Liraglutida de valor

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  • Key challenges of type 2 diabetes
  • Key challenges of type 2 diabetes: outcomeThe study by Ford et al. aimed to examine trends in glycaemic control among US adults with diagnosed diabetes from 1999 to 2004. Data from The National Health and Nutrition Examination Survey (NHANES) 1999–2004 showed that 43% of diabetes patients aged >20 years+ were found to have HbA1c levels above 7%. The results from the study by Ford et al. are consistent with other data suggesting that improvements in glycaemic control have occurred among patients with diabetes in the US. The authors suggest that “as welcome as the recent favorable trends in glycaemic control are, additional efforts are needed to help the 40% of patients with diabetes who do not have adequate glycaemic control.”ReferenceFord et al (NHANES). Diabetes Care. 2008; 31: 102–4.
  • Beta-cell function progressively declinesUKPDS shows that, at the time of diagnosis beta-cell function is already markedly compromised by up to 50%, with beta-cell function continuing to deteriorate in the years following diagnosis. Furthermore, extrapolation of these data tells us that beta-cell function in UKPDS patients may have been suboptimal for 10 years prior to diagnosis.ReferenceUKPDS population: UKPDS 16. Diabetes 1995;44:1249–58.
  • Over time, glycaemic control deterioratesUKPDS clearly showed the need for new diabetes treatmentsIn UKPDS, the yearly median HbA1c in patients receiving conventional treatment increased steadily throughout the trial. In contrast, median HbA1c fell during the first year in patients receiving intensive treatment (glibenclamide, metformin or insulin) but gradually increased subsequently and only remained within the recommended treatment target for the first 3–6 years of treatment (depending on assigned treatment). During the remaining years of follow-up, median HbA1c continued to rise steadily above treatment targets. This failure of existing treatments, even when used intensively in highly motivated patients, highlights the need for new treatments in the management of type 2 diabetes. UKPDS recruited 5102 patients with newly diagnosed type 2 diabetes; 4209 were randomised. The patients were treated for a median of 4.0 years. Conventional therapy aimed to maintain fasting plasma glucose (FPG) at <15 mmol/L (270 mg/dL) using diet alone initially. However, sulfonylureas, insulin or metformin could be added if target FPG was not met.ReferencesUKPDS 34. Lancet 1998;352:854–865.UKPDS 33. Lancet 1998;352:837–853.ADOPTThe more recent ADOPT study supports this. In the ADOPT study, rosiglitazone, metformin, and glibenclamide were evaluated as initial treatment for recently diagnosed type 2 diabetes in a double-blind, randomised, controlled clinical trial involving 4360 patients. The study showed that HbA1c increases with time, irrespective of OAD choice.ReferenceKahn et al. (ADOPT). NEJM 2006;355(23):2427–43.
  • Blood pressure and mortality from heart disease increaseSystolic blood pressureDavis and colleagues have investigated the relationship among self-reported ethnicity, metabolic control and blood pressure during treatment of type 2 diabetes. The study comprised 2999 newly diagnosed type 2 diabetic patients recruited to the UK Prospective Diabetes Study who were randomised to conventional or intensive glucose control policies if their FPG levels remained >6 mmol/L after a dietary run-in.After adjustment for antihypertensive therapy, increase in systolic blood pressure at 9 years was greatest in AC patients (7 mmHg; p<0.01 vs. WC patients).This study shows important ethnic differences in body weight, lipid profiles, and blood pressure, but not glycaemic control, during 9 years after diagnosis of type 2 diabetes. AC patients maintained the most favourable lipid profiles, but hypertension developed in more AC patients than WC or IA patients. Ethnicity-specific glycaemic control of type 2 diabetes seems unnecessary, but other risk factors need to be addressed independently.CHDMortality rates from CHD and from all causes have been ascertained over 10 years in three groups of people participating in the Bedford Survey: newly diagnosed diabetics, borderline diabetics and control subjects with normal glucose tolerance. Age-corrected mortality rates, from all causes and CHD, were highest in the diabetics and intermediate in the borderline diabetics and in both groups were similar in men and women. It was concluded that borderline diabetes (or impaired glucose tolerance) is associated with a relatively greater increase in mortality risk in women than men. ReferencesDavis et al. Diabetes Care 2001;24:1167–74.Jarrett et al. Diabetologia 1982;22:79–84.
  • Current treatments increase risk of hypoglycaemiaMany drugs currently used for the treatment of type 2 diabetes cause hypoglycaemia Rosiglitazone, 10% of patients Metformin, 12%Glibenclamide, 39%ReferencesRiddle et al. Diabetes Care 2003;26:3080.Kahn et al. (ADOPT). NEJM 2006;355:2427–43.
  • Most therapies results in weight gain over timeThe influence of diabetes treatment on weight was evident in the UKPDS study (UKPDS 34): regardless of treatment, patients gained weight. Patients treated with insulin showed the largest weight increase, with an average gain of 4.0 kg more than conventional therapy at 10 years (UKPDS 33). The extent of weight gain observed in UKPDS in insulin-treated patients has been confirmed in subsequent studies. For example, in a 6-month study comparing bedtime insulin glargine with NPH insulin once daily (both agents added to existing oral therapy in a treat-to-target protocol), weight gain at the end of the trial period was 3.0 and 2.8 kg, respectively (Riddle et al., 2003). In the ADOPT study, rosiglitazone, metformin and glibenclamide were evaluated as initial treatment for recently diagnosed type 2 diabetes in a double-blind, randomised, controlled clinical trial involving 4360 patients. The patients were treated for a median of 4.0 years. Rosiglitazone was associated with more weight gain and oedema than either metformin or glibenclamide.Generally, weight gain is the consequence of an increase in calorie intake or a decrease in calorie utilisation. It can result from a number of specific factors:poor glycaemic control increases metabolic rate and, consequently, improving glycaemic control decreases metabolism. If calorie intake is not modified accordingly, then weight will increaseimproving metabolic control reduces glucosuria (excretion of glucose through the urine), thus fewer calories are lost in this mannernormally, insulin suppresses food intake through its effect on CNS appetite control pathways. It has been suggested that this effect of insulin is lost in diabetes patientsfear of hypoglycaemia may lead to increased snacking between meals, thus increasing calorie intakeAdditionally, aside from modifications to calorie intake or utilisation, use of insulin can increase lean body mass through its anabolic nature.ReferencesUKPDS 34. Lancet 1998:352:854–65. Kahn et al. (ADOPT). NEJM 2006;355(23):2427–43.
  • The unmet need in type 2 diabetesProgression of type 2 diabetes is characterised by a decline in beta-cell function and deterioration of glycaemic control. These issues persist despite a large oral antidiabetic armamentarium for the management of patients with type 2 diabetes, and an abundance of treatment guidelines. In fact, currently available treatments can increase risk of weight gain and hypoglycaemia; weight gain can increase the risk of CVD. The development of new treatments may bring us closer to reversing this situation and provide clinicians with the ‘ideal’ antidiabetic therapy.
  • The incretin hormones play a crucial role in a healthy insulin responseThe effect of incretins on insulin secretion is clearly indicated in this study. Healthy volunteers (n=8) fasted overnight before they received an oral glucose load of 50 g/400 mL or an isoglycaemic intravenous glucose infusion for 180 min. As can be seen in the left figure, venous plasma glucose concentration was similar with both glucose interventions. However, insulin concentration was greater following oral glucose ingestion than following intravenous glucose infusion, demonstrating the contribution of incretins on insulin secretion. ReferenceNauck et al. Diabetologia 1986;29:46–52.
  • Insulin responses to physiological levels of GLP-1 are severely impaired in T2D but are restored by pharmacological dosesPhysiological levels of GLP-1: Højberget al., 2009Aim: To investigate the potentiation of glucose-stimulated insulin secretion by GLP-1.Methods: 8 obese patients with type 2 diabetes with poor glycaemic control (HbA1c 8.6±1.3%), underwent a hyperglycaemic clamp (15 mmol/L) with infusion of physiological levels of GLP-1 (0.5 pmol/kg/min). Insulin responses were evaluated as the incremental area under the plasma C-peptide curve. For comparison, 8 matched healthy control participants were studied.Results: in healthy patients,physiological levels of GLP-1 resulted in an increase in insulin secretion. In patients with type 2 diabetes however, the insulin response to physiological levels of GLP-1 was substantially reduced.Reference: Højberget al. Diabetologia2009;52:199-207; .Pharmacological levels of GLP-1: Vilsbøllet al., 2002Aim: Toinvestigate “late phase” insulin responses to GLP-1 stimulation in patients with Type II diabetes.Methods: 8 obese patients with type 2 diabetes (HbA1c 7.4%) underwent a hyperglycaemic clamp (15 mmol/l) with infusion (per kg body weight/min) of 1 pmolGLP-1 (7–36) amide (n=8), For comparison, six matched healthy subjects were examined.Results: In this study, GLP-1 infused at pharmacological levels (1 pmol/kg/min) augmented the “late phase” (20–120 min) insulin secretion to levels similar to those observed in healthy subjects. Reference: Vilsbøll et al. Diabetologia 2002;45:1111–9.
  • GLP-1 increases insulin, and reduces glucagon, lowering glucose levelsNauck et al.Diabetologia1993;36:741–4.
  • 24-h GLP-1 presence is required for 24-h controlBecause of its short half-life, continuous administration of GLP-1 is required to obtain optimal, sustained glycaemic control. This was well demonstrated in a randomised, double-blind, placebo-controlled study of 40 hospitalised type 2 diabetes patients who received infusion of GLP-1 (4 or 8 ng/kg/min) for 16 or 24 h every day for 7 days. In patients receiving GLP-1 for 16 h, phosphate-buffered saline solution was infused for the remaining 8 h of the 24-h period. The maximal blood glucose-lowering effect was reported in patients receiving continuous 24-h infusion of 8 ng/kg/min GLP-1; the average decrease from baseline to day 7 in 24-h glucose area under the curve (AUC) was significantly greater in this group than in the other groups (p <0.05). In patients receiving 16 h of GLP-1 infusion, fasting and nocturnal plasma glucose (04:00 h) at day 7 were significantly higher than in those receiving 24 h of GLP-1 infusion (p<0.05). This study therefore demonstrates that glucose control can only be maintained with GLP-1 during continuous infusion.ReferenceLarsen et al. Diabetes Care 2001;24:1416–21.
  • The family of incretin-based therapiesIncretin-based therapies can be broadly divided into:DPP-4 inhibitors (i.e., sitagliptin, vildagliptin) GLP-1 receptor agonists (exenatide, lirgalutide)Within this second category, however, the GLP-1R agonists can be classed as either:Exendin-based therapies (exenatide, exenatide LAR) which have ~50% sequence identity to human GLP-1 Human GLP-1 analogues (liraglutide), which have share a much higher percentage of amino acids with human GLP-1 (97%)
  • A single dose of liraglutide restores beta-cell glucose sensitivityThe effect of liraglutide on beta-cell sensitivity was assessed using a graded glucose infusion protocol, during which glucose is infused to create gradually rising plasma levels from 5–12 mmol/L (90–216 mg/dL) over 3 h. Approximately 9 h before the graded glucose infusion, patients with type 2 diabetes (n=10) received a single subcutaneous dose of liraglutide (7.5 μg/kg) or a single dose of placebo in a double-blind, crossover design (3–6-week washout period). A group of healthy controls who did not receive any injections were also included. After an overnight fast and prior to glucose infusion, all groups received a small iv bolus of insulin (0.007–0.014 U/kg). This bolus reduced blood glucose to approximately 5 mmol/L (90 mg/dL) in healthy controls, and 6 mmol/L (108 mg/dL) in the liraglutide and placebo groups (this bolus probably explains the horizontal line between the first two measurements). Graded glucose infusion was then initiated and insulin secretion assessed.In all groups, insulin secretion increased concomitantly with increases in glucose concentration. However, after liraglutide dosing, the effect was more pronounced than following placebo, and the secretion rate was similar to that observed in the non-diabetic controls. Thus, a single dose of liraglutide is sufficient to reinstate the insulin response to glucose that is observed in healthy controls.ReferenceStudy 2063. Chang et al. Diabetes 2003;52:1786–91.
