[Cardiovascular aspects of diabetes treatment : Finally a reason for cardiologists to be pleased]. / Kardiovaskuläre Aspekte der Diabetestherapie : Endlich Grund zur Freude für Kardiologen.

Cardiovascular disease significantly determines morbidity and mortality in patients with diabetes mellitus type 2. Large clinical trials in the past left controversial evidence about the effect of blood glucose-lowering treatments on cardiovascular outcomes. In 2008, the regulatory authorities defined new requirements on cardiovascular safety data for the approval of new drugs for the treatment of type 2 diabetes mellitus. Since then, numerous large safety studies have been initiated to prove cardiovascular noninferiority of new antidiabetic drugs. Preliminary data from these safety studies have become available and provided promising results. While treatment with DPP-4 inhibitors and the short acting GLP-1 receptor agonist lixisenatide were shown to be safe, treatment with the SGLT-2 inhibitor empagliflozin and the long-acting GLP-1 receptor agonist liraglutide even significantly improved cardiovascular outcomes in patients with type 2 diabetes mellitus. With the evidence of cardiovascular benefits of the new drugs, new treatment strategies for patients with diabetes mellitus type 2 are expected.

Effect of canagliflozin on liver function tests in patients with type 2 diabetes.

AIMS: To report changes in liver function tests observed with canagliflozin, a sodium glucose co-transporter 2 inhibitor, across phase 3 studies in patients with type 2 diabetes, and to examine the relationship between changes in liver function tests and the weight loss and glycaemic improvements observed with canagliflozin. METHODS: Data were pooled from four 26-week, placebo-controlled studies of canagliflozin 100 and 300mg (n=2313) and two 52-week, active-controlled studies of canagliflozin 300mg versus sitagliptin 100mg (n=1488). Analysis of covariance was performed to determine the contribution of changes in body weight and HbA1c to the changes in liver function tests. RESULTS: Reductions in alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and gamma-glutamyl transferase, and increases in bilirubin were seen with canagliflozin 100 and 300mg versus placebo (nominal P<0.001 for alanine aminotransferase, aspartate aminotransferase and gamma-glutamyl transferase [both doses]; P<0.001 for alkaline phosphatase and P=0.015 for bilirubin [canagliflozin 300mg only]) at week 26 and with canagliflozin 300mg versus sitagliptin 100mg (nominal P<0.001 for alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase and bilirubin, and P<0.01 for alkaline phosphatase) at week 52. Few patients met predefined limits of change criteria for liver function tests, and none met Hy's law criteria. In both populations, alanine aminotransferase, aspartate aminotransferase and gamma-glutamyl transferase reductions were fully explained by HbA1c and body weight reductions. CONCLUSIONS: Canagliflozin provided improvements in liver function tests versus either placebo or sitagliptin treatments that were fully explained by the combined effects of HbA1c and body weight reductions with canagliflozin.

Early fasting glucose measurements can predict later glycaemic response to once weekly dulaglutide.

AIMS: To assess whether early measures of fasting blood glucose predict later glycaemic response with once-weekly dulaglutide in patients with Type 2 diabetes mellitus. METHODS: Post hoc analyses were conducted separately for two phase 3 studies (AWARD-5 and AWARD-1) in patients assigned to once-weekly dulaglutide. Week 2 fasting blood glucose was used as a predictor variable, and glycaemic treatment response was defined by HbA1c response based on a composite efficacy endpoint. The association between fasting blood glucose and the glycaemic response was analysed using chi-square tests. RESULTS: There was a strong association between fasting blood glucose < 7.9 mmol/l at week 2 and achieving the HbA1c composite efficacy endpoint at week 26 (P < 0.01). Higher fasting blood glucose at week 2, however, did not predict absence of glycaemic response and requires further assessment. CONCLUSIONS: Fasting blood glucose measured at 2 weeks may be an early and useful predictor of glycaemic response to once-weekly dulaglutide treatment.

Standardized modulation of the injection site allows for insulin dose reduction without deterioration of metabolic control.

