touchENDOCRINOLOGY touchENDOCRINOLOGY
Diabetes
Read Time: 10 mins

Positioning Glucagon-like-peptide-1-based Treatments within an Optimal Management Regimen for Type 2 Diabetes

Copy Link
Published Online: Nov 16th 2011 European Endocrinology, 2008; 4:44-47; DOI: http://doi.org/10.17925/EE.2008.04.00.44
Authors: Katrine Bagge Hansen, Filip Krag Knop, Tina Vilsb
Quick Links:
Article
Article Information
Article:

Type 2 diabetes is characterised by high blood sugar caused by the inability of the pancreas to produce sufficient insulin, in combination with a loss of the normal reciprocal relationship between glucose and glucagon concentrations in the blood and impaired tissue sensitivity to insulin. In the longer term, high blood glucose concentrations can result in long-term diabetic complications, dramatically increasing the risk of early death.

Type 2 diabetes is characterised by high blood sugar caused by the inability of the pancreas to produce sufficient insulin, in combination with a loss of the normal reciprocal relationship between glucose and glucagon concentrations in the blood and impaired tissue sensitivity to insulin. In the longer term, high blood glucose concentrations can result in long-term diabetic complications, dramatically increasing the risk of early death. Although a range of different antidiabetic oral treatment options exist, current management of type 2 diabetes is often associated with weight gain and a risk of hypoglycaemia, and a combination of antidiabetic agents is often required. Furthermore, most treatment options do not target the multifaceted pathophysiology of type 2 diabetes. In contrast, newly developed incretinbased therapies of type 2 diabetes employ beta-cell-preserving properties, and may restore reduced glucose-induced insulin secretion in type 2 diabetes. In addition, these agents do not appear to promote weight gain or hypoglycaemia. This review focuses on the position of the incretin-based treatments within an optimal management regimen for patients with type 2 diabetes.

Incretin Hormones

The term ‘incretin effect’ refers to the amplification of insulin secretion elicited by hormones secreted from the gastrointestinal tract. The effect is based on the observation that for equivalent levels of glycaemia, oral glucose results in considerably more insulin being released than intravenous (IV) glucose does. It has become clear that augmentation of glucose-stimulated insulin release by hormones secreted from the gut accounts for up to 70% of the insulin secretion following oral glucose ingestion.1 Two known hormones act as incretins: glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). GIP is released from endocrine K cells distributed primarily in the mucosa of the duodenum and upper jejunum. The release of GIP is tightly linked to the presence, digestion and absorption of glucose and fat in the small intestine.2,3 GLP-1 is released from endocrine L cells distributed primarily in the mucosa of the more distal part of the small intestine and colon. Secretion is mediated by the presence and absorption of nutrients,3 but also seems to be mediated by neural signals4,5 eliciting responses before nutrients have actually reached the small intestine. However, recent observations indicate that GIP and GLP-1 are co-localised in a subset of endocrine cells throughout the gastrointestinal tract.6–8 This finding may explain the fast secretory responses following ingestion of nutrients, but other mechanisms – for instance, paracrine interaction between the two incretin hormones, as indicated by data in dogs,9 and intrinsic neuroendocrine mechanisms10 – may be involved.

After the secretion of GIP and GLP-1, both hormones are degraded by the enzyme dipeptidyl peptidase 4 (DPP-4).11–14 While GLP-1 is rapidly degraded in the circulation with an apparent half-life of 1–1.5 minutes,15,16 GIP is degraded more slowly, with a half-life for the intact hormone of seven minutes.17,18 Both hormones possess strong glucosedependent insulinotropic properties. They are active with respect to enhancing glucose-induced insulin secretion from the beginning of a meal and they contribute almost equally to the potentiation of postprandial glucose-induced insulin secretion, but with the effect of GLP-1 predominating at higher glucose levels.19,20 GLP-1 has an inhibitory effect on glucagon secretion, but this is observed only at glucose levels at or above fasting levels, which implies that GLP-1 does not weaken the counter-regulatory response to hypoglycaemia.21 In contrast, GIP has been shown to stimulate glucagon secretion. Furthermore, GLP-1 enhances all steps of insulin biosynthesis and insulin gene transcription, improves beta-cell function (and beta-cell mass, according to data from animal experiments) and prevents apoptosis (programmed cell death) of beta-cells.22 Finally, and very importantly, GLP-1 enhances satiety and reduces food intake, probably due to a combination of activation of GLP-1 receptors in the central nervous system and inhibition of gastrointestinal motility.23,24

