No evidence of compensatory changes in energy balance,despite reductions in body weight and liver fat,during dapagliflozin treatment in type 2 diabetes mellitus: A randomized,double-blind,placebo-controlled,cross-over trial (ENERGIZE)

Aim

This study assessed the impact of dapagliflozin on food intake, eating behaviour, energy expenditure, magnetic resonance imaging (MRI)-determined brain response to food cues and body composition in patients with type 2 diabetes mellitus (T2D).

Materials and Methods

Patients were given dapagliflozin 10 mg once daily in a randomized, double-blind, placebo-controlled trial with short-term (1 week) and long-term (12 weeks) cross-over periods. The primary outcome was the difference in test meal food intake between long-term dapagliflozin and placebo treatment. Secondary outcomes included short-term differences in test meal food intake, short- and long-term differences in appetite and eating rate, energy expenditure and functional MRI brain activity in relation to food images. We determined differences in glycated haemoglobin, weight, liver fat (by ¹H magnetic resonance spectroscopy) and subcutaneous/visceral adipose tissue volumes (by MRI).

Results

In total, 52 patients (43% were women) were randomized; with the analysis of 49 patients: median age 58 years, weight 99.1 kg, body mass index 35 kg/m², glycated haemoglobin 49 mmol/mol. Dapagliflozin reduced glycated haemoglobin by 9.7 mmol/mol [95% confidence interval (CI) 3.91-16.27, p = .004], and body weight (−2.84 vs. −0.87 kg) versus placebo. There was no short- or long-term difference in test meal food intake between dapagliflozin and placebo [mean difference 5.7 g (95% CI −127.9 to 139.3, p = .933); 15.8 g (95% CI −147.7 to 116.1, p = .813), respectively] nor in the rate of eating, energy expenditure, appetite, or brain responses to food cues. Liver fat (median reduction −4.7 vs. 1.95%), but not subcutaneous/visceral adipose tissue, decreased significantly with 12 weeks of dapagliflozin.

Conclusions

The reduction in body weight and liver fat with dapagliflozin was not associated with compensatory adaptations in food intake or energy expenditure.     

Durability of glycaemic control with dapagliflozin,an SGLT2 inhibitor,compared with saxagliptin,a DPP4 inhibitor,in patients with inadequately controlled type 2 diabetes

Dapagliflozin is associated with greater reductions in HbA1c and weight than saxagliptin in management of type 2 diabetes mellitus (T2DM). The present post hoc analyses compared the durability of these effects over short- and long-term follow-up in patients with T2DM who were inadequately controlled with metformin (≥1500 mg/day) and who were receiving either dapagliflozin (10 mg/day) or saxagliptin (5 mg/day). Failure of glycaemiccontrol was assessed using the slope of the change in HbA1c from baseline-over-time regression line (coefficient of failure [CoF]). CoF was compared directly (dapagliflozin vs saxagliptin) over the short term (NCT01606007, 24 weeks) and indirectly (placebo-adjusted) over the long term (NCT00528879 and NCT00121667, 102 weeks). A low CoF value indicated greater durability. CoF was lower for dapagliflozin versus saxagliptin over 18–24 weeks (−1.38%/year; 95% CI, −2.41 to −0.35; P = .009) and 20–102 weeks (−0.37%/year; 95% CI, −0.73 to −0.02; P = .04). Fewer dapagliflozin-treated patients versus saxagliptin-treated patients required rescue medication or discontinued the study because of failure to achieve glycaemic control at 24 weeks (3.4% vs 9.4%; P = .0191). In patients with T2DM who were inadequately controlled with metformin, dapagliflozin was associated with greater durability of glycaemic control than saxagliptin over 18–24 and 20–102 weeks.     

Efficacy and safety of dulaglutide monotherapy compared with glimepiride in East‐Asian patients with type 2 diabetes in a multicentre,double‐blind,randomized, parallel‐arm,active comparator,phase III trial

Aims

To compare the efficacy and safety of once‐weekly glucagon‐like peptide‐1 receptor agonist dulaglutide 1.5 and 0.75 mg with glimepiride in East‐Asian patients with type 2 diabetes (T2D).

Materials and methods

In this phase III, multinational, multicentre, double‐blind, randomized, parallel‐arm, 26‐week study, patients with inadequate glycaemic control were randomized 1:1:1 to once‐weekly dulaglutide 1.5 or 0.75 mg or daily glimepiride (1‐3 mg/d). The primary endpoint was assessment of the non‐inferiority of dulaglutide (1.5 mg), as measured by change in glycated haemoglobin (HbA1c), compared with glimepiride using a 0.4% non‐inferiority margin.

