Thiazolidinediones: comparison of long-term effects on glycemic control and cardiovascular risk factors

OBJECTIVE: To compare the long-term effects on HbA(1c), lipid parameters, body weight, and hepatotoxicity after switching type 2 diabetes patients from troglitazone to either pioglitazone or rosiglitazone. METHODS: Of 125 study candidates from a previous prospective study, 100 patients (51 pioglitazone, 49 rosiglitazone) met criteria for comparing HbA(1c), lipids, body weight, and incidence of hepatotoxicity over 2 successive observation periods (3.1 and 12.6 months). RESULTS: Mean absolute HbA(1c) decreased significantly, 0.53 and 0.27% in the pioglitazone and rosiglitazone groups, respectively, at the 12.6-month observation. Mean triglyceride (TG) decreased in the pioglitazone group at each interval with a cumulative decrease of 26.4% from baseline. In contrast, TG increased in the rosiglitazone patients by 43.3% at 3.1 months and then decreased (but remained above baseline) at 12.6 months. Mean high density lipoprotein (HDL) increased 22.1% with pioglitazone and 13.3% with rosiglitazone. In patients who had a baseline HDL < 35 mg/dL (0.91 mmol/L), pioglitazone treated patients experienced a significant increase at each interval resulting in a 52.6% increase in HDL compared to a 26.9% increase for rosiglitazone patients. Patients in both treatment groups had similar weight increases at each interval and no hepatotoxicity was noted. CONCLUSION: With pioglitazone or rosiglitazone, changes in glycemic control, lipid effects, and body weight appear to continue over time. Pioglitazone treatment resulted in decreased triglyceride levels, while rosiglitazone was associated with an increase in triglyceride levels. HDL increased in both treatment groups, but in patients with a baseline HDL < 35 mg/dL (0.91 mmol/L), pioglitazone improved the HDL to a greater extent than rosiglitazone.     

Glycemic control and treatment failure with pioglitazone versus glibenclamide in type 2 diabetes mellitus: a 42-month,open-label,observational, primary care study

ABSTRACT

Background: Insulin resistance and declining β-cell function are the core defects in type2 diabetes mellitus. It has been suggestedthat deteriorating glycemic control is relatedto baseline hemoglobin A_1c (HbA_1c) values andremaining β-cell function.

Patients and methods: We report glycemic data from a 3.5‐year, open-label, observational, primary care study comparing 30?mg/day pioglitazone with 3.5?mg/day glibenclamide add-on to stable metformin monotherapy in 500 patients with type 2 diabetes. Insulin commencement was considered for patients with HbA_1c ≥ 8.0% or when vascular complications occurred. The change in HbA_1c compared with baseline and the difference in time to failure to maintain glycemic control were calculated.

Results: At endpoint, HbA_1c had decreased by 1.0% in the pioglitazone group (?p < 0.005) and by 0.6% in the glibenclamide group (?p < 0.05). Annual progression rates to insulin treatment were 6.6% (pioglitazone) and 16.4% (glibenclamide; p < 0.001 between-group difference). Mean weight increases of 3.5 ± 0.42?kg in the pioglitazone group and 3.3 ± 0.38?kg in the glibenclamide group were noted. Overall, both treatments were well tolerated.

Conclusions: Pioglitazone add-on to metformin revealed significant benefits in long-term glycemic control compared with glibenclamide. This difference may be explained by a large between-group difference in HOMA-S, which was shown to correlate significantly to the change in HbA_1c. This suggests that a strategy to reduce insulin resistance to lower the burden of the β‐cell is superior to treatment with glibenclamide.     

Efficacy and safety of therapy with metformin plus pioglitazone in the treatment of patients with type 2 diabetes: a double-blind,placebo-controlled,clinical trial

ABSTRACT

Objective: To assess the efficacy and safety of combination therapy with pioglitazone and metformin in Japanese patients with type 2 diabetes.

Research design and methods: During a 12-week observation period 236 patients were treated with metformin 500 or 750?mg/day. 169 patients with a confirmed HbA_1c level ≥ 6.5% were randomized (stratified according to metformin dosage) to receive pioglitazone 15?mg/day for 12 weeks then increased to 30?mg/day for a further 16 weeks (n?=?83), or placebo (n?=?86). Outcome measures included HbA_1c, fasting blood glucose (FBG), percentage of patients achieving HbA_1c?<?6.5%, lipid profile, and other metabolic parameters.

Results: Mean HbA_1c was reduced by 0.67% in patients receiving pioglitazone plus metformin versus an increase of 0.25% in those receiving metformin alone (p?<?0.0001). After 8 weeks’ treatment and until the end of the study, HbA_1c was significantly lower with pioglitazone plus metformin and more patients in this group achieved an HbA_1c?<?6.5% (38.6% vs. 8.1%; p?<?0.0001). FBG was also reduced by a significantly greater amount in patients receiving pioglitazone plus metformin compared with metformin monotherapy (?20.5 vs. 1.9?mg/dl; p?<?0.0001). Combination therapy was associated with significantly increased HDL-cholesterol, total cholesterol, and adiponectin, and significantly decreased levels of fasting insulin, free fatty acids, and homeostasis model assessment insulin resistance (HOMA-R) compared with metformin monotherapy. Overall, combination therapy and monotherapy were equally well tolerated and the incidence of adverse effects ‘possibly’ related to therapy was 15.7% and 11.6% (p?=?0.505), respectively. Edema occurred slightly more often in the combination group (6.0 vs. 1.2%).

