Canagliflozin, a novel inhibitor of sodium glucose co-transporter 2, dose dependently reduces calculated renal threshold for glucose excretion and increases urinary glucose excretion in healthy subjects

Canagliflozin, a potent, selective sodium glucose co-transporter 2 inhibitor in development for treatment of type 2 diabetes, lowers plasma glucose (PG) by lowering the renal threshold for glucose (RT(G) ) and increasing urinary glucose excretion (UGE). An ascending single oral-dose phase 1 study investigated safety, tolerability and pharmacodynamics of canagliflozin in healthy men (N = 63) randomized to receive canagliflozin (n = 48) or placebo (n = 15). Canagliflozin (10, 30, 100, 200, 400, 600 or 800 mg q.d. or 400 mg b.i.d.) was administered to eight cohorts (six subjects/cohort: canagliflozin; two subjects/cohort: placebo). Dose dependently, canagliflozin decreased calculated 24-h mean RT(G) with maximal reduction to approximately 60 mg/dl, and increased mean 24-h UGE. At doses >200 mg administered before breakfast, canagliflozin reduced postprandial PG and serum insulin excursions at that meal. Canagliflozin was generally well tolerated; most adverse events were mild and no hypoglycaemia was reported. These results support further study of canagliflozin.     

Pharmacokinetic and pharmacodynamic study of ipragliflozin in Japanese patients with type 2 diabetes mellitus: A randomized,double-blind,placebo-controlled study

Aims

Ipragliflozin is a novel and highly selective sodium–glucose transporter 2 (SGLT2) inhibitor that reduces plasma glucose levels by enhancing urinary glucose excretion in patients with type 2 diabetes mellitus (T2DM). We examined the pharmacokinetic and pharmacodynamic characteristics of two oral doses of ipragliflozin in Japanese patients with T2DM.

Methods

In this randomized, placebo-controlled, double-blind study, patients were treated with placebo, 50 mg or 100 mg ipragliflozin once daily for 14 days. Plasma and urine pharmacodynamic parameters were measured on Days −1 and 14, and pharmacokinetic parameters on Day 14. Pharmacodynamic characteristics included area under the curve (AUC) for plasma glucose and insulin for 0–3 h (AUC_0–3h) and 0–24 h (AUC_0–24h). Pharmacokinetic characteristics included AUC_0–24h, maximum ipragliflozin concentration (C_max), and time to maximum plasma ipragliflozin concentration (t_max).

Results

Thirty patients were enrolled; 28 were included in pharmacokinetic/pharmacodynamic analyses and 30 in safety analyses. Administration of 50 and 100 mg ipragliflozin significantly reduced fasting plasma glucose, as well as the AUC_0–3h and AUC_0–24h for plasma glucose relative to placebo. Both doses of ipragliflozin also reduced AUC_0–24h for insulin, body weight, and glycoalbumin, while urinary glucose excretion increased remarkably. C_max and AUC_0–24h were 1.7- and 1.9-fold higher, respectively, in the 100-mg group than in the 50-mg group.

Conclusions

Ipragliflozin increased urinary glucose excretion and improved fasting and postprandial glucose, confirming its pharmacokinetic/pharmacodynamic properties in Japanese patients with T2DM.     

Eight weeks of treatment with long-acting GLP-1 analog taspoglutide improves postprandial insulin secretion and sensitivity in metformin-treated patients with type 2 diabetes

Objective

Loss of pancreatic function is pivotal to the deterioration of fasting and postprandial glycemic control in type 2 diabetes (T2D). We evaluated the effects of a long-acting, human glucagon-like peptide-1 analog, taspoglutide, added to metformin, on pancreatic function and peripheral insulin sensitivity.

Materials/methods

We studied 80 T2D patients inadequately controlled [glycosylated hemoglobin (HbA_1c), 7.0%–9.5%] receiving stable metformin for ≥ 12 weeks. They were a subset of participants to a phase 2 trial that received also a 240-min mixed-meal tolerance test (MTT) at baseline and study end. Patients received once weekly (QW) sc injection of taspoglutide 5, 10, or 20 mg (n = 21, 19, or 19), or placebo (n = 21), plus metformin, for 8 weeks. We measured postprandial plasma glucose (PPG) and insulin profiles, insulin secretion rate (ISR), oral glucose insulin sensitivity (OGIS) index; β-cell glucose sensitivity, glucagon/glucose and insulin/glucagon ratios, and insulin sensitivity-to-insulin resistance (or disposition) index.

