Efficacy and safety of sitagliptin monotherapy and combination therapy in Japanese type 2 diabetes patients

(J Diabetes Invest, doi: 10.1111/j.2040‐1124.2012.00221.x, 2012) Aims/Introduction: To determine the efficacy and safety of sitagliptin monotherapy and combination therapy in Japanese type 2 diabetes patients after 3 months’ therapy. Materials and Methods: A retrospective, observational study of 741 type 2 diabetes patients was carried out; 110 received sitagliptin monotherapy, and 631 received combination therapy with sitagliptin when other oral medications were insufficient. The primary outcome measure was glycated hemoglobin (HbA_1c) measured at 0, 4 and 12 weeks of sitagliptin therapy. Results: In the monotherapy and combination therapy groups, HbA_1c decreased significantly after 12 weeks. Target HbA_1c (<7%) was achieved in 39.1% overall. On logistic regression analysis, baseline HbA_1c was the strongest contributing factor for achieving target HbA_1c; baseline body mass index and duration of diabetes were also significant factors. A total of 82 patients (11%) were unresponsive to sitagliptin. These patients’ baseline body mass index was significantly higher and their baseline HbA_1c was significantly lower than those of patients who responded to sitagliptin. The most commonly co‐administered drugs were sulfonylureas (508 patients). In these patients, the dose of sulfonylurea decreased with time. In 66 patients whose sulfonylurea dosage was reduced when sitagliptin was started, HbA_1c and bodyweight decreased significantly after 12 weeks. A total of 24 patients receiving sulfonylureas had mild hypoglycemia, but none discontinued sitagliptin. Conclusions: Sitagliptin was effective and safe as both monotherapy and combination therapy in Japanese type 2 diabetes patients. When sulfonylureas were ineffective, sitagliptin improved glycemic control. In patients whose sulfonylurea dose was reduced at the start of sitagliptin, blood glucose improved and bodyweight decreased after 12 weeks.     

Efficacy and safety of monotherapy of sitagliptin compared with metformin in patients with type 2 diabetes

Aim: To compare the efficacy and safety of monotherapy with sitagliptin and metformin in treatment‐naïve patients with type 2 diabetes. Methods: In a double‐blind study, 1050 treatment‐naïve patients (i.e. not taking an antihyperglycaemic agent for ≥16 weeks prior to study entry) with type 2 diabetes and an HbA_1c 6.5–9% were randomized (1:1) to treatment with once‐daily sitagliptin 100 mg (N = 528) or twice‐daily metformin 1000 mg (N = 522) for 24 weeks. Metformin was up‐titrated from 500 to 2000 mg per day (or maximum tolerated daily dose ≥1000 mg) over a period of 5 weeks. The primary analysis used a per‐protocol (PP) approach to assess whether sitagliptin was non‐inferior to metformin based on HbA_1c change from baseline at week 24. Non‐inferiority was to be declared if the upper boundary of the 95% confidence interval (CI) for the between‐group difference in this endpoint was <0.40%. Results: From a mean baseline HbA_1c of 7.2% in the PP population, HbA_1c change from baseline was ?0.43% with sitagliptin (n = 455) and ?0.57% with metformin (n = 439). The between‐group difference (95% CI) was 0.14% (0.06, 0.21), thus confirming non‐inferiority. Baseline HbA_1c influenced treatment response, with larger reductions in HbA_1c observed in patients with baseline HbA_1c≥8% in the sitagliptin (–1.13%; n = 74) and metformin (–1.24%; n = 73) groups. The proportions of patients at week 24 with HbA_1c values at the goals of <7 or <6.5% were 69 and 34% with sitagliptin and 76 and 39% with metformin, respectively. Fasting plasma glucose changes from baseline were ?11.5 mg/dL (–0.6 mmol/l) and ?19.4 mg/dl (–1.1 mmol/l) with sitagliptin and metformin, respectively (difference in LS mean change from baseline [95% CI] = 8.0 mg /dl [4.5,11.4]). Both treatments led to similar improvements from baseline in measures of homeostasis model assessment‐β cell function (HOMA‐β) and insulin resistance (HOMA‐IR). The incidence of hypoglycaemia was 1.7% with sitagliptin and 3.3% with metformin (p = 0.116). The incidence of gastrointestinal‐related adverse experiences was substantially lower with sitagliptin (11.6%) compared with metformin (20.7%) (difference in incidence [95% CI] = ?9.1% [?13.6,?4.7]), primarily because of significantly decreased incidences of diarrhoea (3.6 vs. 10.9%; p < 0.001) and nausea (1.1 vs. 3.1%; p = 0.032). Body weight was reduced from baseline with both sitagliptin (LS mean change [95% CI] = ?0.6 kg [?0.9,?0.4]) and metformin (–1.9 kg [–2.2, ?1.7]) (p < 0.001 for sitagliptin vs. metformin). Conclusions: In this 24‐week monotherapy study, sitagliptin was non‐inferior to metformin in improving HbA_1c in treatment‐naïve patients with type 2 diabetes. Although both treatments were generally well tolerated, a lower incidence of gastrointestinal‐related adverse experiences was observed with sitagliptin.     

