Subcutaneous Glucagon-like Peptide-1 Research Articles

Randomised comparison of intravenous and subcutaneous routes of glucagon-like peptide-1 administration for lowering plasma glucose in hyperglycaemic subjects with type 2 diabetes.

To perform a direct, double-blind, randomised, crossover comparison of subcutaneous and intravenous glucagon-like peptide-1 (GLP-1) in hyperglycaemic subjects with type 2 diabetes naïve to GLP-1-based therapy. Ten fasted, hyperglycaemic subjects (1 female, age 63 ± 10 years [mean ± SD], glycated haemoglobin 73.5 ± 22.0 mmol/mol [8.9% ± 2.0%], both mean ± SD) received subcutaneous GLP-1 and intravenous saline, or intravenous GLP-1 and subcutaneous saline. Infusion rates were doubled every 120 min (1.2, 2.4, 4.8 and 9.6 pmol·kg-1·min-1 for subcutaneous, and 0.3, 0.6, 1.2 and 2.4 pmol·kg-1·min-1 for intravenous). Plasma glucose, total and intact GLP-1, insulin, C-peptide, glucagon and gastrointestinal symptoms were evaluated over 8 h. The results are presented as mean ± SEM. Plasma glucose decreased more with intravenous (by ~8.0 mmol/L [144 mg/dL]) than subcutaneous GLP-1 (by ~5.6 mmol/L [100 mg/dL]; p < 0.001). Plasma GLP-1 increased dose-dependently, but more with intravenous than subcutaneous for both total (∆max 154.2 ± 3.9 pmol/L vs. 85.1 ± 3.8 pmol/L; p < 0.001), and intact GLP-1 (∆max 44.2 ± 2.2 pmol/L vs. 12.8 ± 2.2 pmol/L; p < 0.001). Total and intact GLP-1 clearance was higher for subcutaneous than intravenous GLP-1 (p < 0.001 and p = 0.002, respectively). The increase in insulin secretion was greater, and glucagon was suppressed more with intravenous GLP-1 (p < 0.05 each). Gastrointestinal symptoms did not differ (p > 0.05 each). Subcutaneous GLP-1 administration is much less efficient than intravenous GLP-1 in lowering fasting plasma glucose, with less stimulation of insulin and suppression of glucagon, and much less bioavailability, even at fourfold higher infusion rates.

Suppressed thyroid stimulating hormone levels after initiation of a subcutaneous glucagon-like peptide-1 receptor agonist in a post-thyroidectomy patient managed with levothyroxine case report

ObjectivesGlucagon-like peptide-1 receptor agonist (GLP-1 RA) therapy has demonstrated an increased risk of thyroid C-cell hyperplasia and C-cell tumors in rodents. Due to this risk, a boxed warning for this drug class exists for people with a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2. There is a lack of data regarding any possible effect of GLP-1 RA therapy on serum thyroid levels. The objective of this case report is to describe a case of suppressed thyroid stimulating hormone levels after initiation of a subcutaneous semaglutide in a post-total thyroidectomy patient managed with levothyroxine in order to highlight the need for closer monitoring of these patients and further research in this area. Case SummaryThe patient described in the case underwent a total thyroidectomy in 2015 with stable thyroid hormone replacement requirements with levothyroxine for 5 years until the initiation and titration of subcutaneous semaglutide. The reduction in thyroid stimulating hormone (TSH) after starting GLP-1 RA therapy necessitated a 25 percent dose reduction of levothyroxine from her original dose. Practice implicationsThis patient experienced suppressed TSH levels following initiation and titration of subcutaneous semaglutide. The etiology of these changes may be related to the direct effects of GLP-1 RA therapy on TSH levels, changes in absorption related to delayed gastric emptying rates, secondary to GLP-1 RA-associated weight loss, or a combination of these proposed mechanisms. It may be prudent to exercise more frequent monitoring of medications that require weight-based dosing and those with a narrow therapeutic index when initiating and titrating GLP-1 RA-based therapies and is an area of potential study.

Cost-effectiveness analysis of once-daily oral semaglutide versus placebo and subcutaneous glucagon-like peptide-1 receptor agonists added to insulin in patients with type 2 diabetes in China.