Results

After 8 weeks of treatment, taspoglutide 5, 10, and 20 mg QW doses vs. placebo improved mean PPG_{0–240 min} (relative change from baseline: − 22.1%, − 25.9%, and − 22.9% vs. − 8.1%; P < 0.005) and mean postprandial ISR_{0–240 min} (+ 14%, + 18%, and + 23% vs. + 1%; P < 0.005 vs dose). Taspoglutide at 20 mg QW dose also resulted in improvements from baseline in OGIS, β-cell glucose sensitivity, glucagon/glucose and insulin/glucagon ratios and the disposition index during the MTT.

Conclusion

Taspoglutide QW significantly improved pancreatic function in patients with T2D treated with metformin.     

Canagliflozin improves glycaemic control over 28 days in subjects with type 2 diabetes not optimally controlled on insulin

Aim: Canagliflozin is a sodium‐glucose co‐transporter 2 (SGLT2) inhibitor that is being investigated for the treatment of type 2 diabetes mellitus (T2DM). Methods: This was a randomized, double‐blind, placebo‐controlled, parallel‐group, 28‐day study conducted at two sites, in 29 subjects with T2DM not optimally controlled on insulin and up to one oral antihyperglycaemic agent. Subjects were treated with canagliflozin 100 mg QD or 300 mg twice daily (BID) or placebo. Safety, tolerability, pharmacokinetic characteristics and pharmacodynamic effects of canagliflozin were examined. Glucose malabsorption following a 75‐g oral glucose challenge was also examined. Results: Canagliflozin pharmacokinetics were dose‐dependent, and the elimination half‐life ranged from 12 to 15 h. After 28 days, the renal threshold for glucose excretion was reduced; urinary glucose excretion was increased; and A1C, fasting plasma glucose and body weight decreased in subjects administered canagliflozin (A1C reductions: 0.19% with placebo, 0.73% with 100 mg QD, 0.92% with 300 mg BID; body weight changes: 0.03 kg increase with placebo, 0.73 kg reduction with 100 mg QD, 1.19 kg reduction with 300 mg BID). Glucose malabsorption was not observed with canagliflozin treatment. There were no deaths, serious adverse events or severe hypoglycaemic episodes. The incidence of adverse events was similar across groups. There were no clinically meaningful changes in routine laboratory safety tests, vital signs or electrocardiograms. Conclusion: In subjects receiving insulin and oral antihyperglycaemic therapy, canagliflozin was well tolerated without evidence for glucose malabsorption, had pharmacokinetic characteristics consistent with once‐daily dosing, and improved glycaemic control.     

Gender and body mass index modify the effect of increasing amounts of caffeinated coffee on postprandial glucose and insulin concentrations; a randomized,controlled, clinical trial

Objective

To examine the effects of different coffee amounts on blood glucose and insulin concentrations of healthy volunteers, and to assess potential effect modification by sex and body mass index category.

Materials/Methods

Thirty-three volunteers [16♀/17♂, 16 normal-weight and 17 overweight/obese, 27.3 ± 7.2 (19–44) y] took part in this randomized, crossover study. Ιn the morning of each experimental day volunteers received a standardized meal along with 200 mL of water or instant coffee containing either 3 or 6 mg of caffeine/kg body weight. Blood samples were obtained and analyzed for glucose and insulin concentrations in the fasting state, immediately after meal/drink consumption and at standard time points for the next 3 h thereafter.

Results

Coffee delayed the rise of insulin in response to the standardized meal and the fall of glucose concentrations from its maximum levels in the entire study sample. Glucose incremental area under the curve (IAUC) was significantly different between interventions (P = .009) with both coffee amounts inducing a greater area compared to water. Secondary, subgroup analysis at the nominal level showed that this might be more evident among females (P_IAUC = .05) and overweight/obese participants (P_IAUC = .03). Furthermore, coffee, mainly the 6 mg dose, could be lowering insulin concentrations the first 30 min after its consumption compared to water in men and overweight/obese participants.

Conclusions

Coffee exerts an acute effect on postprandial glucose and insulin concentrations. This effect may be modified by sex and overweight/obese status. Future research is necessary to elucidate underlying mechanisms.     

