New class of non-insulin anti-diabetic agents Webinar 2: DPP4-1 inhibitors Thursday 18 June 2015 Speaker Professor Merlin Thomas Head, Biochemistry of Diabetic Complications, NHMRC Senior Research Fellow Baker IDI Heart and Diabetes Institute (VIC) Panellist 1 Dr Gary Kilov Principal at Seaport Practice (TAS) Panellist 2 Nicole Frayne Pharmacist, Credentialled Diabetes Educator Koombana Health Network (WA) Panellist 3 Giuliana Murfet Endorsed Nurse Practitioner, Credentialled Diabetes Educator Tasmanian Health Organisation – North West (TAS) Facilitator Rachel McKeown Professional Services Manager at ADEA (NSW)

DPP4 inhibitors New class of anti-diabetic agents ADEA CASE SERIES DPP4 inhibitors New class of anti-diabetic agents Merlin Thomas Gary Kilov Nicole Frayne Facilitator: Rachel McKeown, Professional Services Manager, ADEA (NSW)

<7 The right target... COMPROMISE Motivated/adherent Non-compliant Good self-care Short duration Low hypo risk Long life expectancy No co-morbidity Good resources Non-compliant Poor self-care Longstanding High hypo risk Short life expectancy Co-morbidity Limited resources <7 COMPROMISE Adapted from Inzucchi et al Diabetes Care 2012

? standard ….with the right agent Motivated/adherent Non-compliant Good self-care Short duration Low hypo risk Long life expectancy No co-morbidity Good resources Non-compliant Poor self-care Longstanding High hypo risk Short life expectancy Co-morbidity Limited resources ? standard Adapted from Inzucchi et al Diabetes Care 2012

How does an DPP4 inhibitor lower glucose levels in diabetes? 1. BACKGROUND How does an DPP4 inhibitor lower glucose levels in diabetes?

Incretins in -cell biology3,4 α β Up to 70% of total post-prandial insulin production is determined by incretins The effect and contribution varies with the size of the glucose challenge / the meal composition MEAL carbohydrate protein, fatty & bile acids vagal vagal Pancreas L GLP-1 GLPR Distal small intestine ileum and colon SLIDE 2. INCRETINS IN BETA-CELL BIOLOGY Incretins are gut hormones that amplify insulin secretion after a meal in a glucose-dependent manner. The two best-known incretins are glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) They exert their insulinotropic actions through activating specific G-protein-coupled receptors (3) This not only augments insulin secretion, but also improves glucose sensitivity in beta-cells that are sub-optimally responsive. Experimental data also suggest that GLP-1 may stimulate beta-cell proliferation and/or reduce apotosis (3). Whether this is sufficient to protect the pancreas against the ravages of diabetes is unclear. Every time a meal is eaten, the L-cells of the intestine release the incretin hormone, GLP-1. These L-cells are found the length of the intestine but are in highest concetration in the distal small intestine, ileum and colon. The initial stimulus to release GLP-1 is neurogenic, mediated by activation of the vagal nerve. Subsequently the passage of nutrients to the distal intestine triggers further larger GLP-1 release through activation of so called ‘nutrient sensing’ pathways (4). Glucose is taken up by the SGLT1 transporter in L-cells Oligopeptides are taken up by PEPT1-dependent uptake. Fatty acids (and especially MUFAs) are taken up by free fatty acid receptors. These stimuli acts to mobilise endogenous GLP-1 and amplify insulin secretion from the pancreas. The dramatic increase in GLP-1 after gastric bypass surgery is partly explained by the increasing the distal transit of nutrients to areas of the intestine rich in L-cells. (3) Campbell & Drucker. Cell Metabolism (2013) (4) Diakogiannaki, et al. Physiol. Behav. (2012). Amplified insulin secretion Improved glucose sensitivity -cell proliferation/neogenesis Reduced -cell apoptosis 3. Campbell & Drucker. Cell Metabolism (2013); 4. Diakogiannaki, et al. Physiol. Behav. (2012). 6

