Ipoglicemia: trattamento e strategie di prevenzione

Transcription

1 Ipoglicemia: trattamento e strategie di prevenzione Antonio Ceriello Insititut d'investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) Barcelona Spain

2 Frequency of Hypoglycemia Increases as HbA1c Declines in Patients with Type 2 Diabetes 4 Annual Prevalence (%) Treatment with diet, sulfonylurea or metformin Most Recent HbA1c (%) Wright et al (26) J Diabetes Complications 2:395

3 Classification of Hypoglycemia (Clinical definition) Defined by individual s ability to self-treat or not MILD = self-treated SEVERE = external help required for recovery Severity is not determined by: symptom response conscious level nature of treatment

4 Pathophysiology of High Blood Glucose Excursions Blood coagulation Fibrinogen Prothrombin Factor VII Thrombocyte aggregation Polyol pathway PKC-activation Cell adhesion ICAM; VCAM E-selectin P-selectin Blood Glucose Spikes Inflammation hscrp IL-6 IL-18 TNF-α Endothelial dysfunction Oxidative stress Increased ADMA NO depletion Free fatty acids ADMA: Asymmetrical dimethyl arginine; hscrp: high sensitive C-reactive protein; ICAM: Intercellular adhesion molecule; IL: Interleukin; NO: Nitric oxide; PKC: Protein kinase C; TNF: Tumour necrosis factor; VCAM: Vascular cell adhesion molecule.

5 Pathophysiology of Low Blood Glucose Excursions Blood coagulation Fibrinogen Prothrombin Factor VII Platelet activation/aggregation White blood cells Mobilisation Activation Cell adhesion ICAM; VCAM E-selectin P-selectin Endothelial dysfunction vwf tpa VEGF Hypoglycaemia Inflammation hscrp IL-6 Endothelin-1 CD4 expression scd4l Free fatty acids hscrp: high sensitive C-reactive protein; ICAM: Intercellular adhesion molecule; IL: Interleukin; tpa: tissue plasminogen activator; scd4l: soluble CD4 Ligand; vwf: von Willebrand Factor; VCAM: Vascular cell adhesion molecule; VEGF: Vascular Endothelial Growth Factor.

6 Hypoglycemia as Pro-atherosclerotic factor

7 Frequency of Severe Hypoglycaemia in Types 1 and 2 Diabetes Annual prevalence of severe hypoglycaemia (%) (Severe: requiring external assistance) Type 2 DM Sulfonylureas (n = 13) Type 2 DM <2 years insulin (85) Type 2 DM >5 years insulin (75) Type 1 DM <5 years (46) Type 1 DM >15 years (54) T2DM SU T2DM < 2 yrs T2DM > 5 yrs T1DM < 5 yrs T1DM > 15 yrs Error bars = 95% confidence intervals Adapted from: UK Hypoglycaemia Study Group (27) Diabetologia 5:114.

8 Options for Antidiabetic Treatment Insulin Resistance Insulin Secretion Inhibition of Glucose Absorption Metformin Pioglitazone Canaglifozin Dapagliflozin Glucose independent Sulfonylurea Glinides Exogenous Insulin Glucose dependent DPP-4 Inhibitors (Alogliptin, Linagliptin, Saxagliptin, Sitagliptin, Vildagliptin) GLP-1 RA (Exenatide, Liraglutide, Lixisenatide) α-glucosidase Inhibitors (Acarbose,)

9 Combination Therapy with Non-insulin Antidiabetes Drugs: Hypoglycaemia Risk Meta-analysis analysis of Mixed Treatment Analysis of 24 trials Relative Risk of Hypoglycemia (95% Credible Interval) Phung et al, 21 JAMA 33: 141

10 Hypoglycaemia and Sulfonylureas Severe hypoglycaemia is more likely to occur within the first month of treatment (Asplund K et al. (1983) Diabetologia 24:412. Bodmer M et al. (28) Diabetes Care 31:286) Hypoglycaemia occurs more commonly when patients are treated with low doses (more sensitive to effect of drug) Hypoglycaemia is more common with long-acting preparations like glibenclamide Coma and serious morbidity occur secondary to sulfonylureainduced hypoglycaemia (Asplund K et al. (1983) Diabetologia 24:412. Asplund K et al. (1991) Diabet Med 8:726. Malouf & Brust, (1985) Ann Neurol 17: 421)

11 Hypoglycaemia Associated With Sulfonylureas Prevalence of Hypoglycaemia (%) % Glibenclamide % 14% 11% Chlorpropamide 2 Glibenclamide 3 Glimepiride 3 5% Gliclazide 4 2.9%* Glipizide 5 Sulfonylureas *Hypoglycaemia: capillary blood glucose <2.75 mmol/l ( 5 mg/dl) 1. Glucovance [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; UKPDS Group. Lancet 1998; 352: Draeger KE, et al. Horm Metab Res. 1996; 28: McGavin JK, et al. Drugs 22; 62; Metaglip [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 22