Fasting plasma glucose to avoid a full OGTT in the diagnosis of gestational diabetes

Aims

To evaluate the performance of fasting plasma glucose (FPG) in determining the need for a full oral glucose tolerance test (OGTT) to diagnose gestational diabetes (GDM) by the International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria.

Methods

A multicenter cohort study of 4926 pregnant women 20 years or older consecutively enrolled in prenatal care clinics of the Brazilian National Health Service from 1991 to 1995. All women underwent a single 2 h 75 g OGTT by weeks 24–28 of pregnancy and were followed to detect adverse pregnancy outcomes.

Results

A FPG cut-off value of 80 mg/dl indicated that only 38.7% of all women needed to undergo a complete OGTT, while detecting 96.9% of all GDM cases. When the 85 mg/dl cut-off was used, the corresponding percentages were 18.7% and 92.5%, respectively. The fraction of women labeled with GDM who had adverse pregnancy outcomes was nearly identical when using FPG strategies and universal full testing.

Conclusions

Using a FPG cut-off to diagnose GDM and to determine the need for post-load OGTT measurements is a valid strategy to diagnose GDM by IADPSG criteria. This approach may improve feasibility of applying IADPSG diagnostic criteria by reducing costs and increasing convenience.     

Remogliflozin etabonate, a selective inhibitor of the sodium-dependent transporter 2 reduces serum glucose in type 2 diabetes mellitus patients

Aims: Remogliflozin etabonate (RE) is the pro‐drug of remogliflozin (R), a selective inhibitor of renal sodium‐dependent glucose transporter 2 (SGLT2) that improves glucose control via enhanced urinary glucose excretion (UGE). This study evaluated the safety, tolerability, pharmacokinetics and pharmacodynamics of repeated doses of RE in subjects with type 2 diabetes mellitus (T2DM). Methods: In a double‐blinded, randomized, placebo‐controlled trial, subjects who were drug‐naïve or had metformin discontinued received RE [100 mg BID (n = 9), 1000 mg QD (n = 9), 1000 mg BID (n = 9)], or placebo (n = 8) for 12 days. Safety parameters were assessed, including urine studies to evaluate renal function. Plasma concentrations of RE and metabolites were measured with the first dose and at steady state. RE effects on glucose levels were assessed with fasting glucose concentrations, frequently sampled 24‐h glucose profiles and oral glucose tolerance tests. Results: No significant laboratory abnormalities or safety events were reported; the most frequent adverse events were headache and flatulence. Plasma exposure to RE and R were proportional to administered dose with negligible accumulation. Mean 24‐h UGE increased in RE treatment groups. Compared with the placebo group, 24‐h mean (95% CI) changes in plasma glucose were ?1.2 (?2.2 to ?0.3) (100 mg BID), ?0.8 (?1.7 to 0.2) (1000 mg QD) and ?1.7 (?2.7 to ?0.8) mmol/l (1000 mg BID). Conclusions: Administration of RE for 12 days is well‐tolerated and results in clinically meaningful improvements in plasma glucose, accompanied by changes in body weight and blood pressure in subjects with T2DM.     

Recovery of insulin sensitivity and Slc2a4 mRNA expression depend on T3 hormone during refeeding

Objective

GLUT4 protein, encoded by the Slc2a4 gene, plays a key role in muscle glucose uptake, and its expression decreases in muscles under insulin resistance. Slc2a4/GLUT4 decreases with fasting and rapidly increases with refeeding and the same occurs to plasma glucose, amino acids, insulin and T3. Thus, they might be potential regulators of the Slc2a4 gene, which makes them promising targets for strategies to improve GLUT4 expression. Herein, we investigate the role of metabolic–hormonal parameters triggered by refeeding upon the Slc2a4 expression.

Materials/Methods

Plasma glucose/insulin/T3, and gastrocnemius Slc2a4 mRNA contents were measured in rats studied at the end of 48-h fasting, and subsequently at: i) 2–4 h after spontaneous refeeding; ii) 2–4 h after T3 injection, without refeeding; and iii) 0.5–2 h after intravenous infusion of insulin, insulin + glucose and insulin + amino acids, without refeeding.

