the difference in treatment effect was driven by hospitalization for heart failure (HR 0.73 [95% CI 0.61, 0.88]) (Figure 1), with no clear difference in CV death (HR 0.98 [95% CI 0.82 to 1.17]).
The treatment benefit of dapagliflozin over placebo was observed both in patients with and without established CV disease (Figure 2), with and without heart failure at baseline, and was consistent across key subgroups, including age, gender, renal function (eGFR), and region. (See Figure 3.)
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Major adverse cardiovascular events: Dapagliflozin demonstrated cardiovascular safety (tested as non-inferiority versus placebo for the composite of CV death, myocardial infarction or ischemic stroke [MACE]; one-sided p<0.001).
There were numerically fewer MACE events in the dapagliflozin group compared with the placebo group (HR 0.93 [95% CI 0.84, 1.03]; p=0.172) (Figures 1 and 2).
Nephropathy: Dapagliflozin reduced the incidence of events of the composite of confirmed sustained eGFR decrease, ESKD, renal or CV death (HR 0.76 [95% CI 0.67, 0.87]; nominal p<0.001, Figure 4). The difference between groups was driven by reductions in events of the renal components; sustained eGFR decrease, ESKD and renal death (Figure 1), and was observed both in patients with and without CV disease (Figure 2). (See Figure 4.)
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When evaluating the renal components, there were 127 and 238 events of new or worsening nephropathy (sustained eGFR decrease, ESKD or renal death) in patients in the dapagliflozin and placebo groups, respectively. The HR for time to nephropathy was 0.53 (95% CI 0.43, 0.66) for dapagliflozin versus placebo.
Beneficial effects of dapagliflozin on renal outcomes were also observed for albuminuria, e.g., In patients without pre-existing albuminuria, dapagliflozin reduced the incidence of sustained albuminuria (UACR >30 mg/g) compared with placebo (HR 0.79 [95% CI 0.72, 0.87], nominal p<0.001).
In patients without pre-existing macroalbuminuria, new onset of macroalbuminuria (UACR >300 mg/g) was reduced in the dapagliflozin group compared with the placebo group (HR 0.54 [95% CI 0.45, 0.65], nominal p<0.001).
In patients with pre-existing macroalbuminuria, regression of macroalbuminuria was greater in the dapagliflozin group compared with the placebo group (HR 1.82 [95% CI 1.51, 2.20], nominal p<0.001).
The treatment benefit of dapagliflozin over placebo was observed both in patients with and without existing renal impairment.
Sitagliptin: The Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) was a randomised study in 14,671 patients in the intention-to-treat population with an HbA1c of ≥6.5 to 8.0% with established CV disease who received sitagliptin (7,332) 100 mg daily (or 50 mg daily if the baseline eGFR was ≥30 and <50 mL/min/1.73 m
2 ) or placebo (7,339) added to usual care targeting regional standards for HbA1c and CV risk factors. Patients with an eGFR <30 mL/min/1.73 m
2 were not to be enrolled in the study. The study population included 2,004 patients ≥75 years of age and 3,324 patients with renal impairment (eGFR <60 mL/min/1.73 m
2).
Over the course of the study, the overall estimated mean (SD) difference in HbA1c between the sitagliptin and placebo groups was -0.29% (0.01), 95% CI (-0.32, -0.27); p<0.001.
The primary cardiovascular endpoint was a composite of the first occurrence of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalisation for unstable angina. Secondary cardiovascular endpoints included the first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke; first occurrence of the individual components of the primary composite; all-cause mortality; and hospital admissions for congestive heart failure.
After a median follow up of 3 years, sitagliptin, when added to usual care, did not increase the risk of major adverse cardiovascular events or the risk of hospitalisation for heart failure compared to usual care without sitagliptin in patients with type 2 diabetes mellitus (Table 4). (See Table 4.)
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Clinical safety: Events related to decreased renal function - dapagliflozin: In the 13-study, short-term, placebo-controlled pool, mean serum creatinine levels increased a small amount at Week 1 (mean change from baseline: 0.041 mg/dL dapagliflozin 10 mg versus 0.008 mg/dL placebo) and decreased toward baseline by Week 24 (mean change from baseline: 0.019 mg/dL dapagliflozin 10 mg versus 0.008 mg/dL placebo). There were no further changes through Week 102.