Resistance training improves the metabolic profile in individuals with type 2 diabetes

Aerobic endurance exercise has traditionally been advocated in the treatment of type 2 diabetes, while the potential role of resistance training has often been overlooked. The aim of the present study was to determine the effect of circuit-type resistance training on blood pressure, lipids and long-term glycaemic control (HbA_1c) in type 2 diabetic subjects. Thirty-eight type 2 diabetic subjects were enrolled in the study; 18 participated in a 5-month individualized progressive resistance training programme (moderate intensity, high volume) twice a week, while the remaining 20 served as controls. The exercise group showed improvements in total cholesterol (6.0±.3 vs 5.3±.3 mM; P<0.01), low density lipoprotein (LDL)-cholesterol (3.90±.22 vs 3.35±.21 mM; P<0.01) and triglycerides (1.91±.25 vs 1.53±.22 mM; P<0.01). Also, the difference in the change in HbA_1c between the groups (0.5%) achieved statistical significance (P<0.01). Circuit-type resistance training seems to be feasible in moderately obese, sedentary type 2 diabetic subjects and the inclusion of circuit-type resistance training in exercise training programmes for type 2 diabetic subjects seems appropriate. Received: 14 April 1997 / Accepted in revised form: 25 July 1997     

Outcome survey in unselected hypertensive patients with type 2 diabetes mellitus: effects of ace inhibition

Although the benefit of angiotensin converting enzyme (ACE) inhibitors in diabetic nephropathy is well documented in double-blind randomized, controlled clinical trials, it is uncertain whether the benefit extends to unselected patients with diabetes mellitus and arterial hypertension in general practice. In 2504 unselected patients with type 2 diabetes mellitus (mean age 63 ± 10 years) blood pressure, cardiovascular, renal, and metabolic parameters were assessed at baseline and during a treatment period of 1 year with the ACE inhibitor cilazapril by primary care physicians. The average dose of cilazapril was 2.5 mg/day. Outcome measures were blood pressure, serum creatinine, proteinuria (dip stick), HbA_1c levels, evaluation of edema, and exertional dyspnea. In the study cohort, systolic blood pressure decreased by 24 ± 17 mm Hg and diastolic blood pressure by 12 ± 11 mm Hg. An increase in serum creatinine (> 0.2 mg/dL) occurred more frequently in patients with than in those without renal involvement (19% v 7%; P < .05). Serum creatinine decreased more frequently in patients with renal involvement than in those without (26% ± 4% v 12% ± 3.8%; P < .05). Overall renal function in patients with diabetic nephropathy (n = 318) improved (2.1 ± 1.6 mg/dL v 1.7 ± 1.4 mg/dL; P < .05). The frequency of proteinuria was lower after 1 year than at baseline (62% ± 9% v 82% ± 8%; P < .05). Metabolic control of diabetes mellitus improved in parallel (median HbA_1c 8.0% v 7.0%; P < .01). Scores for edema formation and exertional dyspnea improved as well (P < .01). In this outcome survey of unselected patients with type 2 diabetes mellitus and arterial hypertension, the ACE inhibitor cilazapril effectively lowered blood pressure, which was associated with an improvement in glucose metabolism, cardiac function, and renal function.     

Glycaemia‐independent ethnic differences in HbA1c in subjects with impaired glucose tolerance

Aim To study the ethnic differences in HbA_1c between Whites and South Asians with impaired glucose tolerance. Methods We audited 75g oral glucose tolerance tests (OGTT) performed in Clinical Chemistry, New Cross Hospital, Wolverhampton over 1 year. HbA_1c and glycaemia were compared between Whites and South Asians with impaired glucose intolerance (IGT). Results There were 46 South Asians (22 female) and 88 Whites (41 female). South Asian subjects were younger (59.2 ± 14.31 vs. 67.6 ± 12.63 yrs; P < 0.001) and weighed less (78.1 ± 17.2 vs. 87.47 ± 19.1 kgs; P < 0.001) than White subjects. HbA_1c levels were higher (6.5 ± 0.7 vs. 6.1 ± 0.6%; P < 0.001) in South Asians compared to Whites. Fasting glucose (5.71 ± 0.5 vs. 5.93 ± 0.7; P = 0.039) was lower in South Asians but 2hour glucose (10.5 ± 1.0 vs. 10.40 ± 0.9; P = 0.404) was similar in both ethnic groups. Conclusion South Asians have higher HbA_1c levels than Whites despite lower fasting glucose value on OGTT, indicating ethnic differences in HbA_1c are due to glycaemia‐independent factors     