Conclusion: Pioglitazone plus metformin significantly improved glycemic control (HbA_1c and FBG), and markers associated with increased insulin resistance and cardiovascular risk compared with metformin monotherapy.

Clinical trial registration number: UMIN 000001110.     

Effects of early use of pioglitazone in combination with metformin in patients with newly diagnosed type 2 diabetes

ABSTRACT

Background: Type 2 diabetes is characterised by a progressive decline in HbA_1c control over time. Early combination therapy, rather than sequential introduction of individual oral glucose-lowering agents, has been proposed to prevent this gradual rise in HbA_1c. This observational study assessed the effect of early dual combination oral glucose-lowering therapies within 6 months of diagnosis in newly diagnosed, drug-naïve patients with type 2 diabetes.

Patients and methods: This was an observational, open-label, non-randomised study in newly diagnosed patients with type 2 diabetes, aged 35–70 years, with HbA_1c levels >?8.0% at diagnosis or >?7.0% at the 3–6-month follow-up. Patients were allocated to dietary management alone if the HbA_1c level was 7.0–8.0% at diagnosis. Metformin combined with gliclazide, repaglinide, or pioglitazone was given at diagnosis if the HbA_1c was >?8.0%. Similar treatments were introduced at 3–6 months if the HbA_1c was >?7.0%. Over a 3-year period, HbA_1c was measured at 3-monthly intervals. All patients underwent regular dietetic review. Target HbA_1c was ≤?7.0%.

Results: 416 patients were considered eligible for inclusion, with a mean (±?SD) age of 54.1 ± 9.2 years, BMI of 33.5 ± 6.1?kg/m², and baseline HbA_1c of 8.6 ± 1.7%. A mixed model analysis of variance on the 178 patients who started with combination therapy, either immediately or after a 3–6 month period on diet, showed that metformin plus gliclazide, repaglinide, or pioglitazone was associated with a gradual increase in HbA_1c values. Amongst those patients treated with the metformin/pio­glitazone combination there was an estimated 0.1% increase in HbA_1c/year. This was much less pronounced than the rises seen in HbA_1c/year of 0.5% with the met­formin/gliclazide and metformin/repaglinide combinations.

Conclusions: This preliminary analysis of an obervational, non-randomised, open-label ongoing study has shown that early use of combination therapy at time of diagnosis or within the first 3–6 months following diagnosis with metformin plus pioglitazone in newly diagnosed type 2 diabetes results in a slower deterioration in glycaemic control than that with metformin combined with either gliclazide or repaglinide. This may be due to the β?cell protective properties of pioglitazone. These results need to be confirmed by further studies with a more robust design and methodology.     

Albiglutide,a weekly GLP-1 receptor agonist,improves glycemic parameters in Japanese patients with type 2 diabetes over 1 year when added to single oral antidiabetic drugs

Objective: To evaluate the safety and efficacy of once weekly albiglutide added to a single oral antidiabetic drug (OAD) in Japanese patients with inadequately controlled type 2 diabetes mellitus (T2DM).

Research design and methods: In this phase 3, 1 year study (NCT01777282), patients (N?=?374) received albiglutide 30?mg plus a single OAD (sulfonylurea [n?=?120], biguanide [n?=?67)], glinide [n?=?65], thiazolidinedione [n?=?61], or α-glucosidase inhibitor [n?=?61]). Albiglutide could be increased to 50?mg after Week 4, based on glycemic criteria. Primary endpoints were the incidence of adverse events (AEs) and hypoglycemia; secondary endpoints were changes from baseline at Week 52 in HbA_1c and fasting plasma glucose (FPG), proportion of patients achieving HbA_1c ≤7.0%, and withdrawals due to hyperglycemia.

Results: On-therapy AEs occurred in 78.6% of patients and serious AEs in 2.1%. Common AEs were nasopharyngitis (32.6%), constipation (7.2%), and diabetic retinopathy (5.3%). No serious AEs occurred more than once or were reported in >1 patient. Hypoglycemia occurred in 6.4% of patients, mostly in the albiglutide?+?sulfonylurea (14.2%) and the albiglutide?+?glinide (6.2%) groups. Albiglutide was uptitrated in 53.2% of patients. Mean baseline HbA_1c was 8.1%. Mean decreases from baseline in HbA_1c were observed with the addition of albiglutide to thiazolidinediones (?1.42%), α-glucosidase inhibitors (?1.39%), sulfonylureas (?1.04%), glinides (?0.95%), and biguanides (?0.94%). HbA_1c of <7% in >50% of patients and mean reductions in FPG were achieved in all groups. Mean changes from baseline in body weight ranged from +0.52?kg (albiglutide?+?thiazolidinedione) to ?0.33?kg (albiglutide?+?biguanide). Limitations of the study included open label treatment that was not randomized.

Conclusions: When combined with a single OAD in Japanese patients with inadequately controlled T2DM, albiglutide led to favorable changes in all glycemic parameters, with minor changes in body weight depending on the background OAD. No new safety concerns were noted.     

Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin added to pioglitazone in patients with type 2 diabetes: a randomized,double-blind,placebo-controlled study

ABSTRACT

Objectives: To evaluate the efficacy and safety of alogliptin in patients with type 2 diabetes inadequately controlled by therapy with a thiazolidinedione (TZD).

Research design and methods: In a multicenter, double-blind, placebo-controlled clinical study, 493 patients 18–80 years old with inadequate glycemic control after stabilization (i.e., glycosylated hemoglobin [HbA_1c] 7.0–10.0%) despite ongoing treatment with a TZD were randomly assigned (2:2:1) to treatment with pioglitazone plus alogliptin 12.5?mg, alogliptin 25?mg or placebo once daily. Concomitant therapy with metformin or sulfonylurea at prestudy doses was permitted.

