Management of hyperglycemia associated with pasireotide (SOM230): Healthy volunteer study

Aims

Pasireotide, a multireceptor-targeted somatostatin analogue with efficacy in Cushing's disease and acromegaly, can affect glucose metabolism due to inhibition of insulin secretion and incretin hormone responses. A study was therefore conducted to evaluate different antihyperglycemic drugs in the management of pasireotide-associated hyperglycemia.

Methods

This was a 1-week, Phase I, open-label study. Healthy male volunteers were randomized to pasireotide 600 μg sc bid alone or co-administered with metformin 500 mg po bid, nateglinide 60 mg po tid, vildagliptin 50 mg po bid, or liraglutide 0.6 mg sc qd. An oral glucose tolerance test (OGTT) was performed on days 1 and 7 to evaluate effects on serum insulin, plasma glucose and glucagon levels. Safety/tolerability and pharmacokinetic effects were also evaluated.

Results

Ninety healthy male volunteers were enrolled (n = 18 per arm). After 7 days of treatment, plasma glucose AUC post-OGTT increased by 69% with pasireotide alone. The effect was reduced by 13%, 29%, 45% and 72% with co-administration of metformin, nateglinide, vildagliptin and liraglutide, respectively. On day 7, compared with pasireotide alone, the decrease in serum insulin was attenuated with nateglinide, metformin, liraglutide and vildagliptin co-administration (levels were 3%, 6%, 34% and 71% higher, respectively). Minimal changes in plasma glucagon were observed. Adverse events were consistent with the safety profiles of the drugs used.

Conclusions

Vildagliptin and liraglutide were most effective in minimizing pasireotide-associated hyperglycemia in healthy volunteers.     

Comparative efficacy and acceptability of antidiabetic agents for Alzheimer's disease and mild cognitive impairment: A systematic review and network meta‐analysis

This study (registered with PROSPERO, CRD42018085967) compares the efficacy (i.e. pro‐cognitive effects) and acceptability of antidiabetic agents for Alzheimer's disease (AD) and mild cognitive impairment (MCI). Cochrane Library (CENTRAL), PubMed/MEDLINE, EMBASE and PsycINFO were searched from inception to January 15, 2018 for randomized controlled trials comparing antidiabetic agents with placebo and/or another active antidiabetic agent for the treatment of AD or MCI. Nineteen eligible studies (n = 4855) evaluating the effects of 6 different antidiabetic drugs (i.e. intranasal insulin, pioglitazone, rosiglitazone, metformin, sitagliptin and liraglutide) were included. The results of 29 pairwise comparisons indicated that cognition was significantly improved in subjects treated with antidiabetic agents compared with placebo. Pioglitazone 15 to 30 mg demonstrated the greatest efficacy compared to placebo in network meta‐analysis. No significant differences in acceptability were identified when comparing agents with each other and with placebo. The current findings indicate a pro‐cognitive class effect of antidiabetic agents in AD/MCI. Other antidiabetic agents should also be investigated in future studies.     

Liraglutide ameliorates beta-cell function,alleviates oxidative stress and inhibits low grade inflammation in young patients with new-onset type 2 diabetes

Background

The prevalence of type 2 diabetes in youth is escalating rapidly. We aimed to evaluate the effects of liraglutide on beta-cell function, metabolic productions of oxidative stress, low grade inflammation compared with metformin in young patients with recent onset type 2 diabetes mellitus.

Methods

Sixty patients were randomly assigned to receive 8-week liraglutide or metformin treatment. Beta-cell function was assessed by modified beta cell function index (MBCI), early phase of insulin secretion index (ΔI30/ΔG30), proinsuin to insulin ratio (P/I) and the insulin area under the curve (AUCins). The expression of 8-OH-dG and 8-iso-PGF_2α and hs-C-reactive protein (hs-CRP) were measured as indications of oxidative stress and low grade inflammation.