In the DECLARE study, there were fewer patients with marked laboratory abnormalities of creatinine, creatinine clearance, eGFR, and UACR in the dapagliflozin group compared with the placebo group. Fewer renal events (e.g., decreased renal creatinine clearance, renal impairment, increased blood creatinine, and decreased glomerular filtration rate) were reported in the dapagliflozin group compared with the placebo group: 422 (4.9%) and 526 (6.1%), respectively. There were fewer patients with events reported as acute kidney injury in the dapagliflozin group compared with the placebo group: 125 (1.5%) and 175 (2.0%), respectively. There were fewer patients with SAEs of renal events in the dapagliflozin group compared with the placebo group: 80 (0.9%) and 136 (1.6%), respectively.
Laboratory findings - dapagliflozin: Haematocrit: In the pool of 13 placebo-controlled studies, increases from baseline in mean haematocrit values were observed in dapagliflozin-treated patients starting at Week 1 and continuing up to Week 16, when the maximum mean difference from baseline was observed. At Week 24, the mean changes from baseline in haematocrit were 2.30% in the dapagliflozin 10 mg group versus -0.33% in the placebo group. At Week 102, the mean changes were 2.68% versus -0.46%, respectively. By Week 24, haematocrit values >55% were reported in 1.3% of dapagliflozin 10 mg-treated patients versus 0.4% of placebo-treated patients. Results were similar during the short-term plus long-term phase (the majority of patients were exposed to treatment for more than one year).
Serum inorganic phosphorus: In the pool of 13 placebo-controlled studies, increases from baseline in mean serum phosphorus levels were reported at Week 24 in dapagliflozin 10 mg-treated patients compared with placebo-treated patients (mean increases of 0.13 mg/dL versus -0.04 mg/dL, respectively). Similar results were seen at Week 102. Higher proportions of patients with marked laboratory abnormalities of hyperphosphatemia (≥5.6 mg/dL if age 17-65 or ≥5.1 mg/dL if age ≥66) were reported in dapagliflozin 10 mg group versus placebo at Week 24 (1.7% versus 0.9%, respectively) and during the short-term plus long-term phase (3.0% versus 1.6%, respectively). The clinical relevance of these findings is unknown.
Lipids: In the pool of 13 placebo-controlled studies, small changes from baseline in mean lipid values were reported at Week 24 in dapagliflozin 10 mg-treated patients compared with placebo-treated patients. Mean percent change from baseline at Week 24 for dapagliflozin 10 mg versus placebo, respectively, was as follows: total cholesterol, 2.5% versus 0.0%; high-density lipoprotein (HDL) cholesterol, 6.0% versus 2.7%; low-density lipoprotein (LDL) cholesterol, 2.9% versus -1.0%; triglycerides, -2.7% versus -0.7%. Mean percent change from baseline at Week 102 for dapagliflozin 10 mg versus placebo, respectively, was as follows: total cholesterol, 2.1% versus -1.5%; HDL cholesterol, 6.6% versus 2.1%; LDL cholesterol, 2.9% versus -2.2%; triglycerides, -1.8% versus -1.8%. The ratio between LDL cholesterol and HDL cholesterol decreased for both treatment groups at Week 24.
In the DECLARE study, no clinical important differences in total cholesterol, HDL cholesterol, LDL cholesterol or triglycerides were seen.
Pharmacokinetics: The pharmacokinetics of the individual mono-components were generally similar in healthy subjects and in patients with type 2 diabetes mellitus.
Dapagliflozin/sitagliptin combination: Bioequivalence has been confirmed between the Dapagliflozin/sitagliptin (Sidapvia) 10 mg/100 mg tablet and the individual dapagliflozin 10 mg and sitagliptin 100 mg tablets after single dose co-administration in the fasted state in healthy subjects.
Absorption: Dapagliflozin: Dapagliflozin is rapidly and well absorbed after oral administration and can be administered with or without food. Maximum dapagliflozin plasma concentrations (C
max) are usually attained within 2 hours after administration in the fasted state. The C
max and AUC values increase proportionally to the increment in dapagliflozin dose. The absolute oral bioavailability of dapagliflozin following the administration of a 10 mg dose is 78%. Food has relatively modest effects on the pharmacokinetics of dapagliflozin in healthy subjects. Administration with a high-fat meal decreases dapagliflozin C
max by up to 50% and prolonged T
max by approximately 1 hour, but does not alter AUC as compared with the fasted state. These changes are not considered to be clinically meaningful.