12 Age Distribution of Patients with Type 2 Diabetes with SU-induced Hypoglycaemia (n=139) Age in decades One third of cases were patients in nursing homes or being cared for by a home nursing service Holstein et al (21) Expert Opinion Drug Safety 9: 675

13 Impact of Type of previous Sulfonylurea Therapy on Mortality and CV Outcomes in Diabetic Patients with Acute Myocardial Infarction Gliclazide / Glimepiride (n=459) 18,3 22,5 Glibenclamide (n=263) 2,4 25, ,5 1,9 12,7 7,5 1,6 12,4 5 2,7 Death Arrhythmias, re-mi, stroke Any complication Patients on previous sulfonylurea therapy 2,4 Death Arrhythmias, re-mi, stroke Any complication Propensity score-matched cohorts Zeller et al. J Clin Endocrinol Metab 21; 95:

14 Effects of oral antidiabetic Drugs on HbA1c, Hypoglycemic Events & Weight Gain in 4 randomisied double blind large Studies (Quartet) Number HbA1c of Patients (%) Hypoglycemia (%) Weight Change (kg) Weight Difference (kg) 1 Metformin 1 Pioglitazone ,5-1,4 1, ,5 +1,9 4,4 2 SU 2 Pioglitazone 3 Metformin + Pioglitazone 3 Metformin + SU ,35-1,43-1,5-1, ,5 +1,4,9,1 4 SU + Pioglitazone 4 SU + Metformin ,35-1, ,8-1, 3,8 SU = Sulfonylureas 1 Schernthaner et al; JCEM 24; 89:668 3 Matthews et al; Diab.Metab Res.Rev.25; 21:167 2 Charbonell et al; Diabet Med. 25; 22:399 4 Hanefeld et al; Diab.Care 24;27:141

15 IDF Statement on Personalized Targets and Care in the Glycaemic Management of People with Type 2 Diabetes Properties of currently available blood glucose lowering agents AGIs Metformin SUs Glinides TZDs DPP-Inhibitors GLP 1-agonists Insulin Effect on fasting glucose* Effect on post prandial glucose* Weight** Hypoglycemia risk Side effects Cost*** variable Global availability# Experience with the medication# *Effect: = neutral; + = mild; ++ = moderate; +++ = moderate to marked;++++ = marked **Effect:-= favourable; = neutral; + = mild gain; ++ = moderate gain; +++ = moderate to marked gain; ++++ = marked gain Risk: = neutral; + = mild; ++ = moderate; +++ = moderate to marked;++++ = marked ***Cost: + = cheap; ++ = quite cheap; +++ = expensive; ++++ = very expensive #Availability and experience:+ = very small; ++ = small; +++ = high; ++++ = very high There needs to be unequivocal cost-effectiveness advantages to justify the use of more expensive therapies, especially in poor countries

16 Changes of mean HbA1c by treatment and visit: Vildagliptin or Glimepiride add-on to Metformin Mean HbA1c (%) 7,5 7,25 7, 6,75 Vildagliptin 1 mg/day Glimepiride up to 6 mg/day 6,5 Vildagliptin 1 mg/day n = Glimepiride up to 6 mg/day n = Week Ferrannini et al. Diabetes, Obesity and Metabolism 29; 11:

17 Incidence and Severity of Hypoglycaemic Events with Vildagliptin or Glimepiride during the 52 week treatment period Number of patients with hypoglycaemia Number of hypoglycaemic events Number of severe hypoglycaemic events Vildagliptin 1 mg/day Glimepiride up to 6 mg/day Ferrannini et al. Diabetes, Obesity and Metabolism 29; 11:

18 Vildagliptin vs. gliclazide as add on to metformin Study purpose: to compare the effect of 52 weeks treatment with Vidagliptin 5 mg bid to gliclazide up to 32 mg daily as add-on therapy in patients with type 2 diabetes inadequately controlled with metformin monotherapy Target population: T2DM patients inadequately controlled on a stable metformin monotherapy (baseline HbA1c %) N** = 17 Metformin n=513 Vildagliptin 5 mg bid + Met n=494 Gliclazide up to 32 mg # + Met 4 weeks 52 weeks Filozof and Gautier. Diabetes Medicine. 21; 27:

19 Vildagliptin provides similar HbA1c reduction as gliclazide but with a better tolerability profile Mean HbA1c (%) Mean HbA1c Vilda 5 mg bid + Met Glic up to 32 mg + Met -.81% vilda + met -.84 glic +met Non-inferior Glic= gliclazide; Met= metformin; Vilda= vildagliptin; BL= baseline; EP= end point; * p<.1 Vilda vs Glic, 95% CI (-1.77, -.79), adjusted mean change from BL to EP; b) per protocol population; c) safety population; # All hypoglycemic events: grade 1 EP Time (Week) Mean difference of adjusted values:.4% 95%CI: -.11,.2 Incidence (%) Change Body weight b from BL to week 52 Adjusted Mean Change in body weight (kg) n/n= N= Patients with one or more hypos (%) 5 / 51 5 / 493 1, 1, * Number of events Number of hypoglycemic events# N= Mean BL ~ 85 kg Hypoglycemic events c Filozof and Gautier. Diabetes Medicine. 21; 27:

20 Addition of Sitagliptin to Rosiglitazone and Metformin Study: Incidence of Hypoglycemia at 54 Weeks All-Patients-as-Treated Population a Treatment Group N Patients With 1 Episode, n (%) Total Number of Episodes, n Sitagliptin 1 mg 17 7 (4.1) 1 Placebo 92 1 (1.1) 1 2 a Excluding data after initiation of glycemic rescue therapy. Data on file, MSD.

21 Significant relative weight loss and lower incidence of hypoglycemia with linagliptin compared to glimepiride Adjusted 1 means for body weight change from baseline ± SE Kg - FAS (OC) weeks Significant relative weight loss with linagliptin as compared to glimepiride (p-value <.1) Linagliptin Glimepiride Number of patients Number of patients with hypoglycemia (% of total) Patients with severe hypoglycemic episode 3 (% of patients with hypoglycemia) Incidence of hypoglycemia 2 Percent of patients - Treated set Glimepiride (36.1) 12 (4.3) 4.8x lower Linagliptin (7.5) 1 (1.7) Significantly lower incidence of hypoglycemia with linagliptin as compared to glimepiride (p-value <.1) 1 Model includes baseline HbA1c, baseline weight, number of prior OADs, treatment, week repeated within patients and week by treatment interaction 2 Hypoglycemic episode defined by a blood glucose 7 mg/dl 3 Event requiring assistance of another person to actively administer carbohydrate, glucagon or other resuscitative actions Source: Gallwitz et al. American Diabetes Association, 71th Scientific Sessions, San Diego, CA, June 24-28, 211; 39-LB

22 Cardiovascular events: Saxagliptin controlled Phase 2b/3 pooled population 5 Time to onset of first primary Major Adverse Cardiovascular Event (MACE) First adverse event (%) Control All saxagliptin Patients at risk Weeks Control 1, All saxagliptin 3,35 6 2,615 2,419 2,29 1, Saxagliptin, FDA s Endocrinologic and Metabolic Drugs Advisory Committee Briefing Document for April 29 Meeting: NDA Available at Accessed: 7 May, 9.

23 Objectives of developing IDeg Duration of action: Control fasting blood glucose with one injection in all individuals Flat time action profile: Lower risk of hypoglycaemia Day-to-day variability: Less hypoglycaemia and hyperglycaemia

24 Mean 26-hour Blood Glucose Level 7. Profiles at Steady-state.8U/kg.6U/kg.4U/kg 6.5 Glucose level (mmol/l) Time (hours) Nosek L et al. Diabetologia 211;54(suppl. 1):S429 (155-P); ADA 211;49-LB (NN )

25 Within-subject variability of IDeg and IGlar in T1DM Screening 2 21 days Follow-up 7 21 days IDeg OD (n=27) IGlar OD (n=27) days Inclusion criteria T1DM 12 months HbA 1c 1.% BMI kg/m 2 Age years 24-hour euglycaemic clamp Clinical trial.gov identifier: NCT Heise et al. Diabetes 211;6(Suppl. 1):A263 (Abstract 96-P)

26 Within-subject variability over time IDeg IGlar Heise et al. Diabetes 211;6(Suppl. 1):A263

27 Confirmed Hypoglycaemia Confirmed hypoglycaemia (cumulative events per 1 patients) SAS Comparisons: Estimates adjusted for multiple covariates Time (weeks) IDeg OD + IAsp (n=753) IGlar OD + IAsp (n=251) 18% lower rate p=.36 Hollander et al. IDF 211:P-1442; Diabetologia 211;54(suppl. 1):S421; Garber et al. Diabetes 211;6(suppl. 1):A23 (NN )

28 Hypoglycaemia: nocturnal episodes 2 IDeg OD (n=59) IGlar OD (n=59) % risk reduction RR:.42 p= Time (weeks) 16 Mean cumulative function Birkeland et al. Diabetes Care 211;34:661 5

29 There is increasing Evidence that Hypoglycemia has to be avoided in Risk Situations of Patients with Type 2 Diabetes Long duration of Diabetes/Macrovascular Complications Acute Myocardial Infraction/Stroke Akuter Impaired Renal Function (Chronic Kidney Disease) Myokardinfarkt/Schlaganfall Coronary Revascularisation Intensive Care Unit (CCU) Unawareness to Hypoglycemia High Age with Hypovigilance

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