Dr. Stanley Ho Medical Development Foundation Symposium 2014 18 Jan 2014 Advances in the Management of Type 2 Diabetes Mellitus Dr Ronald Ma Professor Dept of Medicine & Therapeutics Prince of Wales Hospital Chinese University of Hong Kong
Outline Update on Epidemiology of Type 2 diabetes Overview of current guidelines for T2DM Emerging new treatments Novel approach to DM complications Diabetes and cancer
A. 35000 Real GDP per capita (USD) B. Prevalence (%) 30000 25000 20000 15000 10000 5000 0 20 18 16 14 12 10 8 6 4 2 0 Diabetes In Asia India China Malaysia Singapore India China Malaysia Singapore 1981-1987 1988-1994 1995-2001 2002-2008 1981-1987 1988-1994 1995-2001 2002-2008 Ramachandran A, Ma RC and Snehalatha DC, Lancet 2010; 375: Jan 30
Prevalence of DM in China 46,239 adults (> age of 20 years) 9.7% diabetes 15.5% Prediabetes 92.4 million DM 148.2m Prediabetes Yang W et al, NEJM 2010; March 25
Evolving Epidemic of Diabetes and Pre-diabetes Yang W et al, NEJM 2010; March 25 Xu et al, J Am Med Asso 2013; Sept 4
Heterogeneity of Diabetes in Asian populations Type 1 Type 2 Autoimmunity Monogenic DM?other causes T2 DM genes MODY Amylin gene mutations Mitochondrial DM LADA Metabolic syndrome Young-onset DM Only 10% of those with onset < 35 years have classical Type 1 DM 30-50% are insulin resistant In young-onset T2 DM, 10-15% carry either genetic or markers of insulin deficiency Anti-GAD present in 31% of T1DM, 11.8% of normal wt T2DM, 2.9% of obese T2DM Chan JC et al, JAMA 2009
Ectopic lipids Diet Obesity Physical inactivity Mitochondrial dysfunction Stress response Intrauterine env Aging Inflammation Insulin Resistance Diabetes Risk Changes in gene and protein function Type 2 Diabetes Insulin Secretion Genetics Epigenetic changes Gut microbiome Glucose sensing Incretins β-cell growth survival Adapted from Doria A et al, Cell Metab 2008
Outline Update on Epidemiology of Type 2 diabetes Overview of current guidelines for T2DM Emerging new treatments Novel approach to DM complications Other co-morbidities
Type 2 diabetes is a chronic condition with progressive loss of β-cell function over time UKPDS 16 Study β-cell function (% of normal by HOMA) 100 80 60 40 20? ß-cell function = 50% of normal Time of diagnosis HOMA = homeostasis model assessment 0-10 -9-8 -7-6 -5-4 -3-2 -1 0 1 2 3 4 5 6 Holman RR, et al. Diab Res Clin Pract. 1998;40(Suppl):S21 S25. UKPDS Study Group. Diabetes. 1995;44:1249 1258. Years ~50% of ß cell function was already lost at the time of diagnosis in UKPDS
Most current therapies for type 2 diabetes promote weight gain UKPDS 34 Study Change in weight (kg) 8 7 6 5 4 3 2 1 0 0 3 6 9 12 Years from randomization Conventional* (n=411) Glibenclamide (n=277) Metformin (n=342) Insulin (n=409) Up to 5 kg is already gained within just 3 years with a sulphonylurea or insulin *Diet initially then sulphonylureas, insulin and/or metformin if FPG>15 mmol/l UKPDS 34 Study. Lancet 1998:352:854 65
Pathogenesis of Hyperglycaemia in Type 2 DM insulin secretion Neurotransmitter dysfunction lipolysis HYPERGLYCAEMIA é Glucagon Secretion α-cells é Glucose resorption é Hepatic glucose production Incretin effect Glucose uptake Adapted from DeFronzo RA. Diabetes 2009; 58: 773
The incretins GLP-1 and GIP mediate glucose-stimulated insulin release Food intake Pancreas Glucose-dependent insulin secretion β-cells Increases glucose utilisation by muscle and adipose α-cells Glucose-dependent glucagon suppression Decreases hepatic glucose release Intestine Active GLP-1 (7-36) Active GIP Glucose homeostasis GLP-1 = Glucagon-like peptide-1, secreted from L-cells in the distal gut GIP = glucose-dependent insulinotropic peptide, secreted from K-cells in the proximal gut Adapted from Drucker DJ. Expert Opin Invest Drugs. 2003;12(1):87 100. Ahrén B. Curr Diab Rep. 2003;3:365 372.