Sitagliptin: Following oral administration of a 100-mg dose to healthy subjects, sitagliptin was rapidly absorbed, with peak plasma concentrations (median T
max) occurring 1 to 4 hours post dose, mean plasma AUC of sitagliptin was 8.52 μM·hr, C
max was 950 nM. The absolute bioavailability of sitagliptin is approximately 87%. Since co-administration of a high-fat meal with sitagliptin had no effect on the pharmacokinetics, it may be administered with or without food.
Plasma AUC of sitagliptin increased in a dose-proportional manner. Dose-proportionality was not established for C
max and C
24hr (C
max increased in a greater than dose-proportional manner and C
24hr increased in a less than dose-proportional manner).
Distribution: Dapagliflozin: Dapagliflozin is approximately 91% protein bound. Protein binding is not altered in various disease states (e.g., renal or hepatic impairment).
Sitagliptin: The mean volume of distribution at steady state following a single 100-mg intravenous dose of sitagliptin to healthy subjects is approximately 198 litres. The fraction of sitagliptin reversibly bound to plasma proteins is low (38%).
Metabolism: Dapagliflozin: Dapagliflozin is a C-linked glucoside, meaning the aglycone component is attached to glucose by a carbon-carbon bond, thereby conferring stability against glucosidase enzymes. The mean plasma terminal half-life (t
1/2) for dapagliflozin is 12.9 hours following a single oral dose of dapagliflozin 10 mg to healthy subjects. Dapagliflozin is extensively metabolized, primarily to yield dapagliflozin 3-O-glucuronide, which is an inactive metabolite. Dapagliflozin 3-O-glucuronide accounts for 61% of a 50 mg [
14C]-dapagliflozin dose and is the predominant drug-related component in human plasma, accounting for 42% (based on AUC [0-12 hour]) of total plasma radioactivity, similar to the 39% contribution by parent drug. Based on AUC, no other metabolite accounts for >5% of the total plasma radioactivity. Dapagliflozin 3-O-glucuronide or other metabolites do not contribute to the glucose-lowering effects. The formation of dapagliflozin 3-O-glucuronide is mediated by UGT1A9, an enzyme present in the liver and kidney, and CYP-mediated metabolism is a minor clearance pathway in humans.
Sitagliptin: Sitagliptin is primarily eliminated unchanged in urine, and metabolism is a minor pathway. Approximately 79% of sitagliptin is excreted unchanged in the urine.
Following a [
14C]sitagliptin oral dose, approximately 16% of the radioactivity was excreted as metabolites of sitagliptin. Six metabolites were detected at trace levels and are not expected to contribute to the plasma DPP4 inhibitory activity of sitagliptin. In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4, with contribution from CYP2C8.
In vitro data showed that sitagliptin is not an inhibitor of CYP isozymes CYP3A4, 2C8, 2C9, 2D6, 1A2, 2C19 or 2B6, and is not an inducer of CYP3A4 and CYP1A2.
Elimination: Dapagliflozin: Dapagliflozin and related metabolites are primarily eliminated via urinary excretion, of which less than 2% is unchanged dapagliflozin. After administration of 50 mg [
14C]- dapagliflozin dose, 96% is recovered; 75% in urine and 21% in faeces. In faeces, approximately 15% of the dose is excreted as parent drug.
Sitagliptin: Following administration of an oral [
14C] sitagliptin dose to healthy subjects, approximately 100% of the administered radioactivity was eliminated in faeces (13%) or urine (87%) within one week of dosing. The apparent terminal t
1/2 following a 100-mg oral dose of sitagliptin was approximately 12.4 hours. Sitagliptin accumulates only minimally with multiple doses. The renal clearance was approximately 350 mL/min.
Elimination of sitagliptin occurs primarily via renal excretion and involves active tubular secretion. Sitagliptin is a substrate for human organic anion transporter-3 (hOAT-3), which may be involved in the renal elimination of sitagliptin. The clinical relevance of hOAT-3 in sitagliptin transport has not been established. Sitagliptin is also a substrate of P-gp, which may also be involved in mediating the renal elimination of sitagliptin. However, ciclosporin, a P-gp inhibitor, did not reduce the renal clearance of sitagliptin. Sitagliptin is not a substrate for OCT2 or OAT1 or PEPT1/2 transporters. In vitro, sitagliptin did not inhibit OAT3 (IC50=160 μM) or P-gp (up to 250 μM) mediated transport at therapeutically relevant plasma concentrations. In a clinical study sitagliptin had a small effect on plasma digoxin concentrations indicating that sitagliptin may be a mild inhibitor of P-gp.