Results

Refeeding increased plasma glucose/insulin/T3 and muscle Slc2a4 mRNA, reverting insulin resistance. Post-fasting infusions surprisingly induced a further Slc2a4 mRNA decrease (~ 20%, P < 0.05 vs. fasting), but T3 injection induced a ~ 2-fold increase in Slc2a4 mRNA, 2–4 h later (P < 0.001). Moreover, T3 increased glycemia and insulinemia to the 2 h-refed rats levels, suggesting that T3 elevation is a key factor to the mechanisms of metabolic balance during refeeding.

Conclusions

Refeeding induces a rapid increase in muscle Slc2a4 expression, not associated with increased plasma glucose, insulin or amino acids, but highly correlated to increased plasma T3 concentration. This result points out T3 hormone as a powerful Slc2a4 enhancer, an effect that may be acutely explored in situations of insulin resistance.     

Effects of a single bout of aerobic exercise on short-term low-carbohydrate/high-fat intake-induced postprandial glucose metabolism during an oral glucose tolerance test

Objective

A single bout of exercise can improve acute postprandial glucose metabolism aggravated by short-term low-carbohydrate/high-fat diet (HFD). The purpose of this study was to investigate the effect of a single bout of aerobic exercise on short-term HFD-induced postprandial glucose and incretin metabolism during an oral glucose tolerance test (OGTT).

Materials/Methods

Eleven healthy young men (age [mean ± SE] 27 ± 1 years; body mass index, 22 ± 1 kg/m²) performed three, 3-day interventions in randomized order: (1) a normal diet (ND: ~ 22% fat), (2) an HFD (~ 69% fat) and (3) an HFD with a single bout of aerobic exercise (HFDEx). The exercise (50% peak oxygen consumption; ~ 200 kcal) was performed on the third day in HFDEx. An OGTT was performed after each 3-day dietary intervention.

Results

The incremental area under the curve (iAUC) of plasma glucose levels during the OGTT was significantly higher in the HFD and HFDEx trials than in the ND trial (P = 0.001). In addition, the iAUC of glucagon-like peptide-1 (GLP-1) level was significantly higher in the HFD trial than in the ND and HFDEx trials (P = 0.04). The first-phase insulin secretion indexes were significantly lower in the HFD (P = 0.01 and 0.002) and HFDEx trials (P = 0.05 and 0.008) than in the ND trial.

Conclusion

A single bout of aerobic exercise did not improve the short-term HFD-induced aggravation of postprandial glucose and insulin metabolism during the OGTT. However, it did normalize the increased postprandial GLP-1 level induced by HFD.     

Defining the relationship between average glucose and HbA1c in patients with type 2 diabetes and chronic kidney disease

Aims

To examine the relationship between average glucose (AG) and HbA_1c in patients with and without chronic kidney disease (CKD) and type 2 diabetes.

Materials and methods

43 patients with diabetes and CKD (stages 3–5) with stable glycaemic control, and glucose-lowering and erythropoiesis stimulating agent (ESA) doses, were prospectively studied for 3 months and compared to 104 age-matched controls with diabetes, without CKD from the ADAG study. Over 3 months, AG was calculated from 7 to 8 point self-monitored blood glucose measurements (SMBG) and from continuous glucose monitoring (CGMS), and mean HbA_1c was calculated from 4 measurements. AG and HbA_1c relationships were determined using multivariable linear regression analyses.

Results

The CKD and non-CKD groups were well matched for age and gender. Mean AG tended to be higher (p = 0.08) but HbA_1c levels were similar (p = 0.68) in the CKD compared with non-CKD groups. A linear relationship between AG and HbA_1c was observed irrespective of the presence and stage of CKD. The relationship was weaker in patients with stage 4–5 CKD (non-CKD R² = 0.75, stage 3 CKD R² = 0.79 and stage 4–5 CKD R² = 0.34, all p < 0.01). The inclusion of ESA use in the model rendered the effect of CKD stage insignificant (R² = 0.67, p < 0.01).

Conclusions

In patients with type 2 diabetes and CKD there is a linear relationship between HbA_1c and AG that is attenuated by ESA use, suggesting that ESA results in a systematic underestimation of AG derived from HbA_1c.     