Main outcome measures: The primary efficacy endpoint was change in HbA_1c from baseline to Week 26. Secondary endpoints included changes in fasting plasma glucose (FPG) and body weight, and incidences of marked hyperglycemia (FPG?≥?200?mg/dL [11.10?mmol/L]) and rescue for hyperglycemia.

Results: Least squares (LS) mean change in HbA_1c was significantly (p?<?0.001) greater for alogliptin 12.5?mg (?0.66%) or 25?mg (?0.80%) than for placebo (?0.19%). A significantly (p?≤?0.016) larger proportion of patients achieved HbA_1c?≤?7% with alogliptin 12.5?mg (44.2%) or 25?mg (49.2%) than with placebo (34.0%). LS mean decreases in FPG were significantly (p?=?0.003) greater with alogliptin 12.5?mg (?19.7?mg/dL [?1.09?mmol/L]) or 25?mg (?19.9?mg/dL [?1.10?mmol/L]) than with placebo (?5.7?mg/dL [?0.32?mmol/L]). The percentage of patients with marked hyperglycemia was significantly (p?<?0.001) lower for alogliptin (≤25.0%) than placebo (44.3%). The incidences of overall adverse events and hypoglycemia were similar across treatment groups, but cardiac events occurred more often with active treatment than placebo.

Conclusions: Addition of alogliptin to pioglitazone therapy significantly improved glycemic control in patients with type 2 diabetes and was generally well tolerated. The study did not evaluate the effect of combination therapy on long-term clinical outcomes and safety.

Clinical trial registration: NCT00286494, clinicaltrials.gov.     

A cost-effectiveness analysis of pioglitazone plus metformin compared with rosiglitazone plus metformin from a third-party payer perspective in the US*

ABSTRACT

Objective: The long-term cost-effectiveness of using pioglitazone plus metformin (Actoplusmet^?) compared with rosiglitazone plus metformin (Avandamet^?) in treating type 2 diabetes (T2DM) was assessed from a US third-party payer perspective.

Research design and methods: Clinical efficacy (change in HbA_1c and lipids) and baseline cohort parameters were extracted from a 12-month, randomized clinical trial (Derosa et al., 2006) evaluating the efficacy and tolerability of pioglitazone versus rosiglitazone, both in addition to metformin, in adult T2DM patients with insufficient glucose control (n?=?96). A Markov-based model was used to project clinical and economic outcomes over 35 years, discounted at 3% per annum. Costs for complications were taken from published sources. Base-case assumptions were assessed through several sensitivity analyses.

Main outcome measures: Outcomes included incremental life-years, quality-adjusted life-years (QALYs), total direct medical costs, cumulative incidence of complications and associated costs, and incremental cost–effectiveness ratios (ICERs).

Results: Compared to rosiglitazone plus metformin, pioglitazone plus metformin was projected to result in a modest improvement in 0.187 quality-adjusted life-years. Over patients’ lifetimes, total direct medical costs were projected to be marginally lower with pioglitazone plus metformin (difference –$526.), largely due to reduced CVD complication costs. While costs were higher among renal, ulcer/amputation/neuropathy, and eye complications in the pioglitazone plus metformin group, the cost savings for CVD complications outweighed their economic impact. Pioglitazone plus metformin was found to be a dominant long-term treatment strategy in the US compared to rosiglitazone plus metformin. Sensitivity analyses showed findings to be robust under almost all scenarios, including short-term time horizons, 6% discounting, removal of individual lipid parameters, and modifications of patient cohort to more closely represent a US T2DM population. Pioglitazone plus metformin was no longer dominant with 0% discounting, with 25% reduction in its HbA_1c effects, or with a 15% increase in its acquisition price.

Conclusions: Under a range of assumptions and study limitations around cohorts, clinical effects, and treatment patterns, this long-term analysis showed that pioglitazone plus metformin, when compared to rosiglitazone plus metformin, was a dominant treatment strategy within the US payer setting. Results were driven by the combination of modest differences in QALYs and modest savings in total complication costs over 35 years.     

Effect of non-persistent use of oral glucose-lowering drugs on HbA1c goal attainment

ABSTRACT

Objectives: The aim of this study was to quantify the effect of non-persistence with oral glucose-lowering drugs (OGLD) on HbA_1c goal attainment (<?7%) in daily practice.

Methods: From the PHARMO Record Linkage System comprising among others linked drug dispensing and clinical laboratory data from approximately 2.5 million individuals in the Netherlands, new users of OGLD in the period 1999–2004 were identified. Patients with a baseline HbA_1c ≥?7% and at least one HbA_1c measurement in the period of 6–12?months after treatment onset were included in the study cohort. Persistence with OGLD in the first year of treatment was determined using the method of Catalan. In case the first treatment episode overlapped the first HbA_1c measurement within 6–12?months after treatment onset, a patient was considered persistent at that measurement. Patients with a HbA_1c <?7% were defined as having attained goal.

Results: The study cohort included 2023 patients with a mean baseline HbA_1c of 8.9?±?1.8%. Three-quarters (1512 patients) were persistent with any OGLD at the first HbA_1c measurement within 6–12?months after treatment onset; of these, 861 (57%) were at goal. Of the 511 non-persistent patients, 239 (47%) were at goal. Non-persistent patients were about 20% less likely to attain goal (RRadj 0.82; 95%CI 0.74–0.91), compared to persistent OGLD users.