Glucagon-like-peptide (GLP) -1 is degraded by DPP-4 Food intake Pancreas Glucose-dependent insulin secretion β-cells Increases glucose utilisation by muscle and adipose Glucose-dependent glucagon suppression Decreased hepatic glucose release improves overall glucose control α-cells Intestine Active GLP-1 (7-36) DPP-4 Inactive GLP-1 (9-36) amide DPP-4 = Dipeptidyl peptidase-4 His-Ala cleaved from amino terminus Adapted from Drucker DJ. Expert Opin Invest Drugs. 2003;12(1):87 100 Ahrén B. Curr Diab Rep. 2003;3:365 372
Blocking DPP-4 can improve incretin activity and correct the insulin:glucagon ratio in T2DM T2DM Incretin response diminished Insulin Further impaired islet function Hyperglycaemia Glucagon DPP-4 inhibitor Insulin Incretin activity prolonged Improved islet function Improved glycaemic control Glucagon DPP-4=dipeptidyl peptidase-4; T2DM=type 2 diabetes mellitus. Adapted from Unger RH. Metabolism. 1974;23:581 593; Ahrén B. Curr Enzyme Inhib. 2005;1:65 73.
Oral glucose-lowering agents: An overview Effect on weight Risk of hypos Common adverse events Effect on insulin resistance Effect on insulin secretion Metformin x GI disorders DPP-4 inhibitors x Nasopharyngitis * Sulphonylureas Glinides Thiazolidinediones x Hypoglycemia, Weight gain Hypoglycemia Weight gain Weight gain, Fluid retention α-glucosidase inhibitors x GI discomfort * glucose-dependent Fonseca, V., et al. Diabetes Obes Metab. 2011 Apr 11; DeFronzo RA. Ann Intern Med. 1999;131:281 303; UKPDS. Lancet. 1998; 352:837 853; Aschner P, et al. Diabetes Care.2006;29(12):2632-7; ADA and EASD Consensus statement. Diabetes Care. 2009;32:193 203; Nesto RW, et al. Circulation 2003;108:2941 2948; Matthaei S, et al. Endocrine Reviews. 2000;21:585 618; Raptis SA & Dimitriadis GD. J Exp Clin Endocrinol. 2001;109:S265 S287.
The ideal treatment regime for T2DM Effective lowering of blood glucose Minimal risk of hypoglycaemia Reduction of body weight or weight-neutral Preservation of beta-cell function Improvement in cardio-metabolic risk factors Minimal drug interaction Good safety profile in elderly patients Can be safely combined with other oral drugs or insulin Can reduce cardiovascular risk
Individualized ADA / EASD treatment Positional Statement for Type 20122 Diabetes Source: ADA / EASD position statement 2012 : Diabetes Care Publish Ahead of Print, published online April 19, 2012
DPP4-I: a reasonable OAD choice after metformin due to its safety & tolerability profile Source: ADA / EASD position statement 2012 : Diabetes Care Publish Ahead of Print, published online April 19, 2012
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Approximately 40% of type 2 diabetes patients have renal complications CKD prevalence was greater among people with diabetes than among those without diabetes (40.2% versus 15.4%) 2.3 17.7 11.1 9.5 8.6 50.8 Data missing no CKD CKD stage 1 CKD stage 2 CKD stage 3 CKD stage 4/5 CKD Stage egfr (ml/min) No CKD 90* 1 90** 2 60 89 3 30 59 4 15 29 * Normal kidney function, no sign of kidney damage ** Albuminuria kidney damage 5 <15 or dialysis Based on data from 1462 patients aged 20 years with T2DM who participated in the Fourth National Health and Nutrition Examination Survey (NHANES IV) from 1999 to 2004. 1. Koro CE, et al. Clin Ther. 2009;31:2608 17; 2. Saydah S, et al. JAMA. 2007;297(16):1767.