Effect of a mixed meal on plasma lipids,insulin resistance and systemic inflammation in non-obese Indian adults with normal glucose tolerance and treatment naïve type-2 diabetes

Aim

Asian Indians are believed to have a lower capacity to clear a glucose load even during normoglycemia. High post meal glucose levels have been linked to postprandial dyslipidemia and generation of proinflammatory cytokines. Since humans spend most of their time in the postprandial state, the present study aims to evaluate the relationship of insulin resistance (IR) in the basal state with dyslipidemia and systemic inflammation (hs-CRP, IL-6 and TNF-a), in the fasting state, 2 h and 4 h after a mixed meal, in Indian adults with normal glucose tolerance, and new onset type-2 diabetes.

Methods

Forty-eight people with type 2 diabetes and 32 individuals with normoglycemia, 30–70 years age, not on medications, underwent blood sampling after overnight (12 h) fast and 2 and 4 h after a mixed meal (carbohydrates, proteins and fat content 79.1%, 7.7% and 13.2%, respectively).

Results

Triglyceride (TG), TG/HDL-C (high density lipoprotein), HDL-C/LDL-C (low density lipoprotein) ratios, IR parameters, and inflammatory markers were significantly higher among patients with diabetes. There was a fall in total cholesterol (TC), HDL-C and LDL-C at 2 and 4 h after the meal in both groups. Compared with fasting, 4-h postprandial TC, TG and HDL-C were significantly better positively correlated with IR in normal individuals. Postprandial hs-CRP was not significantly different to fasting in both groups. Postprandial IL-6 and TNF-α were significantly lower in both groups.

Conclusion

Consumption of a carbohydrate rich meal is associated with a rise in TG and fall in TC, HDL-C, LDL-C, IL-6 and TNF-α among normal individuals and people with type 2 diabetes.     

Glucoregulatory function among African Americans and European Americans with normal or pre-diabetic hemoglobin A1c levels

Objective

A hemoglobin (Hb) A1c range of 5.7%–6.4% has been recommended for the diagnosis of prediabetes. To determine the significance of such “prediabetic” HbA1c levels, we compared glucoregulatory function in persons with HbA1c levels of 5.7%–6.4% and those with HbA1c < 5.7%.

Methods

We studied 280 nondiabetic adults (142 black, 138 white; mean (± SD) age 44.2 ± 10.6 years). Each subject underwent clinical assessment, blood sampling for HbA1c measurement, and a 75-g oral glucose tolerance test at baseline. Additional assessments during subsequent outpatient visits included insulin sensitivity, using homeostasis model assessment (HOMA)-IR and the hyperinsulinemic euglycemic clamp; insulin secretion, using HOMA-B and frequently samples intravenous glucose tolerance test (FSIVGTT) and disposition index (DI); and measurement of fat mass, using DXA.

Results

Compared to subjects with HbA1c < 5.7%, persons with HbA1c levels of 5.7%–6.4% were older, and had higher body mass index (BMI) and insulin secretion but similar insulin sensitivity. When the two groups were matched in age and BMI, persons with HbA1c 5.7%–6.4% were indistinguishable from those with HbA1c < 5.7% with regard to all measures of glycemia and glucoregulatory function.

Conclusions

Unlike glucose-defined prediabetes status, an HbA1c range of 5.7%–6.4% does not reliably identify individuals with impaired insulin action or secretion, the classical defects underlying the pathophysiology of prediabetes. Thus, HbA1c cannot validly replace blood glucose measurement in the diagnosis of prediabetes. If utilized as a screening test due to convenience, aberrant HbA1c values should be corroborated with blood glucose measurement before therapeutic intervention.     

Kidney protection with canagliflozin: A combined analysis of the randomized CANVAS program and CREDENCE trials

Aim

In the CANVAS Program and CREDENCE trials, the sodium glucose co-transporter 2 inhibitor canagliflozin reduced the risk of cardiovascular and kidney events in patients with type 2 diabetes. The current study analysed a pooled population to ascertain the kidney protection provided by canagliflozin across the full spectrum of kidney parameters.

Methods

This post-hoc pooled analysis of the CANVAS Program (N = 10 142) and CREDENCE trial (N = 4401), assessed the risk of the primary kidney composite (doubling of serum creatinine, end-stage kidney disease, renal death), in all patients and subgroups defined by baseline estimated glomerular filtration rate (<30, 30 to <45, 45 to <60 and ≥60 ml/min/1.73 m²), albuminuria [<30, 30-300, >300 mg/g (<3.39, 3.39-33.9, >33.9 mg/mmol)] and 2012 Kidney Disease: Improving Global Outcomes (KDIGO) classification of chronic kidney disease (low/moderate, high and very high risk).