Incretin Hormones in Type 2 Diabetes

In 1986, it was shown that the incretin effect is strongly reduced in patients with type 2 diabetes (~30% versus ~70% in healthy subjects).25 In the majority of patients with type 2 diabetes, the reduced incretin effect is accompanied by a moderate degree of GLP-1 hyposecretion (a reduction of approximately 15%)26 and a weakened insulinotropic potency of GLP-1 at physiological concentrations, although at supraphysiological doses GLP-1 is able to elicit robust insulin responses in patients with type 2 diabetes.27 As opposed to GLP-1, GIP is secreted normally or even hypersecreted in patients with type 2 diabetes.28 However, beta-cell responsiveness to GIP is greatly reduced with an almost complete loss of late-phase insulin secretion in response to even supraphysiological doses.29

Theoretically, changes in plasma DPP-4 activity and/or the elimination rates of the incretin hormones could contribute to the reduced incretin effect in patients with type 2 diabetes; however, such differences have not been found to exist between patients with type 2 diabetes and healthy control subjects. It is assumed that the incretin-related deficiencies could contribute to the inability of type 2 diabetes patients to adjust their insulin secretion to their needs. The molecular mechanisms underlying the reduced incretin effect, the affected betacell sensitivity to GLP-1 and the near loss of the insulinotropic effect of GIP are currently unknown. However, recent data indicate that the incretin-related deficits are consequences of the diabetic state (and/or insulin-resistant state) rather than primary pathogenetic factors,30–32 implying that it may be possible to correct these deficiencies through intervention. Accordingly, physicians have recently been armed with new antidiabetic drugs based on incretin hormones, adding to the arsenal of existing treatment modalities aimed at controlling glucose homeostasis in type 2 diabetes.

Current Treatment Modalities

The aim of diabetic treatment is to control the glucose homeostasis as tightly as possible to prevent the risk of macro- and microvascular complications and early death, without adverse effects such as hypoglycaemia. With the revision to the 2008 clinical practice recommendation, the glycated haemoglobin (HbA1c) goal for nonpregnant adults in general is below 7%, and for selected individuals below 6%.33 Because of the complex nature of the disease, glycaemic control remains difficult and often requires several antidiabetic drugs in addition to lifestyle interventions (exercise, diet, weight control). Even when the disease is being fought in an optimal interdisciplinary setting with a maximum polypharmaceutical approach, the recommended goals are difficult to achieve. This is partly due to the fact that type 2 diabetes is a progressive disease with an almost linear decline in beta-cell function (probably combined with a decrease in beta-cell mass) over time.

The pre-existing oral antidiabetic drugs reduce blood sugar levels by different mechanisms. Biguanides (e.g. metformin) decrease hepatic glucose production, decrease intestinal glucose absorption and increase glucose uptake by skeletal muscle and fat. Sulphonylureas (e.g. glimeperide) and glinides stimulate pancreatic insulin secretion. Thiazolidinediones decrease hepatic glucose output and increase insulin-dependent glucose uptake in skeletal muscle and fat. Alphaglucosidase inhibitors inhibit pancreatic alpha-amylase and membranebound alpha-glucosidase enzymes and prevent intestinal disaccharide metabolism, thereby reducing glucose utilisation and absorption from ingested carbohydrates. Despite the relatively broad range of different targets within the existing types of oral antidiabetic therapies, a number of shortcomings are associated with them – even when they are used in combination. These include inadequate efficiency in glucose lowering, limited durability of glycaemic response, inconvenient dosing regimens and safety and tolerability issues. The most common adverse effects are gastrointestinal discomfort (especially with biguanide and alpha-glucosidase inhibitors), weight gain (especially with sulphonylureas and thiazolidinediones), hypoglycaemia (sulphonylureas) and elevated liver enzymes (thiazolidinediones, alpha-glucosidase inhibitors).34 None of the abovementioned oral antidiabetic drugs has been shown to preserve pancreatic beta-cell function over time and, notably, sulphonylureas have been shown to accelerate the apoptosis of the human betacells.35 Supplementation of endogenous insulin secretion with subcutaneous (SC) injections of insulin or insulin analogues may be necessary in patients with long-standing type 2 diabetes in order to compensate for their insulin deficiency. The major side effects of insulin treatment are weight gain and risk of hypoglycaemia.

