Incretin-Based therapy for type 2 diabetes: overcoming unmet needs

2 : 15 Incretin-Based therapy for type 2 diabetes: overcoming unmet needs Diabetes is a progressive disease characterised by impaired betacell function, and reduced insulin sensitivity and secretion. Over time, glycaemic control deteriorates and exacerbates the risk of patients experiencing micro- and macrovascular complications (UKPDS, 1998). Although there is an abundance of treatment options and guidelines available for the management of type 2 diabetes, they are unable to avert the natural progression of the disease and sustain glycaemic control in the long term. Furthermore, currently available treatment options (such as sulphonylureas, thiazolidinediones and most insulins) are often associated with hypoglycaemia and weight gain, (Kahn et al.,26; UKPDS et al., 1998: Figure 1 and 2). Such adverse effects can have detrimental health implications for the patient. For example, hypoglycaemia can be an unpleasant side-effect of anti-diabetic therapy which can compromise patient adherence to treatment, and serious hypoglycaemic events, left untreated, can lead to a loss of Patients with hypoglycaemia (%) 45 4 35 3 25 2 15 1 5 p<.5 glibenclamide vs. rosiglitazone 1 12 Rosiglitazone Metformin Glibenclamide Fig. 1 : Hypoglycaemia 39 Patients self-reporting (unconfirmed) hypoglycaemia Klaus Henning Jensen, Denmark consciousness, brain damage or even death. Moreover, obesity is a common co-morbidity in subjects with type 2 diabetes (6-9% of patients diagnosed). Additional weight gain as a consequence of treatment with SU s or insulin for example, can reduce patients quality of life and hinder adherence to treatment. Obesity is also an independent risk factor for cardiovascular disease, further compromising patient outcomes (Hubert et al., 1983; Han et al., 1998; Odegard et al., 27). The greatest challenge in treating patients with type 2 diabetes is optimising therapy to address the current unmet needs: improve glycaemic control without compromising safety i.e. hypoglycaemia preserve beta-cell function provide clinically meaningful weight loss address CV risk factors accompanying diabetes offer a simple and flexible regimen GLP1 receptor agonists may provide solutions to all of these challenges. Change in weigh (kg) UKPDS: up to 8 kg in 12 years 8 7 Insulin (n=49) 7 5 Glibenclamide (n=277) 4 3 2 1 Metformin (n=342) 3 6 9 12 Years from randomisation Conventional treatment (n=411); diet initially then sulphonylurea, insulin and/or metformin if FPG >15 mmol/l weight (kg) ADOPT : up to 4.8 kg in 5 years 1 Fig. 2 : Weight gain over time 1 2 3 4 5 Years Rosiglitazone Metformin Glibenclamide UKPDS 34, Lancet 1998:352:854-65. n=at baseline; Kahn et al (ADOPT). NEJM 26;355(23):2427-43 96 92 88

Medicine Update 21 Vol. 2 plasma insulin secretion observed with oral vs. intravenous glucose administration despite matching glucose profiles (Figure 3). The incretin effect is blunted in subjects with type 2 diabetes (Nauck et al., 1986; Figure 3c). In patients with type 2 diabetes, GLP-1 infusion (but not GIP) markedly improves both the early and late phases of insulin secretion in response to glucose (Vilsboll et al., 22, Hojberg et al., 28). As such, it is GLP-1 rather than GIP that has been the focus of research as a promising treatment for type 2 diabetes. Fig. 3 : Incretin effect Background to the incretin effect GLP-1 and GIP are gut-derived, receptor-specific hormones, known as incretins. The increctin hormones have multiple physiological actions; most importantly they play a crucial role in glucose homeostasis. The action of the incretin hormones accounts for 5 7% of insulin secretion after oral glucose intake. This incretin effect is characterised by the more pronounced GLP-1 and its relevance to treating the unmet needs in T2D The action of GLP-1 on beta-cell receptors enhances insulin secretion in a glucose dependant manner (Nauck et al., 1993) which, in turn minimises the risk of hypoglycaemia. In