Results

In the overall population, the risk for the primary kidney composite outcome was 37% lower in the canagliflozin group versus placebo (HR: 0.63; 95% CI: 0.53, 0.77; p < .001). There was no evidence of heterogeneity in the kidney protective effects of canagliflozin across a range of kidney risks when stratified by baseline estimated glomerular filtration rate, albuminuria or KDIGO risk category (all p_interaction > .05). A statistically significant risk reduction of the primary kidney composite outcome was sustained by approximately 18 months after randomization.

Conclusions

These results emphasize a critical role of canagliflozin in kidney protection across a broad spectrum of participants with type 2 diabetes with varying levels of kidney function.     

Adding glimepiride to insulin + metformin in type 2 diabetes of more than 10 years’ duration—A randomised,double-blind,placebo-controlled,cross-over study

Aims

To investigate the effect on glycaemic control of adding glimepiride to on-going treatment with metformin and insulin in patients with known diabetes more than 10 years.

Methods

Glimepiride 4 mg or placebo was added in randomised order for three months with a washout period of 6 weeks. All insulin regimens were allowed. Insulin doses were reduced if considered necessary. Continuous glucose monitoring was performed at the end of each period.

Results

Forty-three patients, median age 66 years (46–74), diabetes duration 16 (10–30), BMI 30 kg/m² (25–37) and mean HbA_1c 7.1% NGSP, (64 mmol/mol IFCC) were randomised. With placebo there was no change in HbA_1c while a decrease of 0.6%, (7 mmol/mol IFCC) (P < 0.001), was observed with glimepiride even though insulin doses had to be reduced in 23 patients (median change 29%, range 2–100%). Minor hypoglycaemia was reported but no severe hypoglycaemic event was observed. The ratio between C-peptide/glucose increased significantly (P < 0.001) with glimepiride, both fasting and postprandially and, in a stepwise multiple regression analysis of possible predictive factors for response, a more pronounced decrease in HbA_1c was associated with the magnitude of the increment in C-peptide/glucose. Older age was associated with a smaller response. Twenty-nine patients (67%) were defined as responders if this was defined as an HbA_1c decrease ≥0.5% (5 mmol/mol IFCC) or an insulin dose reduction ≥20%.

Conclusions

Even after long duration of diabetes, addition of glimepiride to insulin and metformin can be effective in lowering HbA_1c and/or reducing the need for exogenous insulin.     

Greater impairment of postprandial triacylglycerol than glucose response in metabolic syndrome subjects with fasting hyperglycaemia

Objective

Studies have started to question whether a specific component or combinations of metabolic syndrome (MetS) components may be more important in relation to cardiovascular disease risk. Our aim was to examine the impact of the presence of raised fasting glucose as a MetS component on postprandial lipaemia.

Methods

Men classified with the MetS underwent a sequential test meal investigation, in which blood samples were taken at regular intervals after a test breakfast (t = 0 min) and lunch (t = 330 min). Lipids, glucose and insulin were measured in the fasting and postprandial samples.

Results

MetS subjects with 3 or 4 components were subdivided into those without (n = 34) and with (n = 23) fasting hyperglycaemia (≥ 5.6 mmol/l), irrespective of the combination of components. Fasting lipids and insulin were similar in the two groups, with glucose significantly higher in the men with glucose as a MetS component (P < 0.001). Following the test meals, there were higher maximum concentration (maxC), area under the curve (AUC) and incremental AUC (P ≤ 0.016) for the postprandial triacylglycerol (TAG) response in men with fasting hyperglycaemia. Greater glucose AUC (P < 0.001) and insulin maxC (P = 0.010) were also observed in these individuals after the test meals. Multiple regression analysis revealed fasting glucose to be an important predictor of the postprandial TAG and glucose response.

Conclusion

Our data analysis has revealed a greater impairment of postprandial TAG than glucose response in MetS subjects with raised fasting glucose. The worsening of postprandial lipaemic control may contribute to the greater CVD risk reported in individuals with MetS component combinations which include hyperglycaemia.     

