Behandling af gamle med diabetes herunder Nye diagnostiske kriterier, prævalens, prognose, behandlingsmål og behandlingsguidelines Jan Erik Henriksen Ledende overlæge, klinisk lektor, PhD Endokrinologisk afd. M Odense Universitet Hospital Diagnosen Diabetes 1997 diagnosen 2 timers PG = 11.1 mM FPG = 7.0 mM 2 timers OGTT 11.1 mM FPG = 7.8 mM 2009 diagnosen ! Vurdering af HbA1c som diagnostisk værktøj Hvilken værdi ? HbA1c < 6.5 % stort ser ingen med retinopati Ca 28.000 personer fra ni forskellige lande Begrænsninger! • Omkostninger • Hæmoglobinopatier • Hæmolytisk anæmi • Kronisk malaria • Efter større blødninger – blodtransfusion • Hurtigt indsættende diabetes (fx DM1) • Alder – race ? Prævalens og prognose Model for udvikling af diabetes i DK Antal patienter 700,000 Ultimo år Anders Green Antal diabetikere 2009 0-9 1019 2029 30-39 40-49 50-59 60-69 70-79 Kvinder 304 1.429 2.619 6.972 13.905 20.665 32.998 30.042 23.217 132.151 Mænd 297 1.401 2.117 5.094 13.783 26.990 44.137 31.108 13.907 138.834 I alt 601 2.830 4.736 12.066 27.688 47.655 77.135 61.150 37.124 270.985 80+ I alt Relativ dødelighed Diabetikeres dødelighed set i forhold til den øvrige befolkning Kvinder Mænd Alle 1997 1,83 1,96 1,90 1998 1,79 1,90 1,85 1999 1,75 1,98 1,86 2000 1,76 1,92 1,84 2001 1,70 1,82 1,76 2002 1,64 1,88 1,75 2003 1,68 1,83 1,75 2004 1,60 1,80 1,70 2005 1,62 1,77 1,69 2006 1,60 1,71 1,65 2007 1,54 1,69 1,62 2008 1,51 1,63 1,57 2009 1,48 1,70 1,59 Hvor langt skal Hba1c ned? UKPDS – HbA1c – Endpoints Epidemiology 20 08 0.9 % point in difference between the two groups Difference in HbA1c was only 0.6 % point between the metformin group and the conventional group UKPDS 10-year post-trial monitoring from 1997-2007 ”Metabolic memory” or ”glucose memory” underscoring the importance of optimal glycaemic control from time of diagnosis Multifactorial intervention Steno Type 2 Study-Design • An open, parallel trial comprising 160 Caucasian type 2 diabetic patients with microalbuminuria • With consealed randomisation patients were allocated either to conventional therapy at their GP or intensive treatment at Steno Diabetes Center Conventional n=80 4 years 8 years Microvascular Macrovascular n=160 Endpoint examinations n=80 Intensive Microvascular Macrovascular 4 years 8 years Hba1c Total Kol Syst BT LDL Dia BT Triglycerid Død Kardiovaskulær sygdom Steno-2: Number Needed to Treat for 13 Years to Prevent One --Death Cardiovascular death Major cardiovascular event Progression of nephropathy Dialysis Laser treatment 5 patients 8 patients 3 patients 5 patients 16 patients 7 patients ACCORD ADVANCE VADT de korte ”akutte” studier Standard vs. intensive BG treatment Standard: Goal: HbA1c 7 -7.9% ACCORD Intensive: Goal: HbA1c <6% Standard: SU other than gliclazide MR + any other anti-diabetic drugs. ADVANCE Intensive: Gliclazide MR + any other anti-diabetic drugs Goal: HbA1c <6.5% Standard: Goal: HbA1c 8%-9% VADT Intensive: Goal: HbA1c <6% Tight glycaemic control reduces primary endpoint but not mortality Accord Advance VADT Primary CVD endpoint 10 % 6% 13 % CVD mortality 39 %* 12 % 32 % Total mortality 22 %* 7% 6% What if the trials had been longer than 5 years ? ACCORD ACCORD: Treatment effects on glucose control 9.0 8.5 Standard therapy 8.0 A1C (%) 7.5 7.0 6.5 6.0 0 Intensive therapy 0 1 2 3 4 5 6 Time (years) ACCORD Study Group. N Engl J Med. 2008;358:2545-59. Which patients will benefit of strict glycaemic control? Hazard Ratios for the Primary outcome Post-hoc analyses ACCORD Mortality in relation to treatment and HbA1c Risk of death over a range of HbA1c Steady increase of risk from 6 to 9% HbA1c with intensive