OBJECTIVES: Use of an injection site modulation device (InsuPad) in intensive insulin treatment reduces frequency of hypoglycemia and prandial insulin requirements by enhancing subcutaneous microcirculation. This meal tolerance test (MTT) investigation was performed as a sub-study during the real-world BARMER study to demonstrate non-inferiority of the reduced insulin doses observed in this study with respect to metabolic control. METHODS: The MTT was performed at baseline and after 3 months in insulin treated diabetes patients using the modulation device vs. a control group without device. The dose used for the MTT was individually calculated based on the prandial insulin records from the patient diaries before the test. Blood was drawn for determination of glucose, insulin, C-peptide, proinsulin, triglycerides, free fatty acids, nitrotyrosine, and asymmetric dimethyl-arginine (ADMA) at multiple time-points from 0 to 300 min. A total of 32 patients from one site were included into this MTT study (8 female, 7 type 1 diabetes, age: 49.9 ± 12.5 yrs, HbA1c: 7.2 ± 0.5%). RESULTS: During the BARMER study, mean HbA1c was treated to target (<6.5%) in both groups. The prandial insulin dose decreased in the MTT modulation device group by -17.1%, but remained unchanged in the control group (-0.1%, p < 0.001). No change was seen for the basal insulin dose in both treatment arms. There were no differences between the groups with respect to the postprandial curves for glucose, C-peptide, intact proinsulin, free fatty acids, and triglycerides. Insulin absorption was faster with the modulation device (Tmax: 60 ± 28 min vs. 99 ± 46 min, p < 0.05). Key limitations are the small patient sample size and impossibility to determine the short-term effects of device use. CONCLUSIONS: The results of this meal tolerance sub-study confirm that the observed prandial insulin dose reduction when using the injection site modulation device has no negative impact on postprandial metabolism.

Dose-finding results in an adaptive, seamless, randomized trial of once-weekly dulaglutide combined with metformin in type 2 diabetes patients (AWARD-5).

AIMS: AWARD-5 was an adaptive, seamless, double-blind study comparing dulaglutide, a once-weekly glucagon-like peptide-1 (GLP-1) receptor agonist, with placebo at 26 weeks and sitagliptin up to 104 weeks. The study also included a dose-finding portion whose results are presented here. METHODS: Type 2 diabetes (T2D) patients on metformin were randomized 3 : 1 : 1 to seven dulaglutide doses, sitagliptin (100 mg), or placebo. A Bayesian algorithm was used for randomization and dose selection. Patients were adaptively randomized to dulaglutide doses using available data on the basis of a clinical utility index (CUI) of glycosylated haemoglobin A1c (HbA1c) versus sitagliptin at 52 weeks and weight, pulse rate (PR) and diastolic blood pressure (DBP) versus placebo at 26 weeks. The algorithm randomly assigned patients until two doses were selected. RESULTS: Dulaglutide 1.5 mg was determined to be the optimal dose. Dulaglutide 0.75 mg met criteria for the second dose. Dulaglutide 1.5 mg showed the greatest Bayesian mean change from baseline (95% credible interval) in HbA1c versus sitagliptin at 52 weeks -0.63 (-0.98 to -0.20)%. Dulaglutide 2.0 mg showed the greatest placebo-adjusted mean change in weight [-1.99 (-2.88 to -1.20) kg] and in PR [0.78 (-2.10 to 3.80) bpm]. Dulaglutide 1.5 mg showed the greatest placebo-adjusted mean change in DBP [-0.62 (-3.40 to 2.30) mmHg]. CONCLUSIONS: The Bayesian algorithm allowed for an efficient exploration of a large number of doses and selected dulaglutide doses of 1.5 and 0.75 mg for further investigation in this trial.

Efficacy and safety of canagliflozin over 52 weeks in patients with type 2 diabetes on background metformin and pioglitazone.