Results

A total of 737 patients were randomized (dulaglutide 1.5 mg, n = 244; dulaglutide 0.75 mg, n = 248; glimepiride, n = 245). At week 26, both doses of dulaglutide were non‐inferior and also superior to glimepiride for HbA1c reduction from baseline with a least squares mean difference of ?6.34 mmol/mol (95% confidence interval [CI] ?8.31, ?4.26) or ‐0.58% (95% CI ?0.76, ?0.39) for dulaglutide 1.5 mg and ?3.50 mmol/mol (95% CI ?5.47, ?1.42) or ?0.32% (95% CI ?0.50, ?0.13) for dulaglutide 0.75 mg (P < .001). A greater proportion of patients in the dulaglutide 1.5 mg group achieved the HbA1c target of <53 mmol/mol (<7.0%) compared with the glimepiride group (74.1% vs 57.4%; P < .001). The mean body weight decreased (P < .005) and total hypoglycaemia rates were lower (P < .001) in the dulaglutide groups compared with the glimepiride group. The most common drug‐related adverse events in both dulaglutide groups (≥5% of patients) included diarrhoea, nausea, increased lipase, decreased appetite, abdominal distension and vomiting.

Conclusions

Dulaglutide (both doses) demonstrated superior glycaemic control vs glimepiride, with a favourable tolerability and safety profile in East‐Asian patients with T2D.     

Comparison of tofogliflozin versus glimepiride as the third oral agent added to metformin plus a dipeptidyl peptidase-4 inhibitor in Japanese patients with type 2 diabetes: A randomized, 24-week,open-label,controlled trial (STOP-OB)

Metformin plus a dipeptidyl peptidase-4 inhibitor (DPP-4i) is the most common therapy for Japanese patients with type 2 diabetes. This 24-week, multicentre, open-label, parallel-group trial randomized patients on dual therapy to add-on tofogliflozin (20 mg/day, n = 33) or glimepiride (0.5 mg/day, n = 31). The primary outcome was change in body fat percentage. The secondary outcomes included changes in HbA1c, fat mass, fat-free mass, liver function variables and uric acid. Tofogliflozin and glimepiride reduced HbA1c to a similar extent. Body fat percentage did not change from baseline in either group. Fat mass was reduced by tofogliflozin but was increased by glimepiride (by −2.0 ± 1.7 kg and +1.6 ± 1.6 kg, P = .002). Fat-free mass was also reduced by tofogliflozin and increased by glimepiride (by −1.3 ± 1.3 kg and +0.9 ± 2.0 kg, P < .001). Alanine aminotransferase and uric acid levels were reduced by tofogliflozin (P = .006 and P < .001, respectively). These data provide novel information useful for selecting the third oral agent for patients whose diabetes is inadequately controlled with metformin plus DPP-4i dual therapy.     

Efficacy and safety of the addition of ertugliflozin in patients with type 2 diabetes mellitus inadequately controlled with metformin and sitagliptin: The VERTIS SITA2 placebo‐controlled randomized study

Aims

To assess ertugliflozin in patients with type 2 diabetes who are inadequately controlled by metformin and sitagliptin.

Materials and Methods

In this double‐blind randomized study ( Clinicaltrials.gov NCT02036515), patients (glycated haemoglobin [HbA1c] 7.0% to 10.5% [53‐91 mmol/mol] receiving metformin ≥1500 mg/d and sitagliptin 100 mg/d; estimated glomerular filtration rate [eGFR] ≥60 mL/min/1.73 m²) were randomized to ertugliflozin 5 mg once‐daily, 15 mg once‐daily or placebo. The primary efficacy endpoint was change from baseline in HbA1c at Week 26; treatment was continued until Week 52.

Results

A total of 464 patients were randomized (mean baseline HbA1c, 8.0% [64.3 mmol/mol]; eGFR, 87.9 mL/min/1.73 m²). After 26 weeks, placebo‐adjusted least squares (LS) mean changes in HbA1c from baseline were ?0.7% (?7.5 mmol/mol) and ?0.8% (?8.3 mmol/mol) for ertugliflozin 5 and 15 mg, respectively (both P < .001); 17.0%, 32.1% and 39.9% of patients receiving placebo, ertugliflozin 5 mg or ertugliflozin 15 mg, respectively, had HbA1c <7.0% (53 mmol/mol). Significant reductions in fasting plasma glucose, body weight (BW) and systolic blood pressure (SBP) were observed with ertugliflozin relative to placebo. The positive effects of ertugliflozin on glycaemic control, BW and SBP were maintained through Week 52. A higher incidence of genital mycotic infections was observed in male and female patients receiving ertugliflozin (3.7%‐14.1%) vs placebo (0%‐1.9%) through Week 52. The incidence of urinary tract infections, symptomatic hypoglycaemia and hypovolaemia adverse events were not meaningfully different across groups.