Results

After 8 weeks liraglutide treatment, MBCI, ΔI30/ΔG30, AUCins significantly increased, 8-OH-dG, 8-iso-PGF_2α, P/I and hs-CRP remarkably reduced. The differences before and after 8-week liraglutide treatment in ΔMBCI (11.1 [2.81, 43.08] vs 0.00 [??8.16, 10.47], P?=?0.017), ΔLNΔI30/ΔG30 (0.44 [0.04, 0.85] vs ??0.09 [??0.33, 0.36], P?=?0.049), ΔAUCins (117 [??8, 376] vs ??21 [??314, 109] mIU/L, P?=?0.013), ΔP/I (??0.05 [??0.09, ??0.03] vs ??0.02 [??0.04, 0.01], P?=?0.026)were remarkably enhanced compared to those of the metformin therapy. The expression of 8-OH-dG, 8-iso-PGF_2α and hs-CRP also decreased after 8-week metformin treatment.

Conclusions

These data demonstrated that liraglutide administration was more effective on ameliorating beta-cell function than metformin treatment in young patients with new-onset type 2 diabetes mellitus. Both liraglutide and metformin could alleviate the level of oxidative stress and attenuate low grade inflammatory, we speculate this effect may not the main mechanism of beta-cell function improvement by liraglutide in diabetic patients.Trial registration Chinese Clinical Trials registry, chiCTR1800018008, Registered 27 August 2018—retrospectively registered.

     

Liraglutide and sitagliptin have no effect on intestinal microbiota composition: A 12-week randomized placebo-controlled trial in adults with type 2 diabetes

AimPreclinical data suggest that treatment with either glucagon-like peptide (GLP)-1 receptor agonists or dipeptidyl peptidase (DPP)-4 inhibitors could change the intestinal microbiome and thereby contribute to their beneficial (cardio)metabolic effects. Therefore, our study aimed to investigate the effects of these agents on microbiota composition in adults with type 2 diabetes (T2D).MethodsA total of 51 adults with T2D (mean ± SD: age 62.8 ± 6.9 years, BMI 31.8 ± 4.1 kg/m², HbA_1c 7.3 ± 0.6%) treated with metformin and/or sulphonylureas were included in the 12-week randomized, double-blind trial. Patients were given the GLP-1 receptor agonist liraglutide (1.8 mg sc) or the DPP-4 inhibitor sitagliptin (100 mg), or matching placebos, once daily for 12 weeks. Faecal samples were collected at baseline and at 12 weeks after the start of the intervention. Microbiota analyses were performed by 16S rRNA gene-sequencing analysis. Bile acids were measured in faeces and plasma.ResultsLiraglutide decreased HbA_1c by 1.3% (95% CI: -1.7 to -0.9) and tended to reduce body weight (-1.7 kg, 95% CI: -3.6 to 0.3), but increased faecal secondary bile acid deoxycholic acid. Sitagliptin lowered HbA_1c by 0.8% (95% CI: -1.4 to -0.4) while body weight remained stable (-0.8 kg, 95% CI: -2.7 to 1.0), but increased faecal levels of cholic acid, chenodeoxycholic acid and ursodeoxycholic acid. However, neither liraglutide nor sitagliptin affected either alpha or beta diversity of the intestinal microbiota, nor were changes in microbial composition related to clinical parameters.ConclusionThese data suggest that the beneficial effects of liraglutide and sitagliptin on glucose metabolism, body weight and bile acids, when used as add-on therapies to metformin or sulphonylureas, are not linked to changes in the intestinal microbiota (NCT01744236).     

Efficacy and safety over 26 weeks of an oral treatment strategy including sitagliptin compared with an injectable treatment strategy with liraglutide in patients with type 2 diabetes mellitus inadequately controlled on metformin: a randomised clinical trial

Aims/hypothesis

The aim of this work was to compare treatment intensification strategies based on orally administered vs injectable incretin-based antihyperglycaemic agents in patients with type 2 diabetes mellitus on metformin monotherapy.