addition, animal studies have indicated that GLP-1 has the ability to preserve beta-cell function by suppressing beta-cell apoptosis and stimulating neogenesis and proliferation (Bulotta et al., 22, Farilla et al., 23). Other clinical advantages associated with GLP-1 may be explained by its hormonal influences on the gastrointestinal, CNS and CV systems (Figure 4). GLP-1 has demonstrated the ability to slow gastric emptying and suppress appetite, resulting in satiety and weight loss. GLP-1 also appears to exert a protective effect on the myocardium, particularly in ischaemic conditions. For example, Bose and colleagues reported that an intravenous infusion of GLP-1 in rats, prior to induced ischaemia significantly reduced myocardial infarction compared with saline (Bose et al., 25). Studies have also reported improved myocardial function in patients with type 2 diabetes and congestive heart failure (Thrainsdottir et al 24), and infusion of recombinant GLP-1 has been shown to improve left ventricular function in patients with acute myocardial infarction after primary angioplasty (Nikolaidis Mankad et al 24). Improvement in endothelial function has also been reported with GLP-1; a significant increase in brachial artery diameter was observed in patients with type 2 diabetes (Nystrom et al 24). Furthermore, GLP-1 has been found to reduce systolic blood pressure (SBP). This may be, in part, due to its ability to increase diuresis and natiuresis, thus reducing blood volume and central venous pressure. This is an important observation, since CV disease is a common co-morbidity of type 2 diabetes, and a mean reduction in systolic blood pressure (SBP) of 5.6 mmhg has been shown to reduce mortality from the disease by 18% (Patel et al., 27). Clinical limitations of GLP-1 due to the presence of DPP-4 As active GLP-1 is secreted from L-cells in the distal small intestine, it is rapidly degraded by the enzyme dipeptidyl peptidase IV (DPP-4). An i.v. bolus of GLP-1 has a half-life of 1.5-2.1 minutes 16

Incretin-Based Therapy for Type 2 Diabetes: Overcoming Unmet Needs Pancreas Insulin secretion (glucose-dependent) and beta-cell sensitivity Insulin synthesis Glucagon secretion (glucose-dependent) Beta-cell mass Brain Energy intake Liver GI tract Decreased motility Fig. 4 : Physiological pathways of GLP-1 meaning that a constant infusion of GLP-1 is required to provide any therapeutic value. Development of liraglutide Human GLP-1 Liraglutide 7 9 7 9 Enzymatic degradation by DPP-4 Renal clearance t 1/2 =1.5-2.1 min Knudsen et al. J Med Chem 2;43:1664-9 36 97% homology to human GLP-1 Improved PK: albumin binding and self-association Slow absorption from subcutis Resistant to DPP-4 Long plasma half-life (t 1/2 =13h) acting GLP-1 agents such as liraglutide have been developed. Liraglutide is an analogue of native human GLP-1, in which Lys 34 has been substituted with Arg 34 at the N-terminal and a fatty acid chain added to Lys 26. These modifications mean that liraglutide shares 97% amino acid identity with native human GLP-1 compared with exenatide (a GLP-1 mimetic) which shares just 53% sequence identity. Liraglutide s fatty acid side chain allows it to self-associate and form heptamers. The size of the heptamer and the strong self-association allow liraglutide to be absorbed slowly via the subcutaneous route (Knudsen et al., 2). Maximum plasma concentration levels are achieved between 9 12 h after dosing (Elbrond et al., 22).The fatty acid moiety also allows liraglutide to bind to serum albumin in the bloodstream (Steensgaard 28) and 36 Liraglutide monotherapy vs. SU LEAD 3 Liraglutide+MET vs. SU+MET LEAD 2 Liraglutide+SU vs. TZD+SU LEAD 1 Diet/exercise Start an oral agent Add another oral agent Add a thrid oral or start insulin Fig. 7: Liraglutide implementation throughout the continuum of care In order to overcome the short half-life of native GLP-1, longer- Liraglutide is a once-daily, human GLP-1 analogue resist DPP-4 degradation, resulting in a half-life of approximately 