Giulio Marchesini

Malattie del Metabolismo e Dietetica Clinica,

Università di Bologna

Ipoglicemia -

Come arginare il problema

Disclosures

Giulio Marchesini

• Advisory Board: Sanofi, Roche

• Honoraria: Sanofi, Merck Sharp & Dome,

Novartis

• Clinical Studies: Boehringer Ingelheim,

Sanofi, Lilly, Novo Nordisk, GILEAD,

GENFIT, Jannsen

Hypoglycemia and emergency use

Farmer, Diabet Med 2012

The estimated total cost of the emergency call, initial ambulance attendance and treatment at scene was around £650 000; if transport to hospital was necessary, the additional ambulance transport costs were £223 000 plus emergency department costs of £140 000; and the cost of primary care follow-up was estimated as a further £61 000. The average cost per emergency call was £263.

By extrapolation, we estimate that, in the whole of England, the annual cost of treatment for hypoglycemia by the ambulance service (excluding those aged < 1 year), which does not include the costs of hospital admission, is in the order of £13.6m.

No % (95%CI) % Most commonly implicated medications

Warfarin 33,171 33.3 (28.0–38.5) 46.2 Insulins 3,854 13.9 (9.8–18.0) 40.6 Oral antiplatelet agents 13,263‡ 13.3 (7.5–19.1) 41.5 Oral hypoglycemic agents 10,656 10.7 (8.1–13.3) 51.8 Opioid analgesics 4,778 4.8 (3.5–6.1) 32.4 Antibiotics 4,205 4.2 (2.9–5.5) 18.3 Digoxin 3,465 3.5 (1.9–5.0) 80.5 Antineoplastic agents 3,329‡ 3.3 (0.9–5.8)‡ 51.5 Antiadrenergic agents 2,899 2.9 (2.1–3.7) 35.7 Renin–angiotensin inhibitors 2,870 2.9 (1.7–4.1) 32.6 Sedative or hypnotic agents 2,469 2.5 (1.6–3.3) 35.2 Anticonvulsants 1,653 1.7 (0.9–2.4) 40.0 Diuretics 1,071‡ 1.1 (0.4–1.8)‡ 42.4

Annual National Hospitalizations (N = 99,628)

Proportion of ED Visits Resulting in Hospitalization

Budnitz, NEJM 2011

Nirantharakumar, Diabet Med 2012

Length of stay and inpatient mortality of patients with diabetes who had an episode of hypoglycaemia in a non critical care setting at University Hospital Birmingham, UK 148 admissions (2.3%) with severe hypoglycaemia (</= 2.2 mmol/l), 500 admissions (7.8%) with mild to moderate hypoglycaemia (2.2-3.9 mmol/l) and 5726 admissions with no recorded hypoglycaemic episode (> 3.9 mmol/l). Conclusion: Hypoglycaemia is associated with increased length of stay and inpatient mortality. Whilst causative evidence is lacking, our data are consistent with the need to avoid hypoglycaemia in our current and continued approach for optimal glycaemic control in people with diabetes admitted to hospital.

ADA/EASD position statement: DPP-4 inhibitors as 2nd or 3rd line treatment

Inzucchi SE, et al. Diabetes Care 2012;35:1364–79

Number of participants with severe hypoglycemia (ACCORD Study)

A role for new drugs (incretins, gliptins, glifozins)?

Miller, BMJ 2010

Hypos & cardiovascular outcomes ADVANCE study

Zoungas, N Engl J Med 2010

Hypos & cardiovascular outcomes ADVANCE study

Zoungas, N Engl J Med 2010

New therapeutic targets The patient in the lead

Inzucchi. Diabetologia. 2012

Tailored therapy

Ismail-Beigi . Ann Intern Med 2011

Diabetes Care, 2014

Tailored therapy

Start low e go slow

STENO-2: percentuale di pazienti a target

Gaede, NEJM 2003

CVD prevention in DM

Giorgino, Ann NY Acad Sci 2013

CVD prevention in DM

Giorgino, Ann NY Acad Sci 2013

Hypoglycemia and 5-yr mortality

CCI: Charlson Comorbidity Index

McCoy, Diabetes Care 2012

Data 1020 DM from a diabetes clinic Type 2 diabetes: n = 797 After 5 years, patients who reported severe hypoglycemia had 3.4-fold higher mortality (95% CI 1.5–7.4; P = 0.005) compared with those who reported mild/no hypoglycemia. CONCLUSIONS Self-report of severe hypoglycemia is associated with 3.4-fold increased risk of death. Patient-reported outcomes, including patient-reported hypoglycemia, may therefore augment risk stratification and disease management of patients with diabetes.