Conclusions

Ertugliflozin added to metformin and sitagliptin was well‐tolerated, and provided clinically meaningful, durable glycaemic control, BW and SBP reductions vs placebo over 52 weeks.     

Abdominal adiposity depots are correlates of adverse cardiometabolic risk factors in Caucasian and African-American adults

Objective:

Accumulation of adipose tissue is associated with cardiometabolic risks. Although visceral adipose tissue (VAT) has been strongly implicated in this relationship, there is still some debate regarding the contribution of abdominal subcutaneous adipose tissue (SAT). The purpose of this study was to determine the contribution of abdominal SAT to cardiometabolic risk factors, independent of total and visceral adiposity. These relationships were assessed in Caucasian and African Americans.

Design:

It is a cross-sectional analysis of the Pennington Center Longitudinal Study.

Subjects:

Data were extracted from 1246 participants. Total body fat mass (FM) was measured by dual-energy X-ray absorptiometry, whereas abdominal VAT and SAT areas (cm²) were measured with computed tomography. The cardiometabolic risk factors included resting blood pressure (BP), fasting blood glucose and triglyceride concentrations and high-density lipoprotein cholesterol (HDL-C).

Results:

Positive relationships across tertiles of VAT were seen for the participants with high glucose, high BP and low HDL-C (P<0.043). There was also a significant increase in the percentage of participants with two or more cardiometabolic risk factors across most tertiles of abdominal SAT (P<0.042). Logistic regression analysis showed that in univariate models, all adiposity measures were significantly associated with increased odds of having all risk factors in men and women. In multivariate models, VAT was significantly associated with most risk factors across gender. Abdominal SAT and FM (odds ratios (ORs) 1.3–2.1; all P<0.05) were associated with fewer risk factors after accounting for VAT. VAT (OR=5.9 and 5.3) and SAT (OR=2.0 and 1.8) were both associated with higher odds of the presence of two or more cardiometabolic risk factors in both males and females (P<0.001).

Conclusion:

The data suggest that abdominal SAT is not protective against unfavorable cardiometabolic risk profiles. These conclusions were consistent across ethnic groups.     

Lack of pharmacokinetic interaction between dapagliflozin, a novel sodium-glucose transporter 2 inhibitor, and metformin, pioglitazone, glimepiride or sitagliptin in healthy subjects

Aims: Dapagliflozin increases urinary glucose excretion by selectively inhibiting renal sodium–glucose transporter 2, an insulin‐independent mechanism of action that may be complementary to that of other oral antidiabetes drugs. The current studies assessed the potential for pharmacokinetic (PK) interaction between dapagliflozin and pioglitazone, metformin, glimepiride or sitagliptin in healthy subjects following single‐dose administration. Methods: In open‐label, randomized, three‐period, three‐treatment crossover studies, 24 subjects received 50 mg dapagliflozin, 45 mg pioglitazone or the combination, while 18 subjects received 20 mg dapagliflozin, 1000 mg metformin or the combination. In an open‐label, randomized, five‐period, five‐treatment, unbalanced crossover study, 18 subjects first received 20 mg dapagliflozin, 4 mg glimepiride or the combination, and afterward 100 mg sitagliptin or sitagliptin plus 20 mg dapagliflozin. Blood samples were taken over 72 h of each treatment period. Lack of PK interaction was defined as the ratio of geometric means and 90% confidence interval (CI) for combination:monotherapy being within the range of 0.80–1.25. Results: Co‐administration of dapagliflozin with pioglitazone, metformin, glimepiride or sitagliptin had no effect on dapagliflozin maximum plasma concentration (C_max) or area under the plasma concentration‐time curve (AUC). Similarly, dapagliflozin did not affect the C_max or AUC for the co‐administered drug, except for slight extensions of the 90% CI for the ratio of geometric means for glimepiride AUC (upper limit 1.29) and pioglitazone C_max (lower limit 0.75). All monotherapies and combination therapies were well tolerated. Conclusion: Dapagliflozin can be co‐administered with pioglitazone, metformin, glimepiride or sitagliptin without dose adjustment of either drug.     

A phase 1 study to evaluate the safety,tolerability, pharmacokinetics and pharmacodynamics of danuglipron (PF-06882961), an oral small-molecule glucagon-like peptide-1 receptor agonist,in Japanese adults with type 2 diabetes mellitus

Aims

This study investigated the safety, tolerability, pharmacokinetics and pharmacodynamics of danuglipron (PF-06882961), which is a novel, oral small-molecule glucagon-like peptide-1 receptor agonist, in Japanese participants with type 2 diabetes mellitus (T2DM).

