Hypoglycaemia

1
Hypoglycaemia the hidden problem

• Professor Anthony Barnett
• University of Birmingham and Heart of England NHS
  Foundation Trust
• United Kingdom

2
Hypoglycaemia the hidden problem

• Hypoglycaemia basics

3
Hypoglycaemia

• The major limiting factor to achieving
  intensive glycaemic control for people with
  type 2 diabetes

Briscoe VJ, et al. Clin Diab 200624115-121.
4
Definition of hypoglycaemia

• Plasma glucose lt3.9mmol/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
200624115-21.
5
Hypoglycaemia the hidden problem

• Epidemiology and consequences of hypoglycaemia

6
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 lt 7

1. Diabetes, Obesity and Metabolism 2008 Jun10
Suppl 125-32.
7
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

100
75
62.5
55.7
46.6
50
Patients,
25
n70
n40
n30
0
All patients with diabetes
Type 1 diabetes
Type 2 diabetes
Patients with 1 unrecognized hypoglycemic event,

1. Chico A, et al. Diabetes Care
200326(4)1153-1157. 2. Weber KK, et al. Exp
Clin Endocrinol Diabetes 2007115(8)491-494. 3.
Zick R, et al. Diab Technol Ther
20079(6)483-492.
8
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.
9
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 (plt0.0001)
• Such patients more likely to report barriers to
  adherence (p0.0057)

Alvarez Guisasola F, et al. Diabetes Obes Metab
200810(Suppl.1)25-32.
10
Hypoglycaemia significantly reduces patients
quality of life
Plt0.0001
Vexiau P, et al. Diabetes Obes Metab
200810(S1)16-24.
Reproduced with permission
11
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
287.50
105.60
92
Amiel SA, et al. Diabetic Medicine 2008 25
245-254.
12
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.
200118690-705. 2. Amiel SA, et al. Diabetic
Medicine 200825245-254. 3. Gold AE, et al.
Diabetes Care 199417697-703. 4. Leiter LA, et
al. Can J Diab. 200529(3)186-192.
13
Fear of hypoglycaemia is a burden for patients

• Fear of hypoglycaemia1
• 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. 200529186-192 J Diab Complic
20041860-68 2. Leiter LA, et al. Can J Diab.
200529186-192 3. Frier BM et al. IJCP
Supplement. 200112330-37 4. Currie CJ, et al.
Curr Med Res Opin 2006221523-1534 5. Wild D,
et al. Patient Educ Couns. 20076810-15.
14
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 200417(1)23-26. 2. Horm
Metab Res Suppl 198515105-111. 3. BMJ
2006332812.
15
Hypoglycaemia the hidden problem

• Hypoglycaemia in patients undergoing intensive
  glucose control

16
Recent studies investigating intensive glycaemic
control have highlighted the problem of
hypoglycaemia
Variable VADT (n1,700) ACCORD (n10,250) ADVANCE (n11,140)
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 (0.7301.04) 0.90 (0.781.04) 0.94 (0.841.06)
HR (95 CI) for mortality 1.065 (0.8011.416) 1.22 (1.011.46)b 0.93 (0.831.06)
CAD, coronary artery disease CHF, congestive
heart disease CVD, cardiovascular disease MI,
myocardial infarction
a Conventional vs intensive b p0.04
17
Severe hypoglycaemia was more common with
intensive therapy in three recent trials of
intensive glucose control
25
20
Intensive control
15
Patients with at least one event during the
trial
Standard control
10
5
0
ACCORD
ADVANCE
VADT
18
ACCORD requirement for medical assistance
amongst patients with hypoglycaemia
18
16.2
Requiring any assistance
15
Requiring medical assistance
12
10.5
Patients ()
9
6
5.1
3.5
3
0
Intensive therapy(target HbA1c lt6)
Standard therapy(target HbA1c 7.0 to 7.9)
ACCORD study. N Engl J Med 2008358(24)
2545-2559.
19
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
20
15
Mortality ()
Intensive therapy
10
Standard therapy
5
0
6
5
4
2
0
1
3
Years
No. at Risk Intensive therapy 5128 Standard
therapy 5123
4972 4971
4803 4700
3250 3180
1748 1642
523 499
506 480
N Engl J Med 20083582545-59.
Action to Control Cardiovascular Risk in Diabetes
Reproduced with permission
20
ACCORD higher mortality in participants who
experienced severe hypoglycaemia
3.3
3.5
3.0
2.5
2.0
Overall mortality rate ()
1.2
1.5
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
21
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

