Hypo-glycemia NOT an

innocent side effect

S. Gentile

Department of Clinical and Experimental MedicineSecond University of Naples

Frequency

Economic burden

Quality of life

Adherence

Direct Complications

Chronic complications

?

UK Hypoglycaemia Study Group. Diabetologia. 2007;50:1140-7.

The incidence of severe hypoglycaemic episodes increases with duration of treatment

High risk1 Low risk1,2

Insulin Metformin

Sulphonylureas α-glucosidase inhibitors

Meglitinides ThiazolidinedionesGLP-1 receptor agonistsDPP-4 inhibitorsSGLT-2 inhibitors

1. Nathan DM, et al. Diabetologia. 2009;52:17-306. 2. Cefalu WT. Nature. 2007;81:636-49. 1. Amiel SA, et al. Diabetic Med. 2008;25:245-54. 2. Melander A. Diabetic Med. 1996;13:S143-7

GLUCOSE-LOWERING AGENTS AND RISK OF HYPOGLYCAEMIA

• Hypoglycaemia has been associated with:– Activation of adrenergic response1

– Impaired flexibility in substrate shift in the diabetic myocardium2

– QTc prolongation and cardiac rate/rhythm disturbances3

– Excessive glucose fluctuations with marked activation of oxidative stress4 1. Hilsted J. Clin Physiol. 1993;13:1-10. 2. Avogaro A, et al. Am J Cardiol. 2004;93:13A-16A.

3. Landstedt-Hallin L, et al. J Intern Med. 1999;246:299-307. 4. Monnier L, et al. JAMA. 2006;295:1681-87.

Factors associated with hypoglycaemia

• Advancing age• Restricting or reduced meal ingestion (especially

carbohydrate intake)• Longer diabetes duration• Deterioration of renal and hepatic function• Potentiating effects of alcohol and drug use• Excessive physical activity

1. Amiel SA, et al. Diabetic Med. 2008;25:245-54. 2. Melander A. Diabetic Med. 1996;13:S143-7.

Increased incidence of severe hypoglycaemic events with intensive therapy in ADVANCE, ACCORD and VADT

Standard IntensiveP<0.001 P<0.01P<0.001

1. ADVANCE Collaborative Group. N Engl J Med. 2008;358:2545-59. 2. ACCORD Study Group. N Engl J Med. 2008;358:2545-59. 3. Duckworth W (VADT). N Engl J Med. 2009;360:129-39.

0.4 0.7

4.0

12.0

3

6

9

12

15

VADT3ACCORD2ADVANCE1

1.0

0

Per 100-patients per year

Seve

re h

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emic

eve

nts

Seve

re h

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eve

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Seve

re h

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eve

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3

6

9

12

15

0

3

6

9

12

15

0

3.0

Standard Intensive Standard Intensive

Intensive glucose lowering contributes to an increased risk of hypoglycaemia by 2- to 3-fold, particularly at later stages of type 2 diabetes

Hypoglycaemia: a major predictor of CV-death in the VADT study

Prior event

HbA1c

HDL

Age

3.116 (1.744, 5567)

1.213 (1.038,1.417)

0.699 (0.536, 0.910)

2.090 (1.518, 2877)

120 2 4 6 8 10

P ValueHazard Ratio (HR lower CL, HR upper CL)

Hypoglycaemia 4.042 (1.449,11.276)

Duckworth W.(VADT): results. 2008. Available from http:// webcasts.prous.com/netadmin/webcast_viewer/Preview.aspx?type=0&lid=3853,

<0.01

0.02

0.01

<0.01

0.01

In the ACCORD study and VADT, a clear association between severe hypoglycaemia and CV events was found1,2 (although no cause-effect relationship was proven)

Hypoglycaemia may be of particular concern in Individuals with a long duration of T2DM, elderly patients, especially with previous CV events3,4

Byington RP ACCORD Study Group: 9 Oct 2009. 2. Duckworth W, N EJ M 2009;360:129 3. Del Prato S. Diabetologia. 2009;52:1219. 4. Mannucci E, Nutr Metab Cardi Dis. 2009;19:604

Recent hypoglycaemia is associated with a higher risk of MI in diabetes patients

Miller DR, et al. Poster Presentation at 45th EASD. Sep 29 – 2 Oct 2009, Vienna, Austria.