Materials and Methods

This phase 1, randomized, double-blind, placebo-controlled, parallel-group study enrolled adult Japanese participants with T2DM inadequately controlled on diet and exercise. Participants received twice-daily oral doses of placebo or multiple ascending doses of danuglipron titrated to 40, 80 or 120 mg twice daily over 8 weeks. The primary outcome was the safety and tolerability of danuglipron. Secondary and exploratory outcomes included plasma pharmacokinetics, glycaemic parameters and body weight.

Results

In the 37 participants randomized, the most common treatment-emergent adverse events were nausea, vomiting, abdominal discomfort, diarrhoea and headache. Most treatment-emergent adverse events were of mild or moderate intensity. Dose-proportional increases in danuglipron exposure parameters were observed at steady state (Day 56). Significant reductions from baseline were observed with danuglipron on Day 56 for mean daily glucose [least squares mean (90% confidence interval) placebo-adjusted difference of up to −67.89 (−88.98, −46.79) mg/dl] and on Day 57 for fasting plasma glucose [up to −40.87 (−53.77, −27.98) mg/dl], glycated haemoglobin [up to −1.41% (−2.01%, −0.82%)] and body weight [up to −1.87 (−3.58, −0.17) kg].

Conclusions

In Japanese adults with T2DM, danuglipron exhibited dose-proportional increases in plasma exposure at steady state and robustly reduced glycaemic parameters and body weight after 8 weeks of dosing, with a safety profile consistent with the mechanism of action.     

The fixed combination of pioglitazone and metformin improves biomarkers of platelet function and chronic inflammation in type 2 diabetes patients: results from the PIOfix study

Background

Type 2 diabetes mellitus (T2DM) is characterized by a proinflammatory and procoagulant condition. This study investigates the impact of a pioglitazone plus metformin therapy on biomarkers of inflammation and platelet activation in comparison to a treatment with glimepiride plus metformin.

Methods

The study was designed as a multicenter, randomized, double-blinded two-arm trial. Patients with T2DM and dyslipidemia under metformin monotherapy with hemoglobin A1c value between 6.5% and 9.0% were eligible for trial participation. Blood was drawn at baseline and after 24 weeks of treatment from patients of five centers. Markers of inflammation and thrombocyte function (soluble CD40 ligand, thromboxane, vWillebrand factor, adhesion molecules, clotting reaction) were evaluated subsequently in a central laboratory.

Results

A total of 46 patients were included in the final analyses. Mean (± standard deviation) age was 58.5 ± 9.0 years (13 women, 33 men; disease duration 6.3 ± 5.0 years; body mass index 32.0 ± 4.8 kg/m²). A total of 25 patients were treated with pioglitazone plus metformin, and 21 patients were in the glimepiride arm. There was a significant decline of E-selectin (-3.7 ± 4.8 ng/ml, p < .001 versus baseline), vWillebrand factor (-19.5 ± 32.0%, p < .05), and high-sensitivity C-reactive protein concentrations (-1.08 ± 0.91 mg/liter, p < .05) in the metformin + pioglitazone arm only (metformin + glimepiride, -0.5 ± 3.4 ng/ml, +1.4 ± 33.2%, + 0.08 ± 0.72 mg/liter, respectively, all not significant). Also, all other surrogate markers for platelet function and inflammation showed slight improvements in the metformin + pioglitazone arm but not in the metformin + glimepiride arm.

Conclusions

The fixed metformin + pioglitazone combination treatment showed an overall improvement of laboratory surrogate markers, indicating improvement of platelet function and of chronic systemic inflammation, which was not seen with metformin + glimepiride.     

Front Cover

Aim

Use of sodium-glucose co-transporter-2 inhibitors (SGLT2is) for glycaemic control is increasing in individuals with type 2 diabetes (T2D) for their additional benefits on heart failure and chronic kidney disease. However, SGLT2is generally reduce body weight, which might promote sarcopenia in older individuals. We evaluated the effects of the SGLT2i empagliflozin on muscle mass and strength in addition to glucose control in elderly adults with T2D.

Materials and Methods

Individuals with T2D aged ≥65 years with body mass index ≥22 kg/m² and glycated haemoglobin (HbA1c) 7.0%-10.0% were randomized 1:1 to once-daily empagliflozin 10 mg or placebo for 52 weeks. The primary endpoint was change from baseline in HbA1c at week 52. Secondary endpoints included changes from baseline in muscle mass and strength.

Results

Of the 129 individuals randomized, 72.4% were men, mean age 74.1 years, body mass index 25.6 kg/m² and HbA1c 7.6%. The placebo-adjusted mean change from baseline in HbA1c at week 52 with empagliflozin was −0.57% [95% confidence interval (CI) −0.78, −0.36]. Change in body weight was −3.26 kg and −0.90 kg with empagliflozin and placebo, respectively (placebo-adjusted difference: −2.37 kg; 95% CI −3.07, −1.68). Placebo-adjusted change in muscle mass was −0.61 kg (95% CI −1.61, 0.39), fat mass −1.84 kg (95% CI −2.65, −1.04) and grip strength −0.3 kg (95% CI −1.1, 0.5).