22
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

23
Effect of experimental hypoglycaemia on QT
interval
A
B
QTc 610 ms
QTc 456 ms
HR 61 bpm
HR 66 bpm
5.0mM
2.5mM
International Diabetes Monitor 2009 21(6)
234-241.
Reproduced with permission
24
Hypoglycaemia the hidden problem

• Impact of drug treatment on hypoglycaemic risk

25
Pooled hypoglycaemia results for randomized
trials, by drug comparison
Bolen S, et al. Ann Intern Med 2007147386-399.
Reproduced with permission
26
Oral antidiabetic agents and hypoglycaemic risk
in type 2 diabetes

• Agents with increased hypoglycaemic potential
• Those which enhance insulin secretion/ß-cell
  function in non-glucose dependent manner
• Sulfonylureas
• Short-acting secretagogues (rapaglinide/nateglinid
  e)
• 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)

27
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

28
Rates of hypoglycemia increase as A1C levels
decrease in patients with type 2 diabetes on OADs
40
30
Annual rate ()
20
10
0
0
4
5
6
7
8
9
10
11
Most recent A1C ()
Wright et al. J Diabetes Complications.
200620395-401.
Reproduced with permission
29
Hypoglycaemia with sulphonylureas versus
insulin(UKPDS)
Any
Severe
3.0
40
36.5
2.5
2.3
30
2.0
Mean ()
Mean ()
1.5
17.7
20
1.0
11
10
0.6
0.4
0.5
0.1
1.2
0.0
0
Diet
Chlorpropamide
Glibenclamide
Insulin

• UKPDS 33. Lancet 1998352837-853.

30
Hypoglycaemia with secretagogues vs sensitizers
(the ADOPT study)
All hypoglycemia
Severe hypoglycemia
Percent of patients with episodes
Glyburide Metformin Rosiglitazone
Glyburide Metformin Rosiglitazone
ADOPT Study N Engl J Med 20063552427-2463.
31
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 lt2.2 mmol/l
• The incidence of hypoglycaemia was similar in
  insulin- and SU-treated patients

UK Hypoglycaemia Study Group. Diabetologia.
200750(6)1140-7.
32
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 199531083-8. 2. UKPDS 28
Diabetes Care 21(1)87-92. 3. Adverse Drug React
Toxicol. Rev 200221(4)205-17.
33
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 20073571716-1730.
Reproduced with permission
34
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 199922(1)119-124.
35
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 200017(7)528-531.
36
Severe hypoglycaemia more likely with longer
insulin treatment
8
7
No severe hypos
6
Severe hypos
5
Median duration of insulin therapy (years)
4
3
2
1
0
Type 2 diabetes
Type 1 diabetes
Hepburn et al. Diabetic Med 1993 10(3) 231-7.
37
Hypoglycaemia the hidden problem

• Reducing hypoglycaemic risk in type 2 diabetes

38
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).
39
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
0.0
-0.25
-0.50
HbA1c ()1
-0.75
-1.00
-1.25
-1.50
Pioglitazone metformin
Gliclazide metformin
n317 received PIO MET n313 received GLIC
MET n10 not eligible for this analysis2
1. Matthews et al. Diabetes Metab Res Rev
200521167-174. 2. Charbonnel et al.
Diabetologia 2005481093-1104.
Reproduced with permission
40
Vildagliptin add-on to insulin fewer
hypoglycaemic events
No. of events
No. of severe events

185
200
Vildagliptin insulin
Placebo insulin
10
160
8

113
120
6
Number of events
6
Number of severe events
80
4
40
2
0
0
0
Severe defined as grade 2 or suspected grade 2
hypoglycaemia. plt0.05 plt0.001 between groups.
Fonseca V et al. Diabetologia 2007501148-1155.
41
Hypoglycaemia the hidden problem

• Hypoglycaemia - conclusions

42
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

43
Hypoglycaemia the hidden problem

• Professor Anthony Barnett
• University of Birmingham and Heart of England NHS
  Foundation Trust
• United Kingdom