The limitations of the pre-existing antidiabetic treatment modalities as outlined above make new medical therapies that offer improved efficacy and/or durability, better convenience and an improved safety and tolerability profile absolutely imperative in order to get more patients to glycaemic goal initially and to avoid or delay the need for additional treatment.

Glucagon-like-peptide-1-based Therapy

In 1993 Nauck et al. demonstrated that a four-hour continuous IV infusion of native GLP-1 is capable of normalising blood glucose concentrations in patients with type 2 diabetes.36 However, as a safe, reliable and compliant method of delivery, IV infusions are clearly not of any clinical utility. Next, in 2002 Zander et al. demonstrated that six weeks of continuous SC infusion of native GLP-1 (using an insulin pump) in patients with type 2 diabetes significantly decreased HbA1c and bodyweight and greatly improved the first-phase insulin response and maximal beta-cell secretory capacity.37 However, an important limitation to administration of the native hormone is the short half-life of native GLP-1, making it unsuitable as a therapeutic agent for the treatment of type 2 diabetes.38,39 Therefore, in order to exploit the beneficial actions of the hormone, long-acting stable analogues of GLP-1 – the so-called incretin mimetics – and orally available inhibitors of DPP-4, the enzyme responsible for the rapid degradation of GLP-1 and GIP – the so-called incretin enhancers – have been developed. Below, key points regarding the efficacy, safety and tolerability of the currently available incretin-based strategies will be dealt with in order to accommodate the positioning of incretin-based treatments within an optimal management regimen for type 2 diabetes.

Incretin Mimetics

GLP-1 analogues are agonists for the GLP-1 receptor and take advantage of the physiological actions of GLP-1. Thus, during treatment with these drugs both alpha- and beta-cell dysfunction are targeted, i.e. not only is glucose-induced insulin secretion enhanced, but also the disrupted insulin: glucagon ratio is improved. Furthermore, these drugs elicit the same effects on food intake and bodyweight as native GLP-1, treating one of the presumed cornerstones of type 2 diabetes – namely obesity. Lastly, it is hoped that the beta-cellprotective and beta-cell-trophic effects of the GLP-1 analogues, as observed in animal studies, will target the progressive structural and functional beta-cell deterioration of type 2 diabetes and lead to improvements in long-term pancreatic islet health.

Currently, many GLP-1 analogues are under clinical development, but so far only one drug has been introduced to the market: exenatide (Byetta®). Exenatide was isolated from the venom of the lizard Heloderma suspectum in a search for biologically active peptides.40 Exenatide shares only 53% homology with native GLP-1, but is equipotent and binds to and activates GLP-1 receptors on pancreatic beta-cells, following which insulin secretion and synthesis are initiated.41 Unlike native GLP-1, exenatide is not substantially degraded by DPP-4, but is cleared primarily in the kidneys by glomerular filtration,42 resulting in a plasma half-life for the peptide of approximately 30 minutes after IV administration.43 After SC injection of the maximally tolerated dose, the half-life is approximately two hours, and a significant elevation of exenatide in plasma may be observed for five to six hours, but is negligible after 12 hours postdose; this means that twice-daily doses are needed in order to obtain clinically significant effects on glycaemic control.44

Combining data from studies comparing GLP-1 analogues with placebo injections showed a statistically significant difference in HbA1c (approximately 1%) from baseline in favour of the GLP-1 analogues.45 Addition of exenatide to existing therapy (metformin or sulphonylurea) shows substantial benefits,46 with a 1.1% reduction in HbA1c after 26 weeks and a 2.3kg reduction in bodyweight compared with baseline. In an open-label extension of the study (three years), sustained effects were demonstrated with respect to glycaemic control and bodyweight, with a 1% decrease in HbA1c and a 5.3kg reduction in bodyweight. An important limitation of the study, in addition to its open-label design, was the high drop-out rate due to adverse events, loss of glucose control, patient/investigator decision or protocol violation, with only 217 subjects completing the study (three years) out of 517 randomised subjects.

Exenatide treatment has been compared with insulin glargine or biphasic insulin aspart, and after one year of treatment similar glycaemic control was obtained.47,48 In contrast to insulin therapy, treatment with exenatide resulted in clinically relevant reductions in post-prandial glycaemia and bodyweight after one year (bodyweight difference of more than 5kg).49 The major adverse effects of exenatide include mild to moderate nausea and vomiting; both seem to decline over time. Exenatide treatment is associated with a low risk of hypoglycaemia, apparently because of the glucose-dependent effect of GLP-1 on insulin secretion. However, when combined with sulphonylurea the risk of hypoglycaemia appears to be increased and to be dependent on the dose of sulphonylurea.