strategy Excess risk with intensive strategy vs standard occured above HbA1c 7% Riddle MC et al. Diabetes Care 2010; 33: 983-90. Excess risk with intensive strategy vs standard occured when intensive participants failed to reduce HbA1c in yr 1 Riddle MC et al. Diabetes Care 2010; 33: 983-90. Number of participants with severe hypoglycemia Requiring any assistance Intensive Standard N (%) N (%) P 830 (16.2) 261 (5.1) <0.001 Requiring medical assistance 538 (10.5) 179 (3.5) <0.001 Severe hypoglycaemia in ACCORD study • 5 death of the excess of 57 death in the intensive arm could be explain by hypoglycaemia • Thus the increase risk of death in the intensive arm can not be explained by hypoglycaemia Miller ME et al. BMJ 2010 Compared with Standard Therapy the Intensive Strategy had: • Lower HbA1c • Greater use of medications: - more multiple OAD: 70 % vs 45 % on 3-5 oral classes - more insulin: 77 % vs. 55 % on insulin - more combination OAD and insulin: 62 % vs. 18 % on 3-5 OAD + insulin • More severe hypoglycemia 10.5 % vs. 3.5 % • More weight gain 28 % vs. 14 % > 10 kg Possible Reasons for increased Mortality with Intensive Treatment in ACCORD • • • • Hypoglycemia Rapid glucose lowering Weight gain Medication interactions, ”treatment resistance” ADVANCE ADVANCE: Treatment effect on glucose control 10.0 9.0 8.0 Mean A1C (%) Standard control 7.0 P < 0.001 6.0 Intensive control 5.0 0.0 0 6 12 18 24 30 36 42 48 54 60 66 Follow-up (months) ADVANCE Collaborative Group. N Engl J Med. 2008;358:2560-72. VADT HbA1c-VADT Intensive Glucose-Lowering Therapy Reduces Cardiovascular Disease Events in Veterans Affairs Diabetes Trial Participants With Lower Calcified Coronary Atherosclerosis Reaven PD et al. Diabetes 2009; 58: 2642-48 Intensive Glucose-Lowering Therapy Reduces Cardiovascular Disease Events in Veterans Affairs Diabetes Trial Participants With Lower Calcified Coronary Atherosclerosis Reaven PD et al. Diabetes 2009; 58: 2642-48 VADT-Predictors of CV death HR • • • • • Prior CV events Age/10 yr HDL/10 mg Baseline HbA1c Severe hypoglycaemia 3.1 2.1 0.7 1.2 4.0 p=0.0001 p<0.0001 p<0.008 p<0.02 p<0.008 VADT conclusions • Intensive - CV events slightly reduced (231 vs. 263, ns) - CV mortality slightly increased (19 vs 15, ns) • Main predictor of MI was recent severe hypoglycemic episode • Early glycaemic control is beneficial • Late intensive control (eg. > 12-15 years after diagnosis) produces little extra benefit • No CV risk attributed to any particular therapy What is the optimal level of HbA1c in relation to outcomes and deaths in type 2 diabetes? An epidemiological study from UK Currie CJ et al. Lancet 2010 Hazard ratios for all-cause mortality by HbA1c in people given oral combination and insulin-based therapies. Mean follow-up was 4.5 years and 5.2 years. Insulin OHA Age: 59.7-67.9 yr. Duration: 5.2-5.6 yr. N = 27965. Currie CJ et al. Lancet 2010; Age: 60.3-66.3 yr. Duration: 6.8-8.2 yr. N = 20005. Interpretation • Low and high mean HbA1c values were associated with increased all cause mortality and cardiac events Final HbA1c conclusion Glycaemic control and CVD outcomes • Early intervention and intensive control is worthwhile if it can be obtained without high risk of severe hypoglycaemia and major increase in weight • After long diabetes duration the effect of intensive glycaemic control seems to be minimal and in some groups of patients may even increase mortality • However there are still many unanswered questions, including questions about the choice of agents Behandling af hyperglykæmi Treatments for Type 2 Diabetes GLP1, Exenatide, Liraglutide Acarbose Carbohydrate - Sitagliptin, Vildagliptin, Saxagliptin, Linagliptin DIGESTIVE ENZYMES + Stimulates insulin secretion G G (I) G Metformin - I G Limited effect on insulin resistance I G - G Insulin I Reduces hepatic glucose output + I I I G G G Sulphonylurea Repaglinide (G) e s luco I Glucose G Reduces absorption DPP-4 hæmmere, I G I G - + Thiazolidinediones Reduce Insulin Resistance The Incretin Effect, GLP-1 and Exenatide The Incretin Effect Demonstrates the Response to Oral vs IV Glucose 2.0 11 * C-peptide (nmol/L) Venous Plasma Glucose (mmol/L) Oral Glucose IV Glucose 5.5 1.5 * * * Incretin Effect * 1.0 * * 0.5 0.0 0 01 02 60 120 Time (min) 180 01 02 60 120 Time (min) Mean ± SE; N = 6; *P ≤.05; 01-02 = glucose infusion time. Nauck MA, et al. Incretin effects of increasing glucose loads in man calculated from venous insulin and C-peptide responses. J Clin Endocrinol Metab. 1986;63:492-498. Copyright 1986, The Endocrine Society. 180 The Incretin Effect Is Reduced in Patients With Type 2 Diabetes Intravenous Glucose Oral Glucose Insulin (mU/L) Control Subjects Patients With Type 2 Diabetes 80 80 60 60 40 40 * * * * * * * * 20 * * 20 0 0 0 30 60 90 120 150 180 0 30 Time (min) *P ≤.05 compared with respective value after oral load. Nauck MA, et al. Diabetologia. 1986;29:46-52. Reprinted with permission from Springer-Verlag © 1986. 60 90 120 150 180 Time (min) GLP-1 effekter i mennesket GLP-1 secreted upon the ingestion of food Promotes satiety and reduces appetite Alpha cells: ↓ Postprandial glucagon secretion Beta cells: Enhances glucosedependent insulin secretion Liver: ↓ Glucagon reduces hepatic glucose output Stomach: Helps regulate gastric emptying Adapted from Flint A, et al. J Clin Invest. 1998;101:515-520.; Adapted from Larsson H, et al. Acta Physiol Scand. 1997;160:413-422.; Adapted from Nauck MA, et al. Diabetologia. 1996;39:1546-1553.; Adapted from Drucker DJ. Diabetes. 1998;47:159-169. Mechanism of Action of DPP-4 inhibition Ingestion of food GI tract Pancreas Release of active incretins GLP-1 and GIP DPP-4 inhibitor X Inactive GLP-1 DPP-4 enzyme Glucose dependent Insulin (GLP-1 and GIP) Beta cells Alpha cells Blood glucose in fasting and postprandial states Glucosedependent Glucagon (GLP-1) Inactive GIP Glucose uptake by peripheral tissue Hepatic glucose production • Incretin hormones GLP-1 and GIP are released by the intestine throughout the day, and their levels increase in response to a meal. Concentrations of the active intact hormones are increased by DPP-4 inhibition, thereby increasing and prolonging the actions of these hormones. Nye behandlinger til Type 2 diabetes Byetta (Exenatide) Victoza (Liraglutide) Synthetic version of salivary protein found in the Gila monster Januvia Janumet Galvus Eucreas Onglyza Trajenta Behandling af type 2 diabetes mellitus – anno 2010 Livsstilsintervention (diæt, vægtkontrol og øget fysisk aktivitet) Metformin (glykæmisk kontrol, reduktion i kardiovaskulær sygdom) Ingen hypoglylkæmi, ingen vægtstigning Tillæg af anden (oral) agent (glykæmisk kontrol) SU Billig Hypo Vægt↑ Betacellen? Glinid Hurtig virkning Pris Hypo Vægt↑ TZD DPP-4 GLP-1 α-Gluc. Inhibitor inhibitor analoger Hypo CVD↓? Hypo Sikkerhed! Lille effekt Vægt↑ GI-biv Pris Hypo Vægt↑ Ingen biv. Beta-celle effekt? Pris Insulin Hypo Virker altid Vægttab Hypo CVD/betaVægt↑ celle effekt? Pris Kvalme osv. Pris Algoritme for behandling af hyperglykæmi ved T2DM Debut - 1. valg 1 Metformin Gastrointestinale gives uanset bivirkninger HbA1c.ved Undtagelser: Metformin kan skyldes for hurtig dosis-øgning Metformin 1. Metformin tåles ikke2 : gå til 2. valg, hvis behandlingsmål ikke kan opnås ved Tilføj metformin, når diagnosen