Introduction: Oral semaglutide is a glucagon-like peptide-1 receptor agonist (GLP-1 RA) that improves glycated hemoglobin levels and body weight in patients with type 2 diabetes (T2DM). We aim to evaluate the cost-effectiveness of once-daily oral semaglutide in comparison to placebo and injectable GLP-1 RAs in Chinese patients with T2DM inadequately controlled on basal insulin. Methods: The United Kingdom Prospective Diabetes Study Outcomes Model (UKPDS OM2.1) was used to estimate the cost-effectiveness by calculating the incremental cost-effectiveness ratio (ICER). Baseline characteristics of the simulation cohort were obtained from the PIONEER 8 trial. Utility and safety inputs were derived from a network meta-analysis of 12 trials. Direct medical costs were retrieved from published literature and discounted at an annual rate of 5%. We used a willingness-to-pay (WTP) threshold of $36,528.3 per quality-adjusted life-year (QALY) gained. Scenario analysis, and one-way and probabilistic sensitivity analysis were performed. Results: The effectiveness of oral semaglutide was 10.39 QALYs with a total cost of $30,223.10, while placebo provided 10.13 QALYs at a lower total cost of $20,039.19. Oral semaglutide was not cost-effective at an ICER of $39,853.22 and $88,776.61 per QALY compared to placebo and exenatide at the WTP. However, at an annual price of $1,871.9, it was cost-effective compared with dulaglutide, liraglutide, and lixisenatide. The model was most sensitive to the discount rate and annual cost of oral semaglutide. The price of oral semaglutide needed to be reduced to $1,711.03 per year to be cost-effective compared to placebo and other injectable GLP-1 RAs except for exenatide and semaglutide injection. Conclusion: We found that once-daily oral semaglutide, at a comparable price of semaglutide injection, proves to be a cost-effective add-on therapy to insulin for Chinese patients with T2DM, especially when compared to subcutaneous GLP-1 RAs other than injectable semaglutide and exenatide. However, to achieve cost-effectiveness in comparison to placebo, further cost reduction of oral semaglutide is necessary. The estimated annual cost of $1,711.03 for oral semaglutide demonstrates a more cost-effective option than placebo, highlighting its potential value in the management of T2DM.

A Significant Effect of Oral Semaglutide on Cardiovascular Risk Factors in Patients With Type 2 Diabetes.

The once-daily glucagon-like peptide 1 (GLP-1) analogue, liraglutide has been shown to reduce major adverse cardiovascular events (MACE) and progression of chronic kidney disease (CKD). The once-weekly GLP-1 analogue, semaglutide also reduced MACE and renal events. Based on the evidence for GLP-1 analogues on MACE and renal events, the guideline recommended to treat high-risk diabetic individuals with GLP-1 analogues to reduce MACE and CKD progression. Recently, a once-daily oral semaglutide was developed and shown to reduce MACE. However, its effects on renal outcome and cardiovascular metabolic risk factors remain unknown. We retrospectively picked up patients who had taken oral semaglutide from March 2021 to June 2022 and compared metabolic parameters at baseline with the data at 3, 6 months after the start of oral semaglutide. We found 47 patients who had taken oral semaglutide. Body weight significantly decreased at 3 and 6 months after the start of oral semaglutide, and systolic blood pressure significantly decreased after 6 months. Hemoglobin A1c (HbA1c) tended to decrease after 3 months and significantly deceased after 6 months. Serum low-density lipoprotein cholesterol (LDL-C) levels significantly decreased after 6 months and non-high-density lipoprotein-cholesterol (non-HDL-C) levels tended to decrease after 6 months. Urinary albumin to creatinine ratio (UACR) tended to decrease after 3 and 6 months. Such favorable metabolic changes by oral semaglutide were observed more prominently in patients who had not ever used GLP-1 analogues than in patients who switched from subcutaneous GLP-1 analogues. Our study showed that oral semaglutide improved body weight, blood pressure, HbA1c, LDL-C, non-HDL-C and UACR, in type 2 diabetic obese patients, especially, in patients who had not ever used GLP-1 analogues.

Abstract 14730: Oral Semaglutide Provides Less Value for Money Than Subcutaneous Semaglutide for the Prevention of Major Adverse Cardiovascular Events, but Significantly More Value for Money for the Prevention of Cardiovascular Mortality