Incretins regulate a proportional response SIGNAL AMPLIFICATION OUTPUT AMPLIFIER GLUCOSE GLP-1 increased FOOD AMPLIFICATION INSULIN* of glucose/meal-stimulated insulin secretion (incret-ins)

Incretins and hypoglycaemia NO SIGNAL AMPLIFICATION NO OUTPUT AMPLIFIER No GLUCOSE NO MORE NO FOOD INSULIN GLP1 Reduced risk of hypoglycaemia

What happens to -cells in diabetes? Diabetes is associated with the blunting of hyperglycaemia or postprandial suppression of glucagon secretion Reduced incretin effect Hyperplasia of -cells Increased sensitivity to glucagon Contributes to the inappropriately increased rate of hepatic glucose output characteristic of T2DM SLIDE 9. DIABETES AND THE ALPHA CELL In type 2 diabetes, the production and secretion of glucagon is inappropriately high (in relation to ambient hyperglycaemia)(8). Under healthy conditions, the glycemic load from a meal or hyperglycemia act to suppress glucagon as a means to reduce hepatic glucose output and a time when glucose uptake is required. Part of this suppression is mediated by GLP-1. In type 2 diabetes, the loss of the incretin effect along with alpha cell hyperplasia and increased hepatic sensitivity to glucagon lead to blunting of hyperglycaemia-induced or postprandial suppression of glucagon secretion. This ambivalence to hyperglycemia is euphemistically known as “alpha cell anarchy” And contributes, alongside impaired insulin release and action, to inappropriately increased rates of hepatic glucose output in the fasting state and attenuated reduction after meals. Our patients frequently complain that their glucose levels are high, even if they don’t eat anything. (8). Defronzo. Diabetes (2009) 8. Defronzo. Diabetes (2009)

GLP-1 in -cell biology3,4 β L GLP1 α GLPR  MEAL carbohydrate protein, fatty & bile acids vagal vagal Pancreas β L GLP1 GLPR  α Distal small intestine ileum and colon SLIDE 10. GLP-1 AND ALPHA CELL BIOLOGY Glucagon-like peptide-1 (GLP-1) has significant effects on the glucagon-producing alpha-cells of the endocrine pancreas GLP-1 inhibits glucagon secretion in a glucose-dependent manner (3,4). The mechanism of this action is still debated. Certainly, insulin itself is able to suppress glucagon release from alpha cells, and increased insulin production via the incretin effect may have this action. However, the suppression of glucagon is still present in subjects with type 1 diabetes (although incretin based therapies are not indicated), suggesting that the β cells are not essential for transducing the glucagonostatic actions of GLP-1. There is some data to suggest that GLP-1 is able to stimulate the production of somatostatin from delta cells, which itself acts to suppress glucagon synthesis and release (3). Whatever the mechanism, it means that agents that mimic or increase GLP-1 (e.g. exenatide and saxagliptin respectively) are able to reduce inappropriately increased rates of hepatic glucose output in the fasting state and as well amplify its suppression with meals. Some researchers argue that this may be its major mechanism of action in patients with type 2 diabetes. This strategy is clearly synergistic with interventions like SGLT2 inhibitors that trigger compensatory hyperglucagonemia and increase hepatic glucose output in response to urinary glucose losses (11). (3) Campbell & Drucker. Cell Metabolism (2013) (4) Diakogiannaki, et al. Physiol. Behav. (2012) (11) JCI (2014) Augmented suppression of glucagon release Partly via increased insulin Partly via somatostatin (?) 3. Campbell & Drucker. Cell Metabolism (2013); 4. Diakogiannaki, et al. Physiol. Behav. (2012). 10