Flexible,intensive insulin therapy and dietary freedom in adolescents and young adults with Type 1 diabetes: a prospective implementation study

Aims To assess the outcome of a Diabetes Treatment and Teaching Programme (DTTP) on glycated haemoglobin (HbA_1c), severe hypoglycaemia (SH) and severe ketoacidosis (SKA) in adolescents and young adults with Type 1 diabetes. Methods Quality-assurance project with assessment of participants 1 year after participation in a DTTP (5-day inpatient course, groups ≤ 10 patients, fixed curriculum of education/training, introduction of dietary freedom). Before–after analyses of participants aged 12–15, 15–18, 18–21 and 21–24 years. Main outcome measures were HbA_1c, SH and SKA. Results For the 1592 participants, aged 12 to 24 years, mean age at enrolment was 19 ± 3 years, mean duration of diabetes was 7.3 ± 5.4 (range 0.3–24) years, mean baseline HbA_1c declined from 8.8 ± 2.3% to 8.1 ± 2.0%. The incidence of SH was 0.31 vs. 0.11 events/patient/year; the incidence of SKA 0.17 vs. 0.07 events/patient/year. In mixed effects models taking into account effects of centres, age and diabetes duration, the mean difference was −0.64%[P < 0.001, 95% confidence interval (CI) −0.79 to −0.5] for HbA_1c, −0.2 events/patient/year (P < 0.0001, 95% CI −0.28 to −0.12) for SH and −0.1 events/patient/year (P < 0.0001, 95% CI −0.14 to −0.06) for SKA. Conclusions Adolescents and young adults with Type 1 diabetes benefit from participation in a standard DTTP for flexible, intensive insulin therapy and dietary freedom.     

Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy in patients with type 2 diabetes mellitus

Aims/hypothesis The aim of this study was to assess the efficacy and safety of sitagliptin (MK-0431) as monotherapy in patients with type 2 diabetes mellitus and inadequate glycaemic control (HbA_1c ≥7% and ≤10%) on exercise and diet.Methods A total of 521 patients aged 27–76 years with a mean baseline HbA_1c of 8.1% were randomised in a 1:2:2 ratio to treatment with placebo, sitagliptin 100 mg once daily, or sitagliptin 200 mg once daily, for 18 weeks. The efficacy analysis was based on an all-patients-treated population using an analysis of covariance, excluding data obtained after glycaemic rescue.Results After 18 weeks, HbA_1c was significantly reduced with sitagliptin 100 mg and 200 mg compared with placebo (placebo-subtracted HbA_1c reduction: −0.60% and −0.48%, respectively). Sitagliptin also significantly decreased fasting plasma glucose relative to placebo. Patients with higher baseline HbA_1c (≥9%) experienced greater placebo-subtracted HbA_1c reductions with sitagliptin (−1.20% for 100 mg and −1.04% for 200 mg) than those with HbA_1c <8% (−0.44% and −0.33%, respectively) or ≥8% to 8.9% (−0.61% and −0.39%, respectively). Homeostasis model assessment beta cell function index and fasting proinsulin:insulin ratio, markers of insulin secretion and beta cell function, were significantly improved with sitagliptin. The incidence of hypoglycaemia and gastrointestinal adverse experiences was not significantly different between sitagliptin and placebo. Sitagliptin had a neutral effect on body weight.Conclusions/interpretation Sitagliptin significantly improved glycaemic control and was well tolerated in patients with type 2 diabetes mellitus who had inadequate glycaemic control on exercise and diet. Electronic supplementary material Supplementary material is available in the online version of this article at and is accessible to authorised users.For the Sitagliptin Study 023 Group see electronic supplementary material for list of study investigators.     