Exenatide is recommended as an add-on treatment to patients with type 2 diabetes who cannot achieve adequate glycaemic control on maximum tolerated doses of metformin and/or sulphonylureas. It is given by SC injections twice a day, starting with a dose of 5μg and increasing up to 10μg. Exenatide should not be used in patients with kidney failure.50

Incretin Enhancers

The antidiabetic effects of GLP-1 can also be exploited by protecting endogenous GLP-1 from degradation by the enzyme DPP4.51 Administration of inhibitors of this enzyme (incretin enhancers) increase the circulating levels of active GLP-1 and GIP, which is associated with the expected antidiabetic effects including stimulation of glucose-induced insulin secretion, inhibition of glucagon secretion and, possibly, preservation of beta-cell mass.52 The inhibitors are small molecules that are active upon oral administration, and, as mentioned, they appear to elicit effects on insulin and glucagon secretion that are very similar to those obtained with the incretin mimetics, which all require parenteral administration.53

Treatment with DPP-4 inhibitors does not decrease bodyweight, in contrast to the incretin mimetics (they are bodyweight-neutral). This is presumably because the plasma concentrations of active GLP-1 are dependent on endogenous secreted GLP-1 from the L cells and, therefore, are not high enough to exert this effect.54 Currently, two incretin enhancers are available on the market: sitagliptin (Januvia®) and vildagliptin (Galvus®). Both are administered orally, once and twice daily, respectively. Like the GLP-1 analogues, the DPP-4 inhibitors have been shown to lower HbA1c compared with placebo (by approximately 0.7%)55 and reduce post-prandial and fasting glucose levels.56 Treatment with DPP-4 inhibitors has now been prescribed to more than 4 million patients worldwide. Reported adverse effects in clinical trials and post-marketing studies are low, and close to the numbers seen during controlled trials with placebo treatment.57

Both compounds are recommended in combination with metformin and/or sulphonylureas or thiazolidinediones when diet and exercise plus the above-mentioned drugs do not provide adequate glycaemic control. No hypoglycaemia is associated with DPP-4 inhibitors in combination with metformin or thiazolidinediones, but when administered with a sulphonylurea compound the sulphonylurea dose may be lowered to reduce the risk of hypoglycaemia. Due to the renal clearance of the endogenous incretin hormones, sitagliptin should not be used in patients with kidney failure.58 Vildagliptin is metabolised in the liver; therefore, it should not be given to subjects with impaired liver function, and biochemical liver parameters should be measured on a regular basis.59

Conclusion and Perspectives

Most antidiabetic agents target only one aspect of the multifaceted pathophysiology of type 2 diabetes, and notably do not tackle the progressive deterioration of beta-cell function or the inappropriate glucagon secretion that accompanies type 2 diabetes. In contrast, incretin-based approaches are pleiotropic and, unlike existing therapies, both alpha- and beta-cell dysfunction are targeted. Comprehensive studies indicate that incretin-based therapies, perhaps especially because of their potential trophic effects on the pancreatic beta-cells, may halt the progression of disease that inevitably seems to accompany conventional treatment. The GLP-1-based treatments have shown significant and sustained improved glycaemic control combined with a minimised risk of hypoglycaemia – importantly, fear of hypoglycaemia is a common reason for non-compliance among diabetic patients. The incretin-based treatments have the additional benefit of weight loss (GLP-1 analogues) or sustained weight (DPP-4 inhibitors) in a patient population that is generally overweight or obese and tends to gain weight during most of the pre-existing antidiabetic treatments. The most prominent adverse effect of GLP-1 analogues is nausea, and adverse events during treatment with DPP-4 inhibitors are almost identical to those seen with treatment with placebo. Due to their relatively short history, long-term studies on safety and efficacy are lacking, but so far the GLP-1-based therapies seem to have promising potential to become important agents in the optimal management regimen for type 2 diabetes.■