Introduction: Semaglutide, a subcutaneous Glucagon-Like Peptide-1 receptor agonist, reduces the risk of major adverse cardiovascular events (MACE) in patients with Type 2 diabetes mellitus (T2DM). An oral version of semaglutide is now available, and patients may prefer it over a subcutaneous injection. The value for money of the oral version for the prevention of MACE is not clear. Hypothesis: Oral semaglutide provides less value for money than subcutaneous semaglutide for the prevention of MACE, but more value for money for the prevention of the single endpoint of cardiovascular mortality (CVM). Methods: We calculated the cost needed to prevent (CNT) one MACE, by multiplying the one-year number needed to treat to prevent one event, by the annual cost of the therapy. Efficacy estimates were extracted from published RCT data. The CNT to prevent one event of the single endpoint of CVM was analyzed as a secondary outcome. We performed a sensitivity analysis to mitigate primary differences between the RCTs. Drug costs were calculated as 75% of the US National Average Drug Acquisition Cost listing in June 2020. Results: The CNT to prevent one MACE with subcutaneous semaglutide in SUSTAIN-6 is $641,823 ($402,021-$3,533,533) compared to $855,040 (95% CI: $420,840-∞) with oral semaglutide in PIONEER 6. The lower cost of subcutaneous semaglutide was confirmed in a sensitivity analysis simulating the effects of the drugs in both RCTs. The CNT to prevent one CVM with semaglutide is $16,342,560 ($2,020,704.00-∞) compared to $1,315,720 (95% CI: $921,004-$8,392,414) with oral semaglutide. Conclusions: Subcutaneous semaglutide prescribed for the prevention of MACE in patients with T2DM is moderately cost-saving compared to oral semaglutide for the same purpose. However, for the prevention of CVM, the oral version provides significantly better economic value.

Pharmacokinetics and Clinical Implications of Oral Semaglutide for Type 2 Diabetes Mellitus.

Since the approval of subcutaneous glucagon-like peptide-1 receptor agonists, this therapeutic class has become a preferred choice for the management of type 2 diabetes due to A1C reduction, minimal risk of hypoglycemia, weight loss, and cardiovascular benefit. An oral option, with gastrointestinal absorption, would overcome any potential fear of injection among patients. Oral semaglutide has been studied in randomized controlled trials within the PIONEER program. From a robust pool of literature with a global patient population, oral semaglutide has been an effective option as monotherapy and combination therapy to improve clinical outcomes, such as A1C and body weight from baseline to week 78, depending on the randomized controlled trial. In addition, a noninferiority result was observed with oral semaglutide versus placebo in a cardiovascular outcomes trial in patients with type 2 diabetes with established cardiovascular disease or risk factors. Similar to injectable glucagon-like peptide 1 receptor agonists, transient nausea and vomiting was seen with oral semaglutide. Overall, this new oral option may be a choice for patients with barriers to injectable therapy. This review evaluates and summarizes the pharmacokinetics, pharmacodynamics, and clinical application of oral semaglutide in patients with type 2 diabetes.

&lt;p&gt;Cost–benefit comparison of liraglutide and sitagliptin in the treatment of type 2 diabetes in Thailand&lt;/p&gt;

AimLiraglutide, a once-daily subcutaneous glucagon-like peptide-1 (GLP-1) agonist, is approved for treatment of hyperglycemia in patients with type 2 diabetes mellitus (T2DM). For patients with established cardiovascular diseases, liraglutide has also been shown to reduce major cardiovascular events. However, its cost is relatively higher than other oral antidiabetic drugs. This study aims to compare the costs and benefits of liraglutide vs sitagliptin, in treating T2DM in Thailand.MethodsThis study consists of two parts. In part 1, the cost of keeping T2DM under control per patient (HbA1c<7.0% with no reported hypoglycemia and no body weight gain) with liraglutide (1.2 and 1.8 mg daily) was compared with using sitagliptin (100 mg daily). Costs were based on Thai local data. Clinical outcomes were based on head-to-head randomized controlled trials. Part 2 estimated the cost-per-controlled patient, based on major cardiovascular outcomes (cardiovascular death, nonfatal myocardial infarction, non-fatal stroke). Economic benefit was calculated as the reduction in cardiovascular outcomes.ResultsIn Thailand, liraglutide (1.8 mg daily) costs 7.37-times more than sitagliptin 100 mg. The cost per patient achieving a composite clinical endpoint (HbA1c<7.0%, with no weight gain and no hypoglycemic events) in patients with T2DM receiving liraglutide 1.8 mg is 2.80-times higher than patients receiving sitagliptin 100 mg. When cardiovascular benefits (reduced composite endpoint of major cardiovascular events, ie, cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke) were taken into account, it was found that liraglutide had lower cost than sitagliptin, resulting in estimated savings of 20,085 THB (620 USD) per patient per year.ConclusionThe clinical benefits of liraglutide (HbA1c<7.0%, no hypoglycemia, no weight gain, reduced cardiovascular outcomes) partly offset its high price. Therefore, liraglutide should be considered as an appropriate treatment alternative to sitagliptin, particularly for T2DM patients with high cardiovascular risks.

