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Hypoglycaemia – the hidden problem. Professor Anthony Barnett University of Birmingham and Heart of England NHS Foundation Trust United Kingdom. Hypoglycaemia – the hidden problem. Hypoglycaemia basics. - PowerPoint PPT Presentation
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Hypoglycaemia – the hidden problemProfessor Anthony Barnett
University of Birmingham and Heart of England NHS Foundation TrustUnited Kingdom
Hypoglycaemia – the hidden problemHypoglycaemia basics
Hypoglycaemia
“The major limiting factor to achieving intensive glycaemic control for people
with type 2 diabetes”
Briscoe VJ, et al. Clin Diab 2006;24:115-121.
Definition of hypoglycaemia
• Plasma glucose <3.9mmol/l based on activation of counter-regulatory responses
• In clinical trials threshold ranges between 3-3.9 mmol/l• Others “classify” into “mild” and “severe”
Result: difficult to pinpoint exact incidence!
Briscoe VJ, Davis SN. Clin Diabetes 2006;24:115-21.
Hypoglycaemia – the hidden problemEpidemiology and consequences of hypoglycaemia
Hypoglycaemia in type 2 diabetes
• Hypoglycaemia symptoms are common in type 2 diabetes (38% of patients)1
• Associated with: – Reduced quality of life– Reduced treatment satisfaction– Reduced therapy adherence– More common at HbA1c < 7%
1. Diabetes, Obesity and Metabolism 2008 Jun;10 Suppl 1:25-32.
Asymptomatic episodes of hypoglycemia may go unreported
• In a cohort of patients with diabetes, more than 50% had asymptomatic (unrecognized) hypoglycemia, as identified by continuous glucose monitoring1
• Other researchers have reported similar findings2,3
1. Chico A, et al. Diabetes Care 2003;26(4):1153-1157. 2. Weber KK, et al. Exp Clin Endocrinol Diabetes 2007;115(8):491-494.
3. Zick R, et al. Diab Technol Ther 2007;9(6):483-492.
Patients with ≥1 unrecognized hypoglycemic event, %
0
25
50
75
100
All patients
with diabetes
Type 1 diabetes
Pat
ient
s, %
Type 2diabetes
55.762.5
46.6
n=70 n=40 n=30
Risk factors for hypoglycaemia
• Use of insulin and sulfonylureas1
• Older people2,3 • Long duration diabetes2
• Irregular eating habits3
• Exercise3 • Have lower HbA1c4
• Periods of fasting e.g. Ramadan• Prior hypoglycemia5,6,7
• Hypoglycemia unawareness8
• Alcohol9
See notes for references.
Effects of hypoglycaemia on quality of life (RECAP-DM study)• Hypoglycaemia significantly more likely in patients with
macrovascular complications • Associated with lower treatment satisfaction scores
(p<0.0001)• Such patients more likely to report barriers to adherence
(p=0.0057)
Alvarez Guisasola F, et al. Diabetes Obes Metab 2008;10(Suppl.1):25-32.
Hypoglycaemia significantly reduces patients’ quality of life
19
10.2
0
5
10
15
20
HFS-II Worry subscale
Sco
re
With hypoglycaemia Without hypoglycaemia
Vexiau P, et al. Diabetes Obes Metab 2008;10(S1):16-24.
P<0.0001
Reproduced with permission
Hypoglycaemia increases healthcare costs
0
50
100
150
200
250
300
350
Mild to moderate hypoglycaemia Severe hypoglycaemia
Con
sulta
tion
cost
(£)
GP consultations Practice nurse consultation
£287.50
£92
£330
£105.60
Amiel SA, et al. Diabetic Medicine 2008; 25: 245-254.
• In the UK, the estimated cost of hypoglycaemia due to type 2 diabetes is about £7.4 million1
• Probably an underestimate
Patients have low awareness of hypoglycaemia
• Recognition of warning symptoms is fundamental for self-treatment and to prevent progression to severe hypo1
• Even mild hypoglycaemia induces defects in counter-regulatory responses and impaired awareness2
• Impaired awareness predisposes to six-fold increase in the frequency of severe hypoglycaemia3
• Only 15% of type 2 diabetes patients who experienced a hypoglycaemic event reported the incident to their doctor1,4