Methods

In a 26 week, open-label study, 653 patients (baseline HbA_1c?=?8.2% [66 mmol/mol]) were randomised at 111 sites in 21 countries in a 1:1 ratio to a strategy using oral agents (starting with sitagliptin 100 mg/day) or a strategy using the injectable drug liraglutide starting at a dose of 0.6 mg/day, up-titrated to 1.2 mg/day after 1 week. The following patients with type 2 diabetes mellitus were recruited for the study: those aged 18–79 years, on a stable dose of metformin monotherapy ≥1,500 mg/day for ≥12 weeks, with an HbA_1c ≥7.0% (53 mmol/mol) and ≤11.0% (97 mmol/mol) and a fasting fingerstick glucose (FFG) <15 mmol/l (<270 mg/dl) at the randomisation visit, deemed capable by the investigator of using a Victoza pen injection device (containing 6 mg/ml liraglutide; Novo Nordisk, Bagsværd, Denmark). Women taking part in the study agreed to remain abstinent or use an acceptable method of birth control during the study. Randomisation was performed via a computer-generated allocation schedule using an interactive voice response system. After 12 weeks, patients on sitagliptin with HbA_1c ?≥?7.0% (53 mmol/mol) and fasting glucose >6.1 mmol/l had their treatment intensified with glimepiride; patients on liraglutide with HbA_1c ?≥?7.0% (53 mmol/mol) had the dose up-titrated to 1.8 mg/day. The primary analysis assessed whether the strategy using oral drugs was non-inferior to that using an injectable drug regarding HbA_1c change from baseline at week 26 using a per-protocol (PP) population and a non-inferiority margin of 0.4%.

Results

In the PP population (522 patients included: oral strategy, n?=?269; injectable strategy, n?=?253) antihyperglycaemic therapy was intensified at week 12 in 50.2% and 28.5%, respectively. HbA_1c decreased over 26 weeks in both treatment strategy groups, with a larger initial reduction at week 12 in the injectable strategy group. The LS mean change in HbA_1c at week 26 was ?1.3% (95% CI ?1.4, ?1.2) in the oral strategy group and ?1.4% (95% CI ?1.5, ?1.3) in the injectable strategy group; the study met the non-inferiority criterion. Both treatment regimens were generally well tolerated; hypoglycaemia was reported more often with the oral strategy, while nausea, vomiting, diarrhoea and abdominal pain were reported more often with the injectable strategy.

Conclusions/interpretation

An oral, incretin-based treatment strategy with sitagliptin and, if needed, glimepiride may be a good approach in many patients with type 2 diabetes mellitus for managing inadequate glycaemic control on metformin monotherapy, as compared with an injectable treatment strategy with liraglutide. The oral and injectable strategies had similar effects on HbA_1c and had good overall tolerability. Trial registration ClinicalTrials.gov NCT01296412 Funding The study was sponsored by Merck Sharp & Dohme Corp., a subsidiary of Merck and Co., Inc., Whitehouse Station, NJ, USA.     

2型糖尿病患者应用利拉鲁肽的疗效和安全性系统评价

目的系统评价利拉鲁肽对2型糖尿病患者的疗效和安全性。方法计算机检索MEDLINE、Cochrane图书馆临床对照试验资料库、中国生物医学文献数据库（CBM）、中国知识基础设施工程（CNKI）、万方等数据库,同时筛查纳入文献的参考文献,按纳入与排除标准纳入利拉鲁肽治疗2型糖尿病的随机对照试验。由两名评价员独立评价文献质量、提取资料并交叉核对,而后采用RevMan5．0软件进行荟萃分析。结果共纳入16项临床试验,包括4745例2型糖尿病患者。荟萃分析结果显示：（1）利拉鲁肽组糖化血红蛋白（HbAlC）达标率显著高于磺脲类药物组[RR=2．50,95％CI（1．39,4．47）,P〈0．01],西格列汀组[RR=2．38,95％CI（1．97,2．88）,P〈0．01]和安慰剂组[RR=8．83,95％C1（4．02,19．36）,P〈0．01],差异有统计学意义（P〈0．01）,但利拉鲁肽联用VI服降糖药组与对照组比较差异无统计学意义（P〉0．05）。（2）利拉鲁肽组胰岛13细胞功能指数（HOMA-13）显著高于对照组,差异有统计学意义[加权均数差（WMD）=25．34,95％CI（18．51,32．18）,P〈0．01]。（3）利拉鲁肽组胃肠道不良反应发生率显著高于磺脲类药物组[RR=1．83,95％C1（1．49,2．24）,P〈0．01]及口服降糖药联用组[RR=2．76,95％CI（2．25,3．40）,P〈0．01],差异有统计学意义（P〈0．01）。（4）利拉鲁肽组严重不良反应发生率与其他组比较差异均无统计学意义（P〉0．05）。结论现有证据表明利拉鲁肽降糖疗效优于口服降糖药,胃肠道不良反应是其主要副作用,应密切关注严重不良事件。     