Correlation of glycated albumin but not hemoglobin A1c with endogenous insulin secretion in fulminant type 1 diabetes mellitus

Aims/Introduction: Fulminant type 1 diabetes mellitus (FT1DM) develops as a result of very rapid and almost complete pancreatic β‐cell destruction. We hypothesized that in patients with FT1DM who have less endogenous insulin secretion, disease progression is more rapid, and thus glycated albumin (GA) levels are lower. This study was designed to prove this hypothesis. Materials and Methods: The present study included 42 patients with FT1DM (24 men, 18 women) in whom glycated hemoglobin (HbA_1c), GA and daily urinary C‐peptide (CPR) were measured at the time of diagnosis. Patients with complications, such as liver disease, kidney disease, anemia, or who were pregnant were excluded. Results: Urinary CPR (log transformed) was not correlated with HbA_1c (R = 0.168, P = 0.287), but was positively correlated with GA (R = 0.336, P = 0.030). It was weakly, but not significantly, correlated with GA/HbA_1c ratio (R = 0.281, P = 0.072). In patients with GA < 24.0%, urinary CPR was significantly lower than in patients with GA ≥ 24.0%. In addition, in patients with GA/HbA_1c ratio <3.8, urinary CPR was significantly lower than in patients with GA/HbA_1c ratio ≥ 3.8. Conclusions: Our findings suggest that in patients with FT1DM, GA at the time of diagnosis was correlated with endogenous insulin secretion. GA < 24.0% at the time of diagnosis is predictive for less endogenous insulin secretion in patients with FT1DM. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2010.00050.x, 2010)     

Carotid intima-media thickness and stiffness in relation to type 2 diabetes in Chinese

We investigated carotid intima-media thickness (IMT) and quantitative carotid stiffness (QCS) index in relation to plasma glycosylated hemoglobin A_1C (HbA_1C) and duration of diabetes mellitus in 337 Chinese diabetic patients. In categorical analyses, carotid IMT was 710 μm in subjects with a duration of diabetes mellitus ≤2 years, 760 μm in subjects with a duration of diabetes mellitus more than two years and with plasma HbA_1C < 6.5% (P < 0.05), and 790 μm in subjects with a duration of diabetes mellitus more than two years but with plasma HbA_1C ≥ 6.5% (P < 0.01). The corresponding values for QCS values were 4.5, 4.6 and 5.1 (P < 0.05), respectively. In multiple stepwise regression analyses carotid IMT was significantly associated with the duration of diabetes mellitus, systolic blood pressure and serum concentration of total cholesterol, whereas QCS was significantly associated with age, HbA_1C, systolic and diastolic blood pressure (P < 0.05). In conclusion, carotid IMT as a structural measure of arterial wall is increased in patients with a longer history of diabetes mellitus, whereas QCS as functional index is mainly influenced by the quality of blood glucose control.     

A comparison between islet transplantation and parenteral insulin in the control of diabetes and prevention of renal complications in mice

The control of diabetes and the prevention of renal complications were studied in mice that received different treatment regimes for six months. Transplantation of syngeneic cultured fetal pancreas completely reversed streptozotocin-induced diabetes (mean FBG 5.1 ± 0.4 mmole/liter six months after transplantation, versus 5.8 ± 0.2 mmole/liter in normal mice). The mean fasting blood glucose (FBG) level of insulin-treated mice was lower than the mean FBG level of untreated diabetic mice (9.0 ± 1.2 mmole/liter versus 11.5 ± 1.3 mmole/liter, P < 0.05) but exceeded the FBG level of transplanted mice (P < 0.001) or normal controls (P < 0.001). There were no significant differences between the mean level of glycosylated hemoglobin (HbA_1c) of normal (4.8 ± 0.3%), transplanted (4.5 ± 0.3%), or insulin-treated mice (5.3 ± 0.4%), but the HbA_1c level in the untreated diabetic group was increased (7.0 ± 0.5%; P < 0.001). Six months after transplantation, the thickness of the glomerular capillary basement membrane (GCBM) was not different in the transplanted group and normal controls (156.4 ± 5.7 nm versus 157.3 ± 12.6 nm); the GCBM was thicker in the insulin-treated mice than in the transplanted mice (179.8 ± 4.2 nm versus 156.4 ± 5.7 nm; P < 0.02), but thinner than in untreated diabetic mice (179.8 ± 4.2 nm versus 202.2 ± 4.4 nm; P < 0.001). It is concluded that islet transplantation, in contrast to good control as judged by normalization of HbA_1c levels achieved with parenteral insulin, prevents GCBM thickening in experimental diabetes.     