Special populations: Renal impairment: Dapagliflozin: At steady-state (20 mg once-daily dapagliflozin for 7 days), patients with type 2 diabetes mellitus and mild, moderate, or severe renal impairment (as determined by iohexol clearance) had mean systemic exposures of dapagliflozin that were 32%, 60%, and 87% higher, respectively, than those of patients with type 2 diabetes mellitus and normal renal function. At dapagliflozin 20 mg once-daily, higher systemic exposure to dapagliflozin in patients with type 2 diabetes mellitus and renal impairment did not result in a correspondingly higher renal-glucose clearance or 24-hour glucose excretion. The renal-glucose clearance and 24-hour glucose excretion were lower in patients with moderate or severe renal impairment as compared to patients with normal and mild renal impairment. The steady-state 24-hour urinary glucose excretion was highly dependent on renal function, and 85, 52, 18, and 11 g of glucose/day was excreted by patients with type 2 diabetes mellitus and normal renal function or mild, moderate, or severe renal impairment, respectively. There were no differences in the protein binding of dapagliflozin between renal impairment groups or compared to healthy subjects. The impact of haemodialysis on dapagliflozin exposure is not known.
Sitagliptin: Compared to normal healthy control subjects, plasma AUC of sitagliptin (50 mg) was increased by approximately 1.2-fold and 1.6-fold in patients with mild renal impairment (GFR ≥60 to <90 mL/min) and patients with moderate renal impairment (GFR ≥45 to <60 mL/min), respectively. Because increases of this magnitude are not clinically relevant, dosage adjustment in these patients is not necessary.
Plasma AUC of sitagliptin was increased approximately 2-fold in patients with moderate renal impairment (GFR ≥30 to <45 mL/min), and approximately 4-fold in patients with severe renal impairment (GFR <30 mL/min), including in patients with ESKD on haemodialysis. Sitagliptin was modestly removed by haemodialysis (13.5% over a 3- to 4-hour haemodialysis session starting 4 hours post dose). To achieve plasma concentrations of sitagliptin similar to those in patients with normal renal function, lower dosages are recommended in patients with GFR <45 mL/min.
Hepatic impairment: Dapagliflozin: A single-dose (10 mg) dapagliflozin clinical pharmacology study was conducted in patients with mild, moderate, or severe hepatic impairment (Child-Pugh classes A, B, and C, respectively) and healthy matched controls in order to compare the pharmacokinetic characteristics of dapagliflozin between these populations. There were no differences in the protein binding of dapagliflozin between patients with hepatic impairment compared to healthy subjects. In patients with mild or moderate hepatic impairment, mean C
max and AUC of dapagliflozin were up to 12% and 36% higher, respectively, compared to healthy matched control subjects. These differences were not considered to be clinically meaningful and no dose adjustment from the proposed usual dose of 10 mg once daily for dapagliflozin is proposed for these populations. In patients with severe hepatic impairment (Child-Pugh class C) mean C
max and AUC of dapagliflozin were up to 40% and 67% higher than matched healthy controls, respectively. No dose adjustment is required for patients with severe hepatic impairment.
Sitagliptin: No dose adjustment for sitagliptin is necessary for patients with mild or moderate hepatic impairment (Child-Pugh score ≤9). There is no clinical experience in patients with severe hepatic impairment (Child-Pugh score >9). However, because sitagliptin is primarily renally eliminated, severe hepatic impairment is not expected to affect the pharmacokinetics of sitagliptin.
Age: Dapagliflozin: No dosage adjustment for dapagliflozin from the dose of 10 mg once daily is recommended on the basis of age.
The effect of age (young: ≥18 to <40 years [n=105] and elderly: ≥65 years [n=224]) was evaluated as a covariate in a population pharmacokinetic model and compared to patients ≥40 to <65 years using data from healthy subject and patient studies). The mean dapagliflozin systemic exposure (AUC) in young patients was estimated to be 10.4% lower than in the reference group (90% CI; 87.9, 92.2%) and 25% higher in elderly patients compared to the reference group (90% CI; 123, 129%). These differences in systemic exposure were considered to not be clinically meaningful.