Conclusions

Empagliflozin improved glucose control and reduced body weight without compromising muscle mass or strength in elderly adults with T2D in this trial.     

Visceral Adiposity and Left Ventricular Mass and Function in Patients With Aortic Stenosis: The PROGRESSA Study

Background

Recent studies have reported that obesity, metabolic syndrome, and diabetes are associated with left ventricular (LV) hypertrophy (LVH) and dysfunction in patients with aortic stenosis (AS). The purpose of this study was to examine the association between amount and distribution of body fat and LVH and systolic dysfunction in AS patients.

Methods

One hundred twenty-four patients with AS were prospectively recruited in the PROGRESSA (Metabolic Determinants of the Progression of Aortic Stenosis) study and underwent Doppler echocardiography and computed tomography scan. Presence and severity of LVH was assessed according to LV mass indexed for height^2.7 and LV dysfunction according to global longitudinal strain (GLS). Computed tomography was used to quantify abdominal visceral (VAT) and subcutaneous (SAT) adipose tissue, and total adipose tissue (TAT).

Results

Body mass index (BMI) correlated strongly with TAT (r = 0.85), moderately with VAT (r = 0.70), and SAT (r = 0.69), and weakly with the proportion of VAT (VAT/TAT ratio: r = 0.19). In univariate analysis, greater BMI, TAT, VAT, SAT, and VAT/TAT were associated with increased LV mass index and greater VAT and VAT/TAT ratio were associated with reduced GLS. Multivariate analysis revealed that larger BMI (P < 0.0001) and greater VAT/TAT ratio (P = 0.01) were independently associated with higher prevalence of LVH, and only the VAT/TAT ratio (P = 0.03) was independently associated with reduced GLS.

Conclusions

The results of this study suggest that total and visceral adiposity are independently associated with LVH in patients with AS. Furthermore, impairment of LV systolic function does not appear to be influenced by total obesity but is rather related to excess visceral adiposity. These findings provide impetus for elaboration of interventional studies aiming at visceral adiposity in the AS population.     

Comparison of the effects of sitagliptin and dapagliflozin on time in range in Japanese patients with type 2 diabetes stratified by body mass index: A sub-analysis of the DIVERSITY-CVR study

Aims

To compare the effects of baseline background characteristics in patients treated with dapagliflozin and sitagliptin in the DIVERSITY-CVR study and to analyse the time in range (TIR), a metric for glycaemic control.

Materials and methods

This prospective, randomized, multicentre study included 340 Japanese patients with early-stage type 2 diabetes. To examine the effects of dapagliflozin and sitagliptin on glycaemic variability, we re-examined the primary endpoint (glycated haemoglobin [HbA1c] < 7.0%, body weight loss ≥ 3.0%, and avoidance of hypoglycaemia) achievement rate in participants stratified by baseline background characteristics.

Results

Sitagliptin was significantly superior in achieving HbA1c level <7.0% in the lower body mass index (BMI) group (71.1% vs. 43.6%; P < 0.05), with no significant differences in other subgroups. In the lower BMI group, the rate of achievement of TIR > 70% after 24-week treatment was significantly higher with sitagliptin than with dapagliflozin (91.9% vs. 69.4%; P < 0.05). In contrast, dapagliflozin was superior to sitagliptin in achieving TIR > 70% in the higher BMI group (85.7% vs. 52.9%; P < 0.01).

Conclusion

In Japanese patients with early-stage type 2 diabetes, sitagliptin was associated with improved TIR in patients with a lower BMI. Dapagliflozin was effective in patients with a higher BMI.     

Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, in patients with type 2 diabetes mellitus inadequately controlled on glimepiride alone or on glimepiride and metformin

