Personalized therapeutics in diabetes

Transcription

1 Personalized therapeutics in diabetes Leen M. t Hart Molecular Cell Biology & Molecular Epidemiology Leiden University Medical Center Epidemiology & Biostatistics VU University Medical Center

2 Diabetes mellitus 2015: ~400 million patients (1 million in the Netherlands) 2035: ~600 million patients Diabetic complications are an important cause of death and reduce the quality of life. Cardiovascular disease, retinopathy, nephropathy, neuropathy Bronnen: IDF, RIVM, Diabetes Fonds, NDF Zorgstandaard, juli 2007; Dekker JM et al 2006

3 Chronic treatment of diabetes Treatment goals Normo-glycemia Prevention of (late) complications Fasting glucose 4 8 mmol/l HbA1c < 53 mmol/mol (< 7%) Glycated hemoglobin A1c is less vulnerable to fluctuations and reflects the average glucose levels of the past three months. Bronnen: IDF, RIVM, Diabetes Fonds, NDF Zorgstandaard, juli 2007; Dekker JM et al 2006

4 Diabetes Insulin secretion defects Insulin resistance Diabetes Large heterogeneity in diabetes Need for better classification

5 Personalized medicine Low risk for treatment failure and Adverse effects High risk for treatment failure and Adverse effects Personalized diabetes patients therapeutics Low risk for rapid progression and complications High risk for rapid progression and complications

6 Diabetes Insulin secretion defects Insulin resistance

7 Monogenic diabetes - Often early onset (<25y), multigenerational - Frequently misdiagnosed as type 1 diabetes - treated with insulin - large impact on quality of life Research in the early nineties identified first genetic causes in families with monogenic forms of diabetes

8 Monogenic diabetes Maternally Inherited Diabetes and Deafness (MIDD) van den Ouweland, Lemkes, Maassen et al. Nat Genet 1992 Mutation in the mitochondrial DNA Inherited solely from the mother Maturity Onset Diabetes of the Young (MODY) ~10 subtypes known Severity, progression and risk of developing diabetic complications depending on the gene and mutation involved Neonatal Diabetes Age at onset <6 months Mostly sporadic, some familial Often treated as type 1 diabetes (i.e. insulin injections) Some also have neurological symptoms

9 Monogenic diabetes If a genetic cause for monogenic diabetes is known: - Often no need for insulin therapy! Some subtypes much better treated with oral drugs Better glucose homeostasis Less episodes of hypoglycemia / complications - Large improvement in quality of life - Possibility for early detection of subjects at risk in families National diagnostic center at the LUMC (Dept. of Clinical Genetics)

10 Aims Can we predict who will develop adverse effects, treatment failure or diabetic complications preferably before treatment starts? Better patient stratification and treatment Clinical, biochemical, lifestyle and environmental factors Now complemented with omics research Genetics, transcriptomics, proteomics and metabolomics

11 Type 2 diabetes Insulin secretion defects Insulin resistance Type 2 diabetes Type 2 diabetes is a very heterogeneous disease. - Insulin secretion defects - Insulin resistance - rapid progressors / slow progressors - No diabetic complications / with diabetic complications Currently most patients are treated with the same protocol No tools for patient stratification

12 Treatment of T2DM First start with life style intervention (1-3 months) If not successful start with glucose lowering drug treatment according the guidelines of the Dutch General Practitioners organization (NHG). Step 1 Step 2 Metformin + Sulfonylurea derivative (glicazide) Metformin and SU s have been proven effective, safe and cheap. Step 3 + Insulin One-size fits all protocol Rutten GEHM, et al NHG-Standaard Diabetes mellitus type 2 (derde herziening). Huisarts Wet 2013;56(10):512-25

13 Diabetes Care System West-Friesland T2D patients from the north western part of the Netherlands (>10000 patients) who are treated in the DCS clinics Yearly medical examination Fasting Glucose, HbA1c Cholesterol/ HDL/ LDL/ Triglycerides Renal function BMI, blood pressure, fundus photo, ECG Complications Medication Biobank serum/plasma/dna/rna (n=6000)