Sitagliptin: No dose adjustment is required based on age. Age did not have a clinically meaningful impact on the pharmacokinetics of sitagliptin based on a population pharmacokinetic analysis of Phase 1 and Phase 2 data. Elderly subjects (65 to 80 years) had approximately 19% higher plasma concentrations of sitagliptin compared to younger subjects.
Paediatric and adolescent patients: Dapagliflozin/sitagliptin (Sidapvia) is not indicated in paediatric and adolescent patients (see Dosage & Administration).
Gender: Dapagliflozin: No dosage adjustment from the dose of 10 mg once daily is recommended for dapagliflozin on the basis of gender. Gender was evaluated as a covariate in a population pharmacokinetic model using data from healthy subject and patient studies. The mean dapagliflozin AUC
ss in females (n=619) was estimated to be 22% higher than in males (n=634) (90% CI; 117,124).
Sitagliptin: Gender had no clinically meaningful effect on the pharmacokinetics of sitagliptin based on a composite analysis of Phase 1 pharmacokinetic data and on a population pharmacokinetic analysis of Phase 1 and Phase 2 data.
Race: Dapagliflozin: No dosage adjustment from the dapagliflozin dose of 10 mg once daily is recommended on the basis of race. Race (White, Black, or Asian) was evaluated as a covariate in a population pharmacokinetic model using data from healthy subject and patient studies. Differences in systemic exposures between these races were small. Compared to Whites (n=1,147), Asian subjects (n=47) had no difference in estimated mean dapagliflozin systemic exposures (90% CI range; 3.7% lower, 1% higher). Compared to Whites, Black subjects (n=43) had 4.9% lower estimated mean dapagliflozin systemic exposures (90% CI range; 7.7% lower, 3.7% lower).
Sitagliptin: Race had no clinically meaningful effect on the pharmacokinetics of sitagliptin based on a composite analysis of Phase 1 pharmacokinetic data and on a population pharmacokinetic analysis of Phase 1 and Phase 2 data.
Body weight: Dapagliflozin: In a population pharmacokinetic analysis using data from healthy subject and patient studies, systemic exposures in high-body-weight subjects (≥120 kg, n=91) were estimated to be 78.3% (90% CI; 78.2, 83.2%) of those of reference subjects with body weight between 75 and 100 kg. This difference is considered to be small, therefore, no dose adjustment from the proposed dose of 10 mg dapagliflozin once daily in type 2 diabetes mellitus patients with high body weight (≥120 kg) is recommended.
Subjects with low body weights (<50 kg) were not well represented in the healthy subject and patient studies used in the population pharmacokinetic analysis. Therefore, dapagliflozin systemic exposures were simulated with a large number of subjects. The simulated mean dapagliflozin systemic exposures in low-body-weight subjects were estimated to be 29% higher than subjects with the reference group body weight. This difference is considered to be small, and based on these findings, no dose adjustment from the proposed dose of 10 mg dapagliflozin once daily in type 2 diabetes mellitus patients with low body weight (<50 kg) is recommended.
Sitagliptin: BMI had no clinically meaningful effect on the pharmacokinetics of sitagliptin based on a composite analysis of Phase 1 pharmacokinetic data and on a population pharmacokinetic analysis of Phase 1 and Phase 2 data.
Toxicology: Preclinical safety data: Dapagliflozin/sitagliptin combination: No animal studies have been conducted with the combination of dapagliflozin and sitagliptin. The following data are based on the findings from separate nonclinical studies on dapagliflozin and sitagliptin, respectively.
Carcinogenesis, mutagenesis, impairment of fertility: Dapagliflozin: Dapagliflozin did not induce tumours in either mice or rats at any of the doses evaluated in 2-year carcinogenicity studies. Oral doses in mice consisted of 5, 15, and 40 mg/kg/day in males and 2, 10, and 20 mg/kg/day in females, and oral doses in rats were 0.5, 2, and 10 mg/kg/day for both males and females. The highest doses evaluated in mice were equivalent to AUC exposure multiples of approximately 72 × (males) and 105 × (females) the human AUC at MRHD of 10 mg/day. In rats, AUC exposures were approximately 131 × (males) and 186 × (females) the human AUC at the MRHD.