AIM: To assess the efficacy and safety of a 24-week treatment with sitagliptin, a highly selective once-daily oral dipeptidyl peptidase-4 (DPP-4) inhibitor, in patients with type 2 diabetes who had inadequate glycaemic control [glycosylated haemoglobin (HbA(1c)) >or=7.5% and or=4 mg/day) monotherapy and 229 were on glimepiride (>or=4 mg/day) plus metformin (>or=1,500 mg/day) combination therapy. Patients exceeding pre-specified glycaemic thresholds during the double-blind treatment period were provided open-label rescue therapy (pioglitazone) until study end. The primary efficacy analysis evaluated the change in HbA(1c) from baseline to Week 24. Secondary efficacy endpoints included fasting plasma glucose (FPG), 2-h post-meal glucose and lipid measurements. RESULTS: Mean baseline HbA(1c) was 8.34% in the sitagliptin and placebo groups. After 24 weeks, sitagliptin reduced HbA(1c) by 0.74% (p < 0.001) relative to placebo. In the subset of patients on glimepiride plus metformin, sitagliptin reduced HbA(1c) by 0.89% relative to placebo, compared with a reduction of 0.57% in the subset of patients on glimepiride alone. The addition of sitagliptin reduced FPG by 20.1 mg/dl (p < 0.001) and increased homeostasis model assessment-beta, a marker of beta-cell function, by 12% (p < 0.05) relative to placebo. In patients who underwent a meal tolerance test (n = 134), sitagliptin decreased 2-h post-prandial glucose (PPG) by 36.1 mg/dl (p < 0.001) relative to placebo. The addition of sitagliptin was generally well tolerated, although there was a higher incidence of overall (60 vs. 47%) and drug-related adverse experiences (AEs) (15 vs. 7%) in the sitagliptin group than in the placebo group. This was largely because of a higher incidence of hypoglycaemia AEs (12 vs. 2%, respectively) in the sitagliptin group compared with the placebo group. Body weight modestly increased with sitagliptin relative to placebo (+0.8 vs. -0.4 kg; p < 0.001). CONCLUSIONS: Sitagliptin 100 mg once daily significantly improved glycaemic control and beta-cell function in patients with type 2 diabetes who had inadequate glycaemic control with glimepiride or glimepiride plus metformin therapy. The addition of sitagliptin was generally well tolerated, with a modest increase in hypoglycaemia and body weight, consistent with glimepiride therapy and the observed degree of glycaemic improvement.     

Safety/tolerability,efficacy and pharmacokinetics of 600-μg cotadutide in Japanese type 2 diabetes patients with a body mass index of 25 kg/m2 or higher: A phase I,randomized, double-blind,placebo-controlled study

Aim

To assess the safety/tolerability, efficacy and pharmacokinetics of once-daily, 600-μg cotadutide in Japanese type 2 diabetes patients with a body mass index of 25 kg/m² or higher.

Materials and Methods

This phase I, randomized, double-blind, placebo-controlled study (NCT04208620) enrolled patients to receive subcutaneous cotadutide at an escalating dose to determine the highest tolerated clinical dose (Cohort 1), then applied in Cohort 2. The primary endpoint was safety, including treatment-emergent adverse events (TEAEs); secondary endpoints included glycaemic control and body weight.

Results

Sixteen patients were randomly allocated to receive cotadutide or placebo in a 3:1 ratio. All patients were Asian, 62.5% were male, and the median age and body mass index were 60 years and 27.2 kg/m², respectively. Through the follow-up period of the study, 11/12 (91.7%) patients in the cotadutide group experienced a TEAE versus 1/4 (25.0%) patients in the placebo group. All TEAEs were mild, except for one moderate event. There were no deaths, serious TEAEs or TEAEs leading to study discontinuation. Gastrointestinal-related events were the most common TEAEs. Cotadutide-treated patients achieved significantly improved 7-day mean glucose measured by continuous glucose monitoring; the 7-day mean (standard deviation) at the end of treatment (day 70) was 112.23 (20.79) versus 206.85 (3.62) mg/dL for placebo. Mean respective changes in HbA1c were −1.13% (0.64%) and −0.17% (0.65%); and mean percentage changes in body weight were −6.93% (3.44%) and −1.23% (1.20%).

Conclusions

Cotadutide was well tolerated at doses up to 600 μg; efficacy versus placebo for weight loss and glycaemic control was shown.     

Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with glimepiride: a randomized, 24-week, double-blind, placebo-controlled trial