incretin effect in diabetes? What happens to the incretin effect in diabetes? As a consequence of hyperglycaemia and/or other metabolic manifestations of diabetes itself incretin effect is reduced by ~50% in diabetes8 Normal secretion of GLP-1, but.. Down-regulation of GLP-1 receptor8 Less substrate to act on (β-cells, δ-cells, etc) Gastroparesis8 Resistance to GLP-1 (which needs pharmacological doses to overcome it)8,10 Slide 8. LOSS OF THE INCRETIN EFFECT IN TYPE 2 DIABETES In patients with type 2 diabetes the incretin effect is reduced by approximately half (8). The loss of incretin effect is thought to significantly contribute importantly to the postprandial hyperglycemia in type 2 diabetes (9). The reasons why the incretin effects may be reduced continue to be actively studied. However, it is now thought that the reduction of the incretin effect is a consequence of hyperglycaemia and or other metabolic manifestations of diabetes itself rather than a primary cause of hyperglycemia. Moreover, the mechanism by which the incretin effect is impaired is not related to reduced secretion of GLP-1. In fact, GLP-1 levels appear to be normal in patients with type 2 diabetes (although they should be high give the glucose levels). By contrast there is marked down-regulation of GLP-1 receptor, especially on beta-cells Moreover, the loss of beta cells also means that there is less substrate (β-cells) to act on. Slowing of the stomach emptying in diabetes also attenuates some of the gastrointestinal benefits of GLP-1 that are achieved through slowing stomach emptying (see slide 12) Finally there also appears to be an innate resistance to GLP-1 which means that physiological levels are insufficient to amplify insulin production and pharmacological doses are required to overcome it. This provides the rationale for the high effective doses of GLP-1 Receptor agonists (e.g. exenatide) used in type 2 diabetes. (8) Nauck et al. Diabetologia (2011) (9) De Fronzo R. Diabetes (2009) (10) Vilsbøll T, et al. Diabetologia. (2002) 8. Nauck et al. Diabetologia (2013); 9. De Frionzo Diabetes (2009) 10. Vilsbøll T, et al. Diabetologia. (2002)

Incretin biology and DPP4 MEAL carbohydrate protein, fatty & bile acids Short circulating half life (<2 min) vagal Pancreas Stomach Liver Brain L GLP1 GLPR Distal small intestine ileum and colon Slide 15. DPP4 Despite the many important physiological effects, the actions of incretins in humans are limited by their short circualting half life. Once GIP and GLP-1 enters the capillaries surrounding the intestine, they undergo rapid degradation catalyzed by dipeptidyl peptidase- 4 (DDP-4), which cleaves the two NH2-terminal amino acids of GIP and GLP-1. The apparent half-lives for intact GIP and GLP-1 have been determined as approximately 5 and 2 min, respectively (2) Less that 25% of the GLP-1 leaving the intestine ever reaches the liver. Even less (~10–15%) of newly secreted GLP-1 reaches the systemic circulation and only a fraction of this is in its intact active intact form (2). This has led to the suggestion that direct stimulation of vagal afferents in the intestinal wall or in the portal vein largely mediate the incretin effect. DPP-4 has a widespread organ distribution (liver; gut; endothelial capillaries; acinar cells of mucous and salivary glands, pancreas; uterus; and immune organs such as thymus, spleen and lymph node) with the highest levels found in the kidney. Other physiological substrates of DPP-4 include neuropeptide-Y (NPY) which has role in appetite, energy homeostasis, and blood pressure control) and substance P (which has a role in pain and inflammation) (2) Campbell & Drucker. Cell Metabolism (2013) DPP4 2. Campbell & Drucker. Cell Metabolism (2013); 12

Peptido-mimetic inhibitors of DPP4 Saxagliptin Sitagliptin Mostly free of DPP4 DPP4 GLP-1 Short On/Off Kinetics s1 s2 Low protein binding 75-87% Renal clearance

Peptido-mimetic inhibitors of DPP4 Mostly free of DPP4 Vildagliptin DPP4 GLP-1 Short On/Off Kinetics s1 s2 Low protein binding Renal clearance Twice daily dosing

DPP4 Xanthine base inhibitors of DPP4 GLP-1 s‘1 s’2 The average levels of free linagliptin are 0.3 nmol range Compared with saxagliptin which has 200 nmol/L DPP4 s‘1 s’2 GLP-1 Fast on, slow off (>130h) s1 s2 High affinity (1nM) >95% is bound to DPP4 very little is free No problem with renal impairment Wright et al. Int J Phrmacol Ther (2012).