  • Effect of liraglutide on first-phase insulin secretion and maximal beta-cell insulin secretory capacityThis study assessed the effect of liraglutide on pancreatic beta-cell function. Patients with type 2 diabetes (n=39) were randomised to treatment with 0.65, 1.25 or 1.9 mg/day liraglutide or placebo for 14 weeks. First- and second-phase insulin release were measured by means of the insulin-modified frequently sampled iv glucose tolerance test. Arginine-stimulated insulin secretion was measured during a hyperglycaemic clamp (20 mmol/L). Glucose effectiveness and insulin sensitivity were estimated by means of the insulin-modified frequently sampled iv glucose tolerance test.14 weeks of treatment with liraglutide showed improvements in first- and second-phase insulin secretion, together with improvements in arginine-stimulated insulin secretion during hyperglycaemia. The two highest doses of liraglutide (1.25 and 1.9 mg/day) significantly increased first-phase insulin secretion by 118 and 103%, respectively (p<0.05). Second-phase insulin secretion was significantly increased only in the 1.25 mg/day group vs. placebo. Arginine-stimulated insulin secretion increased significantly at the two highest dose levels vs. placebo by 114 and 94%, respectively (p<0.05). ReferenceVilsboll et al. Diabet Med 2008; 25: 152–6.
  • Liraglutide has multiple direct effects on human physiology1. Pancreas and liverGLP-1 has a direct functional effect on pancreatic cells, influencing secretions from alpha-, beta- and delta-cells. One of its most important effects is to increase insulin secretion. Importantly, however, its insulinotropic action is glucose dependent. Consequently, GLP-1 has the capacity to lower blood glucose while protecting against hypoglycaemia. GLP-1 also regulates glucagon secretion, partly via an increase in somatostatin secretion, and partly via a direct effect on the alpha-cell. This reduction in glucagon secretion serves to decrease hepatic glucose output.2. GLP-1 stimulates beta-cell regeneration and mass in animal modelsStudies have demonstrated that GLP-1 plays an important role in maintaining beta-cells. In animal studies, GLP-1 increases beta-cell mass through the stimulation of beta-cell neogenesis, growth and proliferation. Proliferation results from differentiation and division of existing beta-cells, while neogenesis occurs through differentiation of insulin-secreting cells from precursor cells in the pancreatic ductal epithelium (Bulotta et al., 2002). Additionally, a study using freshly isolated human islets reported a reduction in the number of apoptotic beta-cells following 5 days of in vitro treatment with GLP-1 (Farilla et al., 2003). These observations of increased beta-cell mass and decreased apoptosis are of particular interest in the treatment of type 2 diabetes as progressive beta-cell dysfunction is one of the main pathophysiologies of the disease. 3. GLP-1: effects on the gastrointestinal (GI), cardiac and central nervous systemsThe net effect of GLP-1’s action on the GI system is to delay absorption of food. This is caused by several means, including decreased gastric emptying and acid secretion. For example, the infusion of GLP-1 to generate plasma levels similar to those normally observed following meals delays gastric emptying (Wettergren et al., 1993). Combined, these GI effects serve to flatten the meal-related increase in glucose. This may be important in the management of type 2 diabetes because elevated postprandial glucose excursions are a key feature of type 2 diabetes. Reducing this excursion should therefore be an aim of diabetes treatment. Prolonged presence of food in the stomach through delayed gastric emptying may also reduce food intake by increasing the feeling of satiety. Additionally, GLP-1 receptors are present in several areas in the brain. The receptors in the brainstem (area postrema and subfornical organ) are believed to be involved in inducing feelings of satiety, regardless of the presence of food in the gastric system. This action therefore provides another means for decreasing food intake. Recently, GLP-1 has also been shown to improve spatial and associative learning following its intracerebroventricular infusion in the rat (During et al., 2003). Furthermore, studies have shown that GLP-1 can protect CNS cells against apoptosis (in vitro, Perry et al., 2002), and reduce amyloid levels (in vivo, Perry et al., 2003). GLP-1 has also been associated with cardiovascular function in animal and human studies. Specifically, studies have shown that use of GLP-1 or recombinant GLP-1 can protect myocardium in ischaemic conditions (Bose et al., 2005, Kavianipour et al., 2003), improve myocardial function (Thrainsdottir et al., 2004, Nikolaidis et al., 2004), improve endothelial function (Nystrom et al., 2004), and relax arteries (Nystrom et al. 2005).ReferencesWettergren et al. Dig Dis Sci 1993;38:665–73. Kieffer, et al. Endocr Rev 1999;20:876–913. During et al. Nat Med 2003;9:1173–9. Flint et al. J Clin Invest 1998;101:515–20. Perry et al. J Pharmacol Exp Ther 2002;302:881–8. Perry et al. J Neurosci Res 2003;72:603–12. Bose et al. Diabetes 2005;54:146–51. Kavianipour et al. Peptides 2003;24:569–78. Thrainsdottir et al. Diab Vasc Dis Res 2004;1:40–3. Nikolaidis et al. Circulation 2004;109:962–5. Nystrom et al. Am J Physiol Endocrinol Metab 2004;287:E1209–15. Nystrom et al. Regul Pept 2005;125:173–7. Drucker et al. Proc Natl Acad Sci USA 1987;84:3434–8. Ørskov et al. Endocrinology 1988;123:2009–13. Bulotta et al. J Mol Endocrinol 2002;29:347–60. Farilla et al. Endocrinology 2003;144:5149–58.
  • LEAD: demographicsThe demographics of patients across the LEAD studies are described. Baseline HbA1cs were between 8.2 and 8.5%.
  • Liraglutide reduces HbA1c even further in very poorly controlled patients Study NN2211-1574 presented as poster 898 by Zinman at EASD 2008.
  • Liraglutide reduces both FPG and PPGReferencesMarreet al. Diabetic Medicine 2009;26;268–78 (LEAD-1)Naucket al. Diabetes Care 2009;32;84–90 (LEAD-2)Garber et al.Lancet 2009;373:473–81 (LEAD-3)Zinmanet al.Diabetes Care 2009;32:1224–30(LEAD-4)Russell-Jones et al. Diabetologia2009;52:2046–55 (LEAD-5)
  • Liraglutide presents a low risk of hypoglycaemiaOverall, minor hypoglycaemic episodes with liraglutide were at the placebo level (as evidenced here by LEAD-2 rates).Note that fewer hypos were observed in LEAD-2 compared with LEAD-1 – LEAD-1 combined liraglutide with an SU, which is associated with a known increase in hypoglycaemia risk.ReferencesStudies NN2211-1436, -1572 presented as Marre et al. Diabetes 2008; 57 (Suppl. 1): Abstract 13-OR.Nauck et al. Diabetes 2008; 57 (Suppl. 1): Abstract 504-P.
  • Liraglutide consistently reduces blood pressureLiraglutide reduced SBP across the LEAD studies. Tight blood pressure control reduces CV events and all-cause mortality (UKPDS 38, 1998; Hansson et al., 1998). A reduction of 5.6 mmHg has been shown to reduce death from CV disease by 18% (Patel et al., 2007).ReferencesStudies NN2211-1436, -1572, -1573, and-1697 presented as Marre et al. Diabetes 2008; 57 (Suppl. 1): A4.Nauck et al. Diabetes 2008; 57 (Suppl. 1): A150.Garber et al. Diabetes 2008; 57 (Suppl. 1): LB3.Russell-Jones et al. Diabetes 2008; 57 (Suppl. 1): A159.Study NN2211-1574 presented as poster 898 by Zinman at EASD 2008.UKPDS 38. BMJ 1998:317;703–13.Hansson et al. Lancet 1998;351:1755–62.Patel et al. Lancet 2007;370:829–40.
  • Weight loss with liraglutide increases with higher baseline BMILiraglutide added to OADs results in significant weight loss in subjects with type 2 diabetes, especially those with a high baseline BMI.All BMI sub-groups experienced weight loss with liraglutide, with the greatest decrease in BW occurring in subjects with BMI ≥35 kg/m2. ReferenceRussell-Jones et al. Diabetologia2009;52:2046–55 (LEAD-5)
  • A quarter of patients lose an average of 7.7 kg with liraglutideReferenceNauck et al. Diabetes Care 2009;32;84–90. 26 weeks
  • Liraglutide reduces visceral body fatLiraglutide, a once-daily human GLP-1 analogue:Reduced body weight with concomitant improvement in HbA1cHad a more pronounced effect on fat tissue than on lean tissueReduced body fat percentage with marked reductions in visceral adipose tissue and subcutaneous adipose tissueReduced hepatic steatosisReferenceJendle et al. Diabetes 2008; 57 (Suppl. 1): A32.
  • Few patients withdrew due to nauseaLEAD-1: A listing of all adverse events leading to withdrawal of subjects is included in Appendix 16.2.7, Listing 16.2.7.4.LEAD-2: In the liraglutide groups, the majority of the AE withdrawals were caused by GI disorders such as nausea, diarrhoea and vomiting leading to withdrawal within the first month of randomised treatment (see Appendix 16.2.7)LEAD-3: A summary of the adverse events presented by system organ class for the 54 subjects that discontinued the study early due to an AE is shown in Table 12–6. A listing of the 74 subjects (summarised in Table 12–2) that had adverse events that led to product withdrawal is provided in Selected Data Listing 16.2.7-4.LEAD-4: Table 12–7 Withdrawals and Drug Discontinuations due to Adverse EventsLEAD-5: Table 12–6 Adverse Event WithdrawalsReferencesMarreet al. Diabetic Medicine 2009;26;268–78 (LEAD-1)Naucket al. Diabetes Care 2009;32;84–90 (LEAD-2)Garber et al.Lancet 2009;373:473–81 (LEAD-3)Zinmanet al.Diabetes Care 2009;32:1224–30(LEAD-4)Russell-Jones et al. Diabetologia2009;52:2046–55 (LEAD-5)
  • Liraglutide: greater homology to native human GLP-1, less antibody formationAntibody data are from a meta-analysis of all LEAD studies (data on file).
  • The mean liraglutide (1.8 mg q.d., steady state) concentration-time curve and mean exenatide (10 mg b.i.d.) concentration-time curve are presented in Figure 11–28 and Figure 11–29. Exenatide was administered at timepoints 0 h (morning dose) and 10 h (evening dose).
  • Table 11.3 and 14.2.1 for week 26 valuesWeek 26 data are OC, Change is LOCF.