1. McAulay V, et al. Diabet Med. 2001;18:690-705.2. Amiel SA, et al. Diabetic Medicine 2008;25:245-254.
3. Gold AE, et al. Diabetes Care 1994;17:697-703.4. Leiter LA, et al. Can J Diab. 2005;29(3):186-192.
Fear of hypoglycaemia is a burden for patients• Fear of hypoglycaemia:1
– Is an additional psychological burden on patients– May limit the aggressiveness of drug therapy– Can decrease adherence to diet– May reduce compliance with therapy
• Influences:– Patient health outcomes2 – Post-episode lifestyle changes2
– Other family members-disrupts domestic life3
• A severe hypoglycaemic event is associated with a greater fear of hypo in the future4
• Blood glucose awareness training can reduce levels of fear5
1. Can J Diab. 2005;29:186-192; J Diab Complic 2004;18:60-68; 2. Leiter LA, et al. Can J Diab. 2005;29:186-192; 3. Frier BM et al. IJCP Supplement. 2001;123:30-37;
4. Currie CJ, et al. Curr Med Res Opin 2006;22:1523-1534; 5. Wild D, et al. Patient Educ Couns. 2007;68:10-15.
Clinical consequences of hypoglycaemia
• Hospital admissions:– In a prospective study1 of well-controlled elderly T2D patients, 25% of
hospital admissions for diabetes were for severe hypos
• Increased mortality:– 9% in a study2 of severe SU-associated hypoglycaemia
• Road accidents caused by hypos3:– 45 serious events per month
1. Diab Nutr Metab 2004;17(1):23-26.2. Horm Metab Res Suppl 1985;15:105-111.
3. BMJ 2006;332:812.
Hypoglycaemia – the hidden problemHypoglycaemia in patients undergoing intensive glucose control
Recent studies investigating intensive glycaemic control have highlighted the problem of hypoglycaemia
a Conventional vs intensiveb p=0.04
CAD, coronary artery disease; CHF, congestive heart disease; CVD, cardiovascular disease; MI, myocardial infarction
Variable VADT (n=1,700) ACCORD (n=10,250) ADVANCE (n=11,140)
HbA1c (%)a 8.4 vs 6.9 7.5 vs 6.4 7.3 vs 6.5
Primary outcome MI, stroke, death from CV causes, new or
worsening CHF, revascularisationb and
inoperable CAD, amputation for
ischaemic gangrene
Non-fatal MI, non-fatal stroke, CVD death
Non-fatal MI, non-fatal stroke, CVD death
HR (95% CI) for primary outcome
0.87 (0.730–1.04) 0.90 (0.78–1.04) 0.94 (0.84–1.06)
HR (95% CI) for mortality 1.065 (0.801–1.416) 1.22 (1.01–1.46)b 0.93 (0.83–1.06)
0
5
10
15
20
ACCORD ADVANCE
Intensive controlStandard control
% P
atie
nts
with
at l
east
on
e ev
ent d
urin
g th
e tri
al
25
VADT
Severe hypoglycaemia was more common with intensive therapy in three recent trials of intensive glucose control
ACCORD – requirement for medical assistance amongst patients with hypoglycaemia
ACCORD study. N Engl J Med 2008;358(24): 2545-2559.