AIM: The efficacy and safety of canagliflozin, a sodium glucose co-transporter 2 inhibitor, was evaluated in patients with type 2 diabetes mellitus (T2DM) inadequately controlled with metformin and pioglitazone. METHODS: In this randomized, double-blind, phase 3 study, patients (N = 342) received canagliflozin 100 or 300 mg during a 26-week, placebo-controlled, core period and a 26-week, active-controlled extension in which placebo-treated patients were switched to sitagliptin 100 mg. Efficacy comparisons for canagliflozin versus placebo at week 26 are reported, with no comparisons versus sitagliptin at week 52 (sitagliptin used to maintain double-blind and control for safety). Safety data are reported for canagliflozin and placebo/sitagliptin. RESULTS: Canagliflozin 100 and 300 mg significantly lowered haemoglobin A1c (HbA1c) compared with placebo at week 26 (-0.89%, -1.03% and -0.26%; p < 0.001); reductions with canagliflozin 100 and 300 mg were maintained at week 52 (-0.92% and -1.03%). Relative to placebo, both canagliflozin doses significantly reduced body weight (-2.5 and -3.5 kg), fasting plasma glucose and systolic blood pressure (BP) at week 26 (p < 0.05 for all), with reductions maintained at week 52. Overall adverse event (AE) incidence over 52 weeks was 69.9, 76.3 and 76.5% with canagliflozin 100 and 300 mg and placebo/sitagliptin; AE-related discontinuation and serious AE rates were low. Incidences of genital mycotic infections and AEs related to osmotic diuresis and volume depletion were higher with canagliflozin than placebo/sitagliptin. CONCLUSION: Canagliflozin improved glycaemic control, reduced body weight and systolic BP, and was generally well tolerated in patients with T2DM on metformin and pioglitazone over 52 weeks.

The Barmer study: impact of standardized warming of the injection site to enhance insulin absorption and reduce prandial insulin requirements and hypoglycemia in obese patients with diabetes mellitus.

BACKGROUND: The primary objective of this prospective controlled study was to investigate the impact of standardized injection-site warming on prandial rapid acting insulin dose and glycemic control when studied under real-world conditions. METHODS: All 145 participating patients (51 female, 94 male, 13 type 1 and 132 type 2 patients, age: 61.6 ± 8.4 yrs, HbA1c: 7.19 ± 0.50%) were treated with intensive insulin glargine and short-acting insulin analog therapy. After a 4 week treatment optimization run-in period, patients were randomized to continue therapy for three months without (control) or with a local injection-site warming device (InsuPad * ). Observation parameters included HbA1c, insulin dose, frequency of hypoglycemia, body weight and adverse events. RESULTS: HbA1c improved in both arms until study end (control group: 6.3 ± 0.5%; injection-site warming device: 6.3 ± 0.5%; both p < 0.001 vs. baseline). To achieve this good control, patients in the control group needed to increase the daily prandial insulin dose by 8.1% (from 66 ± 31 U to 71 ± 38 U, p < 0.05) with stable basal insulin requirements. Patients who used the injection-site warming device required less prandial insulin (70 ± 43 U to 55 ± 34 U; -19%, p < 0.001) and slightly more basal insulin (+3.9%). Total daily insulin dose increased in the control group (+3.7%) and decreased with warming device use (-8.6%, p < 0.001). The number of hypoglycemic events (<63 mg/dL) during the observation period was higher in the control group (6.2 ± 9.9/patient vs. injection-site warming device: 3.3 ± 4.8/patient, p < 0.05). Main study limitations can be seen in the open label design reliability of the collected dose information and the very obese patient cohort. CONCLUSION: When treating obese patients to target with insulin therapy, use of an injection-site warming device for 3 months resulted in a lower frequency of hypoglycemic events and a reduction in prandial insulin analog requirements. If these results are confirmed in other patient populations, an injection-site warming device may be useful in achieving treatment targets with a safer and more efficient basal bolus therapy in insulin-treated patients with type 1 and type 2 diabetes.

Performance of blood glucose meters in compliance with current and future clinical ISO15197 accuracy criteria.

