SIMPLICITY IN T2DM MANAGEMENT WITH DPP4 INHIBITORS: SPECIAL POPULATION

SIMPLICITY IN T2DM MANAGEMENT WITH DPP4 INHIBITORS: SPECIAL POPULATION DR ROSE ZHAO-WEI TING ( 丁昭慧醫生 ) MBBS (HK), MRCP (UK), FHKCP, FHKAM (MEDICINE) Specialist in Endocrinology, Diabetes and Metabolism Qualigenics Medical Limited

OUTLINE 1. Quick review - DPP4 inhibitors basic science 2. Use of DPP4 in special population: - As add-on therapy - In obesity patients - Renal impairment, and etc 3. Q&A session

QUICK REVIEW

DPP4 INHIBITORS - Oral incretin-based therapy (injectable one is GLP1 receptor agonist) - prolongs incretin hormones action - increases endogenous insulin secretion in glucosedependent manner - suppress glacagon

MAJOR TARGETED SITES OF ORAL DRUG CLASSES Liver Pancreas Impaired insulin secretion Sulfonylureas Meglitinides DPP-4 inhibitors Muscle, fat, and liver Hepatic glucose overproduction Biguanides TZDs DPP-4 inhibitors Glucose level Gut Glucose absorption α-glucosidase inhibitors Insulin resistance TZDs Biguanides Buse JB et al. In: Williams Textbook of Endocrinology,11th ed. Philadelphia: Saunders; 2008:1329 1389; DeFronzo RA. Ann Intern Med. 1999;131:281 303; Inzucchi SE. JAMA 2002;287:360 372; Porte D et al. Clin Invest Med. 1995;18:247 254.

DPP4 INHIBITION Mulvhill, Endocrine Review, 2014, 35(7): 992-1019

EFFECT OF ORAL DRUGS ON A1C LEVELS Drug class HbA1c reduction Metformin 1 % Sulphonylurea 1.25% Pioglitazone 1% DPP4 inhibitor 0.75% Alpha-glucosidase inhibitor 1% Diabetes Care 33:1859-1864, 2010

CHOICES: DPP4 INHIBITORS Drug Daily Dose Saxagliptin (Januvia ) Vildagliptin (Galvus ) 100mg QD 50mg bd - Baseline LFT - Better to monitor LFT in the first year Saxagliptin (Onglyza ) Linagliptin (Trajenta ) 5mg QD 5mg QD - Reduce dose for those on strong CYP450 3A4/5 inhibitors eg ketonconazole - Eliminated by liver Alogiptin (Nesina ) 25mg QD - Baseline LFT, - Better to monitor LFT in the first year

DPPIV INHIBITORS ADVERSE EFFECTS Overall very well-tolerated Known -Headache -Nasopharyngitis -UTI -GI upset? Increased risk?, pending further evidence: -Acute pancreatitis Not established: - Ca pancreas

USE OF DPP4 INHIBITORS IN SPECIAL POPULATION

USE OF DPPIV - As monotherapy? - As add-on therapy? - In patients already on insulin? - In elderly patients? - In patients with renal failure?

CASE 1: MR CHAN 50/M - Incidental finding of FG = 7.5 mmol/l, HbA1c = 8.0% during body check - Given a trial of metformin 1g tds at GOPD, complained of loose stool, self-stopped the drug a week later - FHx: strong family history of DM - Physical exam: obesity, BMI = 27 Your DM drug regimen for this patient (assuming normal LRFT): A) Metformin extended release B) DPPIV inhibitor (eg: sitagliptin 100mg daily/ vildagliptin 50mg bd) C) Sulphonylurea (eg: gliclazide 160mg bd) D) SGLT2 inhibitor (dapaglipflozin 10 mg daily)

MY SIMPLIFIED VERSION ALWAYS: Healthy eating, weight control, physical activity, diabetes education Monotherapy: metformin (MF) Dural therapy: MF + SU/ TZD/DPP4 inhibitor/sglt2-inhibitor / GLP1RA/insulin (any 1) Triple therapy: MF + oral drug/ GLP1RA/ basal insulin (any 2) Combined injectable therapy: MF + basal + (mealtime insulin / GLP1RA)

CASE 1: MR CHAN 50/M - You gave him metformin extended release 500mg daily, and gradually stepped up to 1500mg daily, - Well-tolerated - 6 months later, HbA1c = 7.5% What s next? A) DPPIV inhibitors (eg: linagliptin 5mg daily) B) SLT2 inhibitors (eg: canaglipflozin 100mg daily) C) Sulphonylurea (eg: gliclazide 80mg bd) D) GLP-1 RA (eg: exenatide 50mcg bd) E) Basal insulin (eg: insulin glargine 8 units nocte)

POINTS FOR CONSIDERATION IN CHOOSING OAD 1. Effectiveness in glucose lowering 2. Extra-glycaemic effects on body weight, CV risk factors, HT, lipid profile 3. Safety profile - CV safety - hypoglycaemia risk 4. Ease of use 5. Cost

EFFECTS OF GLUCOSE LOWERING AS ADD-ON THERAPY Zhong J, DRCP 109 (2015): 378-388

POST-PRANDIAL HYPER AND GLYCAEMIC CONTROL 30% Fasting hyperglycemia 70% 70% Post-prandial hyperglycemia 30% HbA1C: 7.3 8.5 ~ 9.2 10.2 Mild hyperglycemia moderate hyperglycemia severe hyperglycemia Adapted from Monnier L, et al. Diabetes Care. 2003 Mar;26(3):881-5.