13 hours (Agersø et al, 22). These properties make liraglutide suitable for once-daily dosing (Agersø et al, 22). Clinical effects of liraglutide Liraglutide+MET+TZD vs. MET+TZD LEAD 4 Liraglutide+METand/orSU vs. exenatide+met and/or SU LEAD 6 Liraglutide+MET vs. sitagliptin+met 186 The phase 3a development programme for liraglutide, LEAD ( Liraglutide Effect and Action in Diabetes ), is the largest clinical development programme ever conducted by Novo Nordisk in diabetes. LEAD included 6 trials and was designed to investigate the efficacy and safety of liraglutide across the continuum of care of type 2 diabetes versus placebo. In the LEAD trials, liraglutide was also compared against some commonly used anti-diabetic therapies. An additional head-to-head trial against exenatide (LEAD-6) was also completed (Figure 7). HbA 1c, FPG and PPG The LEAD programme demonstrated that liraglutide, used as monotherapy or in with one or two OADs, provides substantial reductions in HbA 1c. Liraglutide reduced HbA 1c levels to a significantly greater extent than its active comparators, with LEAD-2 as the exception, in which HbA 1c reductions with 17

Medicine Update 21 Vol. 2 Fig. 8: Percentage of subjects reaching target ADA <7.% in the LEAD 1-6 trials Baseline category of HbA 1c 7.- 7.5 n=767 7.5-8. n=65 7.5-8.5 n=65 8.5-9. n=431 9.- 1. n=484 1.- 11. n=187 Change in HbA 1c (%) -.5-1 -1.5-2 -2.5-3 Liraglutide 1.8 mg Rosiglitazone Glimepiride Glargine Exenatide Placebo n=1363 n=231 n=49 n=232 n=231 n=524 p<.1 vs liraglutide 1.8 mg Fig. 9: Meta-analysis of LEAD 1-6 showing HbA 1c reduction from baseline according to baseline category of HbA 1c liraglutide were comparable to glimepiride plus metformin (-1.%). Reductions in HbA 1c across the LEAD trials ranged from.84 to 1.6% with the highest doses of liraglutide (1.2 mg and 1.8 mg) relative to baseline (Marre et al., 29; Nauck et al., 29; Garber et al., 29; Zinman et al., 29; Russell-Jones et al., 28; Buse et al., 29). These reductions corresponded with a higher percentage of subjects in the liraglutide-treated groups reaching target HbA 1c <7.% in all LEAD studies compared with active comparators (Figure 8). The greatest reduction in HbA 1c (%) was experienced in the LEAD-3 trial (liraglutide monotherapy) by the subgroup of patients previously on diet and exercise: the true initial monotherapy population (Garber et al., 29). In the head-to-head study of liraglutide 1.8 mg once daily vs. exenatide 1 μg twice daily (as addon to metformin and/or SU therapy), mean HbA 1c reduction was significantly greater with liraglutide treatment than with exenatide: 1.12% versus.79%, p<.1 (Buse et al., 29). A meta-analysis of LEAD trials 1-6 concluded that liraglutide provides the greatest reductions HbA 1c in those patients with the highest HbA 1c levels at baseline (Figure 9). Liraglutide also provided substantial reductions in FPG across the continuum of care. FPG reductions of up to -2.4 mmol/l were reported with liraglutide across the LEAD 1-6 studies ((Marre et al., 29; Nauck et al. 29, Garber et al., 29; Zinman et al., 29; Russell-Jones et al., 28, Buse et al., 29): Figure 1). Liraglutide was also shown to be effective at reducing postprandial glucose; consistent reductions were observed in peak PPG (across all 3 meals) in LEAD 1-5 studies (Marre et al., 29; Nauck et al. 29, Garber et al., 29; Zinman et al., 29; Russell-Jones et al., 28). In the LEAD-6 study, there was a greater reduction in mean PPG after lunch with liraglutide compared with exenatide (2.74 18