Reducing snacks when switching from conventional soluble to lispro insulin treatment: effects on glycaemic control and hypoglycaemia

The lack of significant improvement in HbA_1c during insulin lispro treatment in previous studies may have been due to inadequate dietary adjustments. We tested whether reduction of snacks and a compensatory increase in main meals results in improved metabolic control when switching to lispro treatment. One hundred and forty-one Type 1 diabetic patients, mean ± SD age 36 ± 9 years, diabetes duration 14 ± 10 years, had two daily NPH injections throughout the study. After a baseline visit, the patients used conventional soluble insulin preprandially thrice daily for 12 weeks. Thereafter they were switched to lispro insulin and advised to transfer ≥50 % of their snack carbohydrates to preceding main meals. Mean HbA_1c at baseline was 8.05 %. After the conventional period and the 12-week lispro period, HbA_1c was 7.81 and 7.70 % (p = 0.088), respectively. In those patients who diminished their snacks as advised (n = 67), HbA_1c decreased from 7.91 to 7.66 % (p = 0.014) during lispro, whereas no change was observed in patients not compliant with the dietary change. The number of hypoglycaemic episodes was lower during lispro period (blood glucose <2.5 mmol l⁻¹: 1.43 vs 2.19 episodes, p = 0.004; symptomatic nocturnal hypoglycaemia 1.16 vs 1.67 episodes, p<0.001). When switching from conventional soluble to lispro insulin, reduction of snack carbohydrates is safe and results in slightly improved HbA_1c in patients who are fully compliant with the dietary change. © 1998 John Wiley & Sons, Ltd.     

Predicting steady‐state HbA1c responses to sitagliptin in patients with type 2 diabetes mellitus*

Aims: To develop predictive formulas using short‐term changes in glycaemic parameters [haemoglobin A_1c (HbA_1c) and fasting plasma glucose (FPG)] with sitagliptin, a highly selective dipeptidyl peptidase‐4 inhibitor, to assess longer term steady‐state changes in HbA_1c. Methods: Results from two, 12‐week, double‐blind studies of sitagliptin in Japanese patients with type 2 diabetes mellitus receiving once‐daily sitagliptin 100 mg were used to construct linear models to develop predictive formulas based on study 1 (S1) and to validate them using study 2 (S2). HbA_1c and FPG were the primary and the key secondary end‐point for both studies and were both used to develop predictive formulas. Results: The predictive formulas using HbA_1c ± FPG results (slope of change) from week 0 to week 4 in S1 showed high correlations between fitted and observed week 12 HbA_1c: for HbA_1c alone R² = 0.76, for HbA_1c + FPG R² = 0.89. When using the sitagliptin 100 mg group of S2 data set to assess the validity of the predictive formulas, high correlations for HbA_1c alone (R² = 0.76) and for HbA_1c + FPG (R² = 0.77) were also observed. Data using a lower dose (25 mg once daily) of sitagliptin also demonstrated similar results. Conclusions: The early responses (over 4 weeks) in HbA_1c and FPG with sitagliptin can be used to accurately predict later responses (at week 12) in HbA_1c in Japanese patients with type 2 diabetes mellitus. Additional studies applying this approach to other agents with diverse mechanisms are important.     

Improved glycaemic control and treatment satisfaction with a simple wearable 3‐day insulin delivery device among people with Type 2 diabetes

Aim

To evaluate the PAQ^® (CeQur SA, Horw, Switzerland), a wearable 3‐day insulin delivery device that provides set basal rates and bolus insulin on demand, in people with Type 2 diabetes.

Method

Adults with Type 2 diabetes with HbA_1c concentrations ≥53 and ≤97 mmol/mol (7.0 and 11.0%) while treated with ≥2 insulin injections/day were enrolled in two single‐arm studies comprising three periods: a baseline (insulin injections), a transition and a PAQ treatment period (12 weeks). Endpoints included HbA_1c, seven‐point self‐monitored blood glucose, total daily dose of insulin and body weight. Safety was assessed according to examination, hypoglycaemic episodes and adverse device effects.

Results

A total of 28 adults were enrolled (age 63 ± 7 years, 86% men, BMI 32.3 ± 4.3kg/m², Type 2 diabetes duration 17 ± 8 years, HbA_1c 70 ± 12 mmol/mol (8.6 ± 1.1%), total daily insulin dose 58.7 ± 20.7 U), of whom 24 completed the studies. When transitioned to PAQ, 75% of participants continued on the first basal rate selected. After 12 weeks of PAQ wear, significant improvements from baseline were seen [HbA_1c –16 ± 9 mmol/mol (95% CI –20, –12) or –1.5 ± 0.9% (95% CI –1.8, –1.1) P<0.0001], and at all seven self‐monitored blood glucose readings time points (P ≤0.03). Total daily insulin dose increased by 12.1 ± 19.5 U (95% CI 3.9, 20.4; P=0.0058), the number of meal time boluses increased by 0.9 ± 1.5/day (95% CI 0.3, 1.5; P=0.0081) and body weight remained stable. Six participants had mild to moderate catheter site reactions and one mild skin irritation occurred. No participant experienced severe hypoglycaemia.