Conclusion: Non-persistent use of OGLD leads to a 20% decreased probability of HbA_1c goal attainment in daily practice. This effect of non-persistence seems modest, but represents around 12?000 new and 10?000 prevalent OGLD users a year in the Netherlands in whom OGLD use could be better controlled.     

Pioglitazone versus rosiglitazone treatment in patients with type 2 diabetes and dyslipidemia: cost-effectiveness in the US

ABSTRACT

Objectives: Pioglitazone hydrochloride (Actos) and rosiglitazone maleate (Avandia) are members of the thiazolidinedione (TZD) class of oral anti-diabetic drugs (OADs) and are used to treat type 2 diabetes mellitus (T2DM). Greater beneficial effects on lipids have been demonstrated with pioglitazone, however. Study objectives were to evaluate the long-term cost-effectiveness of pioglitazone compared to rosiglitazone in treating patients with T2DM and dyslipidemia, and determine the extent to which reported beneficial lipid effects of pioglitazone would improve clinical and economic outcomes through reduced macrovascular complications.

Research design and methods: The validated CORE Diabetes Model (CDM) was used to simulate changes in glycosylated hemoglobin (HbA_1c), complications, and direct medical costs. Baseline parameters came from a multi-center, double-blind trial comparing lipid and glycemic effects of pioglitazone (n?=?400) and rosiglitazone (n?=?402) among individuals with T2DM and untreated dyslipidemia. Sensitivity analyses examined the impact of cohort, clinical, and cost inputs on incremental cost effectiveness ratios (ICERs).

Results: In the base case, pioglitazone was associated with mean (standard deviation [SD]) quality-adjusted life years (QALYs) of 7.476 (0.123) vs. 7.326 (0.128) for rosiglitazone. Pioglitazone had $3038 higher total direct costs, but $580 lower complication costs. Risks of four cardiovascular complications were reduced with pioglitazone (relative risks 0.860–0.942), while risks of 17 other complications were slightly higher (relative risks 1.001–1.056). The ICER for pioglitazone treatment was $20?171/QALY. Results were most sensitive to the effects of HbA_1c, high-density lipoprotein-cholesterol, overall lipid effects, and pioglitazone acquisition costs.

Conclusions: Study limitations include issues of generalizability of the trial patient population, as well as inability to capture non-adherence and variation in ‘real-world’ treatment patterns. Nevertheless, pioglitazone (when compared to rosiglitazone) was found to have long-term value as a treatment option for T2DM patients with dyslipidemia treated within the US payer setting.     

Efficacy and safety of initial combination therapy with sitagliptin and metformin in patients with type 2 diabetes: a 54-week study

ABSTRACT

Objective: To assess the 54-week efficacy and safety of initial combination therapy with sitagliptin and metformin in patients with type 2 diabetes and inadequate glycemic control (HbA_1c 7.5–11%) on diet and exercise.

Methods and materials: This was multinational study conducted at 140 clinical sites in 18 countries. Following an initial 24-week, double-blind, placebo-controlled period, patients entered a double-blind continuation period for an additional 30 weeks. Following the week 24 evaluation, patients remained on their previously assigned active, oral treatments: sitagliptin 50?mg b.i.d.?+?metformin 1000?mg b.i.d. (S100?+?M2000), sitagliptin 50?mg b.i.d.?+?metformin 500?mg b.i.d. (S100?+?M1000), metformin 1000?mg b.i.d. (M2000), metformin 500?mg b.i.d. (M1000), and sitagliptin 100?mg q.d. (S100). Patients initially randomized to placebo were switched to M2000 (designated PBO/M2000) at week 24. This report summarizes the overall safety and tolerability data for the 54-week study and presents efficacy results for patients randomized to continuous treatments who entered the 30-week continuation period.

Results: Of the 1091 randomized patients, 906 completed the 24-week placebo-controlled phase and 885 patients continued into the 30-week continuation period (S100?+?M2000 n?=?161, S100+M1000 n?=?160, M2000 n?=?153, M1000 n?=?147, S100 n?=?141, PBO/M2000 n?=?123). At baseline, patients included in the efficacy analysis had mean age of 54 years, mean BMI of 32?kg/m², mean HbA_1c of 8.7% (8.5–8.8% across groups), and mean duration of type 2 diabetes of 4 years. At week 54, in the all-patients-treated analysis of continuing patients, least-squares (LS) mean changes in HbA_1c from baseline were ?1.8% (S100?+?M2000), ?1.4% (S100?+?M1000), ?1.3% (M2000), ?1.0% (M1000), and ?0.8% (S100). The proportions of continuing patients with an HbA_1c?<?7% at week 54 were 67% (S100?+?M2000), 48% (S100?+?M1000), 44% (M2000), 25% (M1000), and 23% (S100). For the patients completing treatment through week 54, LS mean changes in HbA_1c from baseline were ?1.9% (S100?+?M2000), ?1.7% (S100?+?M1000), ?1.6% (M2000), ?1.2% (M1000), and ?1.4% (S100). Glycemic response was generally durable over time across treatments. All treatments improved measures of β-cell function (e.g., HOMA-β, proinsulin/insulin ratio). Mean body weight decreased from baseline in the combination and metformin monotherapy groups and was unchanged from baseline in the sitagliptin monotherapy group. The incidence of hypoglycemia was low (1–3%) across treatment groups. The incidence of gastrointestinal adverse experiences with the co-administration of sitagliptin and metformin was similar to that observed with metformin alone.