Canagliflozin,a sodium glucose co-transporter 2 inhibitor,improves model-based indices of beta cell function in patients with type 2 diabetes

Aims/hypothesis

In rodent models of diabetes, treatment with sodium glucose co-transporter 2 (SGLT2) inhibitors improves beta cell function. This analysis assessed the effects of the SGLT2 inhibitor, canagliflozin, on model-based measures of beta cell function in patients with type 2 diabetes.

Methods

Data from three Phase 3 studies were analysed, in which: (Study 1) canagliflozin 100 and 300 mg were compared with placebo as monotherapy for 26 weeks; (Study 2) canagliflozin 100 and 300 mg were compared with placebo as add-on to metformin?+?sulfonylurea for 26 weeks; or (Study 3) canagliflozin 300 mg was compared with sitagliptin 100 mg as add-on to metformin?+?sulfonylurea for 52 weeks. In each study, a subset of patients was given mixed-meal tolerance tests at baseline and study endpoint, and model-based beta cell function parameters were calculated from plasma glucose and C-peptide.

Results

In Studies 1 and 2, both canagliflozin doses increased beta cell glucose sensitivity compared with placebo. Placebo-subtracted least squares mean (LSM) (SEM) changes were 23 (9) and 18 (9) pmol min^?1 m^?2 (mmol/l)^?1 with canagliflozin 100 and 300 mg, respectively (p?<?0.002, Study 1), and 16 (8) and 10 (9) pmol min^?1 m^?2 (mmol/l)^?1 (p?<?0.02, Study 2). In Study 3, beta cell glucose sensitivity was minimally affected, but the insulin secretion rate at 9 mmol/l glucose increased to similar degrees from baseline with canagliflozin and sitagliptin [LSM (SEM) changes 38 (8) and 28 (9) pmol min^?1 m^?2, respectively; p?<?0.05 for both].

Conclusions/interpretation

Treatment with canagliflozin for 6 to 12 months improved model-based measures of beta cell function in three separate Phase 3 studies. Trial registration: Clinicaltrials.gov NCT01081834 (Study 1); NCT01106625 (Study 2); NCT01137812 (Study 3)     

Empagliflozin as adjunct to insulin in Japanese participants with type 1 diabetes: Results of a 4‐week,double‐blind,randomized, placebo‐controlled phase 2 trial

Aims

This phase 2, double‐blind, randomized, placebo‐controlled trial ( ClinicalTrials.gov NCT02702011) with 4 sites in Japan investigated the pharmacodynamics (PD), pharmacokinetics (PK) and safety profile of empagliflozin in Japanese participants with type 1 diabetes mellitus (T1DM) as adjunctive therapy to insulin.

Materials and methods

Participants using multiple daily injections of insulin for ≥12 months, with HbA1c of 7.5%‐10.0%, entered a 2‐week, open‐label, placebo run‐in period, followed by a 4‐week, double‐blind period during which participants were randomized 1:1:1:1 to receive empagliflozin 2.5 mg (n = 13), empagliflozin 10 mg (n = 12), empagliflozin 25 mg (n = 12) or placebo (n = 11). The primary objective was to assess the effect of empagliflozin vs placebo on urinary glucose excretion (UGE) after 7 days of treatment.

Results

PD: Empagliflozin resulted in a dose‐dependent significant increase in 24‐hour UGE compared with placebo (UGE placebo‐corrected mean [95% confidence interval] change from baseline: 2.5 mg, 65.10 [43.29, 86.90] g/24 h; 10 mg, 81.19 [58.80, 103.58] g/24 h; 25 mg, 98.11 [75.91, 120.31] g/24 h). After 4 weeks of treatment, UGE increase was associated with improved glycaemic control, reduced body weight and decreased insulin needs. Empagliflozin treatment also resulted in dose‐dependent increases in serum ketone bodies and free fatty acids. PK: Plasma empagliflozin levels increased in a dose‐dependent manner and peaked at 1.5 hours. In this short study, empagliflozin was well tolerated, with no increase in rate of hypoglycaemia and no diabetic ketoacidosis events reported.

Conclusions

Based on this short‐duration phase 2 study, the PK/PD profile of empagliflozin in Japanese participants with T1DM is comparable to that of non‐Japanese participants.     

