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