Limitations: The patient population evaluated in the 54-week efficacy analysis was a population of patients who entered the continuation period without receiving glycemic rescue therapy in the 24-week placebo-controlled period. Because the baseline HbA_1c inclusion criteria ranged from 7.5 to 11% and the glycemic rescue criterion was an HbA_1c?>?8% after week 24, there was a greater likelihood of glycemic rescue in the monotherapy groups; this led to more missing data in the continuation all-patients-treated population(CAPT) analysis and fewer patients contributing to the completers analysis in the monotherapy groups.

Conclusions: In this study, initial treatment with sitagliptin, metformin, or the combination therapy of sitagliptin and metformin provided substantial and durable glycemic control, improved markers of β-cell function, and was generally well-tolerated over 54 weeks in patients with type 2 diabetes.     

Transferring type 2 diabetes patients with uncontrolled glycaemia from biphasic human insulin to biphasic insulin aspart 30: experiences from the PRESENT study

ABSTRACT

Aim: The Physician's Routine Evaluation of Safety and Efficacy of NovoMix* 30 Therapy (PRESENT) aims to assess the safety and efficacy of biphasic insulin aspart (BIAsp30) used in routine clinical practice.

Methods: This was a large, multi-national, multi-centre, prospective, 6-month study in type 2 diabetes mellitus patients who were prescribed BIAsp30. Efficacy endpoints included changes in HbA_1c, fasting plasma glucose (FPG), postprandial plasma glucose (PPPG), and proportion who achieved target HbA_1c <?7%. Changes from baseline were analysed using paired t-test. Safety endpoints were incidence and rate of hypoglycaemic episodes. A subgroup of patients previously uncontrolled (HbA_1c ≥?7.0%) on biphasic human insulin (BHI) were analysed.

Results: Glycaemia improved significantly (mean ± SD): HbA_1c by 1.58 ± 1.69% points (from 9.32 ± 1.64% to 7.70 ± 1.29%), FPG by 2.92 ± 3.71?mmol/L and PPPG by 4.75 ± 4.87?mmol/L. The incidence of hypoglycaemic episodes decreased over time, from 38.7% (baseline) to 20.8% (6?months). Episodes were mostly minor (reduced from 37.7 to 20.6% at 6?months), occurring during the day (reduced from 31.5 to 17.1% at 6?months). Major episodes were less frequently reported (reduced from 5.0 to 0.4% at 6?months). The rate of hypoglycaemia (episodes/patient year) from baseline to end of study decreased over time for overall (8.9–2.2), major (0.7–0.1), minor (8.2–2.2) and nocturnal (2.9–0.5) episodes.

Conclusions: In this observational study, in the type 2 diabetes mellitus patients who were poorly controlled on BHI, glycaemia improved when transferred to BIAsp30, and a lower incidence or rate of hypoglycaemia was observed in these patients.     

Effect of saxagliptin monotherapy in treatment-naïve patients with type 2 diabetes

ABSTRACT

Objective: To evaluate the efficacy and safety of once-daily saxagliptin monotherapy in treatment-naïve patients with type 2 diabetes (T2D) and inadequate glycemic control.

Research design and methods: This study included a main treatment cohort (MTC) with 401 patients (HbA_1c?≥?7% and ≤10%) randomized and treated with oral saxagliptin 2.5, 5, or 10?mg once daily or placebo for 24 weeks and a separate open-label cohort (OLC) with 66 patients (HbA_1c?>?10% and ≤12%) who received saxagliptin 10?mg once daily for 24 weeks. Primary endpoint was HbA_1c change from baseline to week 24. Secondary endpoints included change from baseline to week 24?in fasting plasma glucose (FPG), proportion of patients achieving HbA_1c?<?7%, and changes in postprandial glucose area-under-the-curve (PPG-AUC). Efficacy analyses for continuous variables were performed using an ANCOVA model with last-observation-carried-forward methodology.

Results: In the MTC, saxagliptin demonstrated statistically significant decreases in adjusted mean HbA_1c changes from baseline (mean, 7.9%) to week 24 (?0.43%, ?0.46%, ?0.54%) for saxagliptin 2.5, 5, and 10?mg, respectively, vs. +0.19% for placebo (all p?<?0.0001). Adjusted mean FPG was significantly reduced from baseline (?15, ?9, ?17?mg/dL) for saxagliptin 2.5, 5, and 10?mg, respectively, vs. +6?mg/dL for placebo (p?=?0.0002, p?=?0.0074, p?<?0.0001, respectively). More saxagliptin-treated patients achieved HbA_1c?<?7% at week 24 (35% [p?=?NS], 38% [p?=?0.0443], 41% [p?=?0.0133]) for saxagliptin 2.5, 5, and 10?mg, respectively, than placebo (24%). PPG-AUC was reduced for saxagliptin 2.5, 5, and 10?mg (?6868, ?6896, ?8084?mg·min/dL, respectively) vs. placebo (?647?mg·min/dL) with statistical significance demonstrated for saxagliptin 5?mg (p?=?0.0002) and 10?mg (p?<?0.0001). HbA_1c, FPG, and PPG-AUC reductions were also observed in the OLC at 24 weeks. In the MTC, adverse event frequency was similar across all study arms. No cases of confirmed hypoglycemia (symptoms, with fingerstick glucose ≤50?mg/dL) were observed in either cohort. Saxagliptin was not associated with weight gain. Study limitations included the lack of a control group for the OLC and the use of prespecified rescue criteria, which limited the exposure time during which patients could remain on their originally randomized medication without the introduction of additional antihyperglycemic rescue treatment.

Conclusions: Once-daily saxagliptin monotherapy for 24 weeks was generally well tolerated and demonstrated clinically meaningful reductions in key parameters of glycemic control vs. placebo.