Current treatments for type 2 diabetes have limitations when renal function declines Injectables Insulin Liraglutide Exenatide Dose Reduction Dose Reduction Linagliptin Sitagliptin Vildagliptin Saxagliptin Dose Reduction Dose Reduction Dose Reduction Oral drugs Metformin Acarbose Repaglinide Dose Reduction Glimepiride Gliclazide Pioglitazone Dose Reduction Dose Reduction >60 30 60 <30 Declining GFR Adapted from: Schernthaner G, et al. Nephrol Dial Transplant. 2011;26(2):454 7 (in press) and respective SmPCs Hemodialysis
DPP4-I: safe to use in patients with moderate to severe renal impairment Degree of renal impairment Vildagliptin Sitagliptin Saxagliptin Linagliptin Normal 50 mg QD or BID 100 mg QD 5 mg QD 5 mg QD Mild 50 mg QD or BID 100 mg QD 5 mg QD 5 mg QD Moderate 50 mg QD 50 mg QD 2.5 mg QD 5 mg QD Severe 50 mg QD 25 mg QD 2.5 mg QD 5 mg QD Prescribing information of vildagliptin, sitagliptin, saxagliptin & linagliptin
Hypoglycemia is a major concern in the elderly Patient risk factors Advanced age Recent hospitalization Intercurrent illness Chronic liver, renal or cardiovascular disease Endocrine deficiency (thyroid, adrenal, pituitary) Loss of normal counterregulation Lifestyle risk factors Poor nutrition or fasting Prolonged physical exercise Alcohol (ethanol) Drug risk factors Use of sulfonylureas or insulin Drug interactions with SUs Hypoglycemic unawareness SU=sulfonylurea. Adapted from Chelliah A, Burge MR. Drugs Aging. 2004; 21: 511 530.
In this multinational, double-blind, 24 week study, drug-naive or inadequately controlled (HbA1c 7 & 10%) patients with T2DM aged 70 years or older were enrolled Investigators set individualised treatment targets on the basis of age, baseline HbA1c, comorbidities, and frailty status before a validated automated system randomly assigned patients (1:1) to vildagliptin (50 mg once or twice daily as per label) or placebo. Co-primary efficacy endpoints were proportion of patients reaching their investigatordefined HbA1c target HbA1c reduction from baseline to study end
Vildagliptin significantly reduced A1c in elderly patients without increasing AEs Hypoglycemia Vildagliptin Placebo Overall 2.2% 0.7% Severe hypoglycemia 0% 0%
Phenotypic heterogeneity of Diabetes in Asians Kong AP, et al, Nat Rev Endocrinol 2013; May 28 Ma RC and Chan JC. Ann N Y Acad Sci 2013; April Ramachandran A, Ma RC et al, Lancet 2010; 375: 408-18 Chan JC et al, JAMA 2009; May 27
Meta-analysis of 55 DPP4I trials comparing effect in Asians and Non-Asians Combined difference in HbA1c -0.26% Efficacy correlated with baseline BMI Difference most marked for FBG Kim YG et al, Diabetologia 2013; 56: 696-708
Metformin and AcaRbose in Chinese as the initial Hypoglyacemic treatment (MARCH ) Trial -4w 0 24w 48 w Acarbose (N=391) N=351 Acarbose (N=326) Run-in N=942 Monotherapy Monotherapy or add-in therapy Metformin (N=393) N=347 Metformin (N=314) Mean HbA1c reduction at 48w: -1.11% acarbose vs -1.12% metformin Acarbose group lost more weight: -0.63kg (-1.15 to -0.10, p=0.0194) Acarbose group more favourable lipid profile Acarbose less postprandial hyperinsulinaemia Yang W et al, Lancet Diabetes Endocrinol 2013; 18 Oct
Metformin and AcaRbose in Chinese as the initial Hypoglyacemic treatment (MARCH ) Trial Yang W et al, Lancet Diabetes Endocrinol 2013; 18 Oct
Glucose Insulin Glucagon GLP-1
Meal ingestion Postprandial glucose excursion Hyperinsulinaemia Glucagon α- glucosidase distal intestinal absorption of carbohydrates Ma RC. Lancet Diabetes Endocrinol 2014; 2: 6-7
Meal ingestion ê VLDL synthesis ê TG ê Postprandial glucose excursion ê Hyperinsulinaemia ê Glucagon ACARBOSE α- glucosidase Delayed distal intestinal absorption of carbohydrates GLP-1 Delayed gastric emptying Decreased appetite Altered gut microbiome Weight loss Ma RC. Lancet Diabetes Endocrinol 2014; 2: 6-7
Targeting the kidney for treatment of hyperglycaemia SGLT 2 inhibitors Tahrani A et al, Lancet Diabetes Endocrinol 2013; 1: 140-51
Dapagliflozin Added to patients on MF 24 week study 546 patients No increase in hypo Beneficial wt loss Increase in genital infections Bailey C et al, Lancet 2010, June 26
Intensive insulin therapy in newly diagnosed T2 DM- Beneficial effects on beta-cell function Remission rate 1yr 382 patients with newly diagnosed T2 DM Randomized to insulin or OHA Treatment stopped after normoglycaemia 2 weeks 51.1% 44.9% 26.7% Weng J et al. Lancet 2008; 371: 1753-60
Meta-analysis of short-term intensive insulin therapy in T2DM Kramer C et al, Lancet Diabetes Endorinol 2013; 1: 28-34
The Burden of CV Complications in DM The Hong Kong Diabetes Registry (1995 2005) >7,000 DM patients Mean age: 56 years Mean duration of follow-up 6 years Death 10.1% (768) Coronary heart disease 6.7% (507) Cardiac failure 4.5% (340) Stroke 5.6% (422) End stage renal disease 10.5 (799) Cancer 5.4% (413) Composite events 32.9% (2492) Yang, et al. Arch Intern Med. 2008; Am J Cardiol. 2008; Diabetes Care. 2007; Diabetologia. 2007.