Dapagliflozin was negative in the Ames mutagenicity assay and was positive in an in vitro clastogenicity assay, but only in the presence of S9 activation and at concentrations ≥100 μg/mL. Importantly, dapagliflozin was negative for clastogenicity in vivo in a series of studies evaluating micronuclei or DNA repair in rats at exposure multiples >2,100 × the human exposure at the MRHD. These studies, along with the absence of tumour findings in the rat and mouse carcinogenicity studies, support that dapagliflozin does not represent a genotoxic risk to humans.
Dapagliflozin-related gene transcription changes were evaluated in kidney, liver, adipose, and skeletal muscle of Zucker Diabetic Fatty (ZDF) rats treated daily with dapagliflozin for 5 weeks. These organs were specifically selected as they represent target organs in the treatment of diabetes. There was no evidence that dapagliflozin caused transcriptional changes that are predictive of tumour promoters.
Dapagliflozin and its primary human metabolite (3-O-glucuronide) did not enhance the in vitro growth of six human urinary bladder transitional cell carcinomas (TCC) cell lines at concentrations ≥100 × human C
max at the MRHD. In a mouse xenograft study, dapagliflozin administered daily to male and female nude mice implanted with human TCC tumours did not significantly enhance the size of tumours at exposures up to 75 × and up to 0.9 × clinical exposures at the MRHD for dapagliflozin and its 3-O-glucuronide metabolite, respectively. These studies provide evidence that dapagliflozin and its primary human metabolite do not enhance urinary bladder tumour growth.
In a 15-month phenotyping study, there was no evidence of any difference in survival, body weights, clinical pathology parameters, or histopathologic findings observed between SGLT2 KO mice and their wild-type (WT) counterparts. SGLT2 KO mice had glucosuria, unlike the WT mice. Despite a lifetime of glucosuria, there was no evidence of any alteration of renal function or proliferative changes observed in the kidneys or urinary bladders of SGLT2 KO mice. This data strongly suggests that high levels of urinary glucose do not induce urinary tract tumours or accelerate age-related urinary tract pathology.
In a study of fertility and early embryonic development in rats, doses of 15, 75, or 300/210 mg/kg/day dapagliflozin were administered to males (the 300 mg/kg/day dose was lowered to 210 mg/kg/day after 4 days), and doses of 3, 15, or 75 mg/kg/day were administered to females. Dapagliflozin had no effects on mating, fertility, or early embryonic development in treated males or females at any dose tested (at exposure multiples ≤1,708 × and 998 × the MRHD in males and females, respectively). However, at 300/210 mg/kg/day, seminal vesicle and epididymal weights were reduced; sperm motility and sperm counts were reduced; and there were low numbers of morphologically abnormal sperm.
Sitagliptin: Sitagliptin has not been demonstrated to be genotoxic in preclinical studies. Sitagliptin was not carcinogenic in mice. In rats, there was an increased incidence of hepatic adenomas and carcinomas at systemic exposure levels 58 times the human exposure level. Since hepatotoxicity has been shown to correlate with induction of hepatic neoplasia in rats, this increased incidence of hepatic tumours in rats was likely secondary to chronic hepatic toxicity at this high dose. Because of the high safety margin (19-fold at this no-effect level), these neoplastic changes are not considered relevant for the situation in humans.
No adverse effects upon fertility were observed in male and female rats given sitagliptin prior to and throughout mating.
Teratogenicity and impairment of early development: Dapagliflozin: Direct administration of dapagliflozin to weanling juvenile rats and indirect exposure during late pregnancy and lactation (time periods corresponding to the second and third trimesters of pregnancy with respect to human renal maturation) are each associated with increased incidence and/or severity of renal pelvic and tubular dilatations in progeny.
In a juvenile toxicity study, when dapagliflozin was dosed directly to young rats from postnatal day (PND) 21 until PND 90 at doses of 1, 15, or 75 mg/kg/day, renal pelvic and tubular dilatations were reported at all dose levels; pup exposures at the lowest dose tested were ≥15 × the MRHD. These findings were associated with dose-related increases in kidney weight and macroscopic kidney enlargement observed at all doses. The renal pelvic and tubular dilatations observed in juvenile animals did not fully reverse within the approximate 1-month recovery period.