Trial Registration: Clinical Trials NCT00121641     

Efficacy and tolerability of initial combination therapy with nateglinide and metformin in treatment-naïve patients with type 2 diabetes

SUMMARY

Objective: To assess the efficacy and tolerability of the combination of nateglinide (120?mg, ac) and metformin (500?mg, tid) as initial treatment in drug-naïve patients with type 2 diabetes mellitus (T2DM).

Research design and methods: This study reports data from the treatment-naïve (TN) subgroup of patients in a previously published, randomized, multicenter, placebo-controlled, 24-week trial that compared nateglinide, metformin, and the combination therapy (CT) in 701 patients with T2DM with baseline HbA_1c between 6.8% and 11.0%. Of the 401 TN patients, 104, 104, 89, and 104 patients received nateglinide (120?mg, ac), metformin (500?mg, tid), CT, and placebo, respectively. The baseline characteristics of each group were similar, with mean age, BMI, duration of diabetes, HbA_1c, and fasting plasma glucose (FPG) levels of approximately 58 years, 30?kg/m², 4 years, 8.2%, and 10.2?mmol/L, respectively.

Results: In patients receiving initial CT, HbA_1c decreased substantially (? = –1.6 ± 0.1%, p < 0.0001 vs. baseline or placebo) from a mean baseline of 8.2 ± 0.1%, an effect significantly greater than the 0.8% reduction observed with both monotherapies (?p < 0.001); whereas, in placebo-treated patients, HbA_1c increased modestly (? = +0.3 ± 0.1%, p < 0.05) from an identical baseline value. Seventy percent of CT-treated patients achieved a target HbA_1c of < 7.0%. Both fasting plasma glucose (FPG) and the 2-hour postprandial glucose excursion (PPGE) after a liquid meal challenge decreased by 2.3?mmol/L in patients receiving CT, while the changes from baseline values in FPG and PPGE were +0.2 ± 0.3?mmol/L and –0.5 ± 0.2?mmol/L, respectively, in placebo-treated patients. The incremental 30-minute post-load insulin levels increased by 88 ± 32?pmol/L (?p = 0.006) in patients receiving CT and did not change significantly in placebo-treated patients. Gastrointestinal side effects occurred in 27% of patients receiving CT (vs. 27.9% in the metformin monotherapy, and 14.4% in the placebo groups). Confirmed hypoglycemia (glucose ≤ 2.8?mmol/L) occurred in 3.4% of patients receiving CT.

Conclusions: Initial CT with the rapid-acting insulinotropic agent, nateglinide, and metformin, an agent with insulin-sensitizing effects in the liver and periphery, is a safe and effective means of achieving glycemic targets in TN patients with T2DM.     

Differences in Lipid Profiles of Patients Given Rosiglitazone Followed by Pioglitazone

Summary

To compare the effects of rosiglitazone and pioglitazone on patient lipid levels in a clinical practice setting, we retrospectively examined charts of 20 patients in our practice. The patients had been treated for type 2 diabetes for 3 or more months with rosiglitazone (4?mg b.i.d.) followed immediately by 3 or more month^s' treatment with pioglitazone (45?mg once daily). Glycaemic control was excellent and essentially equivalent during the two treatments. At baseline, the mean HbA1c level was 7.6%; it dropped to 6.6% and 6.3% with rosiglitazone and pioglitazone treatment, respectively. Lipid levels, however, differed with the two treatments. Triglyceride levels rose 13% with rosiglitazone treatment, but fell 14% below baseline levels with pioglitazone therapy - a 24% reduction overall (p?=?0.02). Rosiglitazone was associated with a significant increase in low-density

lipoprotein cholesterol (LDL-C) levels (35%, p?<?0.001 vs. baseline) and a significant increase in total cholesterol levels (22%, p?<?0.001 vs. baseline). When pioglitazone replaced rosiglitazone therapy, LDL-C fell 25% (p?<?0.001), and total cholesterol fell 19% (p?<?0.001 between treatments). HDL-C levels did not change significantly during either treatment. Both drugs were otherwise safe and well tolerated. One patient receiving rosiglitazone and one receiving pioglitazone developed oedema that resolved without therapy discontinuation. Liver enzyme levels and blood pressure were unaffected in this group of patients. Because patients with diabetes are at risk for coronary artery disease, physicians should consider each agent's effects on lipid levels when choosing a specific thiazolidinedione.     

Biphasic insulin aspart 30 treatment in patients with type 2 diabetes poorly controlled on prior diabetes treatment: results from the PRESENT study

ABSTRACT

Aim: The safety and efficacy of biphasic insulin aspart (BIAsp30) were evaluated in patients uncontrolled on previous treatment (human insulin ± oral hypoglycaemic agent [OHA] or OHA only) in routine clinical practice.

Methods: This was a large, multi-national, multi-centre, prospective, 6-month study in type 2 diabetes mellitus patients who were prescribed BIAsp30. Changes in glycated haemoglobin (HbA_1c), fasting plasma glucose (FPG), postprandial plasma glucose (PPPG), proportion who achieved target HbA_1c < 7% and rate of hypoglycaemic episodes were assessed. This paper evaluates outcomes in patients by diabetes duration (< 5, 5–10, 10–20 or ≥ 20 years) stratified by prior therapy.

Results: After 6 months of treatment, glycaemia improved significantly across the duration subgroups. The improvement was better in insulin-naïve group versus prior insulin group: HbA_1c decreased ~ 2.2%-points versus ~ 1.6%-points, FPG decreased ~ 4.5?mmol/L versus ~ 2.9?mmol/L and PPPG decreased ~ 6.8?mmol/L versus ~ 5.0?mmol/L. Target HbA_1c was achieved by about one in four patients although insulin-naïve patients achieved this at comparatively lower BIAsp30 dose. Body weight remained relatively unchanged. Hypoglycaemic episodes appeared to be more frequent in the prior insulin group which decreased during the treatment period.