Aims: Progressive deterioration of glycaemic control in type 2 diabetes mellitus (T2DM) often requires treatment intensification. Dapagliflozin increases urinary glucose excretion by selective inhibition of renal sodium‐glucose cotransporter 2 (SGLT2). We assessed the efficacy, safety and tolerability of dapagliflozin added to glimepiride in patients with uncontrolled T2DM. Methods: This 24‐week, randomized, double‐blind, placebo‐controlled, parallel‐group, international, multicentre trial (ClinicalTrials.gov NCT00680745) enrolled patients with uncontrolled T2DM [haemoglobin A1c (HbA1c) 7–10%] receiving sulphonylurea monotherapy. Adult patients (n = 597) were randomly assigned to placebo or dapagliflozin (2.5, 5 or 10 mg/day) added to open‐label glimepiride 4 mg/day for 24 weeks. Primary endpoint was HbA1c mean change from baseline at 24 weeks. Secondary endpoints included change in body weight and other glycaemic parameters. Results: At 24 weeks, HbA1c adjusted mean changes from baseline for placebo versus dapagliflozin 2.5/5/10 mg groups were ?0.13 versus ?0.58, ?0.63, ?0.82%, respectively (all p < 0.0001 vs. placebo by Dunnett's procedure). Corresponding body weight and fasting plasma glucose values were ?0.72, ?1.18, ?1.56, ?2.26 kg and ?0.11, ?0.93, ?1.18, ?1.58 mmol/l, respectively. In placebo versus dapagliflozin groups, serious adverse events were 4.8 versus 6.0–7.1%; hypoglycaemic events 4.8 versus 7.1–7.9%; events suggestive of genital infection 0.7 versus 3.9–6.6%; and events suggestive of urinary tract infection 6.2 versus 3.9–6.9%. No kidney infections were reported. Conclusions: Dapagliflozin added to glimepiride in patients with T2DM uncontrolled on sulphonylurea monotherapy significantly improved HbA1c, reduced weight and was generally well tolerated, although events suggestive of genital infections were reported more often in patients receiving dapagliflozin.     

Incident and recurrent hypoglycaemia with linagliptin and glimepiride over a median of 6 years in the CAROLINA cardiovascular outcome trial

Aim

The CAROLINA trial established non-inferiority of linagliptin versus glimepiride for major adverse cardiovascular events in patients with relatively early type 2 diabetes at increased cardiovascular risk. In pre-specified and post-hoc analyses, we investigated treatment effects on total hypoglycaemic burden in CAROLINA.

Materials and methods

Patients were randomized and treated with 5 mg linagliptin (n = 3014) or 1-4 mg glimepiride (n = 3000) once daily added to standard care. Hypoglycaemia captured from investigator-reported adverse events was analysed with Poisson and negative binomial regressions for the first and total (first plus recurrent) events, respectively. The influence of insulin initiation and glycated haemoglobin (HbA1c) change on the treatment effect for hypoglycaemia was also explored.

Results

Over 6.3 years median follow-up, average HbA1c over time did not differ between linagliptin versus glimepiride (weighted mean difference [95% confidence interval]: 0.00%, [−0.05, 0.05]), nor did insulin initiation (18.6% vs. 19.2% of patients, respectively), whereas body weight was lower with linagliptin (−1.54 kg, [−1.80, −1.28]). Hypoglycaemia frequency was lower with linagliptin across all hypoglycaemia categories, including severe episodes. Rate ratios (95% confidence interval) for first and total events for investigator-reported hypoglycaemia were 0.21 (0.19-0.24) and 0.12 (0.10-0.14), respectively, with 8.7 first and 60.8 total estimated events prevented/100 patient-years with linagliptin versus glimepiride. These differences occurred during night-time and daytime, and in subgroup analyses of total events. Treatment differences in hypoglycaemia were neither impacted by HbA1c changes nor insulin initiation.

Conclusions

Across the severity spectrum, linagliptin substantially reduced the hypoglycaemic burden versus glimepiride in patients with relatively early type 2 diabetes at increased cardiovascular risk.     

The ratio of visceral to subcutaneous fat, a metric of body fat distribution, is a unique correlate of cardiometabolic risk

Aims/hypothesis  

The anatomic location of excess body fat has an impact on associated cardiometabolic morbidity, and visceral adipose tissue (VAT) is more pathogenic than subcutaneous adipose tissue (SAT). However, VAT or SAT alone provides little information regarding the relative distribution of body fat. We hypothesised that the propensity to store energy in VAT relative to SAT depots may be a correlate of cardiometabolic risk, and tested this hypothesis using the VAT/SAT ratio as a metric of fat distribution.     

Bexagliflozin as an adjunct to metformin for the treatment of type 2 diabetes in adults: A 24-week,randomized, double-blind,placebo-controlled trial

Aim

To evaluate the relative safety and effectiveness of bexagliflozin as an adjunct to metformin for the treatment of type 2 diabetes mellitus.

Methods

In total, 317 participants were randomized to receive bexagliflozin or placebo plus metformin. The primary endpoint was the change in glycated haemoglobin (HbA1c) from baseline to week 24, with secondary endpoints for systolic blood pressure (SBP), fasting plasma glucose and weight loss. An open label arm enrolled participants with HbA1c >10.5% and was analysed separately.

Results

The mean change in HbA1c was −1.09% (95% CI −1.24%, −0.94%) in the bexagliflozin arm and −0.56% (−0.71%, −0.41%) in the placebo arm, a difference of −0.53% (−0.74%, −0.32%; p < .0001). Excluding observations after rescue medication, the intergroup difference was −0.70% (−0.92, −0.48; p < .0001). The open label group change in HbA1c was −2.82% (−3.23%, −2.41%). Placebo-adjusted changes from baseline SBP, fasting plasma glucose and body mass were −7.07 mmHg (−9.83, −4.32; p < .0001), −1.35 mmol/L (−1.83, −0.86; p < .0001) and −2.51 kg (−3.45, −1.57; p < .0001). Adverse events affected 42.4% and 47.2% of subjects in the bexagliflozin and placebo arms, respectively; fewer subjects in the bexagliflozin arm experienced serious adverse events.