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

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

Sitagliptin: a novel drug for the treatment of type 2 diabetes

Type 2 diabetes mellitus is a common chronic disease that causes significant morbidity and mortality worldwide. The primary goal of treatment is to target glycemic control by maintaining the glycosylated hemoglobin level near 6-7% without predisposing patients to hypoglycemia. Diabetes results from a combination of increased hepatic glucose production, decreased insulin secretion from beta cells, and insulin resistance in the peripheral tissues. Currently available antidiabetic agents work by different mechanisms to lower blood glucose levels. Unfortunately, each of them has its tolerability and safety concerns that limit its use and dose titration. Sitagliptin is the first antidiabetic agent from the class of dipeptidyl peptidase-4 enzyme inhibitors. It increases the amount of circulating incretins, which stimulate insulin secretion and inhibit glucose production. Sitagliptin was approved by the US Food and Drug Administration (FDA) for use with diet and exercise to improve glycemic control in adult patients with type 2 diabetes. It can be used alone or in combination with metformin or a thiazolidinedione (pioglitazone or rosiglitazone) when treatment with either drug alone provides inadequate glucose control. The usual adult dose is 100 mg once daily. A dose of 25-50 mg once daily is recommended for patients with moderate-to-severe renal impairment. In randomized, placebo-controlled trials that lasted for up to 6 months, sitagliptin lowered glycosylated hemoglobin levels by 0.5-0.8%. In a 52-week clinical trial, sitagliptin was shown to be noninferior to glipizide as an add-on agent in patients inadequately controlled on metformin alone. Sitagliptin was well tolerated with the most common side effects being gastrointestinal complaints (up to 16%), including abdominal pain, nausea and diarrhea; hypoglycemia and body weight gain occurred at similar rates compared with placebo. Overall, sitagliptin provides a treatment option for patients with type 2 diabetes as a monotherapy, or as an adjunct to metformin or a thiazolidinedione when patients achieve inadequate glycemic control while on either of the agents. It is also an alternative therapy for those patients who have contraindications or intolerability to other antidiabetic agents.     

Hyperglycemia induced by pasireotide in patients with Cushing’s disease or acromegaly

Purpose

Cushing’s disease (CD) and acromegaly are characterized by excessive hormone secretion resulting in comorbidities such as impaired glucose metabolism, diabetes and hypertension. Pasireotide is a new-generation, multireceptor-targeted somatostatin receptor ligand approved for CD (subcutaneous [SC] injection formulation) and acromegaly (long-acting release [LAR] formulation). In clinical studies of pasireotide, hyperglycemia-related adverse events (AEs) were frequently observed. This review highlights differences in reported rates of hyperglycemia in pasireotide trials and discusses risk factors for and management of pasireotide-associated hyperglycemia.

Methods

Clinical trials evaluating pasireotide in patients with CD or acromegaly were reviewed.

Results

The frequency of hyperglycemia-related AEs was lower in patients with acromegaly treated with pasireotide LAR (57.3–67.0 %) than in patients with CD treated with pasireotide SC (68.4–73.0 %). Fewer patients with acromegaly treated with pasireotide LAR discontinued therapy because of hyperglycemia-related AEs (Colao et al. in J Clin Endocrinol Metab 99(3):791–799, 2014, 3.4 %; Gadelha et al. in Lancet Diabetes Endocrinol 2(11):875–884, 2014, 4.0 %) than did patients with CD treated with pasireotide SC (Boscaro et al. in Pituitary 17(4):320–326, 2014, 5.3 %; Colao et al. in N Engl J Med 366(10):914–924, 2012, 6.0 %). Hyperglycemia-related AEs occurred in 40.0 % of patients with acromegaly treated with pasireotide SC, and 10.0 % discontinued treatment because of hyperglycemia. Ongoing studies evaluating pasireotide LAR in patients with CD and management of pasireotide-induced hyperglycemia in patients with CD or acromegaly (ClinicalTrials.gov identifiers NCT01374906 and NCT02060383, respectively) will address these key safety issues.