Since 2003, blood glucose meters for patient self testing are approved in Europe based on the accuracy performance criteria as defined by the ISO15197 guideline. A new draft ISO guideline is currently under regulatory review, which suggests more strict accuracy acceptance criteria, and which may not be entirely fulfilled by currently commercialized blood glucose meter systems. In order to investigate the compliance of BG*Star and iBG*Star and several other blood glucose meters with the new draft ISO guideline, we performed a post-hoc analysis of data obtained from a recently performed ISO-conforming clinical accuracy performance study. This study was performed with 106 patients, clinically presenting with blood glucose levels distributed over the entire measurement range and in line with the glucose distribution requirements as demanded by the guideline. The YSI 2300 STAT Plus analyzer (glucose oxidase) served as reference method. While all tested meters had been in a high degree of compliance with the current ISO criteria, performance was lower when analyzed in accordance with the new acceptance criteria (95% of readings have to be within ±15 mg/dL for values <100 mg/dL, and within ±15% for values ≥100 mg/dL). The following meters met the new criteria: Accu-Chek Aviva (95.5%/98.6%), BG*Star (98.5%/97.3%), iBG*Star (98.5%/97.3%), FreeStyle Freedom Lite (95.5%/96.6%), and OneTouch Ultra2 (95.5%/96.5%). One meter failed with low blood glucose values (Contour: 90.9%/95.9%). In conclusion, BG*Star and iBG*Star and several other branded meters met the new draft ISO15197 acceptance criteria, when tested in accordance with the instructions for use and with the ISO accuracy testing protocol in a clinical setting.

Differential effects of vildagliptin and glimepiride on glucose fluctuations in patients with type 2 diabetes mellitus assessed using continuous glucose monitoring.

AIM: To assess whether there is a difference in the effects of vildagliptin and glimepiride on glucose fluctuation in patients with type 2 diabetes mellitus (T2DM) using continuous glucose monitoring (CGM). METHODS: This was an open-label, randomized cross-over study conducted in T2DM patients. A total of 24 patients (age: 58.3 ± 5.56 years, baseline HbA1c: 7.6 ± 0.50%) who were on stable metformin monotherapy (500-3000 mg) were enrolled, and all completed the study. Each patient received two 5-day treatments (vildagliptin 50 mg b.i.d. or glimepiride 2 mg q.d.) in a cross-over manner. Various biomarkers and blood glucose concentrations were measured following breakfast. The 24-h glucose profiles were also measured using the CGM device at baseline and after 5 days of treatment, and fluctuations in glucose levels were estimated from CGM data. RESULTS: Both vildagliptin and glimepiride reduced postprandial glucose levels, based on both CGM data (15% vs. 16%) and measured plasma glucose (13% vs.17%). Vildagliptin showed lower glucose fluctuations than glimepiride as measured by mean amplitude of glycaemic excursions (MAGE, p = 0.1076), standard deviation (s.d., p = 0.1346) of blood glucose rate of change, but did not reach statistical significance attributed to the small sample size. MAGE was reduced by ∼20% with vildagliptin versus glimepiride. Vildagliptin led to statistically significant lowering of the rate of change in the median curve (RCMC) and interquartile range (IQR) of glucose. Treatment with vildagliptin significantly increased the levels of active glucagon-like peptide-1 by 2.36-fold (p ≤ 0.0001) and suppressed glucagon by 8% (p = 0.01), whereas glimepiride significantly increased the levels of insulin and C-peptide by 21% (p = 0.012) and 12% (p = 0.003), respectively. CONCLUSIONS: Vildagliptin treatment was associated with less fluctuation of glucose levels than glimepiride treatment as assessed by 24-h CGM device, suggesting vildagliptin may have the potential to offer long-term beneficial effects for patients with T2DM in preventing the development of complications of diabetes.

Effect of vildagliptin compared to glimepiride on postprandial proinsulin processing in the ß cell of patients with type 2 diabetes mellitus.

This study compared the effect of Glimepiride versus Vildagliptin on ß-cell function and the release of intact proinsulin (PI) in patients with type 2 diabetes mellitus. Patients on metformin monotherapy were randomized to add on treatment with Vildagliptin or Glimepiride. A standardized test meal was given at baseline, after 12 and 24 weeks of treatment. Insulin, PI and blood glucose values were measured in the fasting state and postprandial for 300 min. Fasting PI levels significantly decreased in the Vildagliptin group. The area under the curve for the postprandial release of PI decreased during Vildagliptin and increased during Glimepiride treatment. The proinsulin to insulin ratio declined in the Vildagliptin group, whereas it did not change significantly in the Glimepiride group. Addition of Vildagliptin to ongoing Metformin treatment reconstitutes the disproportionality of the proinsulin to insulin secretion from the ß cell.