Conclusions

Adults with Type 2 diabetes were safely transitioned from insulin injections to the PAQ and had significantly improved glycaemic control and treatment satisfaction with insulin therapy. (ClinicalTrials.gov identifiers: NCT02158078 & NCT02419859)     

Efficacy and safety of sitagliptin added to ongoing metformin and pioglitazone combination therapy in a randomized,placebo-controlled, 26-week trial in patients with type 2 diabetes

AimsTo assess efficacy and safety of sitagliptin, a dipeptidyl peptidase-4 inhibitor, in combination therapy with metformin (≥ 1500 mg/day) and pioglitazone (≥ 30 mg/day) in patients with type 2 diabetes (T2DM) with inadequate glycemic control (hemoglobin A_1c [HbA_1c] ≥ 7.5% and ≤ 11%).MethodsThis placebo-controlled, double-blind study included 313 patients, mean baseline HbA_1c = 8.7%, who were randomized to receive sitagliptin 100 mg/day or placebo for 26 weeks.ResultsThe addition of sitagliptin led to significant (P < .001) mean changes from baseline relative to placebo in HbA_1c (? 0.7%), fasting plasma glucose (? 1.0 mmol/L), and 2-h post-meal glucose (? 2.2 mmol/L). In patients with baseline HbA_1c ≥ 9.0%, mean changes from baseline in HbA_1c were ? 1.6% and ? 0.8% for the sitagliptin and placebo groups, respectively (between-group difference ?0.8%; P < .001). The incidences of reported adverse events were generally similar between the treatment groups. Incidences of symptomatic hypoglycemia were 7/157 [4.5%] and 6/156 [3.8%] in the sitagliptin and placebo groups, respectively (P = .786). Two patients, both in the placebo group, experienced an episode of hypoglycemia that required non-medical assistance.ConclusionsIn this 26-week study, addition of sitagliptin to combination therapy with metformin and pioglitazone improved glycemic control and was generally well tolerated.     

HbA1c levels in non‐diabetic Dutch children aged 8–9 years: the PIAMA birth cohort study

Aim Glycated haemoglobin (HbA_1c) is considered the best index of glycaemic control in established diabetes. It may also be useful in the diagnosis of diabetes and as a screening tool. Little is known about the distribution of HbA_1c in healthy children and its predictors. The aim of this study is to describe the distribution of HbA_1c in non‐diabetic Dutch children aged 8–9 years and to investigate potential associations of HbA_1c in this group. Methods HbA_1c was measured in 788 non‐diabetic children aged 8–9 years participating in the PIAMA birth cohort study. Data on parents and children were collected prospectively by questionnaires. Weight, height and waist and hip circumference of the children were measured when blood samples were taken. Results Mean (sd ) HbA_1c was 4.9 ± 0.33%, range 3.5–6.0%. HbA_1c was significantly higher in boys (4.9 ± 0.31 vs. 4.9 ± 0.33%) and in children of mothers with gestational diabetes (5.0 ± 0.37 vs. 4.9 ± 0.32%). We found a significant inverse association between HbA_1c and haemoglobin (regression coefficient: ?0.169 (95% CI ?0.221 to ?0.118), P < 0.001). HbA_1c was not significantly associated with age, body mass index, waist circumference, parental diabetes or maternal body mass index. Conclusions We found no significant relation between known risk factors for Type 2 diabetes and HbA_1c at age 8–9 years. Moreover, there was a significant inverse association between haemoglobin and HbA_1c. These results suggest that HbA_1c may not only reflect the preceding blood glucose levels, but seems to be determined by other factors as well.     

Does serum 1,5‐anhydroglucitol establish a relationship between improvements in HbA1c and postprandial glucose excursions? Supportive evidence utilizing the differential effects between biphasic insulin aspart 30 and insulin glargine