EFFECTS OF GLUCOSE LOWERING AS ADD-ON THERAPY HbA1C FBP 2hBG Mean Baseline: 8.75 8.54 8.86 8.79 8.22 8.36 11.98 10.98 11.77 * * Diabetol Metab Syndr 2014 May 31;6:69. doi: 10.1186/1758-5996-6-69

CASE 1: MR CHAN 50/M - Incidental finding of FG = 7.5 mmol/l, HbA1c = 8.0% during body check - Given a trial of metformin 1g tds at GOPD, complained of loose stool, self-stopped the drug a week later - FHx: strong family history of DM - Physical exam: obesity, BMI = 27 Your DM drug regimen for this patient (assuming normal LRFT): A) Metformin extended release B) DPPIV inhibitor (eg: sitagliptin 100mg daily/ vildagliptin 50mg bd) C) Sulphonylurea (eg: gliclazide 160mg bd) D) SGLT2 inhibitor (dapaglipflozin 10 mg daily)

CASE 2: MS WONG, 80/F Past medical history: 1. HT 2. Obesity 3. Type 2 DM for 10 years with triopathy, Cr ~ 150 umol/l HbA1c = 8.5% 4. Repeated admissions for CHF Recent admission for AMI, APO; decided for medical treatment Current DM regimen from HA: - Metformin 500g bd, Protaphane HM 10U om (done by son)

MS WONG, 80/F She did not accept great increment in insulin dosage due to moderate severity of lipohypertrophy on the abdomen What s next? A) Continue current drug regimen B) Stop metformin due to renal impairment add pioglitazone with renal dose 7.5 15mg daily C) Stop metformin Add vildagliptin (renal dose 50mg daily) slightly step up Protaphane to 16 units om D) Add SGLT2 inhibitors in view of obesity, and possible improvement in CV outcomes as shown in recent trial

DM AND ELDERLY - Concomitant problems to consider: - hypoglycaemia and its associated complications - heart failure, CHD - renal failure - HbA1c target adjusted for co-mobidities, QOL and duration of DM - Polypharmacy - Poor nutrition - ADL status - Social issues

DPP4 INHIBITORS IN ELDERLY

HYPOGLYCAEMIA - Severe hypoglycemia accounts for almost 20% of all hospitalizations for T2DM in the elderly 1 - Associates with dementia 2 3 1: Van Staa T, J Clin Epidemiol 1997; 50: 735-41, 2: Whitmer RA, JAMA 2009;301(15): 1565-72 3: Cheng D, PLoS One. 2014; 9(10): e111543

DPPV AND CV EFFECTS

CV SAFETFY AND OTHER SAFETY Study (median FU) Primary CV outcomes (vs placebo) Acute pancreatitis Sitagliptin Saxagliptin Alogliptin TECOS (3 years) SAVOR (2.1 years) EXAMINE Non-inferior Non-inferior Non-inferior No signficiant increase No signficant increase Risk similar Other Adverse effects (0.3% vs 0.2 %, p = 0.07) - No increase in Ca pancreas (0.3% vs 0.2%, p = 0.77) - Increased admission rate for heart failure (3.5% vs 2.8%) Linagliptin: CAROLINA study, ongoing

DPP-4 INHIBITOR USE IN RENAL IMPAIRMENT Mild renal impairment Moderate Severe Creatinine Clearance (ml/min) DPP-4 inhibitors 50 30 Sitagliptin 1 Saxagliptin 2 Alogliptin 3 Linagliptin 4 100 mg o.d. 50 mg o.d. 25 mg o.d. 2.5 or 5 mg o.d. 2.5 mg o.d. 25 mg o.d. 12.5 mg o.d. 6.25 mg o.d. 5 mg o.d. Vildagliptin 5 50 mg b.i.d. 50 mg o.d. X

USE WITH INSULIN - With basal insulin? - With prandial insulin? - With multiple dose insulin?

MESSAGES 1. DPP4 inhibitors is one of the incretin-based therapy 2. As other OAD except metformin, not use as first-line monotherapy 3. good efficacy in glucose lowering, low hypoglycaemia risk, neutral effect on body weight suitable as add-on therapy in - obese patients - elderly patients - patient with high risk of hypoglycaemia 4. Reduce dose in patients in moderate to severe renal failure (Except for linagliptin no adjustment) 5. Generally well-tolerated drug Safe on cardiovascular perspective

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