Eduard Montanya

Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6)

BACKGROUND Unlike most antihyperglycaemic drugs, glucagon-like peptide-1 (GLP-1) receptor agonists have a glucose-dependent action and promote weight loss. We compared the efficacy and safety of liraglutide, a human GLP-1 analogue, with exenatide, an exendin-based GLP-1 receptor agonist. METHODS Adults with inadequately controlled type 2 diabetes on maximally tolerated doses of metformin, sulphonylurea, or both, were stratified by previous oral antidiabetic therapy and randomly assigned to receive additional liraglutide 1.8 mg once a day (n=233) or exenatide 10 microg twice a day (n=231) in a 26-week open-label, parallel-group, multinational (15 countries) study. The primary outcome was change in glycosylated haemoglobin (HbA(1c)). Efficacy analyses were by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00518882. FINDINGS Mean baseline HbA(1c) for the study population was 8.2%. Liraglutide reduced mean HbA(1c) significantly more than did exenatide (-1.12% [SE 0.08] vs -0.79% [0.08]; estimated treatment difference -0.33; 95% CI -0.47 to -0.18; p<0.0001) and more patients achieved a HbA(1c) value of less than 7% (54%vs 43%, respectively; odds ratio 2.02; 95% CI 1.31 to 3.11; p=0.0015). Liraglutide reduced mean fasting plasma glucose more than did exenatide (-1.61 mmol/L [SE 0.20] vs -0.60 mmol/L [0.20]; estimated treatment difference -1.01 mmol/L; 95% CI -1.37 to -0.65; p<0.0001) but postprandial glucose control was less effective after breakfast and dinner. Both drugs promoted similar weight losses (liraglutide -3.24 kg vs exenatide -2.87 kg). Both drugs were well tolerated, but nausea was less persistent (estimated treatment rate ratio 0.448, p<0.0001) and minor hypoglycaemia less frequent with liraglutide than with exenatide (1.93 vs 2.60 events per patient per year; rate ratio 0.55; 95% CI 0.34 to 0.88; p=0.0131; 25.5%vs 33.6% had minor hypoglycaemia). Two patients taking both exenatide and a sulphonylurea had a major hypoglycaemic episode. INTERPRETATION Liraglutide once a day provided significantly greater improvements in glycaemic control than did exenatide twice a day, and was generally better tolerated. The results suggest that liraglutide might be a treatment option for type 2 diabetes, especially when weight loss and risk of hypoglycaemia are major considerations. FUNDING Novo Nordisk A/S.

A map of open chromatin in human pancreatic islets

Tissue-specific transcriptional regulation is central to human disease. To identify regulatory DNA active in human pancreatic islets, we profiled chromatin by formaldehyde-assisted isolation of regulatory elements coupled with high-throughput sequencing (FAIRE-seq). We identified ∼80,000 open chromatin sites. Comparison of FAIRE-seq data from islets to that from five non-islet cell lines revealed ∼3,300 physically linked clusters of islet-selective open chromatin sites, which typically encompassed single genes that have islet-specific expression. We mapped sequence variants to open chromatin sites and found that rs7903146, a TCF7L2 intronic variant strongly associated with type 2 diabetes, is located in islet-selective open chromatin. We found that human islet samples heterozygous for rs7903146 showed allelic imbalance in islet FAIRE signals and that the variant alters enhancer activity, indicating that genetic variation at this locus acts in cis with local chromatin and regulatory changes. These findings illuminate the tissue-specific organization of cis-regulatory elements and show that FAIRE-seq can guide the identification of regulatory variants underlying disease susceptibility.

One year of liraglutide treatment offers sustained and more effective glycaemic control and weight reduction compared with sitagliptin, both in combination with metformin, in patients with type 2 diabetes: a randomised, parallel-group, open-label trial

Aim:  The aim of this study was to compare the efficacy and safety of once‐daily human glucagon‐like peptide‐1 analogue liraglutide with dipeptidyl peptidase‐4 inhibitor sitagliptin, each added to metformin, over 52 weeks in individuals with type 2 diabetes.