Aim To investigate the relationship between changes in glycated haemoglobin (HbA_1c) and postprandial glucose excursions on 1,5‐anhydroglucitol (1,5‐AG) in patients with Type 2 diabetes, utilizing the differential effects between biphasic insulin aspart 30 (BIAsp 30) or insulin glargine (IGlar) on postprandial glucose (PPG) levels. Methods 1,5‐AG was measured using the GlycoMark® assay at baseline and after 12 and 28 weeks in the INITiation of Insulin to reach HbA_1c Target (INITIATE) study of 233 patients randomized to either BIAsp 30 or IGlar. Results Baseline 1,5‐AG was low and not significantly different (4.9 ± 3.5 and 4.3 ± 2.6 µg/ml in the BIAsp 30 and IGlar groups, respectively). After 28 weeks, the levels of 1,5‐AG were higher in the BIAsp 30 than in the IGlar group (13.4 vs. 11.1 µg/ml, P = 0.008) and change from baseline was 25% greater with BIAsp 30 than IGlar (8.4 vs. 6.7 µg/ml, P = 0.011). 1,5‐AG levels increased as a function of decreasing HbA_1c or the average change in postprandial plasma glucose (PPG_ave) with significant relationships for 1,5‐AG/ HbA_1c vs. HbA_1c or 1,5‐AG/PPG_ave vs. PPG_ave (both P < 0.0001), respectively. Conclusions As reported in previous publications, 1,5‐AG reflects ambient glycaemic control and increases with reductions in HbA_1c and postprandial glucose. The greater reductions in postprandial excursion achieved with BiAsp 30 compared with glargine were associated with greater increases in 1,5‐AG. Even moderate elevations in HbA_1c substantially lower 1,5‐AG, suggesting that it can be most discriminating in identifying patients with excessive postprandial glucose excursions at HbA_1c levels that approach the upper end of the normal range.     

Efficacy and safety of canagliflozin compared with placebo and sitagliptin in patients with type 2 diabetes on background metformin monotherapy: a randomised trial

Aims/hypothesis

The aim of this work was to evaluate the efficacy and safety of canagliflozin vs placebo and sitagliptin in patients with type 2 diabetes who were being treated with background metformin.

Methods

This randomised, double-blind, four-arm, parallel-group, Phase 3 study was conducted at 169 centres in 22 countries between April 2010 and August 2012. Participants (N?=?1,284) with type 2 diabetes aged ≥18 and ≤80 years who had inadequate glycaemic control (HbA_1c ≥7.0% [53 mmol/mol] and ≤10.5% [91 mmol/mol]) on metformin therapy received canagliflozin 100 mg or 300 mg, sitagliptin 100 mg, or placebo (n?=?368, 367, 366, 183, respectively) for a 26 week, placebo- and active-controlled period followed by a 26 week, active-controlled period (placebo group switched to sitagliptin [placebo/sitagliptin]) and were included in the modified intent-to-treat analysis set. Randomisation was performed using a computer-generated schedule; participants, study centres and the sponsor were blinded to group assignment. The primary endpoint was change from baseline in HbA_1c at week 26; secondary endpoints included changes in HbA_1c (week 52) and fasting plasma glucose (FPG), body weight, and systolic blood pressure (BP; weeks 26 and 52). Adverse events (AEs) were recorded throughout the study.

Results

At week 26, canagliflozin 100 mg and 300 mg reduced HbA_1c vs placebo (?0.79%, –0.94%, –0.17%, respectively; p?<?0.001). At week 52, canagliflozin 100 mg and 300 mg demonstrated non-inferiority, and canagliflozin 300 mg demonstrated statistical superiority, to sitagliptin in lowering HbA_1c (?0.73%, –0.88%,–0.73%, respectively); differences (95% CI) vs sitagliptin were 0% (?0.12, 0.12) and ?0.15% (?0.27, –0.03), respectively. Canagliflozin 100 mg and 300 mg reduced body weight vs placebo (week 26: –3.7%, –4.2%, –1.2%, respectively; p?<?0.001) and sitagliptin (week 52: –3.8%, –4.2%, –1.3%, respectively; p?<?0.001). Both canagliflozin doses reduced FPG and systolic BP vs placebo (week 26) and sitagliptin (week 52) (p?<?0.001). Overall AE and AE-related discontinuation rates were generally similar across groups, but higher with canagliflozin 100 mg. Genital mycotic infection and osmotic diuresis-related AE rates were higher with canagliflozin; few led to discontinuations. Hypoglycaemia incidence was higher with canagliflozin.

Conclusions/interpretation

Canagliflozin improved glycaemia and reduced body weight vs placebo (week 26) and sitagliptin (week 52) and was generally well tolerated in patients with type 2 diabetes on metformin.

Clinical trial registry

ClinicalTrials.gov NCT01106677

Funding

This study was supported by Janssen Research & Development, LLC.     

Lipid Composition of Platelets in Patients with Non-insulin-dependent Diabetes Mellitus: Studies Before and After Treatment of Diabetes

The study was designed to investigate whether impaired composition of platelet lipids in untreated diabetic patients improved after diabetic treatment. Fourteen untreated patients with non-insulin-dependent diabetes mellitus (NIDDM) and 15 healthy control subjects were studied. In the diabetic patients, the ratio of free cholesterol to phospholipid (FC/PL) in platelets of 0.33 ± 0.02 (mean ± SEM) at pre-treatment, which was statistically (p < 0.05) higher than that of 0.26 ± 0.02 in control subjects, was significantly decreased to the value of 0.29 ± 0.02 (p < 0.01) after insulin therapy. Platelet FC level of 9.77 ± 0.77 μg 10^?8 cells pre-treatment was significantly (p < 0.01) reduced to the value of 7.72 ± 0.38 μg 10^?8 cells post-treatment. Platelet PL level showed no significant changes after the treatment. There was a significantly (p < 0.01) positive correlation between the decrease in FC/PL of platelets and that in haemoglobin A_1c (HbA_1c) after treatment for diabetes (rs = ?0.729). These results indicate that the impaired lipid composition in platelets can be improved after an adequate glycaemic control in patients with NIDDM.     