Conclusions: According to this observational study, in clinical practice, initiating or transferring uncontrolled patients to biphasic insulin aspart improved glycaemic control without using a strict insulin algorithm.     

Effects of rosiglitazone added to submaximal doses of metformin compared with dose escalation of metformin in type 2 diabetes: the EMPIRE Study

ABSTRACT

Objective: This study was designed to compare the efficacy, safety and tolerability of rosiglitazone (RSG) added to submaximal doses of metformin (MET) with dose escalation to the maximal effective dose of MET monotherapy in type 2 diabetes mellitus.

Research design and methods: In this multi-center, double-blind, randomized, parallel-group study, 766 subjects with a baseline MET dose of 1000?mg/day were randomized to receive either RSG 4?mg/day (4?mg/1000?mg) or MET 500?mg/day (1500?mg/day total dose) for 8 weeks. Only the RSG dose was increased in the combination group – to 8?mg/day (8?mg/1000?mg) – and only the MET dose was increased in the MET monotherapy group – to 2000?mg/day for the remaining 16 weeks.

Results: After 24 weeks, RSG added to MET (8?mg/1000?mg/day) was at least as effective as 2000?mg/day of MET in improving HbA_1c’, with mean reductions of –0.93% (95% CI: –1.06%, –0.80%) and –0.71% (95% CI: –0.83%, –0.60%), respectively, from baseline in subjects that completed the study according to the investigator (mean treatment effect/difference of –0.20% [95% CI: –0.36%,–0.04%]). In addition, a higher percentage of subjects in the RSG + MET group achieved American Diabetes Association target levels of HbA_1c < 7% (58.1% versus 48.4%) and American Association of Clinical Endocrinologists target levels of HbA_1c ≤ 6.5% (40.9% versus 28.2%). This combination provided significantly greater reductions from baseline in fasting plasma glucose (FPG; –2.29?mmol/L [± 2.37?mmol/L] and –1.12?mmol/L [± 2.41?mmol/L], respectively), with a treatment difference of –0.85?mmol/L (95% Cl: –1.23?mmol/L, –0.47?mmol/L). For the intent-to-treat (ITT) population, the percentage of subjects experiencing a gastrointestinal side-effect was 27.9% and 38.7% for the RSG + MET and MET groups, respectively (OR = 1.63, 95% CI: 1.19, 2.24). Mean body weight (± SD) increased in all randomized subjects treated with the combination therapy (+ 1.79 ± 4.15?kg) compared with a mean weight loss in the up-titrated MET group (–1.78 ± 3.50?kg).

Conclusions: This study suggests that addition of RSG to submaximal doses of MET may be a suitable alternative to the maximal effective dose of MET monotherapy.     

Efficacy and safety of sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes

ABSTRACT

Objective: The purpose of this study was to evaluate the efficacy and safety of sitagliptin as an add-on to metformin therapy in patients with moderately severe (hemoglobin A_1c ≥?8.0% and ≤?11.0%) type 2 diabetes mellitus (T2DM).

Research design and methods: This was a multi­national, randomized, placebo-controlled, parallel-group, double-blind study conducted in 190 patients with T2DM. After ≥?6?weeks of stable metformin monotherapy (≥?1500?mg/day), patients were randomized to either the addition of sitagliptin 100?mg once daily or placebo to ongoing metformin for 30?weeks.

Main outcome measures: The primary efficacy endpoint was reduction in hemoglobin A_1c (HbA_1c) measured after 18?weeks of sitagliptin treatment. Key secondary end­points included reduction in fasting plasma glucose (FPG) and 2-hour (2-h) postprandial plasma glucose (PPG) at 18 weeks, and HbA_1c at 30 weeks. The proportion of patients meeting the goal of HbA_1c <?7.0% was also analyzed.

Results: Sitagliptin significantly reduced HbA_1c, FPG, and 2-h PPG, compared with placebo (all p < 0.001). The net improvement in HbA_1c was –1.0% at both 18 and 30 weeks, and a significantly greater proportion of patients treated with sitagliptin achieved HbA_1c <?7.0% by the end of the study (22.1% vs. 3.3%, p < 0.001). Sitagliptin was well-tolerated. Compared with placebo, sitagliptin had a neutral effect on body weight and did not signif­icantly increase the risk of hypoglycemia or gastro­intestinal adverse events.

Conclusions: Addition of sitagliptin 100?mg once daily to ongoing metformin therapy was well-tolerated and resulted in significant glycemic improvement in patients with moderately severe T2DM who were treated for 30 weeks.

Trial registration: ClinicalTrials.gov identifier: NCT00337610.     

Factors associated with the effect-size of thiazolidinedione (TZD) therapy on HbA1c:a meta-analysis of published randomized clinical trials

ABSTRACT

Objective: To examine factors affecting the size of the HbA^1c response to thiazolidinedione (TZD) therapy.

Research design and methods: Meta-analysis of randomized TZD controlled trials which were identified using PubMed, EBSCO and Sci-lit databases and were published in English. Sociodemographic and clinical data were extracted from each trial. HbA_1c effect size was defined as either a placebo-subtracted change in HbA_1c or a change in HbA_1c from baseline. Weighted multivariable regression was used to examine factors associated with changes in HbA_1c. Bootstrapped smearing estimates were computed to obtain reliable estimates of HbA_1c effect size.