Switching to Once-Daily Liraglutide From Twice-Daily Exenatide Further Improves Glycemic Control in Patients With Type 2 Diabetes Using Oral Agents

OBJECTIVE To evaluate efficacy and safety of switching from twice-daily exenatide to once-daily liraglutide or of 40 weeks of continuous liraglutide therapy. RESEARCH DESIGN AND METHODS When added to oral antidiabetes drugs in a 26-week randomized trial (Liraglutide Effect and Action in Diabetes [LEAD]-6), liraglutide more effectively improved A1C, fasting plasma glucose, and the homeostasis model of β-cell function (HOMA-B) than exenatide, with less persistent nausea and hypoglycemia. In this 14-week extension of LEAD-6, patients switched from 10 μg twice-daily exenatide to 1.8 mg once-daily liraglutide or continued liraglutide. RESULTS Switching from exenatide to liraglutide further and significantly reduced A1C (0.32%), fasting plasma glucose (0.9 mmol/l), body weight (0.9 kg), and systolic blood pressure (3.8 mmHg) with minimal minor hypoglycemia (1.30 episodes/patient-year) or nausea (3.2%). Among patients continuing liraglutide, further significant decreases in body weight (0.4 kg) and systolic blood pressure (2.2 mmHg) occurred with 0.74 episodes/patient-year of minor hypoglycemia and 1.5% experiencing nausea. CONCLUSIONS Conversion from exenatide to liraglutide is well tolerated and provides additional glycemic control and cardiometabolic benefits.

A Review of Efficacy and Safety Data Regarding the Use of Liraglutide, a Once-Daily Human Glucagon-Like Peptide 1 Analogue, in the Treatment of Type 2 Diabetes Mellitus

BACKGROUND Liraglutide, a human glucagon-like peptide 1 (GLP-1) analogue that has received marketing approval from the European Commission, is a treatment for type 2 diabetes mellitus (DM) that is administered as a once-daily subcutaneous injection. OBJECTIVE The aim of this review was to summarize the efficacy and safety data published about liraglutide, focusing on data from Phase III clinical trials. METHODS Relevant English-language publications were identified through a search of MEDLINE and EMBASE (from 1948 to October 2009). The search terms included the following: GLP-1, incretin effect, liraglutide, NN2211, exenatide, sitagliptin, and vildagliptin. Original research papers about liraglutide that were published in peer-reviewed journals were considered. RESULTS The literature search identified 39 relevant publications. The efficacy and tolerability of oncedaily liraglutide at doses of 0.6, 1.2, and 1.8 mg for type 2 DM, in combination with, and compared with, other type 2 DM treatments were investigated in the Liraglutide Effect and Action in Diabetes (LEAD) Phase III clinical trial program. In the LEAD studies, consistent reductions in glycosylated hemoglobin (HbA(1c)) of up to 1.6% were seen with liraglutide, and up to 66% of patients achieved the HbA(1c) goal of <7%. Fasting and postprandial plasma glucose levels were also consistently reduced across the LEAD trials by up to 43 mg/dL (2.4 mmol/L) and 49 mg/dL (2.7 mmol/L), respectively. Hypoglycemia was reported at a rate of 0.03 to 1.9 events per patient annually. Liraglutide significantly improved beta-cell function, as measured by homeostasis model assessment for beta-cell function analysis (20%-44%) and by ratios of pro-insulin to insulin (-0.11 to 0.01). Consistent reductions in systolic blood pressure up to 6.7 mm Hg were also observed for liraglutide treatment. Liraglutide treatment, as monotherapy and in combination with oral antidiabetic drugs (OADs), was associated with weight loss of up to 3.24 kg. Overall, liraglutide was well tolerated. Nausea was the most common adverse event observed with liraglutide treatment, reported by 5% to 29% of patients; however, nausea was generally mild and transient. CONCLUSION Once-daily liraglutide was effective and well tolerated when used as monotherapy or in combination with OADs in patients with type 2 DM, and is therefore a promising new treatment option for the management of type 2 DM.