References

  1. Nauck MA, Homberger E, Siegel EG, et al., Incretin effects of increasing glucose loads in man calculated from venous insulin and C-peptide responses, J Clin Endocrinol Metab, 1986;63(2):492–8.
  2. Ebert R, Creutzfeldt W, Reversal of impaired GIP and insulin secretion in patients with pancreatogenic steatorrhea following enzyme substitution, Diabetologia, 1980;19(3): 198–204.
  3. Knop FK, Vilsboll T, Larsen S, et al., Increased postprandial responses of GLP-1 and GIP in patients with chronic pancreatitis and steatorrhea following pancreatic enzyme substitution, Am J Physiol Endocrinol Metab, 2007;292(1): E324–E330.
  4. Baggio LL, Drucker DJ, Biology of incretins: GLP-1 and GIP, Gastroenterology, 2007;132(6):2131–57.
  5. Vahl T, D’Alessio D, Enteroinsular signaling: perspectives on the role of the gastrointestinal hormones glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide in normal and abnormal glucose metabolism, Curr Opin Clin Nutr Metab Care, 2003;6(4):461–8.
  6. Mortensen K, Petersen LL, Orskov C, Colocalization of GLP-1 and GIP in human and porcine intestine, Ann N Y Acad Sci, 2000;921:469–72.
  7. Mortensen K, Christensen LL, Holst JJ, Orskov C, GLP-1 and GIP are colocalized in a subset of endocrine cells in the small intestine, Regul Pept, 2003;114(2–3):189–96.
  8. Theodorakis MJ, Carlson O, Michopoulos S, et al., Human duodenal enteroendocrine cells: source of both incretin peptides, GLP-1 and GIP, Am J Physiol Endocrinol Metab, 2006;290(3):E550–E559.
  9. Damholt AB, Kofod H, Buchan AMJ, Immunocytochemical evidence for a paracrine interaction between GIP and GLP-1- producing cells in canine small intestine, Cell Tissue Res, 1999;298(2):287–93.
  10. Dube PE, Brubaker PL, Nutrient, neural and endocrine control of glucagon-like peptide secretion, Horm Metab Res, 2004;36(11–12):755–60.
  11. Deacon CF, Nauck MA, Toft-Nielsen M, et al., Both subcutaneously and intravenously administered glucagon-like peptide I are rapidly degraded from the NH2-terminus in type II diabetic patients and in healthy subjects, Diabetes, 1995;44(9):1126–31.
  12. Deacon CF, Nauck MA, Meier J, et al., Degradation of endogenous and exogenous gastric inhibitory polypeptide in healthy and in type 2 diabetic subjects as revealed using a new assay for the intact peptide, J Clin Endocrinol Metab, 2000;85(10):3575–81.
  13. Kieffer TJ, McIntosh CH, Pederson RA, Degradation of glucose-dependent insulinotropic polypeptide and truncated glucagon-like peptide 1 in vitro and in vivo by dipeptidyl peptidase IV, Endocrinology, 1995;136(8):3585–96.
  14. Pederson RA, Kieffer TJ, Pauly R, et al., The enteroinsular axis in dipeptidyl peptidase IV-negative rats, Metabolism, 1996;45(11):1335–41.
  15. Deacon CF, Nauck MA, Toft-Nielsen M, et al., Both subcutaneously and intravenously administered glucagon-like peptide I are rapidly degraded from the NH2-terminus in type II diabetic patients and in healthy subjects, Diabetes, 1995;44(9):1126–31.
  16. Vilsboll T, Agerso H, Krarup T, Holst JJ, Similar elimination rates of glucagon-like peptide-1 in obese type 2 diabetic patients and healthy subjects, J Clin Endocrinol Metab, 2003;88(1):220–24.
  17. Deacon CF, Nauck MA, Meier J, et al., Degradation of endogenous and exogenous gastric inhibitory polypeptide in healthy and in type 2 diabetic subjects as revealed using a new assay for the intact peptide, J Clin Endocrinol Metab, 2000;85(10):3575–81.
  18. Vilsboll T, Agerso H, Lauritsen T, et al., The elimination rates of intact GIP as well as its primary metabolite, GIP 3-42, are similar in type 2 diabetic patients and healthy subjects, Regul Pept, 2006;137(3):168–72.
  19. Vilsboll T, Krarup T, Madsbad S, Holst JJ, Both GLP-1 and GIP are insulinotropic at basal and postprandial glucose levels and contribute nearly equally to the incretin effect of a meal in healthy subjects, Regul Pept, 2003;114(2–3):115–21.