Risk of MI associated with episodes of hypoglycaemia within a given prior period

Any hypoglycaemiain specific periods

Index date or day before

Prior 2 weeks

Previous 5.5 months

Previous 6 months

Previous year

Casesof MI(%)

2.9

1.1

6.0

4.8

9.6

Controls(%)

0.1

0.3

2.5

2.1

4.2

Adjusted risk of MI(95% CI)

—

1.65 (1.50–1.81)

1.20 (1.15–1.25)

1.11 (1.06–1.15)

1.12 (1.08–1.16)

Very low and increasing blood glucose levels at admission are associated with a higher risk of death after myocardial infarction*

0

5

10

15

20

25

22.6%

2.5%

8.0%8.7%

3.2%4.3%

Pinto DS, et al. J Am Coll Cardiol. 2005;1:178-83.

81-99 100-125 126-150 151-199 >199< 81

n=123 n=200 n=196n=62 n=280 n=186

P<0.001

Risk

of d

eath

at 3

0 da

ys (%

)

*Subjects were stratified by thrombolysis in myocardial infarction (TIMI) scoreThe relationship between admission blood glucose <81 mg/dL and increased death was not seen in subjects with a TIMI risk score <4

Blood glucose level (mg/dL)

Hypoglycaemia and Autonomous Nervous System abnormalities

• Cardiovascular impairment is associated with increased mortality1–5

• Impaired baroreflex sensitivity is a predictor of cardiac mortality in post-MI patients4,5

• Cardiovascular autonomic function is attenuated after antecedent hypoglycaemia6

5.0Antecedent Clamp Glucose (mmol/L)

2.8

20.0

17.5

15.0

0.0

12.5

Baro

refle

x Se

nsiti

vity

(m

s/m

mHg

)

P<0.04

5.0Antecedent Clamp Glucose (mmol/L)

2.8

5.0

0.0

-5.0

-15.0

-10.0

Chan

ge in

Bar

orefl

ex

Sens

itivi

ty (m

s/m

mHg

)

Baseline Post-Nitroprusside

70

60

50

0Sym

path

etic

Burs

t Fre

quen

cy

(bur

sts/

min

ute) 40

30

20

P<0.01

A: Baroreflex sensitivity after antecedent euglycaemic ( ) or hypoglycaemic ( ) clamp studies. B: Change in baroreflex sensitivity in individual subjects after antecedent hypoglycaemia versus antecedent euglycaemia. C: MSNA assessed at baseline and after nitroprusside in subject after antecedent euglycaemia ( ) or antecedent hypoglycaemia ( ).

1. Maser RE, et al. Diabetes Care. 2003;26:1895-901. 2. Vinik AI, Ziegler D. Circulation. 2007;115:387-97. 3. Bigger JT, et al. Circulation. 1993;88:927-34. 4. De Ferrari GM, et al. J Am Coll Cardiol. 2007;50:2285-90.

5. La Rovere MT, et al. 1998; Lancet 351:478-84. 6. Adler GK, et al. Diabetes 2009;58:360-6.

A B C

Patients who reported severe hypoglycemia had 3.4-fold higher mortality (p<0.005) compared with those who reported mild/no hypoglycema

Mild/Severe Hypoglycemia HRs

- cardiovascular diseases 2.09 - all-cause hospitalization 2.51 - total mortality 2.48

Symptomatic hypoglycemia (clinically mild or severe) is associated with an increased risk of cardiovascular events, all-cause hospitalization, and all-cause mortality

Diabetes Care 36:894–900, 2013

SUs may increase mortality and CV risk vs metformin:

13

• In a Danish study of 107,806 patients, monotherapy with glimepiride, glibenclamide, glipizide, and tolbutamide was associated with significantly increased all-cause mortality vs metformin in patients with and without previous MI

• Results were similar for CV mortality and the composite CV end point

Schramm TK, et al. Eur Heart J. 2011;32:1900-1908

Hazard Ratio (95% confidence interval) Hazard Ratio (95% confidence interval)

No Previous MI Previous MI

Risk for All-Cause Mortality

SU (vs metformin) Hazard Ratio (95% CI)

Glipizide 1.64 (1.39–1.94)

Glyburide 1.59 (1.35–1.88)

Glimepiride 1.68 (1.37–2.06)

Cleveland Clinic: 23,915 T2DM patients Pantalone KM,, et al. Diabetes Obes Metab. 2012;14(9):803-809.