  • Based on Table 14.2.1Updated with new LOCF data (provided by AJCO) 30/03/09 (EM)
  • LS Mean (SE)Liraglutide 1.8 mg: -1.51 (0.07)Liraglutide 1.2 mg: -1.29 (0.07)Sitagliptin: -0.88 (0.07)Liraglutide 1.8 mg non-inferior to sitagliptinLSMean: -0.63; 95% CI [-0.81; -0.44] Liraglutide 1.8 mg also superior to sitagliptin (p<0.0001)Liraglutide 1.2 mg non-inferior to sitagliptinLSMean: -0.40; 95% CI [-0.59; -0.22] Liraglutide 1.2 mg also superior to sitagliptin (p<0.0001)The estimates are from an ANCOVA model with treatment and country fixed effects and baseline value as a covariate. The p-values correspond to one-sided hypotheses of either superiority or non-inferiority.
  • The incretin hormones play a crucial role in a healthy insulin responseThe effect of incretins on insulin secretion is clearly indicated in this study. Healthy volunteers (n=8) fasted overnight before they received an oral glucose load of 50 g/400 ml or an isoglycemic intravenous glucose infusion for 180 minutes. As can be seen in the left figure, venous plasma glucose concentration was similar with both glucose interventions. However, insulin concentration was greater following oral glucose ingestion than following intravenous glucose infusion, demonstrating the contribution of incretins on insulin secretion. ReferenceNauck et al. Diabetologia 1986;29:46–52
  • What is Glucagon-Like Peptide-1?Glucagon-like peptide-1 (GLP-1) is a 30 amino acid peptide. It is an incretin hormone that is secreted from L-cells in the gastrointestinal system in response to calorie intake, causing the glucose dependent secretion of insulin. Incretins are chemical excitants that promote pancreatic sections (glucose-dependent insulinotropic polypeptide [GIP] is another example).
  • Insulin responses to physiological levels of GLP-1 are severely impaired in T2D but are restored by pharmacological dosesPhysiological levels of GLP-1: Højberget al., 2008Aim: To investigate the potentiation of glucose-stimulated insulin secretion by GLP-1.Methods: 8 obese patients with type 2 diabetes with poor glycaemic control (HbA1c 8.6±1.3%), underwent a hyperglycaemic clamp (15 mmol/L) with infusion of physiological levels of GLP-1 (0.5 pmol/kg/min). Insulin responses were evaluated as the incremental area under the plasma C-peptide curve. For comparison, 8 matched healthy control participants were studied.Results: in healthy patients,physiological levels of GLP-1 resulted in an increase in insulin secretion. In patients with type 2 diabetes however, the insulin response to physiological levels of GLP-1 was substantially reduced.Reference: Højberget al. Diabetologia2009;52:199-207.Pharmacological levels of GLP-1: Vilsbøllet al., 2002Aim: Toinvestigate “late phase” insulin responses to GLP-1 stimulation in patients with Type 2 diabetes.Methods: 8 obese patients with type 2 diabetes (HbA1c 7.4%) underwent a hyperglycaemic clamp (15 mmol/L) with infusion (per kg body weight/min) of 1 pmolGLP-1 (7–36) amide (n=8), For comparison, six matched healthy subjects were examined.Results: In this study, GLP-1 infused at pharmacological levels (1 pmol/kg/min) augmented the “late phase” (20–120 min) insulin secretion to levels similar to those observed in healthy subjects. Reference: Vilsbøll et al. Diabetologia 2002;45:1111–9.
  • GLP-1 has multiple direct effects on human physiology1. Pancreas and LiverGLP-1 has a direct functional effect on pancreatic cells, influencing secretions from alpha-, beta- and delta- cells. One of its most important effects is to increase insulin secretion. Importantly, however, its insulinotropic action is glucose dependent. Consequently, GLP-1 has the capacity to lower blood glucose while protecting against hypoglycaemia. GLP-1 also regulates glucagon secretion, partly via an increase in somatostatin secretion, and partly via a direct effect on the alpha-cell. This reduction in glucagon secretion serves to decrease hepatic glucose output.2. GLP-1 stimulates -cell regeneration and mass in animal modelsStudies have demonstrated that GLP-1 plays an important role in maintaining -cells. In animal studies, GLP-1 increases -cell mass through the stimulation of -cellneogenesis, growth and proliferation. Proliferation results from differentiation and division of existing -cells, while neogenesis occurs through differentiation of insulin-secreting cells from precursor cells in the pancreatic ductal epithelium (Bulotta et al, 2002). Additionally, a study using freshly isolated human islets reported a reduction in the number of apoptotic -cells following 5 days of in vitro treatment with GLP-1 (Farilla et al, 2003). These observations of increased -cell mass and decreased apoptosis are of particular interest in the treatment of type 2 diabetes as progressive -cell dysfunction is one of the main pathophysiologies of the disease. 3. GLP-1: effects on the gastrointestinal, cardiac and central nervous systemsThe net effect of GLP-1’s action on the gastrointestinal system is to delay absorption of food. This is caused by several means, including decreased gastric emptying and acid secretion. For example, the infusion of GLP-1 to generate plasma levels similar to those normally observed following meals delays gastric emptying (Wettergren et al, 1993). Combined, these gastrointestinal effects serve to flatten the meal-related increase in glucose. This may be important in the management of type 2 diabetes because elevated postprandial glucose excursions are a key feature of type 2 diabetes. Reducing this excursion should therefore be an aim of diabetes treatment. Prolonged presence of food in the stomach through delayed gastric emptying may also reduce food intake by increasing the feeling of satiety. Additionally, GLP-1 receptors are present in several areas in the brain. The receptors in the brainstem (area postrema and subfornical organ) are believed to be involved in inducing feelings of satiety, regardless of the presence of food in the gastric system. This action therefore provides another means for decreasing food intake. Recently, GLP-1 has also been shown to improve spatial and associative learning following its intracerebroventricular infusion in the rat (During et al, 2003). Furthermore, studies have shown that GLP-1 can protect CNS cells against apoptosis (in vitro, Perry et al 2002), and reduce amyloid levels (in vivo, Perry et al 2003). GLP-1 has also been associated with cardiovascular function in animal and human studies. Specifically, studies have shown that use of GLP-1 or recombinant GLP-1 can protect myocardium in ischemic conditions (Bose et al 2005, Kavianipour et al 2003), improve myocardial function (Thrainsdottir et al 2004, Nikolaidis, Mankad et al 2004), improve endothelial function (Nystrom et al 2004), and relax arteries (Nystrom et al 2005).ReferencesWettergrenet al. Dig DisSci1993;38:665–73. Kieffer, et al. Endocr Rev 1999;20:876–913. During et al. Nat Med 2003;9:1173–9. Flint et al. J Clin Invest 1998;101:515–20. Perry et al. J Pharmacol Exp Ther2002;302:881–8. Perry et al. J Neurosci Res 2003;72:603–12. Bose et al. Diabetes 2005;54:146–51. Kavianipouret al. Peptides 2003;24:569–78. Thrainsdottiret al. DiabVascDis Res 2004;1:40–3. Nikolaidiset al. Circulation 2004;109:962–5. Nystromet al. Am J PhysiolEndocrinolMetab2004;287:E1209–15. Nystromet al. RegulPept2005;125:173–7. Druckeret al. Proc NatlAcadSci USA 1987;84:3434–8. Ørskovet al. Endocrinology 1988;123:2009–13. Bulottaet al. J Mol Endocrinol2002;29:347–60. Farillaet al. Endocrinology 2003;144:5149–58.Various effectsEfficacious glucose loweringincreased insulin secretion (glucose-dependent), increased insulin biosynthesis, increased -cell glucose sensitivitydecreased glucagon secretion (glucose-dependent)delayed gastric emptyingincreased -cell mass (shown in animal models)Body weight loweringdelayed gastric emptyingincreased fullness and satietydecreased food intakePotential to halt disease progressionincreased -cell glucose sensitivityincreased -cell mass (shown in animal models)GLP-1 stimulates -cell regeneration and mass in animal modelsStudies have demonstrated that GLP-1 plays an important role in maintaining -cells. In animal studies, GLP-1 increases -cell mass through the stimulation of -cell neogenesis, growth and proliferation. Proliferation results from differentiation and division of existing -cells, while neogenesis occurs through differentiation of insulin-secreting cells from precursor cells in the pancreatic ductal epithelium (Bulotta et al. 2002). Additionally, a recent study using freshly isolated human islets reported a reduction in the number of apoptotic -cells following 5 days of in vitro treatment with GLP-1 (Farilla et al. 2003). These observations of increased -cell mass and decreased apoptosis are of particular interest in the treatment of type 2 diabetes as progressive -cell dysfunction is one of the main pathophysiologies of the disease. ReferencesBulotta et al. J Mol Endocrinol 2002;29:347–360 Farilla et al. Endocrinology 2003;144:5149–5158
  • GLP-1 stimulates -cell regeneration and mass in animal modelsStudies have demonstrated that GLP-1 plays an important role in maintaining -cells. In animal studies, GLP-1 increases -cell mass through the stimulation of -cell neogenesis, growth and proliferation. Proliferation results from differentiation and division of existing -cells, while neogenesis occurs through differentiation of insulin-secreting cells from precursor cells in the pancreatic ductal epithelium (Bulotta et al. 2002). Additionally, a recent study using freshly isolated human islets reported a reduction in the number of apoptotic -cells following 5 days of in vitro treatment with GLP-1 (Farilla et al. 2003). These observations of increased -cell mass and decreased apoptosis are of particular interest in the treatment of type 2 diabetes as progressive -cell dysfunction is one of the main pathophysiologies of the disease. ReferencesBulotta et al. J Mol Endocrinol 2002;29:347–360 Farilla et al. Endocrinology 2003;144:5149–5158
  • The effect of GLP-1 on weight:GLP-1 affects the gastrointestinal system and delays absorption of food. This is caused by several means, including decreased gastric emptying and acid secretion. For example, the infusion of GLP-1 to generate plasma levels similar to those normally observed following meals delays gastric emptying (Wettergren et al. 1993).Combined, these gastrointestinal effects reduce the meal-related increase in glucose. Prolonged presence of food in the stomach through delayed gastric emptying may also reduce energy intake by inducing satiety.Additionally, GLP-1 receptors are present in several areas in the brain. The receptors in the brainstem (area postrema and subfornical organ) are believed to be involved in inducing satiety, regardless of the presence of food in the gastric system. This action therefore provides another means for decreasing energy intake.