Pathogenesis of cardio-renal complications in DM Visceral obesity Insulin resistance Hypertension Hyperglycaemia Dyslipidaemia/ FFA Adipokines Ang II AGEs Protein Kinase C Aldose reductase Oxidative stress Inflammation Cellular death Abnormal growth Fibrosis Endothelial dysfunction Low grade infections Loss of structure and function Ma RC and Chan JC, Annals NY Acad Sci 2013 Cardio-renal complications
How to lower CVD risk Reduce LDL-C to <1.8mmol/l (70mg/dL) (statins) Raised HDL-C levels to >1.0mmol/l (>40mg/dL) and lower TG to <1.7mmol/l (<150mg/dL) (fibrates) Reduce BP to <130/<80mmHg (ACEI/ARB, CCB) Lower glucose levels A-A1c B-BP C-Cholesterol (LDL)
Incretin pathways and cardiovascular system CV Effects CV risk factors Endothelial fx Atherosclerosis Ischaemia/ Reperfusion Glucose metab LV function Drucker D. Cell Metab. 2006;3:153 165; Nikolaidis L, et al. Circulation. 2004;109:962.
Safety observations so far are promising, therefore all DPP-4 compounds are currently involved in outcome studies No increased risk of CV events was observed in patients randomly treated with DPP-4 inhibitors DPP-4 inhibitor better Comparator better Total patients in analysis Primary endpoint Comments Linagliptin 1 0.15 0.34 0.74 5,239 CV death, MI, stroke, hospitalisation due to angina pectoris Pre-specified/ independent adjudication Sitagliptin 2 0.41 0.68 1.12 10,246 Med DRA terms for MACE No formal adjudication; Post-hoc analysis Vildagliptin 3 0.62 0.84 1.14 10,988 Acute coronary syndrome, transient ischaemic attack, stroke, CV death Pre-specified/ Independent adjudication Saxagliptin 4 0.23 0.42 0.80 4,607 MI, stroke, CV death Pre-specified/ Independent adjudication Alogliptin 5 0.21 0.63 1.19 3,489 Non-fatal MI, non-fatal stroke, CV death Pre-specified/ Independent adjudication 1/8 1/4 1/2 1 2 4 8 Risk ratio for major CV events 1-5 1. Johansen O-E., et al. ADA 2011 Late breaker 30-LB; 2. Williams-Herman D, et al. BMC Endocr Disord. 2010;10:7. 3. Schweizer A, et al. Diabetes Obes Metab. 2010;12(6):485 494; 4. Frederich R, et al. Postgrad Med. 2010;122(3):16 27; 5. White et al. 2010, ADA Scientific Sessions. Abstract 391-PP
Design of SAVOR Study 16,492 patients with established CV disease (CVD) or multiple risk factors (MRF) and HbA1c levels of 6.5% to 12% were randomized (ITT analysis population) Saxagliptin (n=8,280) 0.5% never took study drug (n=40) 18.4% prematurely discontinued study drug (n=1,527) Placebo (n=8,212) 0.5% never took study drug (n=39) 20.8% prematurely discontinued study drug (n=1,705) 97.6% completed the study (n=8,078) 97.4% completed the study (n=7,998) MEDIAN FOLLOW-UP: 2.1 Years Scirica BM, et al. N Engl J Med. 2013; doi: 10.1056/NEJMoa1307684.