Conclusions

Disease pathophysiology, drug formulation, and physician experience potentially influence the differences in reported rates of pasireotide-induced hyperglycemia in CD and acromegaly. Hyperglycemic effects associated with pasireotide have a predictable pattern, can be managed with antidiabetic agents, and are reversible upon discontinuation.

     

Short‐ and long‐term effect of sitagliptin after near normalization of glycemic control with insulin in poorly controlled Japanese type 2 diabetic patients

Aims/Introduction

The aim of the present study was to examine the short‐ and long‐term effect of sitagliptin on glucose tolerance after near normalization of glycemic control with insulin in poorly controlled type 2 diabetic patients.

Materials and Methods

We consecutively enrolled a total of 30 type 2 diabetic patients whose glycated hemoglobin levels (National Glycohemoglobin Standardization Program) were ≥7.4%, stopped all oral antidiabetic drugs and started insulin therapy. When fasting plasma glucose levels became <140 mg/dL, we carried out the first oral glucose tolerance test (OGTT). After 1‐week sitagliptin treatment (50 mg/day), the second OGTT was carried out. Furthermore, we evaluated the long‐term efficacy of sitagliptin on glucose tolerance after near normalization of glycemic control with insulin.

Results

After 1‐week sitagliptin treatment, the area under the curve of insulin was markedly increased, and the area under the curve of glucagon and glucose was markedly decreased. Duration of diabetes and insulin secretory capacity were correlated with the effect of sitagliptin. Furthermore, interestingly, near normalization of glycemic control with insulin therapy for 1–2 weeks brought out the long‐term effectiveness of sitagliptin on glucose tolerance for 24 weeks, which was not observed with other antidiabetic drugs.

Conclusions

These findings suggest that near normalization of glycemic control with insulin improves the clinical response to sitagliptin in poorly controlled type 2 diabetic patients.     

Efficacy of liraglutide as a follow-up therapy after resolution of glucotoxicity with intensive insulin therapy

ObjectiveTo assess the utility of liraglutide, a GLP-1 receptor agonist, as additional therapy following resolution of glucotoxicity with insulin therapy.MethodsThe subjects were 13 Japanese patients with short-duration type 2 diabetes mellitus (2.0 ± 2.1 years). At first, treatment with insulin therapy consisted of bolus insulin before each meal and basal insulin at bed time commenced to improve every preprandial glucose levels below 130 mg/dL. Then, insulin therapy was replaced with liraglutide monotherapy in case in which 50% or more self-monitoring of blood glucose (SMBG) tests revealed preprandial glucose levels of less than 130 mg/dL at least for one month. Liraglutide dosing was initiated at 0.3 mg/day and increased in weekly or biweekly increments of 0.3 mg/day, to the maximum permissible dose (in Japan) of 0.9 mg/day. The participants were treated with liraglutide for 24 weeks.ResultsThe average insulin therapy period was 13.2 ± 5.4 weeks, and insulin therapy significantly improved HbA1c values from 12.4% ± 1.6% to 6.8% ± 0.9% (P < 0.05). After improvement of hyperglycemia with insulin therapy and switching to liraglutide monotherapy for 24 weeks, HbA1c values remained constant (6.2% ± 1.0% at week 24) and the rates of hypoglycemic episodes significantly decreased (P < 0.05).ConclusionsThese data suggest that liraglutide is proposed as an alternative follow-up therapy subsequent to eliminate glucotoxicity with insulin therapy.     

Sitagliptin for prevention of stress hyperglycemia in patients without diabetes undergoing general surgery: A pilot randomized study

Aim

We investigated if a dipeptidyl peptidase-4 inhibitor, sitagliptin, can prevent perioperative stress hyperglycemia in patients without prior history of diabetes mellitus undergoing general surgery.