Incretin-Based Therapy for Type 2 Diabetes: Overcoming Unmet Needs Monotherapy LEAD-3 MET LEAD-2 SU LEAD-1 MET + TZD LEAD-4 MET + SU LEAD-5 MET + SU LEAD-6 Baseline FPG 9.3 9.5 9.5 9.9 1.1 1. 9.8 9.7 1. 1.1 1.3 1. 9.1 9.1 9.8 9.5 -.8 -.3 -.9 -.4 -.6-1.4-1.7-1.3-1.8-2.2-2.4 Fig. 1 : Change in FPG (mmol/l) in the LEAD 1-6 studies Improving beta-cell function Change in HbA 1C from baseline (%)..2.4.6.8 1. 1.2 1.4 1.6 <22.3 Liraglutide 1.2 mg HOMA-B (%) <22.3 38.6 38.7-65.3 >65.3 Liraglutide 1.8 mg Glimepiride Placebo # p=.5 liraglutide 1.8 mg vs. glimepride; p=.1 liraglutide 1.2 mg vs. glimepriride; p=.3 liraglutide 1.8 mg vs. glimepiride; p=.2 liraglutide 1.2 mg vs. glimepiride; # p=.3 glimpiride > 65.28 vs. glimepiride < 22.32 group Liraglutide significantly different to placebo for all quartiles (p<.1) Fig. 11: versus 2.35; NS). However, exenatide is given twice daily, before morning and evening meals, thus PPG was reduced more with exenatide vs liraglutide during these peak times (Buse et al., 29). Beta-cell function The LEAD trials have reported increases in beta-cell function (as measured by HOMA-B) of 28-34% from baseline after liraglutide treatment (Marre et al., 29; Nauck et al. 29, Garber et al., 29; Zinman et al., 29; Russell-Jones et al., 28, Buse et al., 29). As demonstrated by meta-analysis, the ability of liraglutide to lower HbA 1c remains substantial regardless of baseline HOMA-B (Figure 11). Weight Treatment with liraglutide significantly reduced weight in the A quarter of patients lose an average of 7.7 kg with liraglutide Weight change (kg) 2 1 1 2 3 4 5 6 7 8 9 Q1 Q1-Q2 Q2-Q3 Q3-Q4 Liraglutide 1.8 mg + met + SU -Q1: mean weight change for the 25% of subjects who had the largest weight loss Q1-Q2: mean weight change for the 25-5% weight loss quartile Q2-Q3: mean weight change for the 5-75% weight loss quartile Q3-Q4: mean weight change for the 75-1% weight loss quartile, that is, the 25% who had the smallest weight loss Nuack et al. Diabetes Care 29;32;84-9 (LEAD-2) 19

Medicine Update 21 Vol. 2 Monotherapy LEAD-3 MET LEAD-2 SU LEAD-1 MET + TZD LEAD-4 MET + SU LEAD-5 MET ± SU LEAD-6 Change in SBP (mmhg) 1 1 2 3 4 5 6 7 2.1 3.6.7 2.3 2.8 +.4 +.5.9 2.6 2.8 6.7 5.6 4. 2.5 2. Liraglutide 1.2 mg Liraglutide 1.8 mg Glimepiride Rosiglitazone Glargine Exenatide Table 1: Change in SBP by mean baseline quartile Quartile, mmhg (Baseline) p<.1, p<.1, p<.5 versus baseline Liraglutide 1.8 mg (n = 1363) Liraglutide 1.2 mg (n = 896) LEAD 1 6 trials. Liraglutide has a more positive effect on weight than active comparators (Marre et al., 29; Nauck et al. 29, Garber et al., 29; Zinman et al., 29; Russell-Jones et al., 28) and was similar to the weight reductions reported with exenatide(buse et al., 29). Weight loss also appears to be sustained; a reduction of -2.45 kg was reported in patients treated with liraglutide 1.8 mg monotherapy (LEAD-3, Garber et al., 29). The majority of this weight loss occurred primarily in the first 16 weeks and was maintained throughout the 52-week study period. In this trial, weight reduction was significantly greater with liraglutide vs. glimepiride (+1.12 kg, p<.1; Garber et al., 29). Furthermore, weight loss has been demonstrated to increase with increasing baseline body mass index (BMI). This is of particular advantage in obese subjects and, and those at greater risk of developing CV disease, since they would appear to experience greater weight loss than leaner patients (Russell-Jones et al. 28). Of note, an analysis of body composition (measured by dual energy X-ray absorptiometry (DEXA)) in subjects from the LEAD 2 study suggested that the majority of weight loss observed with liraglutide was due to fat loss; 86% of weight loss reported was fat tissue and the majority of this was found to be visceral (Jendle Fig. 12: Change in SBP across LEAD 1-6 trials Placebo (n = 524) Q1 8 to 12 + 4.8 (1.) +5.4 (1.1) +7.1 (1.3) Q2 12 to 13.4 (.9) +.4 (1.1) +.9 (1.3) Q3 13 to 14 4.7 (1.) 6.2 (1.1) 2.4 (1.3) Q4 14 to 19 11.4 (1.) 11.4 (1.2) 7.7 (1.3) Effect on SBP with baseline SBP quartile was significant (p<.1) Greatest reduction observed in quartile with highest SBP Fonseca et al. Diabetes 29, 58 (Suppl 1): 545-P Patients reaching target (%) 45 LEAD studies 4 39% 35 32% 3 25 24% 2 15 15% 1 8%, 6%, 8%, 5 Liraglutide Liraglutide SU TZD Glargine Exenatide Placebo 1.8 mg 1.2 mg (n=1363) (n=896) (n=49) (n=231) (n=232) (n=231) (n=524) Liraglutide 1.8 mg is superior (p<.1; P<.1) Liraglutide 1.2 mg is superior ( p<.1) Percentages are from logistic regression model adjusted for trial, previous treatment and with baseline HbA 1C and weight as covariates Fig. 13: Percentage of subjects reaching HbA 1c target of <7.