Linagliptin increases post-prandial Linagliptin increases post-prandial* active GLP-1 levels in patients with type 2 diabetes 3.2 fold Increase @ steady state At steady state, linagliptin increases circulating active post-prandial GLP-1 levels 3.2 fold. (Within-linagliptin significance was not measured.) Forst T, et al., The oral DPP-4 inhibitor linagliptin significantly lowers HbA1c after 4 weeks of treatment in patients with type 2 diabetes mellitus Diabetes, Obesity and Metabolism 13: 542–550, 2011 Day 0 Day 29 n=15 Linagliptin 5 mg * Mean plasma levels of active GLP-1 measured 30 min after a meal tolerance test. Forst T, et al. Diabetes Obes Metab. 2011;13: 542–550. 16

All lower the HbA1c by approximately the same amount when added-on metformin 40 RCT (n=17795): 6-12 months trials, added-on after MFM failure McIntosh B et al. Open Med 2011; 5:E35-E48

Add on to MET vs MET alone Comparable efficacy across the class Alogliptin Linagliptin Saxagliptin Sitagliptin Vildagliptin Add on to MET vs MET alone Messori A, et al. Diabetes Ther. 2014 Jun;5(1):341-4.

Starting DPP4 inhibition CASE#1

Graham presents to his GP Patient history Age 50 years Married, 3 children Works as a taxi driver BP 132/85 mmHg BMI 30 kg/m2 Non-smoker Diet and exercise not optimal Graham, aged 50 Medical history Diabetes diagnosed 18 months ago Dyslipidaemia and hypertension diagnosed 3 years ago Current Medications Metformin 1500 mg/day Rosuvastatin 20 mg/day Telmisartan/hydrochlorothiazide 80/12.5 mg fixed dose combination Laboratory parameters HbA1c 7.9% Total cholesterol: 3.8 mmol/L Normal albuminuria and eGFR

What are Graham’s treatment priorities? Compliance Lower HbA1c Weight Sustainability CVD Risk No HYPO Tolerability Cost

What are Graham’s treatment priorities? Compliance Lower HbA1c Weight Loss Sustainability CVD Risk No HYPO Tolerability Cost Question 1. How well will he tolerate an DPP4 inhibitor?

DPP4i have key advantages in terms of a reduced risk of weight gain 30 RCT (n=15265): 6-12 months trials, added-on after MFM failure McIntosh B et al. Open Med 2011; 5:E35-E48

*Mean dose received. Göke B, et al. ADA 2011. 1110-P (Abstract and poster); Onglyza. Summary of product characteristics. Bristol-Myers Squibb/AstraZeneca EEIG, 2011.

Same glucose control but without weight gain1 2.0 1.5 1.0 0.5 -0.5 -1.0 -1.5 -2.0 Glimepiride Linagliptin 28 104 52 78 12 +1.4 Same glucose control but without weight gain1 Linagliptin vs glimepiride (3mg/day) on top of metformin 1500 mg/day or greater for 2-years. Baseline HbA1c 7.7% 1. Gallwitz B et al. Lancet. 2012 Aug 4;380(9840):475-83..

What are Graham’s treatment priorities? Compliance Lower HbA1c Weight Sustainability CVD Risk No HYPO Tolerability Cost Question 2. What about driving on a DPP4 inhibitor?

DPP4i have key advantages in terms of a reduced risk of hypoglycaemia 34 RCT (n=16704): 6-12 months trials, added-on after metformin failure McIntosh B et al. Open Med 2011; 5:E35-E48

DPP4i don’t cause hypoglycemia GLP-1 actions on the β cell are normally tightly coupled to the level of ambient glucose. The insulinotropic actions of GLP-1 are rapidly terminated once the plasma glucose falls into the normal range 7 6 5 4 3 2 1

But they do make it easier for SUs to cause hypoglycemia DPP4 Closer to the edge, reduced food intake as well as uncoupling of GLP-1 from its glucose dependence by sulphonylureas 7 6 5 4 3 2 1

50 y.o. What are Graham’s treatment priorities? Compliance Lower HbA1c Weight Sustainability 50 y.o. CVD Risk No HYPO Tolerability Cost Q3. How well will an DPP4 inhibitor keep working?

