Ipoglicemia: trattamento e strategie di prevenzione Antonio Ceriello Insititut d'investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) Barcelona Spain
Frequency of Hypoglycemia Increases as HbA1c Declines in Patients with Type 2 Diabetes 4 Annual Prevalence (%) 3 2 1 Treatment with diet, sulfonylurea or metformin 4 5 6 7 8 9 1 11 Most Recent HbA1c (%) Wright et al (26) J Diabetes Complications 2:395
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
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.
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.
Hypoglycemia as Pro-atherosclerotic factor
Frequency of Severe Hypoglycaemia in Types 1 and 2 Diabetes Annual prevalence of severe hypoglycaemia (%) (Severe: requiring external assistance) 5 4 3 2 1 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.
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,)
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
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)
Hypoglycaemia Associated With Sulfonylureas Prevalence of Hypoglycaemia (%) 25 2 15 1 5 21.3% Glibenclamide 1 15.3% 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; 24. 2. UKPDS Group. Lancet 1998; 352: 837 853. 3. Draeger KE, et al. Horm Metab Res. 1996; 28: 419 425. 4. McGavin JK, et al. Drugs 22; 62; 1357 1364. 5. Metaglip [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 22
Age Distribution of Patients with Type 2 Diabetes with SU-induced Hypoglycaemia 5 45 4 35 3 25 2 15 1 5 (n=139) 4-49 5-59 6-69 7-79 8-89 9-99 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
Impact of Type of previous Sulfonylurea Therapy on Mortality and CV Outcomes in Diabetic Patients with Acute Myocardial Infarction 3 25 2 Gliclazide / Glimepiride (n=459) 18,3 22,5 Glibenclamide (n=263) 2,4 25,8 15 1 7,5 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; 95:4993-52
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 597 597-1,5-1,4 1,3 1.5-2,5 +1,9 4,4 2 SU 2 Pioglitazone 3 Metformin + Pioglitazone 3 Metformin + SU 626 624 317 317-1,35-1,43-1,5-1,4 1.1 3.5 1.3 11.2 +1.9 +2.8 +1,5 +1,4,9,1 4 SU + Pioglitazone 4 SU + Metformin 319 32-1,35-1,43 1.7 14.1 +2,8-1, 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
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
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 = -4 12 16 24 32 4 52 Week 1118 181 162 181 137 123 992 172 142 111 139 11 989 976 Ferrannini et al. Diabetes, Obesity and Metabolism 29; 11:157-166
Incidence and Severity of Hypoglycaemic Events with Vildagliptin or Glimepiride during the 52 week treatment period Number of patients with hypoglycaemia 25 2 15 1 5 23 224 Number of hypoglycaemic events 6 5 4 3 2 1 39 554 Number of severe hypoglycaemic events 1 8 6 4 2 1 Vildagliptin 1 mg/day Glimepiride up to 6 mg/day Ferrannini et al. Diabetes, Obesity and Metabolism 29; 11:157-166
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 7.5-11%) 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: 318-326.
Vildagliptin provides similar HbA1c reduction as gliclazide but with a better tolerability profile Mean HbA1c (%) 9 8.5 8 7.5 7 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 -4 4 12 16 24 32 4 52 56 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= 3 2 1 N= 1.2.8.4. Patients with one or more hypos (%) 5 / 51 5 / 493 1, 1, 386 393 *.8 1.36 Number of events Number of hypoglycemic events# N= Mean BL ~ 85 kg Hypoglycemic events c 51 493 Filozof and Gautier. Diabetes Medicine. 21; 27: 318-326.
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.
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) 2. 1.5 1..5 -.5-1. -1.5-2. 12 28 52 78 14 weeks Significant relative weight loss with linagliptin as compared to glimepiride (p-value <.1) Linagliptin Glimepiride -2.9 +1.4-1.5 Number of patients 5 4 3 2 1 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 775 28 (36.1) 12 (4.3) 4.8x lower Linagliptin 776 58 (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
Cardiovascular events: Saxagliptin controlled Phase 2b/3 pooled population 5 Time to onset of first primary Major Adverse Cardiovascular Event (MACE) First adverse event (%) 4 3 2 1 Control All saxagliptin 24 37 5 63 76 89 12 115 128 Patients at risk Weeks Control 1,25 1 935 86 774 545 288 144 123 12 57 All saxagliptin 3,35 6 2,615 2,419 2,29 1,638 994 498 436 373 197 Saxagliptin, FDA s Endocrinologic and Metabolic Drugs Advisory Committee Briefing Document for April 29 Meeting: NDA 22-35. Available at http://www.fda.gov/ohrms/dockets/ac/9/briefing/29-4422b1-2-bristol.pdf. Accessed: 7 May, 9.
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
Mean 26-hour Blood Glucose Level 7. Profiles at Steady-state.8U/kg.6U/kg.4U/kg 6.5 Glucose level (mmol/l) 6. 5.5 5. 2 4 6 8 1 12 14 16 18 2 22 24 26 Time (hours) Nosek L et al. Diabetologia 211;54(suppl. 1):S429 (155-P); ADA 211;49-LB (NN125-1987)
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) 6 9 12 days Inclusion criteria T1DM 12 months HbA 1c 1.% BMI 18 28 kg/m 2 Age 18 65 years 24-hour euglycaemic clamp Clinical trial.gov identifier: NCT961324 Heise et al. Diabetes 211;6(Suppl. 1):A263 (Abstract 96-P)
Within-subject variability over time IDeg IGlar Heise et al. Diabetes 211;6(Suppl. 1):A263
Confirmed Hypoglycaemia Confirmed hypoglycaemia (cumulative events per 1 patients) 16 14 12 1 8 6 4 2 4 8 12 16 2 24 28 32 36 4 44 48 52 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 (NN125-3582)
Hypoglycaemia: nocturnal episodes 2 IDeg OD (n=59) IGlar OD (n=59) 15 1 58% risk reduction RR:.42 p=.7 5 4 8 12 Time (weeks) 16 Mean cumulative function Birkeland et al. Diabetes Care 211;34:661 5
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