Efficacy and safety of oral semaglutide with flexible dose adjustment versus sitagliptin in type 2 diabetes (PIONEER 7): a multicentre, open-label, randomised, phase 3a trial

Oral semaglutide is the first oral formulation of a glucagon-like peptide-1 (GLP-1) receptor agonist developed for the treatment of type 2 diabetes. We aimed to compare the efficacy and safety of flexible dose adjustments of oral semaglutide with sitagliptin 100 mg. In this 52-week, multicentre, randomised, open-label, phase 3a trial, we recruited patients with type 2 diabetes from 81 sites in ten countries. Patients were eligible if they were aged 18 years or older (19 years or older in South Korea), had type 2 diabetes (diagnosed ≥90 days before screening), HbA1c of 7·5-9·5% (58-80 mmol/mol), and were inadequately controlled on stable daily doses of one or two oral glucose-lowering drugs (for 90 days or more before screening). Participants were randomly assigned (1:1) by use of an interactive web-response system, stratified by background glucose-lowering medication at screening, to oral semaglutide with flexible dose adjustments to 3, 7, or 14 mg once daily or sitagliptin 100 mg once daily. To approximate treatment individualisation in clinical practice, oral semaglutide dose could be adjusted on the basis of prespecified HbA1c and tolerability criteria. Two efficacy-related estimands were prespecified: treatment policy (regardless of treatment discontinuation or use of rescue medication) and trial product (on treatment and without use of rescue medication) for participants randomly assigned to treatment. The primary endpoint was achievement of HbA1c of less than 7% (53 mmol/mol) at week 52 and the confirmatory secondary efficacy endpoint was change in bodyweight from baseline to week 52. Safety was assessed in all participants who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT02849080, and European Clinical Trials Database, EudraCT number 2015-005593-38, and an open-label extension is ongoing. Between Sept 20, 2016, and Feb 7, 2017, of 804 patients assessed for eligibility, 504 were eligible and randomly assigned to oral semaglutide (n=253) or sitagliptin (n=251). Most participants were male (285 [57%] of 504) with a mean age of 57·4 years (SD 9·9). All participants were given at least one dose of their allocated study drug except for one participant in the sitagliptin group. From a mean baseline HbA1c of 8·3% (SD 0·6%; 67 mmol/mol [SD 6·4]), a greater proportion of participants achieved an HbA1c of less than 7% with oral semaglutide than did with sitagliptin (treatment policy estimand: 58% [134 of 230] vs 25% [60 of 238]; and trial product estimand: 63% [123 of 196] vs 28% [52 of 184]). The odds of achieving an HbA1c of less than 7% was significantly better with oral semaglutide than sitagliptin (treatment policy estimand: odds ratio [OR] 4·40, 95% CI 2·89-6·70, p<0·0001; and trial product estimand: 5·54, 3·54-8·68, p<0·0001). The odds of decreasing mean bodyweight from baseline to week 52 were higher with oral semaglutide than with sitagliptin (estimated mean change in bodyweight, treatment policy estimand: -2·6 kg [SE 0·3] vs -0·7 kg [SE 0·2], estimated treatment difference [ETD] -1·9 kg, 95% CI -2·6 to -1·2; p<0·0001; and trial product estimand: -2·9 kg [SE 0·3] vs -0·8 kg [SE 0·3], ETD -2·2 kg, -2·9 to -1·5; p<0·0001). Adverse events occurred in 197 (78%) of 253 participants in the oral semaglutide group versus 172 (69%) of 250 in the sitagliptin group, and nausea was the most common adverse event with oral semaglutide (53 [21%]). Two deaths occurred in the sitagliptin group during the trial. Oral semaglutide, with flexible dose adjustment, based on efficacy and tolerability, provided superior glycaemic control and weight loss compared with sitagliptin, and with a safety profile consistent with subcutaneous GLP-1 receptor agonists. Novo Nordisk A/S.