16.2
5.1
10.5
3.5
0
3
6
9
12
15
18
Pat
ient
s (%
)
Requiring any assistanceRequiring medical assistance
Intensive therapy(target HbA1c <6%)
Standard therapy(target HbA1c 7.0 to 7.9%)
ACCORD Trial – intensive glucose lowering may be harmful in patients at high CV risk• 22% relative increase in mortality for intensive over standard treatment
65420 1 30
5
25
20
15
10
Mor
talit
y (%
)
Years
Intensive therapy
Standard therapy
No. at RiskIntensive therapy 5128Standard therapy 5123
49724971
48034700
32503180
17481642
523499
506480
N Engl J Med 2008;358:2545-59.Action to Control Cardiovascular Risk in DiabetesReproduced with permission
ACCORD: higher mortality in participants who experienced severe hypoglycaemia
1.2%
3.3%
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
Never experienced SH Experienced SH
Ove
rall
mor
talit
y ra
te (%
)
SH = severe hypoglycaemia
The cause of the increased mortality could not be proven; severe hypoglycaemia was implicated
Explaining the increased hypoglycaemic risk in intensively treated type 2 diabetes• Reduced endogenous insulin secretion leading to
– Unstable free insulin concentrations– Impaired glucagon response– Impaired sympathoadrenal responses with antecedent
hypoglycaemia
• The same factors which influence hypoglycemic risk in type 1 diabetes operate in advanced type 2 diabetes
Potential mechanisms of hypoglycaemia-induced mortality• Cardiac arrhythmias due to abnormal cardiac repolarization in
high-risk patients (IHD, cardiac autonomic neuropathy)• Increased thrombotic tendency/decreased thrombolysis• Cardiovascular changes induced by catecholamines
– Increased heart rate– Silent myocardial ischaemia– Angina and myocardial infarction
Effect of experimental hypoglycaemia on QT interval
5.0mM 2.5mM
BA
QTc= 610 msHR= 61 bpm
QTc= 456 msHR= 66 bpm
International Diabetes Monitor 2009; 21(6): 234-241.Reproduced with permission
Hypoglycaemia – the hidden problemImpact of drug treatment on hypoglycaemic risk
Pooled hypoglycaemia results for randomized trials, by drug comparison
Bolen S, et al. Ann Intern Med 2007;147:386-399.Reproduced with permission
Oral antidiabetic agents and hypoglycaemic risk in type 2 diabetesAgents with increased hypoglycaemic potential• Those which enhance insulin secretion/β-cell function in non-glucose
dependent manner– Sulfonylureas– Short-acting secretagogues (rapaglinide/nateglinide)
Agents with minimal/low hypoglycaemic risk• Improve insulin resistance
– Biguanide-metformin– Thiazolidinediones (pioglitazone/rosiglitazone)
• Incretin-based therapies-enhance insulin secretion in glucose-dependent manner– Incretin enhancers: DPP-IV inhibitors (sitagliptin, vildagliptin, saxagliptin,
alogliptin)• Reduce glucose absorption
– Alpha-glucosidase inhibitors (acarbose, voglibose)– ? Bile-acid sequestrants (colesevelam)
Injectable agents and hypoglycaemic risk in type 2 diabetesAgents with high hypoglycaemic potential• Human insulin preparations
– Regular insulin– NPH insulin– Pre-mixed formulations
Agents with moderate hypoglycaemic potential• Insulin analogue preparations
– Rapid-acting – aspart, glulisine, lispro– Long-acting – glargine, determir
• Amylin analogue – pramlintide
Agents with minimal/low hypoglycaemic potential• Glucagon-like peptide-1 analogue/receptor agonists
– Exenatide– Liraglutide
Rates of hypoglycemia increase as A1C levels decrease in patients with type 2 diabetes on OADs
0
10
20
30
40A
nnua
l rat
e (%
)
0 4 5 6 7 8 9 10 11
Most recent A1C (%)
Wright et al. J Diabetes Complications. 2006;20:395-401.Reproduced with permission
Hypoglycaemia with sulphonylureas versus insulin(UKPDS)
UKPDS 33. Lancet 1998;352:837-853.
Diet Chlorpropamide Glibenclamide Insulin
Any Severe
1.2
11
17.7
36.5
0
10
20
30
40
Mea
n (%
)
0.10.4
0.6
2.3
0.0
0.5
1.0
1.5
2.0
2.5
3.0
Mea
n (%
)
ADOPT Study N Engl J Med 2006;355:2427-2463.
Hypoglycaemia with secretagogues vs sensitizers (the ADOPT study)
38.7
11.69.8
0.6 0.1 0.10
10
20
30
40
Per
cent
of p
atie
nts
with
epi
sode
s
All hypoglycemia
Severehypoglycemia
Glyburide Metformin Rosiglitazone Glyburide Metformin Rosiglitazone
Hypoglycaemic events occur frequently in patients treated with sulphonylureas• In an observational study over 9-12 months in six UK
secondary care diabetes centres: – 39% of patients receiving an SU described mild hypoglycaemia– 7% of patients receiving an SU described severe hypoglycaemia– 14% of patients receiving an SU experienced a blood glucose
<2.2 mmol/l
• The incidence of hypoglycaemia was similar in insulin- and SU-treated patients
UK Hypoglycaemia Study Group. Diabetologia. 2007;50(6):1140-7.