  • GLP 1: cardiovascular effectsSeveral studies suggest that GLP-1 may have effects on the cardiovascular system. Such effects are likely to be important in the treatment of type 2 diabetes because many patients with diabetes also present with cardiovascular disease. GLP-1 appears to exert a protective effect on myocardium, particularly in ischemic conditions. For example, Bose et al (2005) reported that an intravenous infusion of GLP-1 + valinepyrrolidide (an inhibitor of GLP-1 breakdown) before induced ischaemia in rats significantly reduced infarction compared with saline. Additionally, Kavianipour et al (2003) reported that recombinant GLP-1 was associated with lower interstitial levels of pyruvate and lactate during ischemia in ischemic and non-ischemic porcine tissue compared with saline, and infusion of recombinant GLP-1 in dogs with dilated cardiomyopathy resulted in an increase in myocardial glucose uptake (NikolaidisElahi et al 2004). Studies have also reported improved myocardial function in patients with type 2 diabetes and congestive heart failure (Thrainsdottir et al 2004), and infusion of recombinant GLP-1 has been shown to improve left ventricular function in dogs with advanced dilated cardiomyopathy (Nikolaidis, Elahi et al 2003), and in patients with acute myocardial infarction after primary angioplasty (NikolaidisMankad et al 2004). The effect of GLP-1 on endothelial function (assessed using ultrasonography of the brachial artery) was examined in patients with type 2 diabetes and stable coronary artery disease (Nystrom et al 2004). GLP-1 significantly increased relative changes in brachial artery diameter suggesting an improvement in endothelial function. This effect was only observed in patients with type 2 diabetes however; there was no effect in healthy individuals. A subsequent study showed that GLP-1 relaxes arteries: circular sections of rats’ femoral artery were dissected and mounted in a rat organ bath model. Addition of GLP-1 to these baths during a phenylephrine-induced contractile tone resulted in dose-dependent vascular relaxation. This effect also remained evident after the mechanical removal of the endothelium (Nystrom et al 2005) Finally, studies have also shown that GLP-1 infusion increases diuresis and natriuresis. For example, Yu et al (2003) reported that GLP-1 infusion increased urine flow and sodium excretion in rats following an increase in sodium intake. Additionally, GLP-1 infusion in obese men significantly enhanced urinary sodium excretion, reduced H+ secretion, and decreased glomerularhyperfiltration relative to placebo (Gutzwiller et al 2004). These effects may have a positive effect on blood pressure, reducing the risk of arterial hypertension in this patient group. ReferencesBose et al. Diabetes 2005;54:146-151. Gutzwiller et al. J ClinEndocrinolMetab 2004;89:3055-3061. Kavianipour et al. Peptides 2003;24:569-578. Nikolaidis, Elahi et al. Circulation 2004;110:955-961. Nikolaidis, Mankad et al. Circulation 2004;109:962-965. Nystrom et al. RegulPept 2005;125:173-177. Nystrom et al. Am J PhysiolEndocrinolMetab 2004;287:E1209-1215. Thrainsdottir et al. DiabVascDis Res 2004;1:40-43. Yu et al. J Hypertens 2003;21:1125-1135.
  • Y-axis: in vivo myocardial infarct size expressed as a percentage of the risk zone.The study objective was to examine the effect of glucagon-like peptide-1 (GLP-1) on ischemic injury in both the in vivo (in presence of endogenous insulin) and in vitro (in absence of insulin) myocardium of male Sprague-Dawley rats. The endpoint was the size of myocardial infarct. A secondary aim was to describe the mechanism of action of GLP-1 in this setting using the following inhibitors of prosurvival signalling pathways: cyclic adenosine monophosphate (cAMP) inhibitor Rp-cAMPPhosphoinositide 3-kinase (PI3 kinase) inhibitor LY294002 p42/44 mitogen-activated protein kinase inhibitor UO126. GLP-1 receptor antagonist exendin (9–39) was also used in combination with GLP-1. Both isolated perfused rat heart and whole animal models of ischaemia/reperfusion were used. The rats were randomized into in vitro (n=91) or in vivo (n=25) model groups. The in vivo rats were further randomized to one of three groups: Control group received salineValinepyrrolidide (VP) control group received subcutaneous (sc) injection VP 20 mg/kg to inhibit dipeptidylpeptidase-4 (DPP-4) activityGLP-1 + VP group received sc VP 20 mg/kg and iv infusion of GLP-1 (4.8 pmol · kg-1 min-1)The in vitro isolated rat hearts were randomized to 1 of 7 groups:Control group received saline.VP control group received sc injection VP 20 mg/kg. GLP-1 (0.3 nmol) + VP (20 mg/L) group.GLP-1 (0.3 nmol) + VP (20 mg/L) + PI3 kinase inhibitor LY24002 (15 mol/L) group.GLP-1 (0.3 nmol) + VP (20 mg/L) + p44/42 inhibitor UO126 (10 mol/L) group.GLP-1 (0.3 nmol) + VP (20 mg/L) + cAMP inhibitor Rp-cAMP (1.5 mol/L) group.GLP-1 (0.3 nmol) + VP (20 mg/L) + the GLP-1 receptor antagonist exendin (9–39) (3 nmol/L) group.Some additional hearts only received the inhibitors or the antagonists to determine if they have any direct influence on infarction. Investigators induced 30 min of regional ischaemia followed by 120 min of reperfusion in each rat.ReferenceBose et al. Diabetes 2005;54:146–51.
  • This double-blind, placebo-controlled, crossover study investigated the effect of glucagon-like peptide-1 (GLP-1) on urine and sodium excretion in obese (n=16) and non-obese (n=15) humans. Following an overnight fast and bladder emptying, participants received an i.v. infusion of hypertonic saline (0.06 mL/kg/min) for 2 h. A second infusion of 0.9% saline containing GLP-1 or placebo was started at the same time for 3 h. After the initial 2 h, healthy participants were freely allowed to drink water; obese participants could drink water throughout. Water intake and urine excretion during the study were measured; sodium, chloride, H+ and calcium excretion were analyzed in this urine. The two sections of this crossover study were separated by 7 days. This slide shows that in both healthy and obese patients, GLP-1 infusion significantly increased urine volume relative to placebo.ReferenceGutzwiller et al. J Clin Endocrinol Metab 2004;89:3055–61.
  • Native GLP-1 has limited clinical value because of its short half-lifeThe rapid degradation of GLP-1 into its inactive form by DPP-4 means that when administered as an i.v. bolus, it has a half-life of just 1.5–2.1 minutes. Combined with rapid clearance, this means that the action of GLP-1 has a very limited time span. ReferenceVilsbøll et al. J Clin Endocrinol Metab 2003;88:220–224
  • 24-hour GLP-1 presence is required for 24-hour controlBecause of its short half-life, continuous administration of GLP-1 is required to obtain optimal, sustained glycemic control. This was well-demonstrated in a randomized, double-blind, placebo-controlled study of 40 hospitalised type 2 diabetes patients who received infusion of GLP-1 (4 or 8 ng/kg/min) for 16 or 24 hours every day for 7 days. In patients receiving GLP-1 for 16 hours, phosphate-buffered saline solution was infused for the remaining 8 hours of the 24-hour period. The maximal blood glucose lowering effect was reported in patients receiving continuous 24-hour infusion of 8 ng/kg/min GLP-1; the average decrease from baseline to day 7 in 24-hour glucose area under the curve (AUC) was significantly greater in this group than in the other groups (p < 0.05). In patients receiving 16 hours of GLP-1 infusion, fasting and nocturnal plasma glucose (04.00 hours) at day 7 were significantly higher than in those receiving 24 hours of GLP-1 infusion (p < 0.05). This study therefore demonstrates that glucose control can only be maintained with GLP-1 during continuous infusion.ReferenceLarsen et al. Diabetes Care 2001;24:1416–21
  • Mean steady state plasma concentration-time profiles for liraglutide and exenatide.ReferenceRosenstock J, Gumprecht J, Szyprowska E, Bednorczyk-Karuzny M, Zychma MJ, During M, Buse J. Pharmacokinetics of liraglutide vs exenatide in type 2 diabetes: sustained vs fluctuating concentrations over 24 hours. Diabetes 2009;58 (Suppl 1):A150.
  • A single dose of liraglutide restores beta-cell glucose sensitivityThe effect of liraglutide on beta-cell sensitivity was assessed using a graded glucose infusion protocol, during which glucose is infused to create gradually rising plasma levels from 5–12 mmol/L (90–216 mg/dL) over 3 h. Approximately 9 h before the graded glucose infusion, patients with type 2 diabetes (n=10) received a single subcutaneous dose of liraglutide (7.5 μg/kg) or a single dose of placebo in a double-blind, crossover design (3–6-week washout period). A group of healthy controls who did not receive any injections were also included. After an overnight fast and prior to glucose infusion, all groups received a small iv bolus of insulin (0.007–0.014 U/kg). This bolus reduced blood glucose to approximately 5 mmol/L (90 mg/dL) in healthy controls, and 6 mmol/L (108 mg/dL) in the liraglutide and placebo groups (this bolus probably explains the horizontal line between the first two measurements). Graded glucose infusion was then initiated and insulin secretion assessed.In all groups, insulin secretion increased concomitantly with increases in glucose concentration. However, after liraglutide dosing, the effect was more pronounced than following placebo, and the secretion rate was similar to that observed in the non-diabetic controls. Thus, a single dose of liraglutide is sufficient to reinstate the insulin response to glucose that is observed in healthy controls.ReferenceStudy 2063. Chang et al. Diabetes 2003;52:1786–91.
  • Effect of liraglutide on first-phase insulin secretion and maximal beta-cell insulin secretory capacityThis study assessed the effect of liraglutide on pancreatic beta-cell function. Patients with type 2 diabetes (n=39) were randomized to treatment with 0.65, 1.25 or 1.9 mg/day liraglutide or placebo for 14 weeks. First- and second-phase insulin release were measured by means of the insulin-modified frequently sampled iv glucose tolerance test. Arginine-stimulated insulin secretion was measured during a hyperglycemic clamp (20 mmol/L). Glucose effectiveness and insulin sensitivity were estimated by means of the insulin-modified frequently sampled iv glucose tolerance test.14 weeks of treatment with liraglutide showed improvements in first- and second-phase insulin secretion, together with improvements in arginine-stimulated insulin secretion during hyperglycemia. The two highest doses of liraglutide (1.25 and 1.9 mg/day) significantly increased first-phase insulin secretion by 118 and 103%, respectively (p<0.05). Second-phase insulin secretion was significantly increased only in the 1.25 mg/day group vs. placebo. Arginine-stimulated insulin secretion increased significantly at the two highest dose levels vs. placebo by 114 and 94%, respectively (p<0.05). ReferenceVilsboll et al. Diabet Med 2008; 25: 152–6.
  • Liraglutida de valor

    1. 1. Liraglutida Un análogo del GLP-1 humano una vez al día para el tratamiento de la diabetes de tipo 2
    2. 2. Liraglutida Ciencia clínica
    3. 3. Principios generales de la presentación• Problemas principales de la diabetes de tipo 2 (DT2)• El efecto de las incretinas y liraglutida• Liraglutida: Mecanismo de la acción reductora de glucosa• El programa LEAD• Comparación con otras terapias basadas en incretinas• Datos del metanálisis LEAD
    4. 4. Problemas principales de la DT2
    5. 5. Problemas principales de la DT21. La diabetes es una enfermedad progresiva caracterizada por lo siguiente: • Declinación de la función de las células beta. • Deterioro del control de la glucemia. • Aumento del riesgo de enfermedad cardiovascular.2. A medida que se añaden tratamientos de la diabetes para controlar la glucosa, los médicos y los pacientes se enfrentan a inconvenientes como los siguientes: • Hipoglucemia. • Ganancia de peso. • Pautas terapéuticas complejas (administración diaria múltiple y necesidad de automonitorizar la glucemia).
    6. 6. Problemas principales de la DT2: Resultado El 43% de los pacientes diabéticos no alcanzan los objetivos glucémicos de la ADA (HbA1c<7%)ADA: Asociación Norteamericana de DiabetesFord. Diabetes Care 2008;31:102–4.