Postpartum treatment with liraglutide in combination with metformin versus metformin monotherapy to improve metabolic status and reduce body weight in overweight/obese women with recent gestational diabetes: A double-blind,randomized, placebo-controlled study

BackgroundGestational diabetes (GDM) imparts a high risk of developing diabetes postpartum. Insulin resistance appears to be the major contributor. Liraglutide, a glucagon-like peptide-1 analogue, improves peripheral glucose disposal and reduces body weight. We evaluated whether liraglutide in combination with metformin (MET-LIRA) is more effective than metformin monotherapy (MET-P) in improving insulin action and reducing body weight in overweight prior GDM (pGDM) women.MethodsWomen (n = 153; body mass index (BMI) ≥25 kg/m²; 18–45 y; GDM within 12 months) with metabolic abnormalities were randomized to MET-LIRA (MET-2000 mg, LIRA 1.8 mg SC QD) or MET-P (MET-2000 mg, Placebo QD). Study visits at baseline, 36–40, 56–60 and 80–84 weeks included body weight (BW), BMI, waist circumference and waist-to-height ratio measures. Oral glucose tolerance tests (OGTTs) were performed to assess glycemia, mean blood glucose (MBG), lipids, and compute insulin sensitivity and secretion measures.FindingsSeventy-two (47%) participants completed the study. MET-LIRA therapy was significantly better in improving MBG and insulin sensitivity indices [SI_OGTT MET-LIRA from 4.6 (3.2) to 5.9 (2.9) vs. MET-P 5.5 (3.0) to 5.4 (3.2)] and reducing BW and central adiposity [BMI MET-LIRA from 37.2 (8.3) to 33.8 (5.2) vs MET-P 33.8(5.2) to 32.8(6)]. MET–LIRA therapy but not MET-P decreased triglycerides (TRG) and TRG/high density lipoprotein cholesterol (HDL-C) ratios.InterpretationMET-LIRA treatment demonstrated superior efficacy in correcting the metabolic status of pGDM women over 84 weeks of therapy. The addition of liraglutide to metformin therapy resulted in a more dramatic decrease in BW and central adiposity than metformin alone.FundationSupported by an unrestricted investigator initiated grant from Novo Nordisk, Inc. awarded to K.E.H.Meeting presentationThe results from preliminary analyses of this study were presented at 76th meeting of the American Diabetes Association, June 10–14, 2016 New Orleans, LA, and 77th meeting of the American Diabetes Association, June 9–12, 2017San Diego, CA.     

DPP-4 inhibitors and GLP-1 analogues: for whom? Which place for incretins in the management of type 2 diabetic patients?

This review tries to delineate how to insert the GLP-1 based agents, DPP4-inhibitors (sitagliptin and vildagliptin) and GLP-1 analogues (exenatide and liraglutide), in the guidelines and the daily practice for the management of type 2 diabetes (T2DM). Orally administered DPP-4 inhibitors reduce HbA(1c) by 0.5-1.1%, without hypoglycaemic events and no weight gain. The subcutaneous injected GLP-1 analogues show larger reductions in HbA(1c) by 0.8-1.7% and a weight loss (1.75-3.8 kg) with most gastrointestinal common adverse events contributing to a significant treatment interruption. Regarding the efficacy, the cost and the safety of these drugs they will no challenge the use of metformin as the initial therapy of T2DM. In patients'not tolerating metformin or in older patients, DPP-4 inhibitors seem to be an excellent alternative monotherapy. Several studies argue in favour of the use of DPP-4 inhibitors in combination with metformin as a promising second line treatment. This combination offers advantages when compared to others currently used, particularly if one considers the more stringent guidelines with a higher risk of hypoglycaemic events in patient receiving sulfonylureas and mild hyperglycaemia or weight gain with thiazolidinedione (TZD). Oral triple therapy, metformin + TZD + incretin-based drug, has several theoretical advantages but is not supported by any published trial. Finally, obtaining the acceptance of injections once to twice daily vs. oral administration of OADs will probably remain difficult during the first years of treatment in many patients. Nevertheless a long-acting release exenatide formulation (i.e. once weekly), for subcutaneous injection in patients with type 2 diabetes under development shows promising preliminary results. If confirmed, the use of this new class of drugs should be largely developed from monotherapy to combinations (bitherapy or tritherapy), and even instead of insulin or in association with insulin. The long-term effect of GLP-1 based agents on glycaemic control has not yet been established, and their potential impact on beta-cell function in humans remains an area of active investigation. So, further studies are required and will allow progressively determining the use of incretin-based agents in T2DM treatment strategy. Their efficacy, safety and their cost vs. older strategies, will be really evaluated by physicians in the real daily practice and by large and long term systematic surveys, as recently shown in other therapeutic fields.     