Tolerability issues with long-acting insulin secretagogues• Increased risk of hypoglycaemia1,2,3 • The UKPDS noted 4.8kg weight gain over a three year
period2
1. UKPDS 13 BMJ 1995;310:83-8.2. UKPDS 28 Diabetes Care 21(1):87-92.
3. Adverse Drug React Toxicol. Rev 2002;21(4):205-17.
Hypoglycaemia increases with biphasic or prandial versus basal insulin
Patients reporting grade 2 or grade 3 hypoglycaemic events
Holman RR, et al. N Engl J Med 2007;357:1716-1730.
Reproduced with permission
Hypoglycaemic risk with sulphonylurea combination therapy• Metformin is associated with a very low risk of hypoglycaemia
when used as a monotherapy • There is an increased risk of hypoglycaemia when using
sulphonylurea plus metformin that when using either agent alone
• Symptomatic hypoglycemia (incidence)– Metformin: No events – Repaglinide: 0.97 events/patient-year – Combination: 3.20 events/patient-year
• Severe hypoglycemic episodes – None reported
Moses R et al. Diabetes Care 1999;22(1):119-124.
Sulphonylureas - lack of awareness and education
• Patient receive little information on the adverse events of oral medication:– In a UK survey, only 10% of people treated with an SU knew that it
could cause hypos1
• GPs and practice nurses may not be aware of the prevalence of hypos with SUs
1. Browne et al. Diabetes Med 2000;17(7):528-531.
Severe hypoglycaemia more likely with longer insulin treatment
0
1
2
3
4
5
6
7
8
No severe hyposSevere hypos
Med
ian
dura
tion
of in
sulin
th
erap
y (y
ears
)
Type 2 diabetes Type 1 diabetes
Hepburn et al. Diabetic Med 1993; 10(3): 231-7.
Hypoglycaemia – the hidden problemReducing hypoglycaemic risk in type 2 diabetes
Alternatives to sulphonylureas to reduce hypoglycaemic risk• UK NICE guidelines recommend adding a DPP-4 inhibitor
or glitazone to metformin instead of SU if significant risk of hypoglycaemia and its consequences1
1. National Institute of Health and Clinical Excellence. Type 2 diabetes: newer agents for blood glucose control in type 2 diabetes NICE clinical guideline (May 2009).
Pioglitazone with metformin showed sustained efficacy over 2 years and a low incidence of hypoglycaemia
-1.50
-1.25
-1.00
-0.75
-0.50
-0.25
0.00 10 20 30 40 50 60 70 80 90 100 110
HbA
1c (%
)1
Pioglitazone + metforminGliclazide + metformin
Weeks of treatment
n=317 received PIO + MET; n=313 received GLIC + MET; n=10 not eligible for this analysis2
1. Matthews et al. Diabetes Metab Res Rev 2005;21:167-174.2. Charbonnel et al. Diabetologia 2005;48:1093-1104.
Reproduced with permission
Vildagliptin add-on to insulin: fewer hypoglycaemic events
Fonseca V et al. Diabetologia 2007;50:1148-1155.
No. of events No. of severe events†
0
40
80
120
160
200Placebo + insulinVildagliptin + insulin
0
2
4
6
8
10
Num
ber o
f sev
ere
even
ts
113
185
0
6
**
*
Num
ber o
f eve
nts
†Severe defined as grade 2 or suspected grade 2 hypoglycaemia.*p<0.05; **p<0.001 between groups.
Hypoglycaemia – the hidden problemHypoglycaemia - conclusions
Hypoglycaemia - conclusions• Hypoglycaemia is the major factor limiting intensive control in T2D
– May explain mortality associated with intensive treatment in ACCORD
• Costs of hypoglycaemia are grossly underestimated• Can cause severe morbidity and mortality and lower health-related quality of life• Patient awareness of the risk of hypoglycaemia with some antidiabetic therapies is
low• Occurs in a significant proportion of patients on OADs
– Sulphonylureas are associated the highest risk of hypoglycaemia, both alone and in combination
• Insulin therapy is associated with a significant incidence of hypoglycaemia– Addition of a thiazolidinedione to insulin has been shown to reduce the incidence of
hypoglycaemic events
• Replacement of sulphonylureas with alternative OADs may significantly reduce the risk of hypoglycaemia
– NICE recommends adding a DPP-4 inhibitor or glitazone to metformin instead of a sulphonylurea if there is a significant risk of hypoglycaemia
Hypoglycaemia – the hidden problemProfessor Anthony Barnett
University of Birmingham and Heart of England NHS Foundation TrustUnited Kingdom