Comparison of fasting plasma glucose and haemoglobin A1c point-of-care tests in screening for diabetes and abnormal glucose regulation in a rural low income setting

Aims

Glycated haemoglobin (HbA_1C) has been suggested to replace glucose tests in identifying diabetes and pre-diabetes. We assessed agreement between fasting plasma glucose (FPG) and HbA_1C rapid tests in classifying abnormal glucose regulation (AGR), and their utility for preventive screening in rural Africa.

Methods

A population-based survey of 795 people aged 35–60 years was conducted in a mainly rural district in Uganda. FPG was measured using On-Call^® Plus glucometers, and classified using World Health Organization (WHO) and American Diabetes Association (ADA) criteria. HbA_1C was measured using A1cNow^® kits and classified using ADA criteria. Body mass index and blood pressure were measured. Percentage agreement between the two tests was computed.

Results

Using HbA_1C, 11.3% of participants had diabetes compared with 4.8% for FPG. Prevalence of HbA_1C-defined pre-diabetes (26.4%) was 1.2 times and 2.5 times higher than FPG-defined pre-diabetes using ADA (21.8%) and WHO (10.1%) criteria, respectively. With FPG as the reference, agreement between FPG and HbA_1C in classifying diabetes status was moderate (Kappa = 22.9; Area Under the Curve (AUC) = 75%), while that for AGR was low (Kappa = 11.0; AUC = 59%). However, agreement was high (over 90%) among negative tests and among participants with risk factors for type 2 diabetes (obesity, overweight or hypertension). HbA_1C had more procedural challenges than FPG.

Conclusions

Although low in the general sample, agreement between HbA_1C and FPG is excellent among persons who test negative with either test. A single test can therefore identify the majority at lower risk for type 2 diabetes. Nurses if trained can conduct these tests.     

The Effect of α-Cyclodextrin on postprandial lipid and glycemic responses to a fat-containing meal

Objective

α-Cyclodextrin (α-CD), a soluble dietary fiber derived from corn, marketed under the trade name FBCx®, has the potential to help individuals manage their weight and improve their lipid profiles. Initial studies in healthy overweight and/or obese diabetic individuals found that, in those consuming a normal to high fat diet over a 4 or 12 week period, α-CD use was associated with weight loss or maintenance and a reduction in triglyceride (TG) and cholesterol levels in hyperlipidemic individuals. Furthermore, α-CD use was associated with the positive effects of increasing insulin and leptin sensitivities. To date, the immediate post-prandial glucose and lipid responses to a fat-containing meal have not been reported.

Materials/Method

This double blinded placebo controlled cross-over trial examined the effect of 2 g of α-CD taken immediately following consumption of a commercially prepared high-fat breakfast meal on the acute postprandial responses in healthy adults.

Results

The coincidental consumption of α-CD with a fat-containing meal was associated with a significant reduction in postprandial TG responses over time when compared to placebo. When incremental area under the curve was calculated, the area under the curve associated with α-CD consumption was significantly smaller than the Placebo area (0.30 ± 1.07 mmol/L/3 h vs. 0.98 ± 0.88 mmol/L/3 h, p < 0.05). There were no significant changes in glucose or cholesterol levels.

Conclusion

α-Cyclodextrin was shown to significantly lower acute postprandial blood triglyceride levels.     

Renal safety of canagliflozin,a sodium glucose co‐transporter 2 inhibitor,in patients with type 2 diabetes mellitus

The incidence of renal‐related adverse events (AEs) with canagliflozin in patients with type 2 diabetes mellitus from a pooled population of patients in 7 active‐ and placebo‐controlled trials (N = 5598) and in a 104‐week study vs glimepiride (N = 1450) was low and similar in canagliflozin and non‐canagliflozin groups. In the study vs glimepiride, canagliflozin was associated with an initial acute decrease in estimated glomerular filtration rate (eGFR) that attenuated over time, while eGFR declined progressively over 104 weeks with glimepiride. The incidence of renal‐related AEs with canagliflozin was generally stable over time, while the incidence with glimepiride increased over 104 weeks. In the present analysis, based on postmarketing reports from the US Food and Drug Administration Adverse Event Reporting System, a potential signal was identified for acute kidney injury with all approved sodium glucose co‐transporter 2 (SGLT2) inhibitors (ie, canagliflozin, dapagliflozin and empagliflozin). The early onset of acute kidney injury events with SGLT2 inhibitors in postmarketing reports probably reflects the acute changes in eGFR attibutable to the known renal haemodynamic effects of SGLT2 inhibition.