  20. Nauck MA, Heimesaat MM, Behle K, et al., Effects of glucagon-like peptide 1 on counterregulatory hormone responses, cognitive functions, and insulin secretion during hyperinsulinemic, stepped hypoglycemic clamp experiments in healthy volunteers, J Clin Endocrinol Metab, 2002;87(3): 1239–46.
  21. Nauck MA, Heimesaat MM, Behle K, et al., Effects of glucagon-like peptide 1 on counterregulatory hormone responses, cognitive functions, and insulin secretion during hyperinsulinemic, stepped hypoglycemic clamp experiments in healthy volunteers, J Clin Endocrinol Metab, 2002;87(3): 1239–46.
  22. Baggio LL, Drucker DJ, Biology of incretins: GLP-1 and GIP, Gastroenterology, 2007;132(6):2131–57.
  23. Flint A, Raben A, Astrup A, Holst JJ, Glucagon-like peptide 1 promotes satiety and suppresses energy intake in humans, J Clin Invest, 1998;101(3):515–20.
  24. Vilsboll T, Krarup T, Madsbad S, Holst JJ, Both GLP-1 and GIP are insulinotropic at basal and postprandial glucose levels and contribute nearly equally to the incretin effect of a meal in healthy subjects, Regul Pept, 2003;114(2–3):115–21.
  25. Nauck M, Stockmann F, Ebert R, Creutzfeldt W, Reduced incretin effect in type 2 (non-insulin-dependent) diabetes, Diabetologia, 1986;29(1):46–52.
  26. Meier JJ, Nauck MA, Incretins and the development of type 2 diabetes, Curr Diab Rep, 2006;6(3):194–201.
  27. Kjems LL, Holst JJ, Volund A, Madsbad S, The influence of GLP-1 on glucose-stimulated insulin secretion: effects on beta-cell sensitivity in type 2 and nondiabetic subjects, Diabetes, 2003;52(2):380–86.
  28. Toft-Nielsen MB, Damholt MB, Madsbad S, et al., Determinants of the impaired secretion of glucagon-like peptide-1 in type 2 diabetic patients, J Clin Endocrinol Metab, 2001;86(8):3717–23.
  29. Vilsboll T, Krarup T, Madsbad S, Holst JJ, Defective amplification of the late phase insulin response to glucose by GIP in obese Type II diabetic patients, Diabetologia, 2002;45(8):1111–19.
  30. Hojberg PV, Zander M, Vilsboll T, et al., Near normalisation of blood glucose improves the potentiating effect of GLP-1 on glucose-induced insulin secretion in patients with type 2 diabetes, Diabetologia, 2008;51(4):632–40.
  31. Knop FK, Vilsboll T, Hojberg PV, et al., Reduced incretin effect in type 2 diabetes: cause or consequence of the diabetic state?, Diabetes, 2007;56(8):1951–9.
  32. Knop FK, Vilsboll T, Hojberg PV, et al., The insulinotropic effect of GIP is impaired in patients with chronic pancreatitis and secondary diabetes mellitus as compared to patients with chronic pancreatitis and normal glucose tolerance, Regul Pept, 2007;144(1–3):123–30.
  33. American Diabetes Association, Summary of Revisions for the 2008 Clinical Practice Recommandations, Diabetes Care, 2008;31:S3–S4.
  34. Hinnen D, Nielsen LL, Waninger A, Kushner P, Incretin mimetics and DPP-IV inhibitors: new paradigms for the treatment of type 2 diabetes, J Am Board Fam Med, 2006;19(6):612–20.
  35. Maedler K, Carr RD, Bosco D, et al., Sulfonylurea induced beta-cell apoptosis in cultured human islets, J Clin Endocrinol Metab, 2005;90(1):501–6.
  36. Nauck MA, Kleine N, Orskov C, et al., Normalization of fasting hyperglycaemia by exogenous glucagon-like peptide 1 (7-36 amide) in type 2 (non-insulin-dependent) diabetic patients, Diabetologia, 1993;36(8):741–4.
  37. Zander M, Madsbad S, Madsen JL, Holst JJ, Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and beta-cell function in type 2 diabetes: a parallel-group study, Lancet, 2002;359(9309):824–30.
  38. Deacon CF, Johnsen AH, Holst JJ, Degradation of glucagonlike peptide-1 by human plasma in vitro yields an Nterminally truncated peptide that is a major endogenous metabolite in vivo, J Clin Endocrinol Metab, 1995;80(3): 952–7.