Sustainability – the NIKE effect Exhaustion (nike effect) Sustainability – the NIKE effect

3 months 0.7% Onglyza acts to reduce HbA1c within 1 month as add-on to metformin, with sustained glycaemic benefit over 2 years1,2 Adapted from 1. DeFronzo RA, et al. Diabetes 2009;58:A147,Abstract 547; 2. DeFronzo RA, et al. Diabetes Care 2009;32:1649–55.

Sustained HbA1c reductions over 102 weeks1 Placebo-controlled, double-blind Open-label extension 0.0 –0.8% HbA1C reduction at 102 weeks Change in HbA1c (%) from baseline over time -1.0 Open label extensions of key clinical trials have shown that the statistically significant reductions in blood sugar associated with linagliptin therapy are sustained over a period of at least 102 weeks (2 years), with no evidence of loss of efficacy.1 Overall, 1,876 patients were included in the FAS of the 4 initial placebo-controlled 24-weeks trials and randomized to linagliptin. 1,531 of these patients (82%) entered the open-label extension. Patients were on 4 treatment regimens: Monotherapy (n=296), combination with metformin (n=457), combination with metformin + SU (n=544), and initial combination with pioglitazone (n=234). Observed Cases (OC) analysis: n decreases over time due to drop-outs, rescue therapy, and patients not having completed the full trial duration. 60% of patients completing the 24 weeks double-blind period completed 102 weeks of treatment. Coefficient of durability (COD) is defined as HbA1c at week 102 visit – HbA1c at week 24 visit (patients with measured HbA1c values at both visits, n=854). Durability of HbA1c from week 24 to week 102 is defined by COD<0.3%. 1. Linagliptin Data on file. 6 12 18 24 30 42 54 66 78 90 102 n = 1531 1490 1463 1440 1429 1400 1302 1183 1090 1007 948 903 Treatment duration in weeks After 24 weeks double-blind, 78 week open-label extension of 4 randomized, controlled trials. Patients were on 4 treatment regimens: linagliptin monotherapy (n=296); combination with metformin (n=457); combination with metformin & SU (n=544) and initial combination with pioglitazone (n=234). 1. Pre-specified analysis of linagliptin treatment in oral mono-, dual and triple combination therapy (full analysis set, observed cases). 2. Coefficient of durability (COD) is defined as HbA1c at week 102 visit subtracted by HbA1c at week 24 visit Source: Linagliptin data on file.

What are Graham’s treatment priorities? Compliance Lower HbA1c Weight Sustainability CVD Risk No HYPO Tolerability Cost Question 4. Will an DPP4 inhibitor protect his heart?

In a large meta-analysis of CV events, DPP4is were better than the comparator in terms of CV safety1 Meta-analysis of 70 short- and medium-term trials, with 41,959 patients and mean follow-up of 44.1 weeks Odds ratio [95% CI] p-value Major CV event1 0.71 [0.59, 0.86] < 0.001 Acute MI 0.64 [0.44, 0.94] 0.023 Stroke 0.77 [0.48, 1.24] 0.29 Mortality 0.60 [0.41, 0.88] 0.008 CV mortality 0.67 [0.39, 1.14] 0.14 DPP4 inhibitor better Comparator better Approval date: 10102013 0.0 1.0 10.0 1. Analysis of MACE as serious adverse events supports the safety of DPP4 inhibitors, but does not demonstrate their efficacy in reducing CV risk on a long-term basis. Monami M, et al. Diabetes Obes Metab. 2013;15:112–120.

SAVOR-TIMI 53 : Saxagliptin vs placebo * P=0.007 Source: Scirica BM, et al. N Engl J Med. 2013. doi:10.1056/NEJMoa1307684.

EXAMINE: Alogliptin vs placebo Source: White WB, Heller SR. ‘DPP4 inhibitors and CVD. Results from EXAMINE.’ 49th European Association for the Study of Diabetes Annual Meeting. September 24–27, 2013. Barcelona, Spain.