The design of the liraglutide clinical trial programme

Liraglutide is a once-daily human glucagon-like peptide-1 analogue used in the treatment of type 2 diabetes (T2D). It has been prospectively investigated in a series of multinational, randomised, controlled phase 3 trials (the Liraglutide Effect and Action in Diabetes programme), as well as in an additional direct head-to-head study with sitagliptin. These trials were designed to clarify the use and safety of liraglutide in clinical practice across the treatment continuum of T2D, and consequently involved a large number and diverse range of patients. These studies also included active comparisons against antidiabetic agents including metformin, rosiglitazone, glimepiride, insulin glargine, exenatide and sitagliptin, and therefore have helped to examine clinical differences and similarities between liraglutide and these commonly used agents.     

Safety and efficacy of the combination of the glucagon‐like peptide‐1 receptor agonist liraglutide with an oral antidiabetic drug in Japanese patients with type 2 diabetes: Post‐hoc analysis of a randomized, 52‐week,open‐label,parallel‐group trial

Aims/Introduction

The aim of the present post‐hoc analysis was to investigate the safety and efficacy of liraglutide in combination with one oral antidiabetic drug (OAD) across different OAD classes.

Materials and Methods

This was a post‐hoc analysis using data from a 52‐week, open‐label, parallel‐group trial, in which patients with type 2 diabetes inadequately controlled with a single OAD (α‐glucosidase inhibitor, glinide, metformin or thiazolidinedione) were randomized to either pretrial OAD in combination with liraglutide 0.9 mg/day (liraglutide group) or pretrial OAD in combination with an additional OAD (additional OAD group). The primary outcome investigated in this post‐hoc analysis was the incidence of adverse events.

Results

The proportions of patients experiencing adverse events across the different groups of pretrial OADs were comparable between liraglutide and additional OAD (α‐glucosidase inhibitor 74.6 vs 70.0%; glinide 93.1 vs 87.1%; metformin 91.8 vs 87.1%; thiazolidinedione 86.2 vs 96.4%, respectively). Minor hypoglycemia was infrequent (seven episodes in two patients randomized to liraglutide, and two episodes in two patients randomized to additional OAD). The mean reduction in glycated hemoglobin appeared greater with liraglutide therapy, with the estimated mean treatment difference (95% confidence interval [CI]) for liraglutide vs additional OAD ranging from ?0.14%, 95% CI: ?0.48 to 0.21 (?1.5 mmol/mol, 95 CI: ?5.2 to 2.3) to ?0.44%, 95% CI:?0.79 to ?0.09 (?4.8 mmol/mol, 95% CI: ?8.6 to ?1.0).

Conclusions

The present analysis suggests that Japanese patients on OAD monotherapy might benefit from a greater improvement in glycemic control, without impacting tolerability, by combining their OAD with liraglutide rather than another OAD, regardless of which OAD monotherapy they are receiving.

     