Kaplan-Meier Rates of the Primary Composite Endpoint CV Death, MI, or Stroke 14 Pa8ents With Endpoints (%) 12 10 8 6 4 2 HR 1.00; 95% CI, 0.89 1.12 P<0.001 (NI) P=0.99 (superiority) Saxaglip8n: 7.3%* Rate/100 person- yrs 3.7 Placebo: 7.2%* Rate/100 person- yrs 3.7 Placebo Saxaglip8n 0 0 180 360 540 720 900 Days 8212 8280 7983 8071 7761 7836 7267 7313 4855 4920 851 847 *K- M event rates are presented a/er 2 yrs. HR: hazard ra8o; K- M: Kaplan- Meier; Pbo: placebo; Saxa: saxaglip8n Scirica BM, et al. N Engl J Med. 2013.10.1056/NEJMoa1307684. 45
Secondary Composite Efficacy Endpoint: Individual Components 2-Year Event Rate Saxagliptin (n=8,280) Placebo (n=8,212) Hazard Ratio (95% CI) P-value CV death 269 (3.2%) 260 (2.9%) 1.03 (0.87-1.22) 0.72 MI 265 (3.2%) 278 (3.4%) 0.95 (0.80-1.12) 0.52 Ischemic stroke 157 (1.9%) 141 (1.7%) Endpoint 0.38 Hospitalization for HF 289 (3.5%) 228 (2.8%) 1.27 (1.07-1.51) 0.007 Hospitalization for coronary revascularization Hospitalization for unstable angina 423 (5.2%) 459 (5.6%) 0.91 (0.80-1.04) 0.18 97 (1.2%) 81 (1.0%) 1.19 (0.89-1.60) 0.24 One component of the composite secondary endpoint, hospitalization for HF, occurred at a greater rate in the saxagliptin group compared with placebo. Among CV deaths, there was no imbalance in deaths due to HF (44 [0.5%] and 40 [0.5%] for saxagliptin and placebo, respectively). Scirica BM, et al. N Engl J Med. 2013; doi: 10.1056/NEJMoa1307684.
Pancreatitis and Pancreatic Cancer Patients (%) Endpoint Saxagliptin (n=8,280) Placebo (n=8,212) P-value Any pancreatitis* 0.3% 0.3% 0.77 Acute (Definite or possible) 0.3% 0.2% 0.42 Acute (Definite) 0.2% 0.1% 0.17 Acute (Possible) 0.1% 0.1% 0.79 Chronic <0.1% 0.1% 0.18 Pancreatic cancer 5 12 0.095 Independently adjudicated incidence of pancreatitis was similar with saxagliptin and placebo (0.3% for both; P=0.77). The observed rates of pancreatic cancer were lower in the saxagliptin group (5 patients) than in the placebo group (12 patients; P=0.095). *Patients may have had more than one type of event. Scirica BM, et al. N Engl J Med. 2013; doi: 10.1056/NEJMoa1307684.
Outline Update on Epidemiology of Type 2 diabetes Overview of current guidelines for T2DM Emerging new treatments Novel approach to DM complications Diabetes and cancer
Diabetes and Cancer Seshasai et al, Emerging risk factors collaboration NEJM 2011
Hyperglycaemia and cancer risk Hong Kong Diabetes Registry Causes of death In 7000 T2D FU 6 years 1% A1c 18% HR for cancer So WY et al DMRR 2008 Yang XL et al Diabetes 2010
Inzucchi et.al. Diabetologia
Personalized Medicine in Diabetes Treatment selection should be based on patient characteristics: Age Body weight Complications Disease duration Pozzilli P.Del Prato S. Diab Metab Res Rev 2010
Summary Epidemic of diabetes with increasing proportion of young patients with diabetes Improved understanding of the pathogenesis of type 2 diabetes has led to several novel treatment strategies Therapies with complementary mechanisms of action should be used in combinations for optimum glycemic control Safety and efficacy should be given high priorities in the decision of choice of agents for the patient The A1c target must be individualized, based on numerous factors, such as age, co-morbid conditions, risk of hypoglycemia, adherence, etc.