In a separate study of prenatal and postnatal development, maternal rats were dosed from gestation day (GD) 6 through PND 21 (also at 1, 15, or 75 mg/kg/day), and pups were indirectly exposed in utero and throughout lactation. (A satellite study was conducted to assess dapagliflozin exposures in milk and pups). Increased incidence or severity of renal pelvic dilatation was again observed in adult offspring of treated dams, although only at 75 mg/kg/day (associated maternal and pup dapagliflozin exposures were 1,415 × and 137 ×, respectively, the human values at the MRHD). Additional developmental toxicity was limited to dose-related reductions in pup body weights and observed only at doses ≥15 mg/kg/day (associated with pup exposures that are ≥29 × the human values at the MRHD). Maternal toxicity was evident only at 75 mg/kg/day and limited to transient reductions in body weight and food consumption at dose initiation. The no-adverse-effect level (NOAEL) for developmental toxicity, 1 mg/kg/day, is associated with a maternal systemic exposure multiple that is approximately 19 × the human value at the MRHD.
In additional studies of embryo-foetal development in rats and rabbits, dapagliflozin was administered for intervals coinciding with the major periods of organogenesis in each species. Neither maternal nor developmental toxicities were observed in rabbits at any dose tested (20, 60, or 180 mg/kg/day); 180 mg/kg/day is associated with a systemic exposure multiple of approximately 1,191 × the MRHD. In rats, dapagliflozin was neither embryolethal nor teratogenic at doses up to 75 mg/kg/day (1,441 × the MRHD). Doses ≥150 mg/kg/day (≥2,344 × the human values at the MRHD) were associated with both maternal and developmental toxicities. Maternal toxicity included mortality, adverse clinical signs, and decrements in body weight and food consumption. Developmental toxicity consisted of increased embryo-foetal lethality, increased incidences of foetal malformations and skeletal variations, and reduced foetal body weights. Malformations included a low incidence of great vessel malformations, fused ribs and vertebral centra, and duplicated manubria and sternal centra. Variations were primarily reduced ossifications.
Sitagliptin: In a pre-/postnatal development study performed in rats sitagliptin showed no adverse effects.
Reproductive toxicity studies showed a slight treatment-related increased incidence of foetal rib malformations (absent, hypoplastic and wavy ribs) in the offspring of rats at systemic exposure levels more than 29 times the human exposure levels. Maternal toxicity was seen in rabbits at more than 29 times the human exposure levels. Because of the high safety margins, these findings do not suggest a relevant risk for human reproduction. Sitagliptin is secreted in considerable amounts into the milk of lactating rats (milk/plasma ratio: 4:1).
Animal toxicology: Dapagliflozin: Most of the effects observed in pivotal repeat-dose toxicity studies in both rats and dogs were considered to be secondary to pharmacologically mediated increases in urinary glucose, and included decreases in body weights and/or body weight gains, increased food consumption, and increases in urine volumes due to osmotic diuresis. Dapagliflozin was well tolerated when given orally to rats for up to 6 months at doses of ≤25 mg/kg/day (≥346 × the human exposures at the MRHD) and in dogs for up to 12 months at doses of ≤120 mg/kg/day (≥3,200 × the human exposures at the MRHD). Also, single-dose studies with dapagliflozin indicated that the dapagliflozin 3-O-glucuronide metabolite would have been formed in both rat and dog toxicity studies at exposure levels (AUCs) that are greater than, or approximately equal to, anticipated human dapagliflozin 3-O-glucuronide exposures following administration of dapagliflozin at the MRHD. In rats, the most noteworthy nonclinical toxicity finding of increased trabecular bone and tissue mineralization (associated with increased serum calcium) was only observed at high-exposure multiples (≥2,100 × based on human exposures at the MRHD). Despite achieving exposure multiples of ≥3,200 × the human exposure at the MRHD, there was no dose-limiting or target-organ toxicities identified in the 12-month dog study.
Sitagliptin: Renal and liver toxicity were observed in rodents at systemic exposure values 58 times the human exposure level, while the no-effect level was found at 19 times the human exposure level. Incisor teeth abnormalities were observed in rats at exposure levels 67 times the clinical exposure level; the no effect level for this finding was 58-fold based on the 14-week rat study. The relevance of these findings for humans is unknown. Transient treatment-related physical signs, some of which suggest neural toxicity, such as open-mouth breathing, salivation, white foamy emesis, ataxia, trembling, decreased activity, and/or hunched posture were observed in dogs at exposure levels approximately 23 times the clinical exposure level. In addition, very slight to slight skeletal muscle degeneration was also observed histologically at doses resulting in systemic exposure levels of approximately 23 times the human exposure level. A no-effect level for these findings was found at an exposure 6-fold the clinical exposure level.
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