Effects of insulin glargine versus metformin on glycemic variability, microvascular and beta-cell function in early type 2 diabetes.

We investigated whether basal insulin as first-line treatment in recently diagnosed type 2 diabetes (T2D) can improve glucose control, microvascular function and preserve insulin secretion in comparison with metformin (MET). In this open-label, randomized, prospective 36-week study, 75 patients (44 m, 31 f, mean age 60.7 ± 9.2 year) were allocated to treatment with either MET 1,000 mg b.i.d. (n = 36) or insulin glargine (GLA) at bedtime (n = 39). At baseline and study end, we performed a continuous glucose monitoring for assessment of interstitial glucose (IG) and measured microvascular function using Laser-Doppler fluxmetry. GLA versus MET treatment resulted in a more pronounced reduction in FPG (Δ: 3.1 ± 2.5 vs. 1.4 ± 1.5 mmol/l; p < 0.001) and overall IG (Δ AUC. 671 ± 507 vs. 416 ± 537 mmol/l min; p = 0.04). Postprandial PG and IG differences after a standardized test meal did not reach significance. Proinsulin/C-peptide and HOMA B as marker of endogenous insulin secretion were significantly more improved by GLA. Microvascular blood flow improved only in MET-treated patients. Early basal insulin treatment with GLA in T2D patients provided a better control of FPG, overall IG load and biomarker of beta-cell function compared to the standard treatment with MET. MET treatment resulted in an improvement of microvascular function. Studies of longer duration are needed to evaluate the durability of glucose control and ß cell protection with early GLA treatment.

Pharmacodynamic characteristics of lixisenatide once daily versus liraglutide once daily in patients with type 2 diabetes insufficiently controlled on metformin.

AIM: Assess the pharmacodynamics of lixisenatide once daily (QD) versus liraglutide QD in type 2 diabetes insufficiently controlled on metformin. METHODS: In this 28-day, randomized, open-label, parallel-group, multicentre study (NCT01175473), patients (mean HbA1c 7.3%) received subcutaneous lixisenatide QD (10 µg weeks 1-2, then 20 µg; n = 77) or liraglutide QD (0.6 mg week 1, 1.2 mg week 2, then 1.8 mg; n = 71) 30 min before breakfast. Primary endpoint was change in postprandial plasma glucose (PPG) exposure from baseline to day 28 during a breakfast test meal. RESULTS: Lixisenatide reduced PPG significantly more than liraglutide [mean change in AUC(0:30-4:30h) : -12.6 vs. -4.0 h·mmol/L, respectively; p < 0.0001 (0:30 h = start of meal)]. Change in maximum PPG excursion was -3.9 mmol/l vs. -1.4 mmol/l, respectively (p < 0.0001). More lixisenatide-treated patients achieved 2-h PPG <7.8 mmol/l (69% vs. 29%). Changes in fasting plasma glucose were greater with liraglutide (-0.3 vs. -1.3 mmol/l, p < 0.0001). Lixisenatide provided greater decreases in postprandial glucagon (p < 0.05), insulin (p < 0.0001) and C-peptide (p < 0.0001). Mean HbA1c decreased in both treatment groups (from 7.2% to 6.9% with lixisenatide vs. 7.4% to 6.9% with liraglutide) as did body weight (-1.6 kg vs. -2.4 kg, respectively). Overall incidence of adverse events was lower with lixisenatide (55%) versus liraglutide (65%), with no serious events or hypoglycaemia reported. CONCLUSIONS: Once daily prebreakfast lixisenatide provided a significantly greater reduction in PPG (AUC) during a morning test meal versus prebreakfast liraglutide. Lixisenatide provided significant decreases in postprandial insulin, C-peptide (vs. an increase with liraglutide) and glucagon, and better gastrointestinal tolerability than liraglutide.