    7. 7. Declinación progresiva de la función de las células beta 100 Función de las células beta Diagnóstico de diabetes 80 (%, EMHO) 60 40 20 Extrapolación de la función de las células beta antes del diagnóstico 0 –12 –10 –8 –6 –4 –2 0 2 4 6 8 Años a partir del diagnósticoEMHO: Evaluación del modelo de homeostasis.Lebovitz. Diabetes Reviews 1999;7:139–53(Los datos proceden de la población UKPDS: UKPDS 16. Diabetes 1995;44:1249–58).
    8. 8. En el transcurso del tiempo, el control de la glucemia se deteriora UKPDS Convencional* ADOPT Rosiglitazona Glibenclamida (gliburida) Met 9 Metformina (met) Glibenclamida (gliburida) Insulina 8 8,5Mediana de HbA1c (%) 8 7,5 7,5 7 7 Objetivo del tratamiento 6,5 6,5 recomendado <7,0%† 6 6 6,2%: Límite superior del intervalo normal 0 2 4 6 8 10 0 1 2 3 4 5 Años a partir de la aleatorización Tiempo (años) *Dieta inicial seguida de sulfonilureas, insulina y/o met si GPA>15 mmol/l †Recomendaciones del procedimiento clínico de la ADA. UKPDS 34, n=1.704 UKPDS 34. Lancet 1998:352:854–65; Kahn (ADOPT). N Engl J Med 2006;355:2427–43.
    9. 9. La presión arterial sistólica y la mortalidad por enfermedad cardíaca aumentan en la DT2 Raza blanca Mortalidad por cardiopatía coronaria (CC) Raza afrocaribeña ajustada a la edad, durante 10 años, en funciónΔ presión arterial sistólica 12 Raza asiática de origen indio de la glucemia en situación basal 10 Hombres % de mortalidad (CC) 8 20 Mujeres (mmHg) 6 4 2 0 10 -2 3 6 9 -4 Años de diabetes Control Diabetes Diabetes Media (barras) e IC del 99% (líneas verticales) (sin diabetes) limítrofe para cambios transversales.Davis. Diabetes Care 2001;24:1167–74; Jarrett. Diabetologia 1982;22:79–84.
    10. 10. Los tratamientos actuales aumentan el riesgo de hipoglucemia 45 20 40 39Hipoglucemia: Episodios por hipoglucemia** (%) 35 p<0,05 glibenclamida 15 (gliburida) frente a paciente y año* Pacientes con 30 rosiglitazona 25 10 20 15 12 5 10 10 5 0 0 Glargina NPH Rosiglitazona Met Glibenclamida (gliburida) *Todos los episodios hipoglucémicos sintomáticos ** Hipoglucemia autocomunicada (no confirmada) por los pacientes Riddle. Diabetes Care 2003;26:3080; Kahn. (ADOPT). N Engl J Med 2006;355:2427–43.
    11. 11. Episodios hipoglucémicos graves en ACCORD, VADT y ADVANCE ACCORD1 VADT2 ADVANCE3 12 p<0,001 p< 0,01 p<0,001 25 3 Episodios hipoglucémicosEpisodios hipoglucémicos 10 Episodios hipoglucémicos 20 2.5 8 2 graves (%) graves (%) 15 graves (%) 6 1.5 10 4 1 2 5 0.5 0 0 0 Estándar intensivo Standard Estándar Intensive intensivo Estándar intensivo (n=5.123) (n=5.128) Standard Intensive (n=899) (n=892) Standard Intensive (n=5.569) (n=5.571)Estándar: Objetivo de HbA1c: 7,0 a 7,9% Intensivo: Reducción absoluta de la Estándar: Normas localesintensivo: Objetivo de HbA1c: <6,0% HbA1c del 1,5% frente a estándar Intensivo: Objetivo de HbA1c: ≤6,5%Hipoglucemia grave: Hipoglucemia que requiere asistencia de terceros.1. The ACCORD Study Group. N Engl J Med 2008;358:2545–59; 2. Duckworth. N Engl J Med 2009;360:129–39;3. The ADVANCE Collaborative Group. N Engl J Med 2008;358:2560–72.
    12. 12. La mayoría de las terapias resultan en ganancia de peso en el transcurso del tiempo UKPDS: Hasta 8 kg en 12 años ADOPT: Hasta 4,8 kg en 5 años 100 8Cambio en el peso (kg) 7 Insulina (n=409) 6 96 Peso (kg) 5 Glibenclamida 4 (gliburida; n=277) 92 3 2 88 1 0 Met (n=342) 0 3 6 9 12 0 0 1 2 3 4 5 Años a partir de aleatorización Tiempo (años) Tratamiento convencional (n=411); dieta inicial Rosiglitazona seguida de sulfonilureas, insulina y/o met si GPA Met >15 mmol/l Glibenclamida (gliburida) n= En situación basal. UKPDS 34. Lancet 1998:352:854–65; Kahn. N Engl J Med 2006;355:2427–43.
    13. 13. Necesidad no resuelta todavía en la DT2 A medida que la DT2 progresa: La función de las células beta declina La HbA1c, la GPA y la GPP se deterioran Las terapias actuales se asocian a ganancia de peso y/o hipoglucemia La presión arterial sistólica aumenta Volver al menú principal
    14. 14. El efecto de las incretinas y liraglutida
    15. 15. Las hormonas incretinas desempeñan un papel crucial en una respuesta sana de la insulina Glucosa plasmática Respuesta de la insulina Glucosa plasmática (mg/dl) Carga de glucosa oral (50 g) 15 80 270 Infusión iv de glucosaGucosa plasmática Insulina (mU/l) 60 10 180 (mmol/l) Efecto de 40 las incretinas 5 90 20 0 0 0 –10 –5 60 120 180 –10 –5 60 120 180 Tiempo (min) Tiempo (min) • La respuesta de la insulina es mayor tras glucosa oral que tras glucosa iv, a pesar de una concentración de glucosa plasmática similar Voluntarios sanos (n=8) Nauck. Diabetologia 1986;29:46–52.
    16. 16. En la DT2, la infusión del péptido análogo de glucagón-1 (GLP- 1) incrementa notablemente la secreción de insulinaEl GLP-1 (pero no el PIG) incrementa la secreción de insulina tanto en laetapa inicial como en la etapa tardía 3000 Infusión iv contínua durante el clamp 2500 hiperglucémico (15 mmol/l) Insulina (pmol/l) 2000 GLP-1 (1 pmol) PIG (16 pmol) 1500 1000 500 0 –20 0 30 80 120 Tiempo (min)Los datos son medias EEM. PIG: Péptido inhibidor gástrico; pacientes con DT2 (n=8)Vilsbøll. Diabetologia 2002:45:1111–9.
    17. 17. Aunque las respuestas de insulina a niveles fisiológicos de GLP- 1 se deterioran gravemente en la DT2, se restablecen con dosis farmacológicas Niveles fisiológicos de GLP-11 Niveles farmacológicos de GLP-12 (0,5 pmol/kg/min de clamp hiperglucémico) (1,0 pmol/kg/min de clamp hiperglucémico) Periodo de infusión de GLP-1 Periodo de infusión de GLP-1 6.000 6.000Insulina (pmol/l) Insulina (pmol/l) 5.000 5.000 GLP-1 plasmático: GLP-1 plasmático: 4.000 46 pmol/l 4.000 126 pmol/l Sano DT2 3.000 3.000 2.000 2.000 GLP-1 plasmático: 41 pmol/l 1.000 DT2 1.000 0 0 0 30 60 90 120 0 45 90 135 180 Tiempo (min) Tiempo (min) 1. Højberg. Diabetologia 2009;52:199-207; 2. Vilsbøll. Diabetologia 2002;45:1111–9.
    18. 18. El efecto del GLP-1 es glucosa dependiente Infusión Infusión Infusión 15 270 300 Glucagón (pmol/l) 20Glucosa (mmol/l) Insulina (pmol/l) Glucosa (mg/dl) 10 * 180 200 * * * 10 * * * * * * * * * 5 90 100 * * * * * * 0 0 0 0 -30 0 60 120 180 240 -30 0 60 120 180 240 -30 0 60 120 180 240 Tiempo (min) Tiempo (min) Tiempo (min) Placebo (PBO) GLP-1 humano nativo Media (EE); n=10; *p<0,05; pacientes con DT2 (n=10) Nauck. Diabetologia 1993;36:741–4.
    19. 19. La presencia de GLP-1 durante 24 horas es necesaria para el control de la glucosa durante 24 horas 25 25Glucosa plasmática (mmol/l) 20 20 15 15 10 10 5 5 Infusión de GLP-1 Infusión de GLP-1 durante 24 horas durante 16 horas 04 08 12 16 20 00 04 04 08 12 16 20 00 04 Tiempo (h) Tiempo (h) Curvas de glucemia: Antes del tratamiento con GLP-1 humano nativo Después de 7 días de tratamiento con GLP-1 humano nativo Pacientes con DT2 (n=40) Larsen. Diabetes Care 2001;24:1416–21.
    20. 20. La familia de las terapias basadas en incretinas Terapias basadas en incretinas Inhibidores de la Agonistas del DPP-4, por receptor GLP-1 ejemplo, sitagliptina , saxagliptina Análogos del GLP-1 Terapias basadas en humano, por exendinas, por ejemplo, liraglutida ejemplo, exenatidaDPP-4: Dipeptidilpeptidasa-4
    21. 21. La liraglutida es un análogo del GLP-1 humano una vez al día GLP-1 humano nativo Ácido graso C-16 Liraglutida (palmitoilo) 7 9 His Ala Glu Gly Thr Phe Thr Ser Asp Degradación enzimática Val por DPP-4 Ser Glu Lys Ala Ala Gln Gly Glu Leu Tyr Ser 7 9 Glu Phe 36 His Ala Glu Gly Thr Phe Thr Ser Asp Val Ile Ala Trp Leu Val Arg Gly Arg Gly Ser Homología de aminoácidos del 97% para el GLP-1 Lys Ala Ala Gln Gly Glu Leu Tyr Ser endógeno (7-37); mejora de la FC: fijación de Glu 36 albúmina a través de acilación; formación de Phe heptámeros Ile Ala Trp Leu Val Lys Gly Arg Gly • Absorción lenta a partir del subcutis T½=1,5–2,1 min • Resistente a DPP-4 • Semivida plasmática prolongada (T½=13 h)Knudsen. J Med Chem 2000;43:1664–9; Degn. Diabetes 2004;53:1187–94.
    22. 22. La administración de liraglutida una vez al día produce niveles farmacológicos elevados del análogo de GLP-1 8000 Liraglutida plasmática 6000 (pmol/l) 4000 2000 Curva individual única: El estado de equilibrio se alcanza después de tres dosis 1 2 3 4 5 6 7 8 9 Tiempo (días) Volver al menúCurva modelo ajustada para 30 puntos de datosAgersø. Diabetologia 2002;45:195–202. principal
    23. 23. Liraglutida: Mecanismo de la acciónreductora de glucosa
    24. 24. Efecto de una dosis única de liraglutida sobre la sensibilidad de la glucosa de las células beta• Los pacientes con DT2 14 Controles sanos (n=10) Tasa de secreción de insulina recibieron una inyección 12 Liraglutida 7,5 μg/kg única de liraglutida o Placebo placebo 9h antes del 10 (pmol/min/kg) ensayo (cruzado). 8• Se midió la secreción de 6 insulina.• La liraglutida restableció 4 la reactividad de las 2 células betas a la mmol/l glucosa elevada hasta el 0 4 6 8 10 12 nivel de los voluntarios sanos. 80 100 120 140 160 180 200 220 Glucosa (mg/dl)Los datos son media EEM; pacientes con DT2 (n=10)Chang. Diabetes 2003;52:1786–91.