14 Pharmacogenetics of metformin Metformin In this project we collaborated with research groups from Europe and the USA Metformin Genetics Consortium (MetGen) ~13000 type 2 diabetes patients from different ethnicities treated with metformin that have genetic data (GWAS) Endpoints: - Decrease in HbA1c level after metformin treatment - Ability to reach the clinical target of an HbA1c below 53 mmol/mol (7%)

15 Zhou et al. (2016) Nat genet 48: Metformin treatment and GLUT2 Gene Several potentially interesting gene variants that influence the response to metformin were identified by the consortium. The GLUT2 gene encodes a passive glucose transporter Interesting functional candidate A gene variant (SNP) in this gene showed evidence for a positive effect on metformin treatment in the various cohorts

16 MetGen consortium GLUT2 signal for metformin response Effect shown as decease in HbA1c (%) after treatment P=6.6*10-14 Worse 0 Better Reduction in HbA1c per C allele: 1.9 mmol/mol Similar effect size in ~2500 Hispanics/African Americans Zhou et al. (2016) Nat genet 48:

17 GLUT2 SNP a potential marker for stratification in obese Type 2 DM Patients stratified based on BMI (<30 vs 30 kg/m2 ) Reduction in HbA1c (mmol/mol) Non-Obese TT TC CC Ref Obese TT TC CC Ref - Obese homozygous C-alele carriers have a 4.8 mmol/mol greater HbA1c reduction compared to T allele homozygotes. - This equates to the effect of about one tablet (500mg) of metformin. Average dose at 1 yr ~1100mg Zhou et al. (2016) Nat genet 48:

18 Pharmacogenetics of GLP-1 based therapies

19 Pharmacogenetics of GLP-1 based therapies Incretins - Hormones released by the gut after ingestion of a meal to rapidly normalize post-prandial hyperglycemia. Glucagon-like peptide-1 (GLP-1) - GLP-1 Stimulates: insulin secretion Reduces: glucagon secretion, food intake and gastric emptying - Endogenous GLP-1 half-life ~2 min rapidly inactivated by the enzyme dipeptidyl peptidase IV (DPP4) Development of GLP-1 based drugs -GLP-1 receptor agonist with prolonged half-life Liraglutide, Exenatide -DPP4 inhibitors Vildagliptin, Sitagliptin, Saxagliptin

20 LM t Hart et al. Diabetes 2013 Genes affecting GLP-1 stimulated insulin secretion Which genes affect the insulin response after GLP-1 stimulation? 232 volunteers tested with intravenous stimulation with GLP-1. insulin secretion Gene expression Enzyme activity * P 8.8*10-7

21 Pharmacogenetics of GLP-1 based therapies Is this gene also associated with response to GLP-1 based drugs in type 2 diabetes patients?? 173 patients treated with a GLP-1 receptor agonist From VUmc and GoDARTS 354 patients treated with a DPP4 inhibitor Change in HbA1c after ~1 year treatment

22 Pharmacogenetics of GLP-1 based therapies - No effect on GLP-1 receptor agonist treatment CTRB1/2 gene and DPP4 inhibitor treatment } 5.6 mmol/mol difference The observed associations with gene expression in the pancreas and enhanced activity in the gut are plausible mechanisms for diabetes risk and treatment effects. LM t Hart et al. Diabetes 2013

23 Towards optimal treatment in type 2 diabetes patients Conclusions: Like for many other drugs there is evidence that the effectiveness of glucose lowering drugs is affected by genes. GLUT2, ATM, CTRB1/2, GLP1R, others In addition small metabolites in blood are associated with diabetes progression and development of diabetic complications However, before this can be used to individualize treatment of patients additional research is needed. - Joint effect of multiple gene variants - Interactions with other drugs i.e. proton pump inhibitors, other drugs and metformin metformin intolerance - Lifestyle and the environment obese vs non-obese male vs female etc.

24 Our team VU University Medical Center G Nijpels JM Dekker AAW vd Heijden F Rutters P Elders J Beulens Leiden University Medical Center N v Leeuwen RC Slieker 24 Insert > Header & footer 27-Nov-17