Pronounced skin capillary ischemia in the feet of diabetic patients with bad metabolic control

Summary Skin capillary circulation is impaired during postocclusive reactive hyperaemia (PRH) in toes of diabetic patients independent of diabetes duration and macrocirculation. The aim of this study was to examine its relation to metabolic control. The skin microcirculation was investigated in 20 patients with insulin-dependent diabetes mellitus: 10 patients with bad [HbA_1c > 7.5 (8.7 ± 0.8) %], and 10 patients with good metabolic control [HbA_1c < 7.5 (6.3 ± 1.0) %]. The diabetes duration was similar in both groups (16 ± 9 and 16 ± 6 years, respectively). None had macroangiopathy. Thirteen healthy subjects served as controls. The capillary blood cell velocity (CBV) in the nailfold of the great toe was investigated by videophotometric capillaroscopy, and the total skin microcirculation by laser Doppler fluxmetry (LDF). CBV and LDF were studied during rest and after 1-min arterial occlusion. The vibration perception thresholds (VPT) of the feet were higher (p < 0.05) in the patients with bad (34 ± 12 V), as compared to patients with good metabolic control (18 ± 10 V) and to healthy subjects (13 ± 3 V). Peak CBV during PRH was reduced in both patient groups (p < 0.01), and lowest in the patients with bad metabolic control (p < 0.05). Time to peak CBV was prolonged (p < 0.01) in the patients with bad, while normal in the patients with good metabolic control. LDF was similar in all groups. An inverse correlation was found between HbA_1c and peak CBV during PRH (r = 0.60; p = 0.008), while positive correlations were found to time to peak CBV (r = 0.62; p = 0.004) and VPT (r = 0.60; p = 0.01). No associations were seen between VPT and the microcirculatory variables. The results indicate that the metabolic control is of importance for the nutritive capillary circulation and the peripheral nerve function in the diabetic foot. [Diabetologia (1998) 41: 410–415] Received: 22 October 1997     

Addition of vildagliptin to insulin improves glycaemic control in type 2 diabetes

Aims/hypothesis Type 2 diabetes is difficult to manage in patients with a long history of disease requiring insulin therapy. Moreover, addition of most currently available oral antidiabetic agents increases the risk of hypoglycaemia. Vildagliptin is a dipeptidyl peptidase-IV inhibitor, which improves glycaemic control by increasing pancreatic beta cell responsiveness to glucose and suppressing inappropriate glucagon secretion. This study assessed the efficacy and tolerability of vildagliptin added to insulin therapy in patients with type 2 diabetes. Materials and methods This was a multicentre, 24-week, double-blind, randomised, placebo-controlled, parallel-group study in patients with type 2 diabetes that was inadequately controlled (HbA_1c = 7.5–11%) by insulin. Patients received vildagliptin (n = 144; 50 mg twice daily) or placebo (n = 152) while continuing insulin therapy. Results Baseline HbA_1c averaged 8.4 ± 0.1% in both groups. The adjusted mean change from baseline to endpoint (AMΔ) in HbA_1c was −0.5 ± 0.1% and −0.2 ± 0.1% in patients receiving vildagliptin or placebo, respectively, with a significant between-treatment difference (p = 0.01). In patients aged ≥65 years, the AMΔ HbA_1c was −0.7 ± 0.1% in the vildagliptin group vs −0.1 ± 0.1% in the placebo group (p < 0.001). The incidence of adverse events was similar in the vildagliptin (81.3%) and placebo (82.9%) groups. However, hypoglycaemic events were less common (p < 0.001) and less severe (p < 0.05) in patients receiving vildagliptin than in those receiving placebo. Conclusions/interpretation Vildagliptin decreases HbA_1c in patients whose type 2 diabetes is poorly controlled with high doses of insulin. Addition of vildagliptin to insulin therapy is also associated with reduced confirmed and severe hypoglycaemia. ClinicalTrials.gov ID no.: NCT 00099931. Electronic supplementary material The online version of this article (doi:) contains a complete list of investigators which is available to authorised users.