Addition of metformin to exogenous glucagon-like peptide–1 results in increased serum glucagon-like peptide–1 concentrations and greater glucose lowering in type 2 diabetes mellitus

Glucagon-like peptide–1 (GLP-1) is an incretin hormone that lowers blood glucose after meals in type 2 diabetes mellitus. The therapeutic potential of GLP-1 in diabetes is limited by rapid inactivation by the enzyme dipeptidylpeptidase-4 (DPP-4). Metformin has been reported to inhibit DPP-4. Here we investigated the acute effects of metformin and GLP-1 alone or in combination on plasma DPP-4 activity, active GLP-1 concentrations, and glucose lowering in type 2 diabetes mellitus. Ten subjects with type 2 diabetes mellitus (8 male and 2 female; age, 68.7 ± 2.6 years [mean ± SEM]; body mass index, 29.6 ± 1.7 kg/m2; hemoglobin A1c, 7.0% ± 0.1%) received 1 of 3 combinations after an overnight fast in a randomized crossover design: metformin 1 g orally plus subcutaneous injection saline (Metformin), GLP-1 (1.5 nmol/kg body weight subcutaneously) plus placebo tablet (GLP-1), or metformin 1 g plus GLP-1(Metformin + GLP-1). At 15 minutes, glucose was raised to 15 mmol/L by rapid intravenous infusion of glucose; and responses were assessed over the next 3 hours. This stimulus does not activate the enteroinsular axis and secretion of endogenous GLP-1, enabling the effect of exogenously administered GLP-1 to be examined. Mean area under curve (AUC) 0-180 minutes plasma glucose responses were lowest after Metformin + GLP-1 (mean ± SEM, 1629 ± 90 mmol/[L min]) compared with GLP-1 (1885 ± 86 mmol/[L min], P < .002) and Metformin (2045 ± 115 mmol/[L min], P < .001). Mean AUC serum insulin responses were similar after either Metformin + GLP-1 (5426 ± 498 mU/[L min]) or GLP-1 (5655 ± 854 mU/[L min]) treatment, and both were higher than Metformin (3521 ± 410 mU/[L min]; P < .001 and P < .05, respectively). Mean AUC for plasma DPP-4 activity was lower after Metformin + GLP-1 (1505 ± 2 μmol/[mL min], P < .001) and Metformin (1508 ± 2 μmol/[mL min], P < .002) compared with GLP-1 (1587 ± 3 μmol/[mL min]). Mean AUC measures for plasma active GLP-1 concentrations were higher after Metformin + GLP-1 (820 × 104 ± 51 × 104 pmol/[L min]) compared with GLP-1 (484 × 104 ± 31 × 104 pmol/[L min], P < .001) and Metformin (419 × 104 ± 34 × 104 pmol/[L min], P < .001), respectively. In patients with type 2 diabetes mellitus, metformin inhibits DPP-4 activity and thus increases active GLP-1 concentrations after subcutaneous injection. In combination with GLP-1, metformin significantly lowers plasma glucose concentrations in type 2 diabetes mellitus subjects compared with GLP-1 alone, whereas insulin responses were similar. Metformin enhances serum concentrations of injected active GLP-1(7-36)amide, and the combination results in added glucose-lowering potency.

No increased risk of hypoglycaemic episodes during 48 h of subcutaneous glucagon‐like‐peptide‐1 administration in fasting healthy subjects

It is uncertain whether the ability to avoid hypoglycaemia during fasting is preserved, and the risk of reactive hypoglycaemia after an oral glucose stimulus following a prolonged fasting period is increased at augmented glucagon-like peptide-1 (GLP-1) levels. A randomized, double-blind placebo-controlled cross-over study in eight healthy men to assess the safety, in terms of hypoglycaemia, of a continuously infused pharmacological dose of native GLP-1 during long-term fasting. After an overnight fast the fasting period continued for 48 h and was followed by a 3-h oral glucose tolerance test (OGTT). GLP-1(7-36 amide) or placebo was continuously infused subcutaneously and titrated to a dose of 4.8 pmol/kg per min. Two subjects in the GLP-1 group and one subject in the placebo group were withdrawn due to protocol specified plasma glucose (PG) < or = 2.8 mm and neuroglycopaenic symptoms. The infusion of GLP-1 resulted in pharmacological levels of intact GLP-1. During the fasting period PG, insulin and C-peptide levels declined and glucagon, GH and free fatty acid (FFA) levels increased with no differences between GLP-1 and placebo. During OGTT circulating levels of insulin and C-peptide were higher with GLP-1 infusion. However, PG was similar during GLP-1 vs. placebo infusions. GLP-1 infusion increased norepinephrine and cortisol levels during OGTT. The counter-regulatory response during 48 h of subcutaneous GLP-1 infusion was preserved despite long-term fasting with no apparent increased risk of hypoglycaemic episodes. No reactive hypoglycaemia was observed when the fast was followed by an OGTT. Thus use of long-acting GLP-1 analogues may not increase the risk of hypoglycaemia.