  39. Deacon CF, Danielsen P, Klarskov L, et al., Dipeptidyl peptidase IV inhibition reduces the degradation and clearance of GIP and potentiates its insulinotropic and antihyperglycemic effects in anesthetized pigs, Diabetes, 2001;50(7):1588–97.
  40. Eng J, Kleinman WA, Singh L, et al., Isolation and characterization of exendin-4, an exendin-3 analogue, from Heloderma suspectum venom. Further evidence for an exendin receptor on dispersed acini from guinea pig pancreas, J Biol Chem, 1992;267(11):7402–5.
  41. Thorens B, Porret A, Buhler L, et al., Cloning and functional expression of the human islet GLP-1 receptor. Demonstration that exendin-4 is an agonist and exendin-(9-39) an antagonist of the receptor, Diabetes, 1993;42(11):1678–82.
  42. Simonsen L, Holst JJ, Deacon CF, Exendin-4, but not glucagon-like peptide-1, is cleared exclusively by glomerular filtration in anaesthetised pigs, Diabetologia, 2006;49(4): 706–12.
  43. Edwards CM, Stanley SA, Davis R, et al. Exendin-4 reduces fasting and postprandial glucose and decreases energy intake in healthy volunteers, Am J Physiol Endocrinol Metab, 2001;281(1):E155–E161.
  44. Kolterman OG, Kim DD, Shen L, et al., Pharmacokinetics, pharmacodynamics, and safety of exenatide in patients with type 2 diabetes mellitus, Am J Health Syst Pharm, 2005;62(2): 173–81.
  45. Amori RE, Lau J, Pittas AG, Efficacy and safety of incretin therapy in type 2 diabetes: systematic review and metaanalysis, JAMA, 2007;298(2):194–206.
  46. Klonoff DC, Buse JB, Nielsen LL, et al., Exenatide effects on diabetes, obesity, cardiovascular risk factors and hepatic biomarkers in patients with type 2 diabetes treated for at least 3 years, Curr Med Res Opin, 2008;24(1):275–86.
  47. Heine RJ, Van Gaal LF, Johns D, et al., Exenatide versus insulin glargine in patients with suboptimally controlled type 2 diabetes: a randomized trial, Ann Intern Med, 2005;143(8): 559–69.
  48. Nauck MA, Duran S, Kim D, et al., A comparison of twicedaily exenatide and biphasic insulin aspart in patients with type 2 diabetes who were suboptimally controlled with sulfonylurea and metformin: a non-inferiority study, Diabetologia, 2007;50(2):259–67.
  49. Nauck MA, Duran S, Kim D, et al., A comparison of twicedaily exenatide and biphasic insulin aspart in patients with type 2 diabetes who were suboptimally controlled with sulfonylurea and metformin: a non-inferiority study, Diabetologia, 2007;50(2):259–67.
  50. European Medicines Agency, European Public Assessment Report Byetta, EMEA/H/C/698, 2006.
  51. Holst JJ, Deacon CF, Inhibition of the activity of dipeptidylpeptidase IV as a treatment for type 2 diabetes, Diabetes, 1998;47(11):1663–70.
  52. Deacon CF, Holst JJ, Dipeptidyl peptidase IV inhibitors: a promising new therapeutic approach for the management of type 2 diabetes, Int J Biochem Cell Biol, 2006;38(5–6): 831–44.
  53. Ahren B, Gomis R, Standl E, et al., Twelve- and 52-week efficacy of the dipeptidyl peptidase IV inhibitor LAF237 in metformin-treated patients with type 2 diabetes, Diabetes Care, 2004;27(12):2874–80.
  54. Deacon CF, MK-431 (Merck), Curr Opin Investig Drugs, 2005;6(4):419–26.
  55. Aschner P, Kipnes MS, Lunceford JK, et al., Effect of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy on glycemic control in patients with type 2 diabetes, Diabetes Care, 2006;29(12):2632–7.
  56. Amori RE, Lau J, Pittas AG, Efficacy and safety of incretin therapy in type 2 diabetes: systematic review and metaanalysis, JAMA, 2007;298(2):194–206.
  57. Amori RE, Lau J, Pittas AG, Efficacy and safety of incretin therapy in type 2 diabetes: systematic review and metaanalysis, JAMA, 2007;298(2):194–206.
  58. European Medicines Agency, European Public Assessment Report Januvia, EMEA/H/C/722, 2008.
  59. European Medicines Agency, European Public Assessment Report Galvus, EMEA/H/C/771, 2008.