Efficacy and Safety of Switching From the DPP-4 Inhibitor Sitagliptin to the Human GLP-1 Analog Liraglutide After 52 Weeks in Metformin-Treated Patients With Type 2 Diabetes: A randomized, open-label trial

OBJECTIVE To assess the efficacy and safety of switching from sitagliptin to liraglutide in metformin-treated adults with type 2 diabetes. RESEARCH DESIGN AND METHODS In an open-label trial, participants randomized to receive either liraglutide (1.2 or 1.8 mg/day) or sitagliptin (100 mg/day), each added to metformin, continued treatment for 52 weeks. In a 26-week extension, sitagliptin-treated participants were randomly allocated to receive instead liraglutide at either 1.2 or 1.8 mg/day, while participants originally randomized to receive liraglutide continued unchanged. RESULTS Although 52 weeks of sitagliptin changed glycosylated hemoglobin (HbA1c) by −0.9% from baseline, additional decreases occurred after switching to liraglutide (1.2 mg/day, −0.2%, P = 0.006; 1.8 mg/day, −0.5%, P = 0.0001). Conversion to liraglutide was associated with reductions in fasting plasma glucose (FPG) (1.2 mg/day, −0.8 mmol/L, P = 0.0004; 1.8 mg/day, −1.4 mmol/L, P < 0.0001) and body weight (1.2 mg/day, −1.6 kg; 1.8 mg/day, −2.5 kg; both P < 0.0001) and with an increased proportion of patients reaching HbA1c <7% (from ∼30% to ∼50%). Overall treatment satisfaction, assessed by the Diabetes Treatment Satisfaction Questionnaire, improved after switching to liraglutide (pooled 1.2 and 1.8 mg/day, 1.3; P = 0.0189). After switching, mostly transient nausea occurred in 21% of participants, and minor hypoglycemia remained low (3–4% of participants). Continuing liraglutide treatment at 1.2 mg/day and 1.8 mg/day for 78 weeks reduced HbA1c (baseline 8.3 and 8.4%, respectively) by −0.9 and −1.3%, respectively; FPG by −1.3 and −1.7 mmol/L, respectively; and weight by −2.6 and −3.1 kg, respectively, with 9–10% of participants reporting minor hypoglycemia. CONCLUSIONS Glycemic control, weight, and treatment satisfaction improved after switching from sitagliptin to liraglutide, albeit with a transient increase in gastrointestinal reactions.

Improved outcome of islet transplantation in insulin-treated diabetic mice : effects on beta-cell mass and function

Summary Insulin treatment may improve the outcome of islet transplantation. To determine the effects of insulin treatment on transplanted islets, 4 groups of streptozotocin-diabetic C57BL/6 mice were transplanted with 100 islets, an insufficient beta-cell mass to restore normoglycaemia. Groups 1 (n = 12) and 2 (n = 12), were kept normoglycaemic with insulin treatment from day 10 before transplantation to day 14 after transplantation; groups 3 (n = 12) and 4 (n = 18), were not treated with insulin. Grafts were harvested 14 (groups 1 and 3) or 60 (groups 2 and 4) days after transplantation and beta-cell mass and replication were measured. When insulin was discontinued all mice maintained normoglycaemia; in contrast, non-insulin-treated groups remained hyperglycaemic throughout the study. Fourteen days after transplantation the beta-cell mass was reduced both in group 1 (0.09 ± 0.01 mg) and group 3 (0.14 ± 0.02 mg) compared to the initially transplanted mass (0.22 ± 0.02 mg, p < 0.01); beta-cell replication and area did not change in group 1, but were increased in group 3. Insulin content, expressed as a function of beta-cell mass, was maintained in group 1 grafts (12.5 ± 2.0 μg/mg), but was severely reduced in group 3 (1.0 ± 0.2 μg/mg) compared to non-transplanted islets (20.4 ± 3.3 μm/mg). In group 2, beta-cell mass increased when insulin was discontinued; 60 days after transplantation beta-cell mass was similar to the initially transplanted mass (0.23 ± 0.04 mg), glucose levels after an intraperitoneal glucose challenge were normal, and insulin content was preserved (19.6 ± 2.7 μg/mg). In contrast, beta-cell mass was progressively reduced in group 4 (0.08 ± 0.02 mg, p < 0.001). In summary, insulin treatment reduced the beta-cell mass needed to achieve normoglycaemia in islet transplantation. Islets transplanted to insulin-treated mice showed better beta-cell function, preserved insulin content, and were able to increase their beta-cell mass to meet an increased functional demand. [Diabetologia (1997) 40: 1004–1010]

Stem cells and diabetes.