% with no hypoglycaemic events and no weight gain et al., 28). Systolic blood pressure Liraglutide provides clinically significant reductions in SBP and has been demonstrated across all LEAD trials (Marre et al., 29; Nauck et al., 29; Zinman et al., 29; Russell-Jones et al., 28, Buse et al., 29; Figure 12). SBP has also been shown to improve rapidly (as early as 2 weeks) following liraglutide initiation, and prior to significant treatmentinduced weight loss. As demonstrated in the meta-analysis, the effect on SBP with baseline SBP quartile was significant (p<.1), since the greatest reduction observed was in that with the highest SBP (Table 1). 11

Incretin-Based Therapy for Type 2 Diabetes: Overcoming Unmet Needs Safety and tolerability Since liraglutide acts in a glucose-dependent manner (Nauck et al., 23) the risk of hypoglycaemia is low. Throughout all the LEAD trials major hypoglycemia was rare; of the 6 cases reported, one of these patients was undergoing treatment with liraglutide 1.8 mg plus glimepiride (Marre et al., 29) and the other five were treated with liraglutide 1.8 mg in with glimepiride and metformin (Russel-Jones et al. 28). Since hypoglycaemic risk is a recognised feature of SU treatment we can assume these reports are a consequence of combining liraglutide with SU. Indeed, when liraglutide was used in with OADs (other than SUs) and as monotherapy, no major hypoglycaemia was observed (Nauck et al. 29, Garber et al., 29; Zinman et al., 29, Buse et al., 29). Minor hypoglycaemia is not uncommon with existing diabetes treatments, however, there was a lower number of minor hypoglycemia events reported with liraglutide treatment compared to that encountered with conventional diabetes treatments. To exemplify this, reports of minor hypoglycaemia with liraglutide 1.2 mg and 1.8 mg was at placebo level and lower than glimepiride treatment in the LEAD 2 study:.3 and.9 events/patient/year (liraglutide 1.2 mg and 1.8 mg, respectively) vs..13 (placebo) and 1.23 events/patient/year (glimepiride) (Nauck et al., 29). Overall, liraglutide is generally well tolerated with most adverse events across the LEAD studies reported as mild or moderate in severity and frequently gastrointestinal- related. Nausea was the most common adverse effect; it was reported by up to 4% of patients but tended to dissipate after a period of 4 weeks (Marre et al., 29; Nauck et al. 29, Garber et al., 29; Zinman et al., 29; Russell-Jones et al., 28, Buse et al., 29). This may be explained by liraglutide s ability to delay gastric emptying. Of note, very few adverse effects were serious and withdrawals were rare; majority of these withdrawals were due to nausea (Marre et al., 29; Nauck et al. 29, Garber et al., 29; Zinman et al., 29; Russell-Jones et al., 28, Buse et al., 29). Conclusion The role of GLP-1 receptor agonists as a treatment option for type 2 diabetes is rapidly evolving. Liraglutide, the first human GLP-1 analogue, has the potential to overcome the shortcomings of conventional therapies and address the current unmet needs of patients with type 2 diabetes. Liraglutide has with the once daily administration demonstrated superior clinical efficacy and a favourable safety profile in recent clinical trials versus standard therapies; glycaemic control improved substantially with liraglutide and hypoglycaemia was uncommon. Moreover, there is indication that liraglutide may have a positive effect not only on beta-cell function, but also on betacell mass that implies potential long-term benefits. Liraglutide has also been found to promote weight loss and reduce SBP, which in turn, may reduce the risk of cardiovascular disease. For type 2 diabetes patients, liraglutide offers a new and flexible treatment alternative to standard therapies which may help to overcome the unmet needs of current therapies. References 1. AACE Diabetes Mellitus Clinical Practice Guidelines Task Force. (27). American Association of Clinical Endocrinologists medical guidelines for clinical practice for the management of diabetes mellitus. Endocrine Practice, 13(Suppl. 