TECOS : Sitagliptin vs placebo Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352

DPP4 inhibition in older patients CASE#2 DPP4 inhibition in older patients

Pam presents to her GP Patient history Medical history Age 71 years BP 142/75 mmHg BMI 27 kg/m2 Non-smoker Diet and exercise not optimal Pam, aged 71 Medical history Diabetes diagnosed 18 months ago Gestational DM Dyslipidaemia and hypertension diagnosed 3 years ago Dizzy spells Occasional bladder problems Current Medications Metformin 2g/day Rosuvastatin 20 mg/day Telmisartan/hydrochlorothiazide 80/12.5 mg fixed dose combination Laboratory parameters HbA1c 8.2% Total cholesterol: 3.8 mmol/L eGFR 55 ml/min/1.73m2

What are Pam’s treatment priorities? Compliance Lower HbA1c Weight Sustainability CVD Risk No HYPO Tolerability Cost Question 5. How well will she tolerate an DPP4 inhibitor?

ADA Guidelines In the aged, the choice of agent should focus on drug safety, especially protecting against hypoglycaemia, heart failure, renal dysfunction, bone fractures and drug interactions. Strategies specifically minimising the risk of low blood glucose may be preferred. Inzucchi et al Diabetes Care 2012

Linagliptin for patients 70 or over did not increase hypoglycaemia unless SU background therapy Overall With SU With Insulin Without SU With Metformin = = = = Approval date: 20131121 16/10/2013: Corrected n numbers (n numbers were previously the wrong way round for linagliptin and placebo) INS, insulin (with or without metformin); MET, metformmin only; SU, sulphonylurea (with or without other antidiabetes drugs). Treated set. Confirmed plasma glucose concentration of 3.9 mmol/L or less, or symptoms attributed to hypoglycaemia, or both. Source: Barnett AH, et al. Lancet. 2013;382:1413–1423

OTHER SIDE EFEFCTS OF SECOND LINE THERAPY HYPO POLYURIA BLADDER ISSUES FRACTURES BONE LOSS GI EFFECTS BLOATING FLATULANCE INJECTION PANCREAS? WEIGHT GAIN GENITAL INFECTION FLUID RETENTION CHF NAUSEA VOMITING DPP4i SU SGLT2 TZD ACI GLP1 Equivalent to placebo

“A rare event not significantly increased in any study” Pancreatitis “A rare event not significantly increased in any study”

What are Pam’s treatment priorities? Compliance Lower HbA1c Weight Sustainability CVD Risk No HYPO Tolerability Cost Question 6. What about her renal function?

Complicated management in DKD.. Increased hypoglycaemia risk Increased cardiovascular risk Increased heart failure risk Increased cancer risk Increased fracture risk Increased side-effects risk Dose adjustments Poly-pharmacy

Drugs that have limitations in CKD Metformin: accumulation & lactic acidosis SU : accumulation, inflexibility, hypoglycemia TZD: fluid retention & bone thinning Insulin: variable accumulation, hypoglycemia GLP-1 agonists: accumulation & tolerability SGLT2i: lack efficacy & hypovolaemia

Diabetes management in CKD VS DPP4 6 7 8 9 Compromise target No compromise treatment

HbA1c reduction with linagliptin in patients with severe renal impairment (eGFR<30) Adjusted1 HbA1c (%) mean change (SE) 0.2 -0.2 -0.4 -0.6 -0.8 -1.0 -0.72%2 Linagliptin (n = 66) Placebo (n = 62) Treatment duration (weeks) 4 8 12 18 24 30 36 42 48 52 -0.60% + no signficiant increase in HYPOs Note: Baseline HbA1c linagliptin 8.2%, placebo 8.2%. Full analysis set, last observation carried forward. 1. Model includes treatment, continuous HbA1c, creatinine clearance at baseline and background antidiabetes drugs. 2. Treatment difference after 52 weeks: –0.72 [95% CI –1.03, –0.41]; p<0.0001. Source: McGill JB, et al. Diabetes Care. 2012;36:237–244.