    25. 25. Efecto de la liraglutida sobre la secreción de insulina de primera fase y la capacidad secretora máxima de insulina de las células beta Curvas medias de clamp para insulina Capacidad secretora 2.716 máxima de las células beta 2.477 256 241 Concentration (pmol/L) Concentración (pmol/l) 226 2.238 211 1.999 195 180 Liraglutida Placebo 165 1.761 150 135 1.522 119 104 1.283 89 0 2 4 6 8 10 12 14 16 18 20 1.044 805 Respuesta de insulina de primera 567 fase 328 89 0 15 30 45 60 75 90 105 Embolada 135 150 de arginina Tiempo (min)Medido por la respuesta de insulina de primera fase y la capacidad secretora máxima de las células beta; curvasmedias de insulina durante la embolada de glucosa (inserción), el clamp hiperglucémico y la prueba deestimulación de arginina; pacientes con DT2 (n=39).Degn. Diabetes 2004;53:1187–94.
    26. 26. La liraglutida no induce secreción de insulina en presencia de niveles bajos de glucosa 4,3 3,7 3,0 2,3 Meseta de glucosa plasmática (77) (67) (54) (41) controlada, mmol/l (mg/dl) Tasa de secreción de (pmol/kg/min) 1 Liraglutida insulina Placebo Además, no se produce la supresión de la secreción de glucagón 0 durante la hipoglucemia 0 60 120 180 240 Tiempo (min)Los datos son media SEM; pacientes con DT2 (n=11)Nauck. Diabetes 2003;52(Suppl. 1):A128 (Presentado como póster en ADA 2003).
    27. 27. La liraglutida produce efectos directos múltiples sobre la fisiología humana Páncreas Cerebro Secreción de Aporte de energía insulina (glucosa dependiente) y Hígado sensibilidad de las Producción hepática células beta. de glucosa Síntesis de insulina. Tubo digestivo Secreción de Motilidad glucagón (glucosa dependiente). Masa de células beta* Volver al menú*En estudios de experimentación animal. principal
    28. 28. El programa LEAD
    29. 29. El LEAD cubre la asistencia continua de la DT2 Monoterapia con liraglutida frente a SU Añadir un tercer agente LEAD-3 oral o iniciar insulina Liraglutida+met frente a SU + met LEAD-2 Liraglutida+SU frente a Añadir otro Liraglutida+met+TZD TZD+SU agente oral frente a met+TZD LEAD-1 LEAD-4 Liraglutida+met+SU frente a glargina+met+SU LEAD-5 Iniciar un agente oral Liraglutida+met y/o SU frente a exenatida+met y/o SU LEAD-6 Dieta/ejercicioLEAD: Liraglutide Effect and Action in Diabetes. Marre. Diabetic Med 2009;26;268–78 (LEAD-1); Nauck. Diabetes Care2009;32;84–90 (LEAD-2); Garber. Lancet 2009;373:473–81 (LEAD-3); Zinman. Diabetes Care 2009; 32:1224–30 (LEAD-4);Russell-Jones. Diabetologia 2009;52:2046–55 (LEAD-5); Buse. Lancet 2009; 374:39–47 (LEAD-6).
    30. 30. LEAD: Demografía LEAD-2 LEAD-1 LEAD-4 LEAD-5 LEAD-6 LEAD-3 Combinación Combinación Combinación Combinación Combinación Monoterapia con Met con SU con Met+TZD con Met+SU con Met±SUPacientes 746 1.091 1.041 533 581 464aleatorizadosDuración delestudio 52 26 26 26 26 26(semanas)Edad (años) 53,0 56,8 56,1 55,1 57,5 56,7Duración de ladiabetes 5,4 7,4 7,9 9,2 9,4 8,2(años)GPA (mg/dl) 171,0 180,0 176,4 181,8 165,6 172,8HbA1c (%) 8,3 8,4 8,4 8,3 8,2 8,2IMC (kg/m2) 33,1 31,0 29,9 33,5 30,5 32,9Peso (kg) 98,8 88,6 81,6 96,3 85,4 93,1Marre. Diabetic Med 2009;26;268–78 (LEAD-1); Nauck. Diabetes Care 2009;32;84–90 (LEAD-2); Garber. Lancet 2009;373:473–81 (LEAD-3); Zinman. Diabetes Care 2009; 32:1224–30 (LEAD-4); Russell-Jones. Diabetologia 2009;52:2046–55 (LEAD-5);Buse. Lancet 2009; 374:39–47 (LEAD-6).
    31. 31. HbA1c <7,0% al cabo de 52 semanas con monoterapia de 1,8 mg de liraglutida Cambio en la HbA1c (%)* LEAD-3, pacientes tratados con dieta y ejercicio -0,2 previos -0,4 -0,6 Glimepirida 8 mg -0,8 −0,9 9,0 Monoterapia de liraglutida 1,2 mg -1,0 −1,2 -1,2 Monoterapia de liraglutida 1,8 mg -1,4 −1,6 8,5 -1,6HbA1c (%) 8,0 7,5 * ** 7,0 Objetivo de la ADA 6,5 0 4 8 12 16 20 24 28 32 36 40 44 48 52 Tiempo Los datos son media (DE); población ITT (semanas) *Liraglutida 1,2 mg frente a glimepirida, p=0,0376; **Liraglutida 1,8 mg frente a glimepirida, p=0,0016 Garber. Lancet 2009;373(9662):473–81 (LEAD-3)
    32. 32. HbA1c <7,0% durante 2 años con monoterapia de 1,8 mg de liraglutida Cambio en HbA1c (%) 0Extensión de LEAD-3, población global -0,2 -0,4 -0,6 -0,6 -0,8 -0,9 -1 -1,1 -1,2 Liraglutida 1,8 mg 8,5 Liraglutida 1,2 mg 8,0 Glimepirida 8 mgHbA1C (%) 7,5 7,0 *** 6,5 6,0 0 8 16 24 32 40 48 56 64 72 80 88 96 104 Tiempo (semanas) ***p<0,0001 frente a glimepirida Media 2EE observada; sin imputación para valores omitidos. Análisis de sujetos que completaron Garber et al., Diabetes Obes Metab 2011; 13:346-58 (LEAD-3 ext)
    33. 33. Programa LEAD: Efecto de la liraglutida sobre la HbA1c LEAD-3 LEAD-2 LEAD-1 LEAD-4 LEAD-5 LEAD-6 Monoterapia Combinación Combinación Combinación Combinación Combinación con Met con SU con Met+TZD con Met+SU con Met SU HbA1c 8,4 8,6 8,6 8,4 8,28,2 8,4 8,5 8,6 8,3 8,5 8,5 8,6 8,4 8,3 8,1 8,3 8,2 8,1basal % 0,2Cambio en la HbA1c (%) 0,2 0,1 0,0 -0,2 -0,2 -0,4 -0,4 -0,5 -0,5 -0,6 -0,8 -0,8 -0,8 ** -1,0 -1,0 -1,0 -1,0 -1,1 -1,1 -1,1 -1,1 -1,1 -1,2 *** *** *** -1,3 *** -1,4 -1,5 -1,5 ** -1,6 *** *** Liraglutida 1,2 mg Liraglutida 1,8 mg Glimepirida Rosiglitazona Placebo Glargina Exenatida**p<0,01, ***p≤0,0001 frente a fármaco de comparación activo.Marre. Diabetic Med 2009;26;268–78 (LEAD-1); Nauck. Diabetes Care 2009;32;84–90 (LEAD-2); Garber. Lancet 2009;373:473–81 (LEAD-3); Zinman. Diabetes Care 2009; 32:1224–30 (LEAD-4); Russell-Jones. Diabetologia 2009;52:2046–55 (LEAD-5);Buse. Lancet 2009; 374:39–47 (LEAD-6).
    34. 34. Cambio en la HbA1c con liraglutida por cuartil basal de HbA1c en LEAD-4 HbA1c basal HbA1c basal HbA1c basal HbA1c basal Cuartil 1 Cuartil 2 Cuartil 3 Cuartil 4 <7,4 7,4–8,3 8,3–9,2 ≥9,2 0Cambio en la HbA1c (%) -0,5 -1,0 -1,5 -2,0 Liraglutida+met+rosiglitazona -2,5 2,3% 1,2 mg 1,8 mg Zinman et al. Diabetes Care 2009;32:1224–30 (LEAD-4; cambio en la HbA1c por cuartil basal de HbA1c )
    35. 35. Tanto por ciento de pacientes que alcanzaron los objetivos de la ADA cuando se añadía liraglutida Liraglutida 1,2 mg Liraglutida 1,8 mg Glimepirida Rosiglitazona Placebo Glargina Exenatida 70alcanzaron el objetivo 60 *** 58 *** *** ** *** Pacientes que 50 54 53 54 51 ** *** 46 40 43 42 42 43 (%) ** 35 36 35 30 28 28 20 22 10 0 LEAD-3 LEAD-2 LEAD-1 LEAD-4 LEAD-5 LEAD-6 Monoterapia Combinación Combinación Combinación Combinación Combinación con Met con SU con Met+TZD con Met+SU con Met SU **p<0,01, ***p≤0,0001 frente a fármaco de comparación activo. Marre. Diabetic Med 2009;26;268–78 (LEAD-1); Nauck. Diabetes Care 2009;32;84–90 (LEAD-2); Garber. Lancet 2009;373: 473–81 (LEAD-3); Zinman. Diabetes Care 2009;32:1224–30 (LEAD-4); Russell-Jones. Diabetologia 2009;52:2046–55 (LEAD-5); Buse. Lancet 2009;374:39–47 (LEAD-6).
    36. 36. Efecto de la liraglutida sobre la GPA y la GPP Efecto de la liraglutida sobre Cambio en la GPP media durante 3 comidas la GPA (antes de 2 semanas) Mono Combi Combi Combi Combi 180 LEAD-3 Met SU Met Met LEAD-2 LEAD-1 +TZD +SU Liraglutida 1,8 mg+met+SU LEAD-4 LEAD-5 Insulina glargina+met+SU 0 Reducción de la GPP 160GPA (mg/dl) (mmol/l) 1 140 2 120 3 0 2 8 12 18 26 Liraglutida 1,2 mg LEAD-5 Semana Liraglutida 1,8 mg Marre. Diabetic Med 2009;26;268–78 (LEAD-1); Nauck. Diabetes Care 2009;32;84–90 (LEAD-2); Garber. Lancet 2009;373: 473–81 (LEAD-3); Zinman. Diabetes Care 2009; 32:1224–30 (LEAD-4); Russell-Jones. Diabetologia 2009;52:2046–55 (LEAD-5).