Risk for Overall Mortality

Incidence of all reported hypoglycaemic AEs were similar in patients:with a history of CVD (7.2% vs 6.2%) and without (7.8% vs 6.9%)

Cook, et al. Presented at EASD 2012; poster #837

Incidence of hypoglycaemic AEs was generally similar for saxagliptin and placebo across groups 6.7 vs 6.32%) Allen, et al. Presented at EASD 2012; poster #838

Intern J Clin Prac 2013; 67(4), 307–316

SBP=systolic blood pressure; WMD=weighted mean difference; I2=heterogeneity

Systematic review and meta-analysis of SGLT2 inhibitors in patients with T2DM

SGLT2-i have a favourable effect on HbA1c, systolic blood pressure weight and incidence of hypoglycaemia (RR=0.24 [95% CI: 0.06, 0.98] versus active competitors)

Type of comparisonChange in HbA1c (%) from baseline Change in SBP (mm Hg) from baseline

Studies N. WMD [95 % CI]; I2 studies N. WMD [95 % CI]; I2

SGLT2 ivs Placebo, first line treatment 4 / 532

–0.77 [-0.96, -0.57]; 61%

4 / 532 –1.45 [-2.42, -0.47];

81%

SGLT2 i vs Placebo, add on treatment 10 / 2338 –0.59 [-0.66, -0.51]; 0% 10 / 2440 –1.92 [-2.18, -1.66]; 0%

SGLT2 i vs other hypoglycaemic medication (first line or add on) 6 / 1792 –0.07 [-0.21, 0.07]; 46% 6 / 1838 –2.03 [-3.51, -0.54];

95%

SGLT2-i are associated with an increased risk for urinary tract infections compared with active comparators (RR=1.51 [1.08, 2.09]) and for genital infections compared with both placebo (RR 3.28, 95% CI 2.19 to 4.90) or other hypoglycaemic medications (RR=4.57 [2.80, 7.45])

ADA/EASD algorithm considerations

Tsapas, et al. Presented at EASD; OP #241

v

RR=relative risk; CI=confidence interval

Ben-Ami H, et al. Arch Intern Med. 1999;159:281-4.

17–20

Age range (Years)

Num

ber o

f sub

ject

s 30

35

40

20

15

0

25

10

5

Retrospective medical record review of individuals with diabetes who were admitted with DIHC or developed DIHC during hospitalisation.

21–30 31–40 41–50 51–60 61–70 71–80 81–90

Hypoglycaemic coma requiring hospitalisation is more common in elderly people with type 2 diabetes

THE HYPOGLYCAEMIA IN ELDERLY• In the elderly, hypoglycaemia can have serious, sometimes life-threatening,

consequences for the heart or brain• Elderly patients have a HIGHER RISK OF COMPLICATIONS:

– Falls and injury, cognitive decline, depression, degraded quality-of-life

• SYMPTOMS MAY BE DIFFERENT from younger patients:– Blurred vision, instability– Often blunted by an autonomous neuropathy or impaired cognitive function (‘silent’

hypoglycaemia)

• FAVOURING FACTORS for hypoglycaemia other than age are:– Multiple co-morbid conditions– Renal impairment– Multiple medications– More frequent, poorly-adapted behaviour response– Rare use of self monitoring– Absence of patient and caregiver education

Lecomte P. Diabetes Metab, 2005;31:5S105-5S111.

Impaired renal function enhances the risk of hypoglycaemia in elderly people with T2DM

• Subjects with T2DM hospitalised with severe hypoglycaemia and loss of consciousness, 24 out of 35 cases presented with renal failure1

– Those with renal failure were older than those with normal renal function (74.3 vs 32.8 years)

• Impaired renal function enhances the risk of drug-induced hypoglycaemia in individuals treated with insulin secretagogues or exogenous insulin2

1. Hasslacher C, Wittmann W. Dtsch Med Wochenschr. 2003:128:253-6.2. Snyder RW, Berns JS. Semin Dial. 2004;17:365-70.