Diabetes mellitus is a metabolic disorder affecting 2-5% of the population. Transplantation of isolated islets of Langerhans from donor pancreata could be a cure for diabetes; however, such an approach is limited by the scarcity of the transplantation material and the long-term side effects of immunosuppressive therapy. These problems may be overcome by using a renewable source of cells, such as islet cells derived from stem cells. Stem cells are defined as clonogenic cells capable of both self-renewal and multilineage differentiation. This mean that these cells can be expanded in vivo or in vitro and differentiated to produce the desired cell type. There exist several sources of stem cells that have been demonstrated to give rise to pluripotent cell lines: 1) embryonic stem cells; 2) embryonic germ cells; 3) embryonic carcinoma cells; and 4) adult stem cells. By using in vitro differentiation and selection protocols, embryonic stem cells can be guided into specific cell lineages and selected by applying genetic selection when a marker gene is expressed. Recently, differentiation and cell selection protocols have been used to generate embryonic stem cell-derived insulin-secreting cells that normalise blood glucose when transplanted into diabetic animals. Some recent reports suggest that functional plasticity of adult stem cells may be greater than expected. The use of adult stem cells will circumvent the ethical dilemma surrounding embryonic stem cells and will allow autotransplantation. These investigations have increased the expectations that cell therapy could be one of the solutions to diabetes.

Short-Term Culture with the Caspase Inhibitor z-VAD.fmk Reduces Beta Cell Apoptosis in Transplanted Islets and Improves the Metabolic Outcome of the Graft:

In the initial days after transplantation islets are particularly vulnerable and show increased apoptosis and necrosis. We have studied the effects of caspase inhibition on this early beta cell death in syngeneically transplanted islets. Streptozotocin-diabetic C57BL/6 mice were transplanted with 150 syngeneic islets, an insufficient mass to restore normoglycemia, preincubated with or without the pan-caspase inhibitor z-VAD. fmk 2 h before transplantation. Beta cell apoptosis was increased in control islets on day 3 after transplantation (0.28 ± 0.02%) compared with freshly isolated islets (0.08 ± 0.02%, p< 0.001), and was partially reduced in transplanted islets preincubated with z-VAD.fmk 200 μM (0.14 ± 0.02%, p = 0.003) or with z-VAD.fmk 500 μM (0.17 ± 0.01%, p = 0.012), but not with a lower z-VAD.fmk (100 μM) concentration. Diabetic mice transplanted with islets preincubated with z-VAD.fmk 500 μM showed an improved metabolic evolution compared with control and z-VAD.fmk 200 μM groups. The z-VAD.fmk 500 μM group showed an overall lower blood glucose after transplantation (p = 0.02), and at the end of the study blood glucose values were reduced compared with transplantation day (15.7 ± 3.6 vs. 32.5 ± 0.5 mmol/L, p = 0.001). In contrast, blood glucose was not significantly changed in control and z-VAD.fmk 200 μM groups. Four weeks after transplantation beta cell mass was higher in z-VAD.fmk 500 μM group (0.15 ± 0.02 mg) than in the control group (0.10 ± 0.02 mg) (p = 0.043). In summary, the treatment of freshly isolated islets with the caspase inhibitor z-VAD.fmk reduced the subsequent apoptosis of the islets once they were transplanted and improved the outcome of the graft.

Report from IPITA-TTS Opinion Leaders Meeting on the Future of β-Cell Replacement

At the time the first pancreas transplant was performed by Kelly and Lillehei in 1966, insulin therapy for diabetes was generally available but administered in a form that is known today as “conventional therapy.”1 In this era, as many as half of all juvenile onset diabetics did not reach the age of 55 years. Early mortality from accelerated cardiovascular disease, renal failure, and hypoglycemia-related events were commonplace. The early low success rate and mortality of pancreas transplantation by comparison were also suboptimal. As will be characterized in the succeeding 8 chapters, the outcome of “best medical therapy” with newer forms of insulin and insulin delivery systems along with dramatically improved outcomes of islet and pancreas transplantation and novel β-cell sources hold great promise for those afflicted.