    37. 37. Efecto de la liraglutida sobre la función de las células beta medido por EMHO-B en LEAD-1 p≤0,05 p≤0,05 p≤0,05 120 100 porcentual con respecto al 28 80 36,0 EMHO-B (cambio 13 60 valor basal) 40 20 71,0 56,0 46,0 56,0 0 -4 Liraglutida 1,2 mg Liraglutida 1,8 mg Rosiglitazona 4 mg Placebo -20El color entero= Basal (%); color escalonado = Cambio (%);EMHO-B: Evaluación del modelo de homeostasis de la función de las células beta.Marre. Diabet Med 2009;26:268–78 (LEAD-1).
    38. 38. Episodios hipoglucémicos menores con liraglutida en combinación con metformina 1,4menores por paciente 1,2 Hipoglucemias 1,0 0,8 y año 0,6 0,4 0,2 0 Liraglutida Liraglutida Placebo Glimepirida 1,2 mg 1,8 mg • Los episodios hipoglucémicos menores corresponden al nivel placebo (LEAD-2, arriba) • Se registra un riesgo pequeño aunque aumentado de hipoglucemia menor en combinación con las SU (0,51 y 0,47 episodios por paciente y año con liraglutida 1,2 mg y liraglutida 1,8 mg frente a 0,12 y 0,17 episodios por paciente y año con rosiglitazona y placebo; LEAD-1) Nauck. Diabetes Care 2009;32:84–90 (LEAD-2); Marre. Diabetic Med 2009;26:268–78 (LEAD-1).
    39. 39. Efecto de la liraglutida sobre la presión arterial sistólica cuando se administra para tratar la DT2 Monoterapia Combinación Combinación Combinación Combinación Combinación LEAD-3 con Met con SU con Met + TZD con Met + SU con Met SU 1 LEAD-2 LEAD-1 LEAD-4 LEAD-5Cambio en la PAS (mmHg) LEAD-6 0 0,4 0,5 -1 -0,7 -0,9 -1,1 -2 -2,0 -2,1 -2,3 -2,5 -3 * -2,6 -2,8 -2,8 * -4 -3,6 -4,0 * *** -5 -5,6 -6 * -6,7 -7 * Liraglutida 1,2 mg Liraglutida 1,8 mg Glimepirida Rosiglitazona Placebo Glargina Exenatida Todos los sujetos. ***p≤0,0001, **p<0,001, *p<0,05 frente a fármaco de comparación Marre. Diabetic Med 2009;26;268–78 (LEAD-1); Nauck. Diabetes Care 2009;32;84–90 (LEAD-2); Garber. Lancet 2009;373: 473–81 (LEAD-3); Zinman. Diabetes Care 2009;32:1224–30 (LEAD-4); Russell-Jones. Diabetologia 2009;52:2046–55 (LEAD-5); Buse. Lancet 2009;374:39–47 (LEAD-6).
    40. 40. Curso cronológico del efecto de la liraglutida sobre la PAS: Un metanálisis del programa LEAD 134 Liraglutida 1,8 mg; n=1363 Liraglutida 1,2 mg; n=896Medias de MC de la PAS 133 Placebo; n=524 132 131 (mmHg) *** 130 129 ** * 128 127 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 Tiempo (semanas) • Metanálisis de seis ensayos LEAD: Efecto del tratamiento con liraglutida (1,8 mg, n=1.363; 1,2 mg, n=896) o placebo (n=524) sobre la PAS por cuartil de PAS basal Reducción media de la PAS con respecto al valor basal en la semana 26: *2,59 mmHg (p=0,0008), **2,49 mmHg (p=0,003),***−0,24 mmHg (p=0,7828). Datos mostrados para la PAS expresados como medias de mínimos cuadrados IC del 95%. Fonseca. Diabetes 2009;58(Suppl 1):A146
    41. 41. Cambio en el peso durante 52 semanas con liraglutida Liraglutida 1,2 mg Liraglutida 1,8 mg Glimepirida 8 mg 98 Peso corporal (kg) 96 94 92 90 88 0 0 4 8 12 16 20 24 28 32 36 40 44 48 52 Tiempo (semanas)Media 2EEGarber et al. Lancet 2009;373:473–81 (LEAD-3)
    42. 42. Cambio en el peso corporal en el transcurso del tiempo: Sujetos que completaron 2 años 1,5 Cambio en el peso 1 corporal (kg) 0,5 1,1 0 -0,5 -1 -1,5 -2,1 Cambio en el peso corporal -2 4 -2,5 -2,7 -3 3 2 1 (kg) 0 0 8 16 24 32 40 48 56 64 72 80 88 96 104 -1 -2 -3 -4 Tiempo (semanas) Liraglutida 1,8 mg Liraglutida 1,2 mg Glimepirida 8 mgMedia 2EE observada; sin imputación para valores omitidos.Garber et al., Diabetes Obes Metab 2011; 13:346-58 (LEAD-3 ext).
    43. 43. Cambio en el peso corporal por IMC basal con liraglutida en LEAD-5 IMC<25 25≤IMC<30 30≤IMC<35 IMC≥35 4 Cambio en el peso corporal 3 2 1 (kg) 0 -1 -2 -3 -4 Liraglutida 1,8 mg+met+SU Glargina+met+SUUnidad de IMC: kg/m2Russell-Jones et al. Diabetes. 2008; 57 (suppl. 1); A593 (extracto 2147-PO; presentado en ADA 2008)
    44. 44. Cambio en el peso corporal por cuartil de pérdida de peso en LEAD-2 2 0peso corporalCambio en el -2 (kg) -4 -6 -8 -10 Q3-Q4 C1 ≤Q1 C2 Q1-Q2 C3 Q2-Q3 C4 >Q3 Liraglutida 1,8 mg+met C1: Cambio medio en el peso para el ≤25% de los pacientes que presentaron la mayor pérdida de peso. C2: Cambio medio en el peso para el cuartil de pérdida de peso >25–≤50%. C3: Cambio medio en el peso para el cuartil de pérdida de peso >50–≤75%. C4: Cambio medio en el peso para el cuartil de pérdida de peso >75–100%, es decir, el 25% que presentaron la menor pérdida de peso. Nauck et al. Diabetes Care 2009;32;84–90 (LEAD-2; cambio en el peso corporal por cuartil de pérdida de peso).
    45. 45. Cambio en la grasa corporal visceral con liraglutida en un subestudio de LEAD-2 Cambio en la grasa corporal Grasa visceral frente a grasa Exploración AXED subcutánea Exploración TCCambio en la grasa corporal 3 +1,1 10 Visceral Subcutánea (+0,4) +3 Cambio en la grasa 2 5 1 0 kg (%) 0 5 (%) –1 –10 −5 −8** –15 −9*** –2 –3 −1,6*** –20 (–1,1*)−2,4 *** −16* –4 (–1,2*) –25 −17* Liraglutida 1,2 mg+met Liraglutida 1,8 mg+met Glimepirida+met Los datos son media EE; *p<0,05; **p<0,001; ***p≤0,0001 frente a glim+met; n=160; TC: Tomografía computadorizada; AXED: Absorciometría de rayos X de energía dual. Jendle. Diabetes Obes Metab 2009;11:1163–72.
    46. 46. La nausea causada por liraglutida es transitoria (LEAD-3)Proporción de sujetos con nausea por semana y tratamiento: Población de seguridad 16 Liraglutida 1,8 mg 14 Liraglutida 1,2 mg 12 Glimepirida Sujetos (%) 10 8 6 4 2 0 0 4 8 12 16 20 24 28 32 36 40 44 48 52 Tiempo (semanas) Garber et al. Lancet 2009;373:473–81 (LEAD-3; nausea en el trascurso del tiempo)
    47. 47. Retirada de pacientes debida a nausea Nausea Retiradas debidas a nausea (%) (n/total pacientes) LEAD-3 Liraglutida 1,8 mg 29 6/246 Mono Glimepirida 8 0/248 LEAD-2 Liraglutida 1,8 mg 19 15/242 Combinación con Met Glimepirida 3 0/242 LEAD-1 Liraglutida 1,8 mg 7 2/234Combinación con SU Rosiglitazona 3 0/231 LEAD-4 Liraglutida 1,8 mg 40 16/178 Combinación con Met+TZD Placebo 9 0/175 LEAD-5 Liraglutida 1,8 mg 14 2/230 Combinación con Met+SU Glargina 1 0/232Marre. Diabetic Med 2009;26;268–78 (LEAD-1); Nauck. Diabetes Care 2009;32;84–90 (LEAD-2); Volver al menúGarber. Lancet 2009;373: 473–81 (LEAD-3); Zinman. Diabetes Care 2009; 32:1224–30 (LEAD-4);Russell-Jones. Diabetologia 2009;52:2046–55 (LEAD-5). (Withdrawal rates due to nausea) principal
    48. 48. Comparación con otras terapias basadasen incretinas
    49. 49. La concentración de liraglutida activa es mayor que la concentración de GLP-1 con un inhibidor de DPP-4 Liraglutida activa después de 7 días con Niveles de GLP-1 después de 28 días 6 µg/kg de liraglutida una vez al día* (n=13)1 con 100 mg de vildagliptina dos veces al día (n=9)2 120 120 Dosis de liraglutidareceptor de GLP-1 GLP-1 (pmol/l) Agonista del 90 90 (pmol/l) Dosis del inhibidor de la 60 60 DPP-4 (vildagliptina) 30 30 0 0 8 12 16 20 24 8 12 16 20 24 Tiempo (h) Tiempo (h) *Niveles de GLP-1 para liraglutida calculados como 1,5% de liraglutida libre. 1. Adaptado de Degn et al. Diabetes 2004;53:1187–94; 2. Mari et al. J Clin Endocrinol Metab 2005;90:4888–94.
    50. 50. Ref/datos actualizados Estructura del GLP-1 nativo, liraglutida y exenatida Pacientes con aumento de GLP-1 humano nativo anticuerpos (%)1 70 61,1 Liraglutida 60 Homología de 50 aminoácidos del 97% para 40 GLP-1 30 endógeno (7- Exenatida 37) 20 Homología de 10 aminoácidos del 2,6 53% para GLP-1 0 humano Liraglutida* Exenatida# *Al cabo de 78 semanas #Al cabo de 26 semanas Duración del estudio: Liraglutida, 26 semanas; exenatida, 30 semanas. Buse et al. J Clin Endocrinol Metab 2011; en prensa
    51. 51. Comparación directa entre liraglutida y exenatida: Niveles FC en estado de equilibrio durante 24 h 18 16 140 Liraglutida Concentración de exenatida Concentración total de 14 n=7 120 liraglutida (nmol/l) 12 100 (pmol/l) 10 80 8 60 6 Exenatida 4 n=6 40 2 20 0 0 0 2 4 6 8 10 12 14 16 18 20 22 24 Tiempo desde la primera dosis del día (h)Se inyectó exenatida por la mañana (momento 0 h) y por la tarde (momento 10 h)(señalado con flechas.)Rosenstock. Diabetes 2009;58(Suppl 1):558-P.