Addition of liraglutide in patients with Type 2 diabetes well controlled on metformin monotherapy improves several markers of vascular function.

AIMS: The aim of this study was to investigate the vascular effects of liraglutide in patients well controlled on metformin monotherapy. METHODS: Forty-four patients with Type 2 diabetes were included in the study. Main inclusion criteria were: pretreatment with metformin on a stable dosage, HbA(1c) < 53 mmol/mol (7.0%), age 30-65 years. Patients were randomized to receive additional liraglutide or to remain on metformin monotherapy. After 6 weeks (1.2 mg) and after 12 weeks (1.8 mg), venous blood was taken for the measurement of several laboratory markers characterizing vascular and endothelial function. In addition, retinal microvascular endothelial function and arterial stiffness were measured. RESULTS: HbA(1c) levels declined from 45 ± 4 mmol/mol (6.3 ± 0.4%; mean ± SD) to 40 ± 3 mmol/mol (5.8 ± 0.3%) during liraglutide treatment. Asymmetric dimethylarginin was reduced by liraglutide treatment from 0.39 ± 0.08 to 0.35 ± 0.06 µmol/l, E-selectin from 43.6 ± 15.4 to 40.8 ± 15.1 ng/ml, plasminogen activator inhibitor 1 from 861.6 ± 584.3 to 666.1 ± 499.4 ng/ml and intact proinsulin from 9.0 ± 7.2 to 7.0 ± 4.8 pmol/l at 12 weeks of treatment. The microvascular response to flicker light increased from 7.0 ± 15.1 to 15.4 ± 11.5% after 6 weeks and to 11.1 ± 9.9% after 12 weeks. No change could be observed for high-sensitivity C-reactive protein, monocyte chemotactic protein 1, vascular cell adhesion molecule or arterial stiffness parameters. CONCLUSIONS: In patients with Type 2 diabetes, well controlled with metformin monotherapy, addition of liraglutide improves several cardiovascular risk markers beyond glycaemic control.

[Glycosuria with SGLT-2 inhibitors--a new treatment approach for type 2 diabetes mellitus]. / Glukosurie mittels SGLT-2-Inhibitoren. Ein neuesTherapieprinzip bei Diabetes mellitusTyp 2.

BACKGROUND: A new mechanism of action in the form of sodium-glucose co-transporter-(SGLT-)2 inhibitors will be available shortly for the treatment of type 2 diabetic patients. METHOD: Overview. RESULTS AND CONCLUSIONS: Fasting and postprandial blood glucose and HbA(1c) concentrations are indirectly reduced by the inhibition of glucose reabsorption and increased glycosuria. SGLT-2 inhibitors also have a positive impact on body weight and blood pressure of type 2 diabetics. In the available registration trials conducted to date, the SGLT-2 inhibitors appeared overall as a safe class of drugs. The clinical importance of an increased incidence of genital infections--in particular in special patientpopulations--requires further clarification. Long-term trials are currently underway to verify safety and in particular cardiovascular effects of this drug class.

Self-assessment and objective determination of dexterity in patients with type 1 or type 2 diabetes mellitus.

OBJECTIVE: Insulin-treated patients perform complex treatment activities during daily routine, such as blood glucose measurements and insulin injections. We aimed to identify suitable dexterity and cognitive function tests for diabetes patients, and to compare the patient self-assessment of their dexterity skills with the test results (Jebsen-Taylor hand function test, (JHFT), motoric performance test (MLS), number connection test). METHOD: We enrolled 90 diabetes patients (36 females, 54 males): 15 type 1 with clinically suspected dexterity impairment (A: age: 60 ± 9 years), 30 type 2 with clinically suspected dexterity impairment (B: 61 ± 10 years), 30 type 1 or type 2 patients with visual impairment (C: 64 ± 6 years), and 15 type 1 or type 2 patients without obvious impairment (control group: D: 64 ± 5 years). RESULTS: There were no differences regarding neuropathy and slight impairments in the number connection test in all groups. Patient self-assessment revealed that 33.4% in group A, 33.3% in group B, 36.7% in group C and 13.7% in group D, considered themselves to have dexterity impairment. However in the JHFT test, all patients from A (100%) and B (100%), 33% from C, and 0% from D presented with dexterity impairment by only passing less than four subtests. CONCLUSIONS: Impairment of dexterity was much more frequent than believed by the patients themselves. It may be worthwhile to consider these findings when classifying patients regarding their capabilities to perform certain treatments or when assessing diabetes technology with human subjects.