Results: Forty-two trials yielded 60 trial arms which represented 8322 patients treated with thiazolidinediones. Weighted placebo-subtracted change in HbA_1c was –0.99% ± 0.02% with an average baseline HbA_1c of 9.1% ± 1.0%. Weighted bootstrapped smearing estimate of the placebo-subtracted change in HbA_1c was –1.02% ± 0.004%. After controlling for other variables, the baseline HbA_1c level had a significant negative association with placebo-subtracted HbA_1c change (?p = 0.004) and also with change in HbA_1c from baseline (?p = 0.002). Longer trial duration was associated with greater placebo-subtracted HbA_1c change (?p = 0.01) but not with the change in HbA_1c from baseline. The multivariable models explained 72% of the variation in placebo-subtracted HbA_1c change. It was not possible to estimate effects of the run-in period and obesity on TZD effect size.

Conclusion: Baseline HbA_1c and trial duration significantly impacted the effect size of TZD therapy on HbA_1c. Age, gender, duration of diabetes and prior use of anti-diabetic therapy were not associated with the TZD effect size.     

Effect of pioglitazone on metabolic syndrome risk factors: results of double-blind,multicenter, randomized clinical trials

ABSTRACT

Objective: To evaluate the effect of pioglitazone, metformin, and/or sulfonylurea on metabolic syndrome and its component parameters after a year of treatment.

Methods: Adult patients with poorly controlled type 2 diabetes were enrolled in 4 multicenter, double-blind studies and received pioglitazone, sulfonylurea, metformin, or a combination of any 2 agents. Post hoc analyses were performed on data from patients with evaluations at baseline and week 52, and treatment groups were compared to determine change from baseline in metabolic syndrome status and its component variables by using the McNemar test and analysis of covariance, respectively.

Results: Most patients (72.1%) had metabolic syndrome at baseline. Change in the proportion of patients with metabolic syndrome status was significant in each monotherapy and the pioglitazone plus metformin combination groups. Pioglitazone alone or in combination with metformin resulted in a significantly greater percent decrease from baseline in triglycerides (pioglitazone vs. metformin, 10.3%; pioglitazone vs. sulfonylurea, 6.5%; pioglitazone plus metformin vs. sulfonylurea plus metformin, 13.4%; P < 0.05) and a greater percent increase from baseline in high-density lipoprotein (HDL) cholesterol (pioglitazone vs. metformin, 9.1%; pioglitazone vs. sulfonylurea, 12.6%; pioglitazone plus metformin vs. sulfonylurea plus metformin, 17.8%; P < 0.001) at week 52 than did the respective comparison groups. A significant decrease from baseline in the ratio of urinary albumin to creatinine was found only with pioglitazone monotherapy (–1.764?mg/mmol; P < 0.001), which was significantly greater than the change in the metformin monotherapy group (2.1%; P < 0.05). Significant decrease in blood pressure was observed in the pioglitazone monotherapy and pioglitazone plus sulfonylurea groups, with no significant treatment group differences.

Conclusions: Treatment with pioglitazone as monotherapy or combination therapy led to sustained, positive effects on important components of metabolic syndrome in patients with type 2 diabetes, independent of effects on blood glucose control and, as such, could be translated to potential for reducing the risk of cardiovascular disease.     

Once-daily insulin detemir in a cohort of insulin-naïve patients with type 2 diabetes: a sub-analysis from the PREDICTIVE study

ABSTRACT

Objective: PREDICTIVE^* is a large, observational study of the empirical use of insulin detemir in patients with type 1 or type 2 diabetes (T1DM/T2DM). This post hoc analysis evaluates insulin-naïve patients with T2DM uncontrolled on oral antidiabetic drugs (OADs) who were initiated and remained on once-daily insulin detemir for 12 weeks.

Research design and methods: This observational, multinational, multi-center, open-label prospective study evaluated the efficacy and safety of insulin detemir in 1653 insulin-naïve patients with T2DM (mean age 60.8?±?10.9 years, BMI 29.8?±?4.8?kg/m², and HbA_1C 8.82?±?1.50%). Statistical comparisons were made between baseline and 12-week follow up data. Our study was subject to the usual limitations of observational studies.

Main outcome measures: Endpoints were: incidence of serious adverse drug reactions, including number of hypoglycemic events (total, major, and nocturnal), glycemic parameters, and weight change.

Results: Following insulin initiation, no significant change occurred in the number of nocturnal hypoglycemic events or total hypoglycemic events (p?=?0.4513), and no serious adverse drug reactions were observed during the 12 weeks of treatment. HbA_1C decreased by a mean 1.25% (SD?±?1.25%; p?<?0.0001), with 30% of patients (n?=?383) achieving HbA_1C <7% at 12 weeks. Mean changes in fasting blood glucose and fasting blood glucose variability were –3.62?mmol/L (SD?±?2.93; p?<?0.0001) and ?0.48?mmol/L (SD?±?1.03; p?<?0.0001), respectively. Body weight decreased by a mean 0.5?kg (SD?±?3.3; p?<?0.0001), with weight loss or no weight change occurring in a substantial percentage of patients in each BMI category (<25, 25–30, 30–35, and >35?kg/m²). Patients with higher baseline BMI lost the most weight, with the greatest weight loss (–1.20?kg) reported in those with BMI >35?kg/m².

Conclusions: Empirical use of insulin detemir as an insulin initiation strategy can improve glycemic control with good tolerability, including a low risk of hypoglycemia and a weight benefit, in a majority of insulin-naïve patients uncontrolled on OADs.