1), 1-68. 2. Bose AK, et al. Diabetes 25; 54: 146 51. 3. Bose et al. Diabetes 25;54:146-151. 4. Bulotta et al. J Mol Endocrinol 22;29:347 36 5. Buse J, Rosenstock J, Sesti G, Schmidt WE, Montanya E, Brett J, Zychma M, Blonde L; for the LEAD 6 study group. (29). Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6). Lancet 374(9683), 39-47. 6. Defronzo, R.A., Ratner, R.E., Han, J., Kim, D.D., Fineman, M.S., Baron, A.D. (25). Effects of exenatide (exendin-4) on glycemic control and weight over 3 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care, 28, 192-11. 7. Elbrønd, B., Jakobsen, G., Larsen, S., Agersø, H., Jensen, L.B., Rolan, P., Sturis, J., Hatorp, V., Zdravkovic, M. (22). Pharmacokinetics, pharmacodynamics, safety, and tolerability of a single-dose of NN2211, a long-acting glucagon-like peptide 1 derivative, in healthy male subjects. Diabetes Care, 25: 1398-144. 8. Farilla et al. Endocrinology 23;144:5149 5158 9. Garber A, Henry R, Ratner R, Garcia-Hernadez PA, Rodriguez-Pattzi H, Olvera-Alvarez I, et al. Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): randomised, 52-week, phase III, double-blind, parallel-treatment trial. Lancet 28; DOI: 1.115/ S14-6736(8)61246-5. (LEAD 3) 1. Han TS et al., Am J public health 1998;88;1814-2. 11. Højberg PV, et al. Diabetologia 29; 52: 199 27. 12. Jendle J, et al. Diabetes 28; 57 (Suppl.1): P16 13. Kahn et al. (ADOPT). NEJM 26;355(23):2427 43. 14. Knudsen LB, et al. Potent derivatives of glucagon-like peptide-1 with pharmacokinetic properties suitable for once daily administration. J Med Chem 2; 43: 1664 9. 15. Marre, M., Shaw, J., Brändle, M., Bebakar, W.M., Kamaruddin, N.A., Strand, J., Zdravkovic, M., Le Thi, T.D., Colagiuri, S.; LEAD-1 SU study group. (29). Liraglutide, a once-daily human GLP-1 analogue, added to a sulphonylurea over 26 produces greater improvements in glycaemic and weight control compared with adding rosiglitazone or placebo in subjects with type 2 diabetes (LEAD-1 SU). Diabetic Medicine, 26, 268-278. 16. Nathan, D.M., Buse, J.B., Davidson, M.B., Ferrannini, E., Holman, R.R., Sherwin, R., Zinman, B.; American Diabetes Association; European Association for Study of Diabetes. (29). Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care, 32(1), 193-23. 17. Nauck et al. Diabetologia 1986;29:46 52. 18. Nauck, M., Frid, A., Hermansen, K., Shah, N.S., Tankova, T., Mitha, I.H., Zdravkovic, M., Düring, M., Matthews, D.R.; LEAD-2 Study Group. (29). Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in with metformin in type 2 diabetes. Diabetes Care, 32, 84-9. 19. Nikolaidis, Mankad et al. Circulation 24;19:962-965. 2. Nystrom et al. Regul Pept 25;125:173-177. 21. Nyström T, et al. Am J Physiol Endocrinol Metab 24; 287: E129 15. 111

Medicine Update 21 Vol. 2 22. Nyström T, et al. Regul Pept 25; 125: 173 7.Hubert HB et al., Circulation 1983;67:968-77 23. Odegard PS et al., Diabetes Educ 27;33:114-29. 24. Russell-Jones D, Vaag A, Schmitz O et al. Significantly better glycemic control and weight reduction with liraglutide, a once-daily human GLP- 1 analog, compared with insulin glargine: all as add-on to metformin and a sulfonylurea in type 2 diabetes. Diabetes 28; 57(Suppl. 1): A159 (Abstract 536-P). 25. Thrainsdottir et al. Diab Vasc Dis Res 24;1:4-43. 26. UK Prospective Diabetes Study (UKPDS) Group. (1998). Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet, 352, 837-853. 27. Vilsbøll et al. Diabetologia 22;45:1111 9. 28. Zinman, B., Gerich, J., Buse, J.B., Lewin, A., Schwartz, S., Raskin, P., Hale, P.M., 29. Zdravkovic, M., Blonde, L. (29). Efficacy and safety of the human GLP- 1 analog liraglutide in with metformin and TZD in patients with type 2 diabetes mellitus (LEAD-4 Met+TZD). Diabetes Care, 32, 1224-123. 112