Non-glycemic effects of insulin therapy: a comparison between insulin aspart and regular human insulin during two consecutive meals in patients with type 2 diabetes.

OBJECTIVE: To control postprandial hyperglycemia in insulin-treated type 2 diabetic patients, prandial therapy with regular human insulin (HI) or fast acting insulin analogs is used. Postprandial hyperglycemia seems to be reduced more effectively with insulin analogs than with normal insulin, but there are no data concerning the effect on lipolysis or pancreatic insulin and proinsulin secretion of normal insulin in comparison to insulin analogs. DESIGN AND METHODS: We included 13 patients with type 2 diabetes mellitus (age 62.2±10.3 years) with preexisting insulin therapy in this crossover, prospective, open-labeled, randomized trial comparing regular HI with insulin aspart (IA) in the setting of a standardized breakfast and a standardized lunch 4 h later. Blood samples for determination of glucose, free fatty acids (FFA), triglycerides, C-peptide, and intact proinsulin were drawn during fasting and every 30 min until 4 h after the second test meal. Statistical analysis was performed with ANOVA for repeated measurements and paired Student's t-test. RESULTS: The mean increase in blood glucose was significantly lower after IA (24.18±16.33 vs 34.92±29.07 mg/dl, P=0.02) compared with HI. Both therapies reduced FFA; however, the mean reduction was significantly higher after IA than after HI (-0.47±0.16 vs -0.35±0.15 µmol/l, P<0.001). The mean increase in intact proinsulin was significantly lower after IA than after HI (10.53±5 vs 15.20±6.83 pmol/l, P<0.001). No differences were observed in the C-peptide levels between the two groups. CONCLUSION: In the setting of two consecutive meals, IA reduces lipolysis and proinsulin secretion more effectively than HI.

The oral DPP-4 inhibitor linagliptin significantly lowers HbA1c after 4 weeks of treatment in patients with type 2 diabetes mellitus.

AIM: To investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of linagliptin in patients with type 2 diabetes mellitus (T2DM). METHODS: After screening and a 14-day washout, subjects received linagliptin 2.5, 5 or 10 mg or placebo once-daily for 28 days in this randomized, double-blind, parallel, placebo-controlled within-dose groups study. RESULTS: Seventy-seven patients entered the study (linagliptin: 61; placebo: 16). Four patients withdrew prematurely. There was little evidence of linagliptin accumulation. Exposure, maximum and trough plasma concentrations of linagliptin increased less than dose-proportionally. Rapid and sustained inhibition of dipeptidyl peptidase-4 reached 91-93% across linagliptin doses at steady state. At the end of the 24-h dosing interval, inhibition was still high (82-90%). There were marked increases in plasma glucagon-like peptide-1 after 28 days of dosing. Compared to placebo, all linagliptin doses resulted in statistically significant decreases of the area under the glucose curve following a meal tolerance test on day 29, that is, 24 h after the last study drug intake. After 28 days of treatment with linagliptin the placebo-corrected mean change in haemoglobin A1c (HbA1c) (median baseline 7.0%) was -0.31% (2.5-mg dose), -0.37% (5-mg dose) and -0.28% (10-mg dose). The frequency of adverse events was similar for linagliptin (31%) and placebo (34%). There were no notable safety concerns. CONCLUSIONS: Linagliptin administration led to attenuation of postprandial glucose excursions and, despite a low HbA1c at baseline, statistically significant reductions in HbA1c after only 4 weeks of treatment. Linagliptin had a safety and tolerability profile similar to placebo in T2DM patients.

Linagliptin (BI 1356), a potent and selective DPP-4 inhibitor, is safe and efficacious in combination with metformin in patients with inadequately controlled Type 2 diabetes.

