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In the name of GOD

Hypoglycaemia in Type1Diabetes Mellitus&

Glycaemic Variablity

F.Sarvghadi M.DEndocrinologist.Associate prof. Research institute for endocrine sciences. Shahid Beheshti University of Medical Sciences. 08/12/1393

Agenda

• Introduction• Glucose variability • Pathophysiology• Clinical manifestations• Impact of hypoglycemia• Risk factors• Prevention• Treatment

Diabetes – Greatly Increases Risk of Microvascular and Macrovascular Disease

Microvascular• Nephropathy (up to 37%)* • Retinopathy (up to 50%)* • Neuropathy ( up to 60%) *

Macrovascular Overall CVD (2-3 x risk)2

MI (3-6 x risk)3

Stroke (up to 12%)4*

Amputation (up to 12%)4*

Eastman RC and Garfield RA. Prevention and treatment of microvascular and neuropathic complications of diabetes. Prim Care 1999;26:791-807.

2. Kannel, WB, McGee DL. Diabetes and cardiovascular diseases. The Framingham Study. JAMA1979;241:2035-2038.

3. Hanefeld M, et al. Diabetes Intervention Study multi-intervention trial in newly diagnosed NIDDM. Diabetes Care 1991;14:308-317.

4. Stratton IM, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 2000;321:405-12.

Hypoglycemia: benefits and risks (DCCT)

DCCT Research Group. N Engl J Med 1993;329:977–86

1413121110987650

20

40

60

80

100

Sev

ere

hypo

glyc

emia

(p

er 1

00 p

atie

nt-y

ears

)

HbA1c (%)

0

2

4

6

8

10

12

14

16 Retinopathy

(per 100 patient-years)

Conventional group

Intensive groupRetinopathy

DCCT, Diabetes Control and Complications Trial

ADA / EASD consensus

“The selection of glycaemic targets and glucose-lowering treatments should be individualised on the

basis of patient specific factors (age, stage of diabetes, cardiovascular risk factors, weight, risk associated

with hypoglycaemia, etc.) and of effects on multiple pathophysiological aspects of type 2 diabetes”

ADA, American Diabetes Association; EASD, European Association for the Study of DiabetesADA/EASD. Position statement. 2012. http://care.diabetesjournals.org/content/early/2012/04/17/dc12-0413.full.pdf

Diabetes care 2015; 35:1364 -1379

Glucose variability

Characterizing Hyperglycemia/Hypoglycemia and Oscillations

B

A

D

C

Beyond Hemoglobin A1c

Today glucose control must combine HbA1c & glucose data• Optimize HbA1c, overall average glucose control• Minimize hypoglycemia• Minimize glucose variability (swings in blood sugar)

Hirsch I, Brownlee M; JAMA, June 2010, 303(22);2291-2292

Key factors that Affect variability

• Medications

– Action, dose, timing, route of administration

• Carbohydrate intake

– Amount, type, timing, synchronizing with medication and activity

• Physical activity

– Amount, type, timing, synchronizing with food and medication

– Role of stress?

Hypoglycemia is the result of a mismatch between

insulin dose, food consumed, and recent exercise and is

rarely, if ever, a spontaneous event

Pediatric Diabetes 2009: 10(Suppl. 12): 134–144

HYPOGLYCEMIA IN T1DM

Hypoglycemia is the most common endocrine medical emergency

And leading limiting factor with some glucose-lowering therapy

Epidemiology of hypoglycemia

In general, the frequency is greater in patients with type1 diabetes ( 62 per 100 patient –year) than in those with type 2 diabetes ( 4 per 100 patiant – year ) .

More often during intensified insulin therapy than during conventional insulin therapy.

Short-acting insulin are associated with a greater frequency of hypoglycemia than are the long-acting .

Definition

• All episodes of an abnormally low plasma glucose concentration that expose the individual to potential harm.

• A single threshold value for plasma glucose concentration that defines hypoglycemia in diabetes cannot be assigned because there are varying threshold for symptoms.

Seaquist ER et al J Clin Endocrinol Metab, 2013, 98(5):1845–1859

Hypoglycemia categories as defined by the ADA , the Endocrine Society and ISPAD

ADA defines hypoglycemia as BG ≤3.9 mmol/L (70 mg/dL)

Alsahli M et al .Endocrinol Metab Clin N Am 42 (2013) 657–676

Mild – Moderate

Sever

AsymptomaticProbable SymptomaticRelative hypoglycemia

Frequency

• Event rates for severe hypoglycemia for patients with type 1 diabetes range from 62 to 320 per 100 patient-years.

• An estimated 6% of deaths of diabetic patients• aged below 40 years have been attributed to dead in bed’

syndrome.

Diabetologia. 2007;50: 1140–1147

Pediatric Diabetes 2009: 10(Suppl. 12): 134–144

Hypoglycemia is FrequentlyUnrecognized by Patients

• Many episodes are asymptomatic; CGMS data show that unrecognized hypoglycemia is common in people with insulin-treated diabetes.

