Behandling af gamle med diabetes. Jan Erik Henriksen

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1 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

2 Diagnosen Diabetes

3 1997 diagnosen 2 timers PG = 11.1 mm FPG = 7.8 mm FPG = 7.0 mm 2 timers OGTT 11.1 mm

4 2009 diagnosen! Vurdering af HbA1c som diagnostisk værktøj

5 Hvilken værdi? HbA1c < 6.5 % stort ser ingen med retinopati Ca personer fra ni forskellige lande

6 Begrænsninger! Omkostninger Hæmoglobinopatier Hæmolytisk anæmi Kronisk malaria Efter større blødninger blodtransfusion Hurtigt indsættende diabetes (fx DM1) Alder race?

7 Prævalens og prognose

8 Model for udvikling af diabetes i DK Antal patienter 700,000 Ultimo år Anders Green

9 I alt Mænd Kvinder I alt Antal diabetikere 2009

10 Relativ dødelighed Diabetikeres dødelighed set i forhold til den øvrige befolkning Kvinder Mænd Alle ,83 1,96 1, ,79 1,90 1, ,75 1,98 1, ,76 1,92 1, ,70 1,82 1, ,64 1,88 1, ,68 1,83 1, ,60 1,80 1, ,62 1,77 1, ,60 1,71 1, ,54 1,69 1, ,51 1,63 1, ,48 1,70 1,59

11 Hvor langt skal Hba1c ned?

12 UKPDS HbA1c Endpoints Epidemiology

13 20 08

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15 0.9 % point in difference between the two groups

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17 Difference in HbA1c was only 0.6 % point between the metformin group and the conventional group

18 UKPDS 10-year post-trial monitoring from

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22 Metabolic memory or glucose memory underscoring the importance of optimal glycaemic control from time of diagnosis

23 Multifactorial intervention

24 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 4 years 8 years n=80 Microvascular Macrovascular n=160 Endpoint examinations n=80 Microvascular Macrovascular Intensive 4 years 8 years

25 Hba1c Total Kol Syst BT LDL Dia BT Triglycerid

26 Død Kardiovaskulær sygdom

27 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

28 ACCORD ADVANCE VADT de korte akutte studier

29 Standard vs. intensive BG treatment Standard: Goal: HbA1c 7-7.9% ACCORD Intensive: Goal: HbA1c <6% ADVANCE Standard: SU other than gliclazide MR + any other anti-diabetic drugs. Intensive: Gliclazide MR + any other anti-diabetic drugs Goal: HbA1c <6.5% VADT Standard: Goal: HbA1c 8%-9% Intensive: Goal: HbA1c <6%

30 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?

31 ACCORD

32 ACCORD: Treatment effects on glucose control Standard therapy A1C (%) Intensive therapy Time (years) 6 ACCORD Study Group. N Engl J Med. 2008;358:

33 Which patients will benefit of strict glycaemic control?

34 Hazard Ratios for the Primary outcome Post-hoc analyses ACCORD

35 Mortality in relation to treatment and HbA1c

36 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:

37 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:

38 Number of participants with severe hypoglycemia Intensive Standard P N (%) N (%) Requiring any assistance 830 (16.2) 261 (5.1) <0.001 Requiring medical assistance 538 (10.5) 179 (3.5) <0.001

39 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

40 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

41 Possible Reasons for increased Mortality with Intensive Treatment in ACCORD Hypoglycemia Rapid glucose lowering Weight gain Medication interactions, treatment resistance

42 ADVANCE

43 ADVANCE: Treatment effect on glucose control Mean A1C (%) Standard control P < Intensive control Follow-up (months) ADVANCE Collaborative Group. N Engl J Med. 2008;358:

44 VADT

45 HbA1c-VADT

46 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:

47 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:

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49 VADT-Predictors of CV death HR Prior CV events 3.1 p= Age/10 yr 2.1 p< HDL/10 mg 0.7 p<0.008 Baseline HbA1c 1.2 p<0.02 Severe hypoglycaemia 4.0 p<0.008

50 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. > years after diagnosis) produces little extra benefit No CV risk attributed to any particular therapy

51 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

52 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. OHA Age: yr. Duration: yr. Insulin Age: yr. Duration: yr. N = N = Currie CJ et al. Lancet 2010;

53 Interpretation Low and high mean HbA1c values were associated with increased all cause mortality and cardiac events

54 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

55 Behandling af hyperglykæmi

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58 Treatments for Type 2 Diabetes Acarbose Reduces absorption - Carbohydrate DIGESTIVE ENZYMES Glucose GLP1, Exenatide, Liraglutide DPP-4 hæmmere, Sitagliptin, Vildagliptin, Saxagliptin, Linagliptin Sulphonylurea Repaglinide Stimulates insulin secretion Metformin Reduces hepatic glucose output + Limited effect on insulin resistance - + Glucose (G) Insulin (I) I I I G I G G I G I G I G I G Thiazolidinediones Reduce Insulin Resistance G I G G G

59 The Incretin Effect, GLP-1 and Exenatide

60 The Incretin Effect Demonstrates the Response to Oral vs IV Glucose Oral Glucose IV Glucose Venous Plasma Glucose (mmol/l) C-peptide (nmol/l) Time (min) Time (min) * * * * * Incretin Effect * * Mean ± SE; N = 6; *P.05; = 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: Copyright 1986, The Endocrine Society.