Is Exenatide Improving the Treatment of Type 2 Diabetes? Analysis of the Individual Clinical Trials with Exenatide

The obesity epidemic in the developed and developing world is being followed by an epidemic of type 2 diabetes. In type 2 diabetes, subjects cannot manage glucose properly because they do not produce enough insulin, and the peripheral tissues have become resistant to insulin. Glucagon-like peptide 1 (GLP-1) is an intestinal peptide hormone that is secreted in response to food to regulate the postprandial blood glucose concentration. One of the actions of GLP-1 is to stimulate insulin secretion. In subjects with type 2 diabetes, intravenous or subcutaneous GLP-1 stimulated insulin production and decreased blood glucose levels. However, as GLP-1 is rapidly metabolised, it is not suitable for use in most subjects with type 2 diabetes. Exendin-4 is a 39-amino acid peptide that acts as an agonist at the GLP-1 receptor. After subcutaneous administration, synthetic exendin-4 (exenatide) decreased postprandial concentrations of glucose and insulin, and fasting glucose levels in subjects with type 2 diabetes, and the effects lasted several hours. Subsequently, exenatide was been trialled in subjects taking metformin only, a sulfonylurea only, or metformin and a sulfonylurea, and shown to improve glycemic control with few adverse events, initially over 30 weeks, and then extended to 82 weeks. Exenatide may also be as effective as insulin glargine in subjects with type 2 diabetes not adequately controlled with the oral agents. In conclusion, exenatide represents a new and beneficial addition to the medicines used to treat type 2 diabetes.

Glucagon-like peptide 1 (GLP-1) and incretin mimetics for the treatment of diabetes

Glucagon-like peptide 1 (GLP-1) was discovered as an insulinotropic (‘incretin’) hormone, suggesting a physiological role in the potentiation of insulin secretory responses after oral glucose or meals. The incretin effect (i.e. the phenomenon that more insulin is secreted in response to oral as compared to intravenous glucose) is reduced/lost in patients with type 2 diabetes. GLP − 1(a) stimulates insulin secretion in a glucose-dependent manner, (b) suppresses glucagon, (c) reduces appetite and food intake, (d) decelerates gastric emptying, (e) stimulates pancreatic β cell neogenesis, growth and differentiation in animal and tissue culture experiments, and (f) inhibits β cell apoptosis in vitro. Intravenous GLP-1 normalises and subcutaneous GLP-1 significantly lowers plasma glucose in the majority of patients with type 2 diabetes. GLP-1 itself, however, is not useful for chronic antidiabetic treatment, because it is too rapidly inactivated by proteolysis (DPP-4) and eliminated from the circulation. Agents interacting with GLP-1 receptors in pancreatic islets or the (central) nervous system have been found (like exendin-4) or developed as ‘incretin mimetics’ (like liraglutide). Clinical trials with exenatide (two injections per day) and liraglutide (one injection per day) have shown reductions in glucose concentrations and HbA1c by approximately 1%, associated with moderate weight loss (2-3 kg), but also some nausea and, rarely, vomiting. This new class of antidiabetic agents will be available for clinical use pending completion of phase 3 trials and/or approval by regulatory agencies after 2005 (USA) and 2007 (Europe). Copyright © 2005 John Wiley & Sons, Ltd.

Glucagon-like Peptide 1 (GLP-1) in the Treatment of Diabetes

Glucagon-like peptide 1 (GLP-1) was discovered as an incretin (insulinotropic gut) hormone. Biological actions of GLP-1 in healthy and type 2 diabetic subjects include (a) stimulation of insulin secretion in a glucose-dependent manner, (b) suppression of glucagon, (c) reduction in appetite and food intake, (d) deceleration of gastric emptying. In animal experiments, in addition, (e) stimulation of beta-cell neogenesis, growth and differentiation in animal and tissue culture experiments, and (f) in vitro inhibition of beta-cell apoptosis induced by different agents have been observed. Since the incretin effect--the higher insulin secretory response to oral as compared to intravenous glucose loads - is reduced in patients with Type 2 diabetes, GLP-1 has been used to pharmacologically replace incretin. Intravenous GLP-1 can normalise, and subcutaneous GLP-1 can significantly lower plasma glucose in the majority of patients with Type 2 diabetes. The magnitude of this effect does not greatly depend on patient characteristics such as age, sex, obesity, or baseline insulin and glucagon, with minor influences of previous antidiabetic therapy and actual metabolic control. GLP-1 itself, however, is inactivated rapidly in vivo by the protease DPP IV and can only be used for short-term metabolic control, such as in intensive care units (potentially useful in patients with acute myocardial infarction, coronary surgery, cerebrovascular events, septicaemia, during the perioperative period and while on parenteral nutrition). For more long-term metabolic control, incretin mimetics (agonists at the GLP-1 receptor) with more favourable pharmacokinetic profiles should be used.