er verificeret og behandlingen stabiliseret livsstilsændring. Akutte tilstande med manglende fødeindtagelse og/eller potentielt 2. Svær hyperglykæmi med symptomer3 og /eller akutte tilstande4: start insulin – behandling. Skift til eller suppler med metformin når tilstanden erbehandles stabiliseret. ustabil hæmodynamik og/eller nyrefunktion: Hyperglykæmien 3. Nedsat nyrefunktion5: Absolut kontraindíkation hvis eGFR < 30 ml/min, med hurtigt virkende insulin indtil erSulfonylurinstof stabil. med kort halveringstid, eller - Vælg Insulin, tilstanden evt. DPP4-hæmmer, forsigtighed (dosishalvering og regelmæssigpioglitazon kontrol afkontrol nyrefunktion) ved eGFR 30-60 ml/min. under af nyrefunktion. 2. Valg6,7 Tabletbehandling DPP4Sulfonylurinstof (SU)8 hæmmer9 /repaglinid10 Undgå ved svært nedsat nyrefunktion. Erfaringsgrundlaget ved langtidsbehandling er begrænset. Undgå ved/hos: øget risiko for hypoglykæmi, alkoholmisbrug, ældre eneboende, erhvervschauffører, stilladsarbejdere , svært nedsat nyrefunktion. Injektionsbehandling GLP-111 Insulin Til udvalgte patienter, hvor et vægttab er central i behandlingen. Erfaringsgrundlaget er begrænset. Behandlingen skal gives subcutant. Altid behandlingen ved svær hyperglykæmi og kan bruges som 2. valg til alle. Behandlingsmålet bør dog primært søges opnået med anden behandling ved svær overvægt, øget risiko for hypoglykæmi, alkoholmisbrug, ældre eneboende, erhverschauffører, stilladsarbejdere og lignende. I særlige tilfælde Pioglitazon12 Svær insulinresistens og/eller fedtlever. Undgå ved: Hjerteinsufficiens, Osteoporose, Svært nedsat nyrefunktion, Leverinsufficiens. Intensiveret behandling6 Insulin Insulin er det naturlige valg ved behov for intensivering: 1. Fortsæt metformin og tillæg insulin. 2. Intensiver igangværende insulinbehandling. 3. Hos udvalgte patienter kan kombination af insulin + DPP-4 eller GLP-1 + evt. metformin forsøges (specialistopgave) 13. Ole Snorgaard 2010 Andre kombinationsmuligheder (max. 3 lægemidler, specialistopgave): 1. Metformin + DPP-4/GLP-1 + Sulfonylurinstof. 2. Metformin + Sulfonylurinstof + pioglitazon. 3. DPP-4/GLP-1 + Sulfonylurinstof + pioglitazon. 4. Acarbose kan indgå i stedet for én af de øvrige i kombinationerne. Metformin kan kombineres med alle de øvrige lægemidler. SU kan kombineres med de øvrige, men på grund af risikoen for hypoglyæmi kun med insulin i særlige tilfælde og aldrig med meglitinid. Hvis GLP-1 tillægges SUbehandling, bør SU dosis halveres indtil man har overblik over effekten og hvis HbA1c er < 70 mmol/mol (8,5%). GLP-1 og DPP4-hæmmer i kombination er ikke undersøgt. GLP-1 kan kombineres med glitazon, mens GLP-1 - insulin kombinationen undersøges i øjeblikket. DPP4-hæmmer kan kombineres med glitazon, mens DPP4 - insulin kombinationen undersøges i øjeblikket. Acarbose kan kombineres med alle de øvrige. Glitazoner og insulin i kombination bruges flere steder i udlandet, i Danmark er det ikke rekommanderet. Algoritmer for insulinbehandling af type 2 diabetes Start på insulinbehandling: Basal (langsomvirkende) insulin 1-2 gange dagligt Blandingsinsulin (langsom- og hurtigvirkende) morgen og/eller aften Intensivering: Basal/bolus: Tillæg af hurtigtvirkende 1-3 gange dagligt Blandingsinsulin (langsom- og hurtigvirkende) Morgen, middag og aften Basal/bolus: Basal 1-2 gange og hurtigtvirkende 3 gange dagligt Final conclusion • New diagnostic criteria • Rapid growing population • Glycaemic target should be individualized based on – – – – – – diabetes duration co-morbidities (CVD) risk of hypoglycemia risk of weight gain “risk of” polypharmacia Age • New promising drugs on the market
© Copyright 2024