61 The Incretin Effect Is Reduced in Patients With Type 2 Diabetes Intravenous Glucose Oral Glucose 80 Control Subjects 80 Patients With Type 2 Diabetes Insulin (mu/l) * * * * * * * * * * Time (min) Time (min) *P.05 compared with respective value after oral load. Nauck MA, et al. Diabetologia. 1986;29: Reprinted with permission from Springer-Verlag 1986.

62 GLP-1 secreted upon the ingestion of food GLP-1 effekter i mennesket 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: ; Adapted from Larsson H, et al. Acta Physiol Scand. 1997;160: ; Adapted from Nauck MA, et al. Diabetologia. 1996;39: ; Adapted from Drucker DJ. Diabetes. 1998;47:

63 Mechanism of Action of DPP-4 Ingestion of food Release of active incretins GI tract GLP-1 and GIP DPP-4 inhibitor Inactive GLP-1 X DPP-4 enzyme Inactive GIP inhibition Pancreas Beta cells Alpha cells Glucosedependent Glucose dependent Insulin (GLP-1 and GIP) Glucagon (GLP-1) Glucose uptake by peripheral tissue Hepatic glucose production Blood glucose in fasting and postprandial states 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.

64 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

65 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 Glinid TZD α-gluc. Inhibitor DPP-4 inhibitor GLP-1 analoger Insulin Billig Hypo Vægt Betacellen? Hurtig virkning Pris Hypo Vægt Hypo Sikkerhed! Vægt Pris CVD? Hypo Lille effekt GI-biv Hypo Vægt Ingen biv. Beta-celle effekt? Pris Hypo Vægttab CVD/betacelle effekt? Kvalme osv. Pris Virker altid Hypo Vægt Pris

66 Algoritme for behandling af hyperglykæmi ved T2DM Debut - 1. valg Metformin 1 Undtagelser: Metformin Gastrointestinale gives uanset bivirkninger HbA1c. ved Metformin kan skyldes for hurtig dosis-øgning 1. Metformin tåles ikke 2 : gåtil 2. valg, hvis behandlingsmålikke 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 symptomer 3 og /eller akutte tilstande 4 : start insulin ustabil hæmodynamik og/eller behandling. nyrefunktion: Skift til eller suppler med Hyperglykæmien metformin når tilstanden er behandles stabiliseret. Absolut kontraindíkation 3. Nedsat nyrefunktion 5 : med hurtigt hvis egfr virkende < 30 insulin ml/min, -Vælg indtil Insulin, tilstanden evt. DPP4-hæmmer, er Sulfonylurinstofmed stabil. kort halveringstid, eller forsigtighed (dosishalvering og regelmæssig kontrol af nyrefunktion) ved egfr ml/min. DPP4- hæmmer 9 Undgåved svært nedsat nyrefunktion. Erfaringsgrundlaget ved langtidsbehandling er begrænset. Sulfonylurinstof(SU) 8 /repaglinid 10 Undgåved/hos: øget risiko for hypoglykæmi, alkoholmisbrug, ældre eneboende, erhvervschauffører, stilladsarbejdere, svært nedsat nyrefunktion. pioglitazon under kontrol af nyrefunktion. 2. Valg 6,7 Tabletbehandling Injektionsbehandling I særlige tilfælde GLP-1 11 Til udvalgte patienter, hvor et vægttab er central i behandlingen. Erfaringsgrundlaget er begrænset. Behandlingen skal gives subcutant. Insulin Altid behandlingen ved svær hyperglykæmi og kan bruges som 2. valg til alle. Behandlingsmåletbør dog primært søges opnået med anden behandling ved svær overvægt, øget risiko for hypoglykæmi, alkoholmisbrug, ældre eneboende, erhverschauffører, stilladsarbejdere og lignende. Pioglitazon 12 Svær insulinresistens og/eller fedtlever. Undgå ved: Hjerteinsufficiens, Osteoporose, Svært nedsat nyrefunktion, Leverinsufficiens. Intensiveret behandling 6 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. 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. Acarbosekan indgåi stedet for én af de øvrige i kombinationerne. Ole Snorgaard 2010

67 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.

68 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.

69 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

70 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