Appetite regulation: from the gut to the hypothalamus.

these proportions had increased to 26% and 22%, respectively, with 55% of women and 66% of men being overweight (BMI > 25 kg/m 2 ; Health Survey for England, 2001), reflecting a worldwide trend which is most marked in, but not restricted to, the developed world. Most of us in affluent countries live in a privileged land of plenty where high calorie foods are easily available and in which we have a limited need for exercise. The rising prevalence of obesity in children is of particular concern (Chinn & Rona, 2001).

Preproglucagon derived peptides and thyrotropin (TSH) secretion in the rat: Robust and sustained lowering of blood TSH levels in exendin-4 injected animals

We have investigated the acute effects of preproglucagon derived peptides (PGDP) - glucagon, glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2 (GLP-2), and exendin-4 (EX4), a GLP-1 receptor agonist, on thyrotropin (TSH) secretion in the rat. Within 120 min after subcutaneous injection, neither glucagon nor GLP-1 or GLP-2 had an effect on blood rTSH concentration in adult female rat. On the contrary, EX4 injection significantly lowered the plasma thyrotropin level. A potent inhibitory effect of EX4 administration on blood rTSH level was seen even 12 h after bolus peptide administration, whereas EX4-induced elevation in blood glucose concentration returned to normal values after 6 h of experiment. EX4 administration in doses from 0.05 to 1.00 nmol/100 g body weight resulted in very similar drop in blood rTSH levels. To check whether EX4-induced lowering in blood rTSH concentrations may be prevented by exendin-(9-39) [EX(9-39)], rats were treated with EX4 and/or EX(9-39). Both the bolus administration and the 3-day treatment with EX(9-39) notably lowered blood rTSH concentration of studied rats. Administration of EX(9-39) did not change blood rTSH response to EX4. Results of our in vivo studies are rather unexpected and raise serious questions on the specificity of EX4 and EX(9-39) action in vivo. Since both the native EX4 molecule as well as its truncated form [EX(9-39)] exerts a similar inhibitory effect on TSH secretion in the rat, it seems legitimate to suggest that this action depends only on 9-39 amino acid sequence of EX4. Moreover, obtained results suggest that both EX4 and EX(9-39)-evoked inhibition of TSH secretion in the rat is not dependent on their interaction with GLP-1 receptor only. Detailed mechanism of such action remains to be elucidated.

Subcutaneous glucagon-like peptide-1 improves postprandial glycaemic control over a 3-week period in patients with early Type 2 diabetes

1.Glucagon-like peptide-1 (7-36) amide (GLP-1) is released into the circulation after meals and is the most potent physiological insulinotropic hormone in man. GLP-1 has the advantages over other therapeutic agents for Type 2 diabetes of also suppressing glucagon secretion and delaying gastric emptying. One of the initial abnormalities of Type 2 diabetes is the loss of the first-phase insulin response, leading to postprandial hyperglycaemia.2. To investigate the therapeutic potential of GLP-1 in Type 2 diabetes, six patients were entered into a 6-week, double-blind crossover trial during which each received 3 weeks treatment with subcutaneous GLP-1 or saline, self-administered three times a day immediately before meals. A standard test meal was given at the beginning and end of each treatment period.3.GLP-1 reduced plasma glucose area under the curve (AUC) after the standard test meal by 58% (AUC, 0-240 min: GLP-1 start of treatment, 196+/-141 mmol.min-1.l-1; saline start of treatment, 469+/-124 mmol.min-1.l-1; F=16.4, P<0.05). The plasma insulin excursions were significantly higher with GLP-1 compared with saline over the initial postprandial 30 min, the time period during which the GLP-1 concentration was considerably elevated. The plasma glucagon levels were significantly lower over the 240-min postprandial period with GLP-1 treatment. The beneficial effects of GLP-1 on plasma glucose, insulin and glucagon concentrations were fully maintained for the 3-week treatment period. 4. We have demonstrated a significant improvement in postprandial glycaemic control with subcutaneous GLP-1 treatment. GLP-1 improves glycaemic control partially by restoring the first-phase insulin response and suppressing glucagon and is a potential treatment for Type 2 diabetes.