    52. 52. Comparación directa entre liraglutida y exenatida: Cambio en la HbA1c (0 a 26 semanas) Basal 8,2% Basal 8,1% 0,0 Cambio en la HbA1c (%) -0,5 -0,79 -1,0 -1,12 p<0,0001 -1,5 Liraglutida 1,8 mg una vez al día Exenatida 10 μg dos veces al díaDiferencia terapéutica estimada para cambios con respecto al valor basal.Media de mínimos cuadrados: –0,33; IC del 95% [–0,47; –0,18]Media (2EE)Buse et al. Lancet 2009;374:39–47 (LEAD-6)
    53. 53. Comparación directa entre liraglutida y exenatida: Cambio en la HbA1c (26 a 40 semanas) Semana 26: 7,2% Semana 26: 7,0% 0,0 Cambio en la HbA1c (%) -0,1 NS -0,06 -0,2 -0,3 -0,4 -0,32 -0,5 p<0,0001 -0,6 Exenatida liraglutida Liraglutida liraglutidaMedia (2 EE)NS: No significativoBuse et al Diabetes Care 2010;33:1300–3 (LEAD-6 ext.)
    54. 54. Efecto sobre la HbA1c (0 a 40 semanas) en el momento de cambiar de exenatida a liraglutida Grupo exenatida cambiado a liraglutida (semana 26) 8.5 Exenatida liraglutida Liraglutida liraglutida 8.0(%) (%) 7.5 Objetivo HbA1c 1cHbA de la ADA 7.0 6.5 Exenatida Liraglutida 6.0 0 0 4 8 12 16 20 24 28 32 36 40 Tiempo (semanas) Media (2 EE) Los datos de las semanas 0 a 26 competen únicamente a los pacientes que participaron en la fase de extensión de LEAD-6. Buse et al. Lancet 2009;374 (9683):39–47 (LEAD-6); Buse et al. Diabetes Care 2010;33:1300-03 (LEAD-6 Ext)
    55. 55. GPA en el transcurso del tiempo (0 a 40 semanas) Exenatide group 10,5 switched to liraglutide 10,0 (week 26) 9,5 Exenatida GPA (mmol/l) Liraglutida Exenatide liraglutide 9,0 Liraglutide liraglutide 8,64 8,5 *** p<0,0001 8,0 7,73 7,5 7,0 0 0 4 8 12 16 20 24 28 32 36 40 Tiempo (semanas)Los datos para las semanas 0 a 26 competen únicamente a los pacientes que participaron en la fase deextensión de LEAD-6***Diferencia terapéutica estimada en cambios para la poblacíón completa , p<0,0001Buse et al. Lancet 2009;374 (9683):39–47 (LEAD-6); Buse et al. Diabetes Care 2010;33:1300-03 (LEAD-6 Ext)
    56. 56. Comparación directa entre liraglutida y exenatida: Cambio en el peso corporal (0 a 26 semanas) Basal Tiempo (semanas) 93,1 kg 93,0 kg 0 4 8 12 16 20 24 26 0 0,0Cambio en el peso Cambio en el peso (kg) -1,0 corporal (kg) -1 -2,0 -2 -2,87 -3,0 -3,24 -3 -4,0 -4 Liraglutida 1,8 mg una vez al día -5,0 n=235 n=232 Liraglutida Exenatida 1,8 mg una 10 μg dos vez al día veces al día Media (2EE) Buse. Lancet 2009;374:39–47 (LEAD-6); Data on file, Novo Nordisk.
    57. 57. Peso corporal en el transcurso del tiempo (0 a 40 semanas) Exenatide group switched to liraglutide 98 (week 26) Peso corporal (kg) Exenatide liraglutide 94 Liraglutide liraglutide 90 Exenatida Liraglutida 86 0 0 4 8 12 16 20 24 28 32 36 40 Tiempo (semanas)Los datos para las semanas 0 a 26 competen únicamente a los pacientes que participaron en la fase deextensión de LEAD-6.Media (2 EE)Buse et al. Lancet 2009;374 (9683):39–47 (LEAD-6); Buse et al. Diabetes Care 2010;33:1300-03 (LEAD-6 Ext)
    58. 58. Tasas de nausea (0 a 40 semanas)•Los datos de las semanas 0 a 26 competen únicamente a los pacientes que participaron enla fase de extensión de LEAD-6 18 Exenatida 10 μg BID Grupo exenatida cambiado Liraglutida 1,8 mg ODProporción de sujetos (%) 16 a liraglutida (semana 26) 14 Exenatida liraglutida 12 Liraglutida 10 8 6 *** 4 2 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 Tiempo (semanas) Los datos corresponden al número (%) de pacientes expuestos al tratamiento (población de seguridad); diferencia terapéutica estimada en cambios para la población completa en la semana 26 *** p<0,0001 (índice de tasa terapéutica estimada para liraglutida frente a exenatida, 0,448). Buse et al. Lancet 2009;374 (9683):39–47 (LEAD-6); Buse et al. Diabetes Care 2010;33:1300-03 (LEAD-6 Ext)
    59. 59. Comparación directa entre liraglutida y sitagliptina: Cambio en la HbA1c (0 a 52 semanas) Basal: 8,4% 8,4% 8,5% 0,0 Cambio en la HbA1c (%) -0,5 -0,88 -1,0 -1,29 -1,51 -1,5 p=0,0179 p<0,0001 -2,0 p<0,0001Ref/datos actualizados Liraglutida 1,2 mg Liraglutida 1,8 mg Sitagliptina 100 mg Diferencia terapéutica estimada (ANCOVA): Liraglutida 1,2 mg frente a sitagliptina 0,40; liraglutida 1,8 mg frente a sitagliptina 0,63 (ambos p<0,0001) Los datos son media (1,96 EE) a partir de FAS UOT Pratley et al. Lancet 2010:375;1447–56; Pratley et al. Int J Clin Pract 2011;65:397-407
    60. 60. Comparación directa entre liraglutida y sitagliptina: Cambio en la GPA (0 a 52 semanas) 11.0 Liraglutide 1.2 mg Liraglutida 1,2 mg 10.5 Liraglutide 1.8 mg Liraglutida 1,8 mg Sitagliptina 100 mg Sitagliptin 100 mg 10.0 9.5 -0,59 GPA (mmol/l) 9.0 Ambas p<0,0001 8.5 –1,71 –2,04 8.0 7.5 7.0 0,0 6.5 -2 0 4 10 16 22 28 34 40 46 52Ref/datos actualizados Tiempo (semanas) Media (1,96 EE); los datos proceden de FAS UOT. Pratley et al. Lancet 2010:375;1447–56; Pratley et al. Int J Clin Pract 2011;65:397-407
    61. 61. Comparación directa entre liraglutida y sitagliptina: Cambio en el peso corporal (0 a 52 semanas) Tiempo (semanas) Basal: 93,7 kg 94,6 kg 93,1 kg 0 -2 4 10 16 22 28 34 40 46 52 0,0 Cambio en el peso corporal (kg)Cambio en el peso corporal (kg) 0,0 -1,16 -0,5 -1,0 -1,0 –1,16 -1,5 -2,0 -2,78 Ambas -2,0 p<0,0001 -2,5 -3,0 -3,68 –2,78 -3,0 -3,5 -4,0 NS p<0,0001 –3,68 -4,0 -5,0 p<0,0001 -4,5 Liraglutida 1,2 mg Liraglutida 1,8 mg Liraglutida 1,2 mg Sitagliptina 100 mg Liraglutida 1,8 mg Ref/datos actualizados Sitagliptina 100 mgMedia (1,96 EE); los datos proceden de FAS UOTPratley et al. Lancet 2010:375;1447–56; Pratley et al. Int J Clin Pract 2011;65:397-407
    62. 62. Comparación directa entre liraglutida y sitagliptina: Notificaciones de nausea por semana (0 a 52 semanas) 16 14 Liraglutida 1,2 mg Liraglutida 1,8 mg Sitagliptina 100 mg Pacientes (%) 12 10 8 6 4 2 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 Tiempo (semanas)• La nausea con liraglutida fue inicialmente mayor aunque transitoria.• Durante las semanas 27 a 52, la incidencia de nausea fue comparable entre los grupos • 1,9; 1,1 y 1,8% con liraglutida 1,2 mg, liraglutida 1,8 mg y sitagliptina, respectivamente. Los datos proceden del conjunto de análisis de seguridad. Ref/datos actualizados Pratley et al. Lancet 2010:375;1447–56; Pratley et al. Int J Clin Pract 2011;65:397-407
    63. 63. Algoritmo de ADA y EASD para el tratamiento de la DT2 • Reforzar las intervenciones sobre el estilo de vida en cada visita y comprobar la HbA1c cada 3 meses hasta que la HbA1c alcance <7% y luego, por lo menos, cada 6 meses. Las intervenciones deben cambiarse si HbA1c es ≥7% Nivel 1: Terapias básicas bien validadas En el Estilo de vida y Estilo de vida y momento del metformina metformina diagnóstico: + insulina basal + insulina intensiva Estilo de vida Estilo de vida y + metformina metformina + sulfonilureaa Etapa 1 Etapa 2 Etapa 3 Nivel 2: Terapias menos bien validadas Estilo de vida y metformina Estilo de vida y + pioglitazona metformina Ausencia de hipoglucemia edema/insuficiencia cardíaca + pioglitazona congestiva ; pérdida ósea + sulfonilureaa Estilo de vida y metformina + agonista de GLP-1b Estilo de vida yRef/datos actualizados Ausencia de hipoglucemia; metformina pérdida de peso + insulina basal Nausea/vómito aSulfonilureas (SU) distintas de glibenclamida (gliburida) o clorpropamida bUso Volver al menú clínico insuficiente para tener confianza con respecto a la seguridad principal Nathan et al. Diabetologia 2009;52:17-30
    64. 64. Liraglutida Ciencia: GLP-1 y el desarrollo de liraglutida
    65. 65. Principios generales de la presentación• GLP-1, PIG y el efecto de las incretinas.• El GLP-1 produce numerosos efectos fisiológicos • Efectos pancreáticos. • Efectos gastrointestinales y sobre el peso. • Efectos CV. • Efectos sobre el SNC.• El GLP-1 como objetivo terapéutico.• Desarrollo inicial de la liraglutida.• Estudios de farmacología clínica con liraglutida.• Resumen. Volver al menúSNC: Sistema nervioso central; CV: Cardiovascular; GI: Gastrointestinal; PIG: Polipéptidoinsulinotrópico dependiente de glucosa; GLP-1: Péptido análogo de glucagón 1. principal
    66. 66. GLP-1, PIG y el efecto de las incretinas
    67. 67. Las hormonas incretinas, GLP-1 y PIG, son segregadas por los intestinos en respuesta a la ingestión de comidas Alimento Duodeno y yeyuno Hormonas incretinas: proximal PIG Íleon y colon GLP-1Baggio. Gastroenterology 2007;132:2131–57
    68. 68. Las hormonas incretinas desempeñan un papel crucial en una respuesta de insulina sana Glucosa plasmática Respuesta de insulina 15 270 80Glucosa plasmática Glucosa plasmática Insulina (mU/l) 60 (mmol/l) 10 180 (mg/dl) Efecto de 40 las incretinas 5 90 20 0 0 0 –10 –5 60 120 180 –10 –5 60 120 180 Tiempo (min) Tiempo (min) Carga de glucosa oral (50 g) Infusión iv de glucosa • La respuesta de insulina es mayor tras la administración de glucosa oral que de glucosa iv, a pesar de una concentración de glucosa plasmática similar. iv: Intravenosa Nauck. Diabetologia 1986;29:46–52, voluntarios sanos (n=8)

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