All other DPP-4 inhibitors are: Primarily excreted by kidneys Share of renal excretion Linagliptin1 Sitagliptin2 All other DPP-4 inhibitors are: Primarily excreted by kidneys Require dose-adjustment, or Not recommended in patients with renal impairment Drug-related kidney monitoring may also be required Vildagliptin3 Saxagliptin4 Alogliptin5 Linagliptin almost exclusively undergoes biliary excretion This means that its pharmacokinetics are unaffected by renal function – this is particularly important given the large proportion of type 2 diabetes patients who experience some degree of renal impairment during their lifetime All other DPP-4 inhibitors are largely excreted through the kidneys, meaning that dosage adjustment and regular monitoring of renal function may need to be considered in patients with renal impairment1-4 In contrast linagliptin dose does not need to be adjusted, even in patients with severe renal impairment5 Linagliptin - US Prescribing Information Vincent SH., Reed JR., Bergman AJ., Elmore CS., Zhu B., Xu S., Ebel D., Larson P., Zeng W., Chen L., Dilzer S., Lasseter K., Gottesdiener K., Wagner JA., Herman GA. Metabolism and excretion of the dipeptidyl peptidase 4 inhibitor [14C]sitagliptin in humans. Drug Metab Dispos. 2007; 35(4): 533-538 He H., Tran P., Yin H., Smith H., Batard Y., Wang L., Einolf H., Gu H., Mangold JB., Fischer V., Howard D. Absorption, metabolism, and excretion of [14C]vildagliptin, a novel dipeptidyl peptidase 4 inhibitor, in humans. Drug Metab. Dispos. 2009 37(3):545-554 Saxagliptin US Prescribing information Christopher R., Covington P., Davenport M., Fleck P., Mekki QA., Wann ER., Karim A. Clin Ther. Pharmacokinetics, pharmacodynamics, and tolerability of single increasing doses of the dipeptidyl peptidase-4 inhibitor alogliptin in healthy male subjects.2008;30(3):513-27 1. Linagliptin US PI. 2. Vincent SH et al. Drug Metab Dispos 2007;35(4):533–538. 3. He H, et al. Drug Metab. Dispos 2009;37(3):545–554. 4. Saxagliptin US PI. 5. Christopher R et al. Clin Ther 2008;30(3):513–527. *Of currently globally approved DPP-4 inhibitors Data from multiple trials, includes metabolites and unchanged drug; excretion after single dose administration of [14C] labeled drug LD/ELB/05/2013/285

Dosing of DPP4 inhibitors in CKD 12.5mg od 6.7mg od 5mg od 2.5mg od 50mg bd 50mg od 60 50 40 30 20 Estimated GFR (ml/min/1.73m2) Saxagliptin should be taken after the dialysis session since a single 4 h dialysis session removes 23% of the dose.

DPP4 inhibition in addition to insulin CASE#3 DPP4 inhibition in addition to insulin

Kevin presents to his GP Patient history Age 50 years BP 142/75 mmHg BMI 37 kg/m2 Non-smoker Diet and exercise not optimal Kevin aged 50 Medical history Diabetes diagnosed 5 years ago Failed oral therapy Now on insulin injections But control is still suboptimal Current Medications Metformin 2g/day Insulin 100U/day Rosuvastatin 20 mg/day Telmisartan/hydrochlorothiazide 80/12.5 mg fixed dose combination Laboratory parameters HbA1c 8.2% Total cholesterol: 5.8 mmol/L eGFR 125 ml/min/1.73m2

Weight What are Kevin’s treatment priorities? Compliance Lower HbA1c Weight Sustainability CVD Risk No HYPO Tolerability Cost Q 6. How well will an DPP4 inhibitor work for Kevin (on top of his insulin regimen)?

DPP4 inhibitors New class of anti-diabetic agents ADEA CASE SERIES DPP4 inhibitors New class of anti-diabetic agents Merlin Thomas Gary Kilov Nicole Frayne

Thank you for your participation Please complete the participant survey: https://www.surveymonkey.com/r/18June15Webinar A certificate of attendance will be issued within 10 working days. A recording of this session will be sent to you and available on http://www.adea.com.au/?p=12349580 Registration for webinar 3 ‘GLP-1’ is available via http://www.adea.com.au/?p=12349580 adea.com.au