Conclusions

Bexagliflozin produced clinically meaningful improvement in glycaemic control, estimated glomerular filtration rate and SBP when added to metformin in a population of adults with diabetes.     

Visceral/epicardial adiposity in nonobese and apparently healthy young adults: Association with the cardiometabolic profile

Objective

We investigate associations of regional adipose tissues with cardiometabolic profile of nonobese and apparently healthy young adults.

Methods

Four hundred twenty-five nonobese and apparently healthy individuals were assessed for blood pressure and fasting lipid profile, blood glucose and adiponectin. Subcutaneous abdominal adipose tissue (SAT) and ectopic fat depots (visceral abdominal adipose tissue [VAT], epicardial adipose tissue [EAT] and hepatic fat fraction [HFF]) were quantified by magnetic resonance imaging.

Results

According to anthropometric measurements, blood pressure and blood markers, the population (18–35 years, 54% women) had a low cardiometabolic risk. Compared to women, men had more VAT, EAT and HFF, but less SAT. Regional adipose tissues were positively correlated with each other. VAT and EAT carried significant correlations with all markers of cardiometabolic risk, while SAT and HFF correlated variably with these markers. While taking into account age and gender, SAT, VAT and EAT were associated with most cardiometabolic markers, while HFF was only associated with total cholesterol/high-density lipoprotein ratio (TC/HDL-C) and triglycerides (TG). When comparing SAT, VAT and EAT head-to-head, VAT was the only adipose tissue location maintaining significant association with most markers of cardiometabolic risk. Greater VAT (≥50th percentile) was associated with a worse cardiometabolic profile, whether individuals were overweight or normal weight.

Conclusion

Even in nonobese and apparently healthy young women and men, accumulation of ectopic visceral adiposity in general, and of VAT in particular, is associated with a worse cardiometabolic profile whether individuals were overweight or normal weight.     

Effects of intensive insulin therapy alone and in combination with pioglitazone on body weight, composition, distribution and liver fat content in patients with type 2 diabetes

Aim: To evaluate the effects of intensive insulin therapy alone and with added pioglitazone on body weight, fat distribution, lean body mass (LBM) and liver fat in type 2 diabetic patients. Methods: Twenty‐five insulin‐treated, obese patients with type 2 diabetes were randomized to addition of pioglitazone 45 mg (n = 12) or placebo (n = 13) and treated intensively for 12–16 weeks. Dual‐energy X‐ray absorptiometry/abdominal computed tomography scans were performed before/after treatment. LBM, visceral/subcutaneous adipose tissue (VAT/SAT) and liver/spleen (L/S) attenuation ratios were measured pre‐/posttreatment (a ratio <1 represents fatty liver). Results: Intensive insulin alone and insulin + pioglitazone significantly improved glycaemic control (7.8 ± 0.3 to 7.2 ± 0.3% and 7.6 ± 0.3 to 7.1 ± 0.4%, respectively). Body weight gain was greater with insulin + pioglitazone (4.9 ± 4.5 kg) versus insulin therapy alone (1.7 ± 0.7 kg). SAT increased significantly with pioglitazone + insulin therapy (393.9 ± 48.5 to 443.2 ± 56.7 cm², p < 0.01) compared to a non‐significant increase with insulin therapy alone (412.9 ± 42.5 to 420.8 ± 43.8 cm²). VAT decreased non‐significantly in both groups (240.3 ± 41.7 to 223.8 ± 38.1 cm² with insulin + pioglitazone and 266.6 ± 27.4 to 250.5 ± 22.2 cm² with insulin therapy). LBM increased significantly by 1.92 ± 0.74 kg with insulin + pioglitazone treatment. The L/S attenuation ratio in the placebo + insulin group decreased from 1.08 ± 0.1 to 1.04 ± 0.1 (p = ns) and increased from 1.00 ± 0.1 to 1.08 ± 0.05 (p = 0.06) in the pioglitazone + insulin group. Conclusions: Intensification of insulin therapy in type 2 diabetic patients causes modest weight gain and no change in body fat distribution, LBM or liver fat. In contrast, the addition of pioglitazone, at equivalent glycaemia, increases weight gain, fat mass and SAT; increases LBM and tends to decrease liver fat. These changes in fat distribution may contribute to the beneficial effects of pioglitazone, despite greater weight gain.