Lipska, JAMA Intern Med 2014

Lipska, JAMA Intern Med 2014

Lipska, JAMA Intern Med 2014

Malnutrition, psychiatric diseases, dementia & functional disability are frequently associated with hypoglycemia and poor outcome

33,3

13,9 13,3 10,7

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20

40

Warfarin Insulin Antiplateletagents

Oral hypoglycemicagents

Insulin and oral hypoglycemic agents are implicated in about 25% of emergency hospitalizations for adverse drug events

Proportion of emergency department visits resulting in hospitalization

46.2 40.6 41.5 51.8

National Electronic Injury Surveillance System-Cooperative Adverse Drug Event Surveillance

Budnitz, N Engl J Med 2011

%

Emergency Hospitalization for Adverse Drug Events in Older Americans (65 years of age or older)

Lombardo, PloS ONE 2013

Lombardo, PloS ONE 2013

Lombardo, PloS ONE 2013

2001 32,096 56.3 14.4 (13.8–15.1) 1,794 3.1 0.81 (0.84–0.77)

2002 30,304 53.1 13.7 (13.1–14.3) 1,758 3.1 0.80 (0.76–0.83)

2003 30,072 51.7 13.5 (12.9–14.1) 1,615 2.8 0.72 (0.69–0.76)

2004 27,694 46.9 11.9 (11.3–12.4) 1,492 2.5 0.64 (0.61–0.67)

2005 26,861 44.7 11.0 (10.5–11.6) 1,466 2.4 0.60 (0.57–0.63)

2006 26,512 43.5 10.2 (9.7–10.7) 1,445 2.3 0.56 (0.53–0.58)

2007 25,177 40.7 9.3 (8.9–9.7) 1,463 2.3 0.54 (0.52–0.56)

2008 24,732 39.3 8.6 (8.3–9.0) 1,371 2.1 0.48 (0.46–0.50)

2009 22,052 34.5 7.7 (7.3–8.0) 1,275 1.9 0.44 (0.42–0.46)

2010 20,874 32.4 7.1 (6.8–7.4) 1,167 1.7 0.39 (0.38–0.41)

Acute Diabetic Complications

Hospital admission rates for acute diabetic complications in Italy, 2001–2010.

Rate /100,000

Residents

Rate / 1000

Diabetics N

Hypoglycemic coma

Rate /100,000

Residents

Rate / 1000

Diabetics N

Geller, JAMA Intern Med 2014

NICE-Sugar study Intensive treatment & outcome

Finfer. N Engl J Med 2009

Hypos and survival in critically ill pts NICE-SUGAR study

NICE-Sugar Study Investigators, N Engl J Med 2011

In critically ill patients, intensive glucose control leads to moderate and severe hypoglycemia, both of which are associated with an increased risk of death

Hypoglycaemia in T2DM: A possible link to increased CV risk/events

• Haemodynamic changes: ‒ Activation of autonomic nervous system ‒ 10–50 fold increased secretion of

adrenaline and noradrenaline

• Haemorheological changes: ‒ Platelet activation ‒ Increased viscosity

• ECG changes: ‒ Longer QT interval ‒ Hypokalaemia

Possible mechanisms1,2 Hypoglycaemia as link to tissue ischaemia3

Study of 72-h continuous glucose monitoring and simultaneous cardiac Holter monitoring in patients with T2DM treated with insulin and history of frequent hypoglycaemia and coronary artery disease (n=19) 54 episodes of hypoglycaemia reported (BGL <70 mg/dL) 59 episodes of hyperglycaemia reported (BGL >200 mg/dL)