Subcutaneous glucagon-like peptide-1 improves postprandial glycaemic control over a 3-week period in patients with early Type 2 diabetes

Subcutaneous glucagon-like peptide-1 improves postprandial glycaemic control over a 3-week period in patients with early Type 2 diabetes

Mechanisms of the antidiabetic action of subcutaneous glucagon-like peptide-1(7-36)amide in non-insulin dependent diabetes mellitus

Twelve patients with non-insulin dependent diabetes mellitus (NIDDM) under secondary failure to sulfonylureas were studied to evaluate the effects of subcutaneous glucagon-like peptide-1(7-36)amide (GLP-1) on (a) the gastric emptying pattern of a solid meal (250 kcal) and (b) the glycemic and endocrine responses to this solid meal and an oral glucose tolerance test (OGTT, 300 kcal). 0.5 nmol/kg of GLP-1 or placebo were subcutaneously injected 20 min after meal ingestion. GLP-1 modified the pattern of gastric emptying by prolonging the time to reach maximal emptying velocity (lag period) which was followed by an acceleration in the post-lag period. The maximal emptying velocity and the emptying half-time remained unaltered. With both meals, GLP-1 diminished the postprandial glucose peak, and reduced the glycemic response during the first two postprandial hours by 54.5% (solid meal) and 32.7% (OGTT) (P < 0.05). GLP-1 markedly stimulated insulin secretion with an effect lasting for 105 min (solid meal) or 150 min (OGTT). The postprandial increase of plasma glucagon was abolished by GLP-1. GLP-1 diminished the postprandial release of pancreatic polypeptide. The initial and transient delay of gastric emptying, the enhancement of postprandial insulin release, and the inhibition of postprandial glucagon release were independent determinants (P < 0.002) of the postprandial glucose response after subcutaneous GLP-1. An inhibition of efferent vagal activity may contribute to the inhibitory effect of GLP-1 on gastric emptying.

Exogenous Administration of Subcutaneous Glucagon-Like Peptide-1 (7–36) Amide Causes Hypoglycaemia in Fasted Healthy Volunteers

Exogenous Administration of Subcutaneous Glucagon-Like Peptide-1 (7–36) Amide Causes Hypoglycaemia in Fasted Healthy Volunteers

Pharmacokinetic, insulinotropic, and glucagonostatic properties of GLP-1 [7?36 amide] after subcutaneous injection in healthy volunteers. Dose-response-relationships

Intravenous infusions of glucagon-like peptide 1 (GLP-1) [7-36 amide] are glucose-dependently insulinotropic and glucagonostatic and normalize plasma glucose concentrations in non-insulin-dependent diabetic patients. It was the aim of this study to investigate whether subcutaneous GLP-1 [7-36 amide] also has an influence on insulin and glucagon secretion, and which doses are required for significant effects. Therefore, eight healthy volunteers (24 +/- 2 years, body mass index [BMI] 21.9 +/- 2.3 kg/m2) were studied in the fasting state on five occasions in randomized order. Placebo (0.9% NaCl with 1% human serum albumin) or GLP-1 [7-36 amide] in doses of 0.15, 0.5, 1.5 or 4.5 nmol/kg body weight (volume 1 ml or, at the highest dose, 2 ml) was administered subcutaneously. An intravenous glucose bolus (0.33 g/kg body weight) was injected 30 min later. Blood was drawn for the measurement of glucose, insulin, C-peptide, GLP-1 [7-36 amide], and glucagon using specific radioimmunoassays. There were dose-related increments in GLP-1 [7-36 amide] concentrations (p < 0.0001). However, basal values were reached again after 90-120 min. Before glucose administration, insulin (p < 0.0001) and C-peptide (p < 0.0004) increased, whereas glucagon (p = 0.0018) and glucose (p < 0.0001) decreased in a dose-dependent manner. After glucose stimulation, integrated increments in insulin (p = 0.0007) and C-peptide (p = 0.02) were augmented and kG-values increased (p < 0.0001) in a dose-related fashion. The extent of reactive hypoglycaemia was related to the GLP-1 [7-36 amide] dose.(ABSTRACT TRUNCATED AT 250 WORDS)