Further Resources

Share this Article
Related Content In Diabetes
  • Copied to clipboard!
    accredited arrow-down-editablearrow-downarrow_leftarrow-right-bluearrow-right-dark-bluearrow-right-greenarrow-right-greyarrow-right-orangearrow-right-whitearrow-right-bluearrow-up-orangeavatarcalendarchevron-down consultant-pathologist-nurseconsultant-pathologistcrosscrossdownloademailexclaimationfeedbackfiltergraph-arrowinterviewslinkmdt_iconmenumore_dots nurse-consultantpadlock patient-advocate-pathologistpatient-consultantpatientperson pharmacist-nurseplay_buttonplay-colour-tmcplay-colourAsset 1podcastprinter scenerysearch share single-doctor social_facebooksocial_googleplussocial_instagramsocial_linkedin_altsocial_linkedin_altsocial_pinterestlogo-twitter-glyph-32social_youtubeshape-star (1)tick-bluetick-orangetick-red tick-whiteticktimetranscriptup-arrowwebinar Sponsored Department Location NEW TMM Corporate Services Icons-07NEW TMM Corporate Services Icons-08NEW TMM Corporate Services Icons-09NEW TMM Corporate Services Icons-10NEW TMM Corporate Services Icons-11NEW TMM Corporate Services Icons-12Salary £ TMM-Corp-Site-Icons-01TMM-Corp-Site-Icons-02TMM-Corp-Site-Icons-03TMM-Corp-Site-Icons-04TMM-Corp-Site-Icons-05TMM-Corp-Site-Icons-06TMM-Corp-Site-Icons-07TMM-Corp-Site-Icons-08TMM-Corp-Site-Icons-09TMM-Corp-Site-Icons-10TMM-Corp-Site-Icons-11TMM-Corp-Site-Icons-12TMM-Corp-Site-Icons-13TMM-Corp-Site-Icons-14TMM-Corp-Site-Icons-15TMM-Corp-Site-Icons-16TMM-Corp-Site-Icons-17TMM-Corp-Site-Icons-18TMM-Corp-Site-Icons-19TMM-Corp-Site-Icons-20TMM-Corp-Site-Icons-21TMM-Corp-Site-Icons-22TMM-Corp-Site-Icons-23TMM-Corp-Site-Icons-24TMM-Corp-Site-Icons-25TMM-Corp-Site-Icons-26TMM-Corp-Site-Icons-27TMM-Corp-Site-Icons-28TMM-Corp-Site-Icons-29TMM-Corp-Site-Icons-30TMM-Corp-Site-Icons-31TMM-Corp-Site-Icons-32TMM-Corp-Site-Icons-33TMM-Corp-Site-Icons-34TMM-Corp-Site-Icons-35TMM-Corp-Site-Icons-36TMM-Corp-Site-Icons-37TMM-Corp-Site-Icons-38TMM-Corp-Site-Icons-39TMM-Corp-Site-Icons-40TMM-Corp-Site-Icons-41TMM-Corp-Site-Icons-42TMM-Corp-Site-Icons-43TMM-Corp-Site-Icons-44TMM-Corp-Site-Icons-45TMM-Corp-Site-Icons-46TMM-Corp-Site-Icons-47TMM-Corp-Site-Icons-48TMM-Corp-Site-Icons-49TMM-Corp-Site-Icons-50TMM-Corp-Site-Icons-51TMM-Corp-Site-Icons-52TMM-Corp-Site-Icons-53TMM-Corp-Site-Icons-54TMM-Corp-Site-Icons-55TMM-Corp-Site-Icons-56TMM-Corp-Site-Icons-57TMM-Corp-Site-Icons-58TMM-Corp-Site-Icons-59TMM-Corp-Site-Icons-60TMM-Corp-Site-Icons-61TMM-Corp-Site-Icons-62TMM-Corp-Site-Icons-63TMM-Corp-Site-Icons-64TMM-Corp-Site-Icons-65TMM-Corp-Site-Icons-66TMM-Corp-Site-Icons-67TMM-Corp-Site-Icons-68TMM-Corp-Site-Icons-69TMM-Corp-Site-Icons-70TMM-Corp-Site-Icons-71TMM-Corp-Site-Icons-72