Transcript Document

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
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 problem
Epidemiology 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
100
Patients, %
75
62.5
55.7
46.6
50
• Other researchers have
reported similar findings2,3
25
0
• In a cohort of patients with
diabetes, more than 50%
had asymptomatic
(unrecognized)
hypoglycemia, as identified
by continuous glucose
monitoring1
n=70
All
patients
with
diabetes
n=40
n=30
Type 1
diabetes
Type 2
diabetes
Patients with ≥1 unrecognized
hypoglycemic event, %
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.
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
P<0.0001
19
20
Score
15
10.2
10
5
0
HFS-II Worry subscale
With hypoglycaemia
Reproduced with permission
Without hypoglycaemia
Vexiau P, et al. Diabetes Obes Metab 2008;10(S1):16-24.
Hypoglycaemia increases healthcare costs
• In the UK, the estimated cost of hypoglycaemia due to type 2 diabetes
is about £7.4 million1
• Probably an underestimate
£330
Consultation cost (£)
350
300
£287.50
250
200
150
100
£105.60
£92
50
0
Mild to moderate hypoglycaemia
GP consultations
Severe hypoglycaemia
Practice nurse consultation
Amiel SA, et al. Diabetic Medicine 2008; 25: 245-254.
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 problem
Hypoglycaemia in patients undergoing intensive glucose control
Recent studies investigating intensive glycaemic control
have highlighted the problem of hypoglycaemia
Variable
VADT (n=1,700)
ACCORD (n=10,250)
ADVANCE (n=11,140)
8.4 vs 6.9
7.5 vs 6.4
7.3 vs 6.5
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)
HbA1c (%)a
Primary outcome
CAD, coronary artery disease; CHF, congestive heart disease; CVD, cardiovascular disease; MI, myocardial infarction
a
b
Conventional vs intensive
p=0.04
Severe hypoglycaemia was more common with intensive
therapy in three recent trials of intensive glucose control
% Patients with at least
one event during the trial
25
20
Intensive control
15
Standard control
10
5
0
VADT
ACCORD
ADVANCE
ACCORD – requirement for medical assistance
amongst patients with hypoglycaemia
18
16.2
Requiring any assistance
Patients (%)
15
12
Requiring medical assistance
10.5
9
6
5.1
3.5
3
0
Intensive therapy
(target HbA1c <6%)
Standard therapy
(target HbA1c 7.0 to 7.9%)
ACCORD study. N Engl J Med 2008;358(24): 2545-2559.
ACCORD Trial – intensive glucose lowering may be
harmful in patients at high CV risk
• 22% relative increase in mortality for intensive over standard treatment
25
Mortality (%)
20
15
Intensive therapy
10
Standard therapy
5
0
0
No. at Risk
Intensive therapy
Standard therapy
1
2
3
4
5
6
Years
5128
5123
4972
4971
Action to Control Cardiovascular Risk in Diabetes
4803
4700
3250
3180
1748
1642
523
499
506
480
N Engl J Med 2008;358:2545-59.
Reproduced with permission
Overall mortality rate (%)
ACCORD: higher mortality in participants who
experienced severe hypoglycaemia
3.3%
3.5
3.0
2.5
2.0
1.5
1.2%
1.0
0.5
0.0
Never experienced SH
Experienced SH
The cause of the increased mortality could not be proven;
severe hypoglycaemia was implicated
SH = severe hypoglycaemia
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
A
B
QTc= 456 ms
HR= 66 bpm
QTc= 610 ms
HR= 61 bpm
5.0mM
2.5mM
International Diabetes Monitor 2009; 21(6): 234-241.
Reproduced with permission
Hypoglycaemia – the hidden problem
Impact 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 diabetes
Agents 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 diabetes
Agents 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
Annual rate (%)
40
30
20
10
0
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)
Any
40
Severe
3.0
36.5
2.5
2.3
20
17.7
Mean (%)
Mean (%)
30
2.0
1.5
1.0
11
0.6
10
0.4
0.5
0.1
1.2
0.0
0
Diet
Chlorpropamide
Glibenclamide
Insulin
UKPDS 33. Lancet 1998;352:837-853.
Hypoglycaemia with secretagogues vs sensitizers
(the ADOPT study)
Percent of patients with episodes
All
hypoglycemia
40
Severe
hypoglycemia
38.7
30
20
11.6
10
9.8
0.6
0
Glyburide Metformin Rosiglitazone
0.1
0.1
Glyburide Metformin Rosiglitazone
ADOPT Study N Engl J Med 2006;355:2427-2463.
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 insulinand 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
Median duration of insulin
therapy (years)
8
7
No severe hypos
Severe hypos
6
5
4
3
2
1
0
Type 2 diabetes
Type 1 diabetes
Hepburn et al. Diabetic Med 1993; 10(3): 231-7.
Hypoglycaemia – the hidden problem
Reducing 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
Weeks of treatment
0
10 20 30 40 50 60 70 80 90 100 110
HbA1c (%)1
0.0
% With Symptoms Compatible with
Hypoglycaemia
14%
-0.25
12%
-0.50
10%
-0.75
8%
-1.00
6%
-1.25
4%
-1.50
Pioglitazone + metformin
Gliclazide + metformin
n=317 received PIO + MET; n=313 received GLIC + MET;
n=10 not eligible for this analysis2
2%
0%
Piogliazone + metformin Gliclazide + metformin (n
(n = 317)
= 313)
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
No. of severe events†
No. of events
**
185
Vildagliptin + insulin
160
120
Number of severe events
Number of events
200
113
80
40
0
Placebo + insulin
10
8
*
6
6
4
2
0
0
†Severe
defined as grade 2 or suspected grade 2 hypoglycaemia.
*p<0.05; **p<0.001 between groups.
Fonseca V et al. Diabetologia 2007;50:1148-1155.
Hypoglycaemia – the hidden problem
Hypoglycaemia - 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 problem
Professor Anthony Barnett
University of Birmingham and Heart of England NHS Foundation Trust
United Kingdom