AIMS: The efficacy and safety of the dipeptidyl peptidase-4 inhibitor, linagliptin, added to ongoing metformin therapy, were assessed in patients with Type 2 diabetes who had inadequate glycaemic control (HbA(1c) ≥ 7.5 to ≤ 10%; ≥ 58.5 to ≤ 85.8 mmol/mol) with metformin alone. METHODS: Patients (n=333) were randomized to receive double-blind linagliptin (1, 5 or 10 mg once daily) or placebo or open-label glimepiride (1-3 mg once daily). The primary outcome measure was the change from baseline in HbA(1c) at week 12 in patients receiving combination therapy compared with metformin alone. RESULTS: Twelve weeks of treatment resulted in a mean (sem) placebo-corrected lowering in HbA(1c) levels of 0.40% (± 0.14); 4.4 mmol/mol (± 1.5) for 1 mg linagliptin, 0.73% (± 0.14); 8.0 mmol/mol (± 1.5) for 5 mg, and 0.67% (± 0.14); 7.3 mmol/mol (± 1.5) for 10 mg. Differences between linagliptin and placebo were statistically significant for all doses (1 mg, P = 0.01; 5 mg and 10 mg, P < 0.0001). The change in mean (sem) placebo-corrected HbA(1c) from baseline was -0.90% (± 0.13); -9.8 mmol/mol (± 1.4) for glimepiride. Adjusted and placebo-corrected mean changes in fasting plasma glucose were -1.1 mmol/l for linagliptin 1 mg (P = 0.002), -1.9 mmol/l for 5 mg and -1.6 mmol/l for 10 mg (both P < 0.0001). One hundred and six (43.1%) patients reported adverse events; the incidence was similar across all five groups. There were no hypoglycaemic events for linagliptin or placebo, whereas three patients (5%) receiving glimepiride experienced hypoglycaemia. CONCLUSIONS: The addition of linagliptin to ongoing metformin treatment in patients with Type 2 diabetes was well tolerated and resulted in significant and clinically relevant improvements in glycaemic control, with 5 mg linagliptin being the most effective dose.

Prevalence of CYP450 gene variations in patients with type 2 diabetes.

BACKGROUND: Drug degradation in the human organism is driven by detoxification mechanisms that can be affected in their efficiency by genetic mutations. The purpose of this pilot investigation was to investigate whether Type 2 diabetes is associated with mutations in prominent members of the CYP 450 isoenzyme family. METHODS: Genomic DNA was isolated from EDTA blood samples of 203 Caucasian subjects (101 patients with Type 2 diabetes and 102 non-diabetic subjects, age (mean +/- STD): 49 +/- 16 years) was analyzed. Genomic DNA was isolated from EDTA blood. Mutation analysis for CYP2C8 (*2/*3/*4), CYP2C9 (*2/*3), CYP2C19 (*2/*3), CYP2D6 (*3/*4/*5/*6) and PPARgamma (P12A) was performed by means of real-time PCR methods (Light-Cycler, Roche Diagnostics, Indianapolis, IN, USA). RESULTS: The genotyping revealed the following allele frequency distributions for the two investigated groups: CYP2C8: *2 (type 2 diabetes 3% vs. 1%, n.s.), *3 (16% vs. 3%, n.s.), *4 (15% vs. 2%, p < 0.05), CYP2C9: *2 (20% vs. 24%, n.s.), *3 (22% vs. 21%, n.s.), CYP2C19: *2 (23% s. 33%, n.s.), *3 (0% vs. 0%, n.s.), CYP2D6: *3 (3% vs. 4%, n.s.), *4 (40% vs. 37%, n.s.), *5 (3% vs. 2%, n.s.), *6 (0% vs. 0%, n.s.), PPARgamma P12A (15% vs. 21%, n.s.), i.e. all but one mutation (CYP2C8*4) were found with equal prevalence in the two cohorts. CONCLUSIONS: In this pilot investigation, we found an increased prevalence of the CYP2C8*4 mutation in the Type 2 diabetic patient group. This may result in a modification of drug degradation and drug efficacy in these patients and may have an influence, e.g. on the choice of anti-diabetic drugs. However, further trials are necessary in order to confirm our findings.