利拉鲁肽和西格列汀对超重和肥胖2型糖尿病患者的疗效和安全性比较

目的 比较利拉鲁肽和西格列汀与二甲双胍联合应用时对超重和肥胖的2型糖尿病患者疗效和安全性.方法 选取2012年4月至10月住院的体质指数（BMI）＞25 kg/m2的2型糖尿病患者86例,按随机数字表法分为利拉鲁肽治疗组（40例）和西格列汀治疗组（46例）,于用药前、用药4周、12周和24周后分别测定患者的空腹静脉血糖（FPG）、餐后2h血糖（PPG）、糖化血红蛋白（HbA1c）、体重、腰围、血压、甘油三酯（TG）、总胆固醇（TC）、高密度脂蛋白胆固醇（HDL-C）、低密度脂蛋白胆固醇（LDL-C）、肝功能、肾功能、24 h尿微量白蛋白（UMA）.记录用药期间的低血糖发生情况和其他不良反应.采用t检验和重复测量资料方差分析进行数据分析.结果 （1）两组患者的血糖和HbA1c在治疗后均出现下降,但两组间差别无统计学意义（均P＞0.05）.（2）利拉鲁肽组患者用药24周后体重较用药前下降[（80±7）比（85 ±8）kg,t=2.9,P＜0.05],西格列汀组患者用药24周后体重较用药前下降[（82±7）比（84±7） kg,t =2.78,P＜0.05];用药24周后两组间差别有统计学意义[（80±7）比（82 ±7） kg,t=-3.5,P＜0.05].（3）利拉鲁肽组患者用药24周后较用药前腰围下降[分别为（101±7）比（106±8）cm,t =13.35,P＜0.05],西格列汀组用药24周后腰围较用药前减少[分别为（102 ±6）比（105 ±6） cm,t =3.3,P＜0.05],用药24周后两组间差别有统计学意义[（101±7）比（102±6）cm,t=-3.1,P＜0.05].（4）利拉鲁肽组患者用药24周后收缩压较用药前下降[（138±7）比（143±6） mmHg,1 mmHg=0.133 kPa,=3.69,P＜0.05],西格列汀组用药24周后较用药前收缩压下降[（139±4）比（141 ±5） mmHg,t=2.8,P＜0.05],用药24周后两组间差异有统计学意义[（138±7）比（139 ±4） mm Hg,t=-3.0,P＜0.05];利拉鲁肽组患者用药4周后较用药前舒张压下降[（89±2）比（93±2）mmHg,t=2.6,P＜0.05],西格列汀组用药24周后较用药前舒张压下降[（89±3）比（92±3）mmHg,t=3.5,P＜0.05],两组间差异无统计学意义（P＞0.05）.（5）利拉鲁肽组患者的上消化道不良反应多于西格列汀组,差异具有统计学意义（30.0％比4.3％,t=2.86,P＜0.05）.结论 利拉鲁肽联合二甲双胍与西格列汀联合二甲双胍降低超重和肥胖的2型糖尿病患者的即时血糖和HbA1c的能力相同,利拉鲁肽能够更有效地降低患者体重、腰围和血压,西格列汀具有良好的安全性.     

Effects of a fixed-dose combination of sitagliptin and metformin versus respective monotherapies in newly diagnosed type 2 diabetic subjects

Metformin is considered as a backbone therapy for type 2 diabetes (T2DM) management. Many patients need treatment with combination therapy. In India, multiple fixed-dose combinations with metformin are available. The study was done to compare the efficacy and safety of sitagliptin plus metformin combination versus metformin and sitagliptin monotherapy in newly diagnosed T2DM subjects. This was an open-label, randomized, parallel group, prospective and single centre study, in 60 subjects with T2DM. The subjects received either metformin 500 mg, sitagliptin 50 mg or fixed-dose combination of metformin 500 mg plus sitagliptin 50 mg. All study medicines were given twice daily for 12 weeks. Glycaemic control (HbA1c, fasting and postprandial blood glucose) and body mass index (BMI) were evaluated as efficacy parameters while safety was evaluated by reporting adverse events. Significant reduction in HbA1C level was seen in all three groups (P?=?0.0001). HbA1C reduction was significantly higher in the combination group compared to metformin monotherapy (P?=?0.0072). Fasting blood glucose (FBG) level reduced significantly in all three groups (P?=?0.0001). The reduction in fasting blood glucose was significantly higher with combination compared to sitagliptin monotherapy (P?=?0.0060). Postprandial blood glucose (PPG) also reduced significantly in all three groups (P?=?0.0001). The reduction with sitagliptin was statistically higher compared to metformin (P?=?0.0155). The combination treatment resulted in significantly higher reduction of PPG compared to sitagliptin monotherapy (P?=?0.0160). Body mass index reduced significantly in all three groups (P?=?0.0001). Reduction in BMI was significant with combination treatment compared to sitagliptin monotherapy (P?<?0.05). Overall, study medications were well tolerated. The incidence of adverse event was 11.7 %. No serious adverse event was reported in the study. In newly diagnosed, drug naïve, type 2 diabetes mellitus management, fixed-dose combination of sitagliptin plus metformin is effective and well tolerated. Due to its multiple benefits, it can be used as a suitable option for selected subjects requiring combination therapy in type 2 diabetes mellitus.     

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

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