1Desouza CV et al. Diabetes Care 2010;33:1389–94 2Robert TC et al. Diabetes 2003;52:1469–74 3Desouza C et al. Diabetes Care 03; 26:1485–9

*P <0.01 vs episodes during hyperglycaemia and normoglycaemia

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Hsu, Diabetes Care 2013

Declining renal function increases risk of severe hypoglycaemia

Around 74% of sulphonylurea-induced severe hypoglycaemic events (loss of consciousness) occur in patients with reduced renal function

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+ CKD + Diabetes

– CKD + Diabetes

+ CKD – Diabetes

– CKD – Diabetes

1. Moen MF, et al. Clin J Am Soc Nephrol. 2009 Jun;4(6):1121–1127

RIFLESSIONI: trial di prevenzione CV

• Tutti i grandi trial di prevenzione CV degli ultimi 5-6 anni CON QUALSIASI PROTOCOLLO hanno fallito (ACCORD, ADVANCE, VADT, ORIGIN, NICE-SUGAR)

• Nella maggior parte dei casi si documenta un effetto negativo dell’ipoglicemia (pazienti fragili), che aumenta il rischio CV

• Il rischio non era evidente negli studi più vecchi, con target meno ambiziosi (Effetto LEGACY)

• Mortalità CV nei trial scesa da 3% a <1%: statine, antipertensivi, rivascolarizzazione …..

• Come giungere ad un controllo ottimale senza ipoglicemia?

• Quali effetti questo potrebbe avere sul rischio CV?

• Quali regole?

Vantaggi/svantaggi degli inibitori del DPP-4

VANTAGGI

• Ben tollerati

• Basso rischio di ipolicemie

• Efficacia simile ai vecchi antidiabetici orali (dati AIFA: HbA1c - 0.9%)

• Effetto neutro sul peso

• Associabili ad altre terapie (anche insulina)

• Utilizzabili anche in IRC

• Maggiore efficacia su glicemia post-prandiale

SVANTAGGI

• Alto costo

• Scarsi dati su uso prolungato

Vantaggi/svantaggi delle incretine

VANTAGGI

• Riduzione peso (dati AIFA: – 3.5 kg)

• Buona efficacia (dati AIFA: HbA1c – 1.1%)

• Basso rischio di ipoglicemia

• Associabili ad altri farmaci (anche insulina)

• Maggiore efficacia su iperglicemia post-prandiale

• Potenziali effetti protettivi sulla beta-cellula

SVANTAGGI

• Somministrazione iniettiva

• Alto costo

• Scarsi dati su uso prolungato

• Effetti avversi (nausea, vomito, diarrea)

Composite endpoints DPP-4i & GLP-1a

Composite endpoints DPP-4i & GLP-1a

Vantaggi/svantaggi degli SGLT2-inibitori

VANTAGGI

• Riduzione peso (3-5 kg)

• Buona efficacia (HbA1c – 1.1%)

• Basso rischio di ipoglicemia

• Associabili ad altri farmaci (anche insulina)

• Maggiore efficacia su iperglicemia post-prandiale

SVANTAGGI

• Scarsi dati su uso prolungato

• Effetti avversi (infezioni vie urinarie)

• Costo (?)

Phase III pooled efficacy data - Empaglifozin

Placebo corrected values

Canaglifozin – Effects on body weight

Cefalù, ADA Chicago 2013

Canaglifozin – Episodes of hypoglycemia

Cefalù, ADA Chicago 2013

Prevalenza e costi del DM farmaco-trattato: periodo 1997-2012

Prevalenza 1997-2012 (15 anni): +70%

Documento regionale incretine Aggiunta di 2° farmaco a metformina

Al 31 Dicembre 2013

Documento regionale incretine Aggiunta di 2° farmaco a metformina

Al 31 Dicembre 2013

Documento regionale incretine Cross da SULF a INCR

Aprile-Settembre 2013

Personalised Medicine

“E’ molto più importante sapere che tipo di persona

ha una malattia piuttosto che quale malattia abbia una

certa persona

Ippocrate, 400 a.C.

Il paziente al centro