– In one study, 63% of patients with type 1 diabetes and 47% of patients with type 2 diabetes had unrecognized hypoglycemia as measured by CGMS (n=70)1

CGMS, continuous glucose monitoring system

Chico et al. Diabetes Care 2003;26(4):1153–7

74% of all events occurred at night

Defense against hypoglycemia

B.S < 80 Insulin

< 65 Glucagon

Epinephrine

G.H - Cortisol

< 48 Glu.auto regulation

< 40 Lethargy

< 30 Coma, Convulsion

< 20 Permanent damage

< 10 Death

Neuroglycopenic

Neuradrenergic

Symptoms of Hypoglycemia

Pathophysiology of glucose counter-regulation

TIDMAbsolute insulin deficiency

Insulin - Glucagon -

Insulin therapy

Hypoglycemia

Hypoglycemia defective glucose unawareness counter regulation

Autonomic Response

Symptoms Epinephrine

Hypoglycemia-Associated Autonomic Failure

(HAAF)

• Reduced counterregulatory hormone responses, which result in impaired glucose generation.

• Hypoglycemia unawareness, which precludes appropriate behavioral responses, such as eating .

HAAF

• Patients with impaired counterregulation have at least a 25-fold increased risk for severe hypoglycemia compared with patients with a defective glucagon response but normal epinephrine responses

• Hypoglycemia unawareness occurs in 20–25% of adults T1DM and is associated with 6-fold increased risk for severe hypoglycemia.

Risk factors for HAAF

• Absolute endogenous insulin deficiency.

• History of severe hypoglycemia, hypoglycemia unawareness, or both.

• Recent antecedent hypoglycemia. • Prior exercise.• Sleep.

• Aggressive glycemic therapy per se (lower HbA1c, lower glycemic goals).

HAAF is largely preventable and/or reversible

• A little as 2–3 week of scrupulous avoidance of treatment-induced hypoglycemia reverses hypoglycemia unawareness, and improves the reduced epinephrine component of defective glucose counterregulation in most affected patients.

Diabetes,1994, 43:1426–1434Lancet , 1994,344:283–287

Risk factors

Absolute or relative insulin or insulin secretagogues excess

• Excessive doses• Decreased clearance (eg, renal impairment, liver failure, and

hypothyroidism)• Decreased glucose production (eg, liver or kidney disease and

alcohol ingestion)• Increased glucose use (eg, exercise)• Increased insulin sensitivity (eg, exercise, weight loss, and use

of insulin sensitizers)• Intentional hypoglycemia (overdose)

Mismatch between insulin or insulin secretagogues and food absorption

• Ill-timed insulin doses• Missed meals• Gastroparesis• Post gastric bypass surgery• Gastrointestinal disease with malabsorption (eg,

celiac disease)

Glucose Counterregulation factors

• Defective hypoglycemia counterregulation• Hypoglycemia unawareness• Autonomic neuropathy• Deficiency of hormones needed for hypoglycemia

counterregulation (eg, adrenal insufficiency and growth hormone deficiency

Drugs

• Drugs capable of causing hypoglycemia by themselves (eg, alcohol, insulin, sulfonylureas)

• Drugs that could cause hypoglycemia only in combination with insulin or insulin secretagogues (eg, metformin, angiotensin-converting enzyme inhibitors)

• Drugs that can compromise hypoglycemia awareness (eg, b-blockers)

• Sudden decrease in drugs that cause hyperglycemia (eg, discontinuing glucocorticosteroids or glucose infusion during hospitalization in insulin-treated patients)

COMPLICATIONS OF HYPOGLYCEMIA

Nonsevere nocturnal hypoglycemia event (NSNHE) impacts daily function

• International survey of 2,108 patients with T1DM or T2DM who reported a NSNHE in the prior month

• Impact on well-being10.4% woke up from the NSNHE and did not go back to sleep

79.3% said the event impacted their functioning the following day

60.7% reported moderate to severe impact on next day functioning

63.7% said emotional functioning was impacted

43.7% said social functioning was impacted

Brod M et al. Diabetes Obes Metab. 2013;15:546-557

74.2% used insulin The rest took monotherapy with oral agents

32.1% had several NSNHE events

The rest did not report experiencing several NSNHE events

SAGLB.DIA.14.06.0065a / 2014.06

Impact of hypoglycemia

• The youngest patients are most vulnerable to the adverse consequences of hypoglycemia.

• Recent studies have examined the impact of hypoglycemia on cognitive function and cerebral structure in children and found that those who experience this complication before the age of 5 years seem to be more affected than those who do not have hypoglycemia until later.

Pediatr Diabetes. 2008;9:87–95

Hypoglycemia has a negative impact on patient care• Negative impact on QoL and physical, mental and social functioning.• Deterioration of glycemic control.

• Decreased work productivity.

• Loss of self confidence.

• Fear of future episodes.

• Limits titration efforts and treatment optimization and therefore target achievement.

• Higher risk of glucose-lowering treatment discontinuation.

• Increased costs to patient, healthcare system and society,

• Adverse long-term complications,

– Weight gain– Increased risk for major macro- and microvascular events– Development of cognitive dysfunction and dementia– Death from cardiac and/or any cause

1. Brod M et al. Diabetes Obes Metab. 2013;15:546-557; 2. Seaquist ER et al. Diabetes Care. 2013;36:1384-95; 3. Ahrén B. Vasc Health Risk Man. 2013;9:155-163;4. Peyrot M et al. Diabet Med. 2012;29:682-689; 5. Bron M et al. Postgrad Med. 2012;124:124-32; 6. Chou E, et al. Presented at ADA 2014; Abstract 254-OR; 7. Xie L et al. J Med Econ. 2013;16:11; 8. Ward A et al. J Med Econ. 2014;17:176-83;9. Zoungas S et al. N Engl J Med. 2010;363:1410-1418; 10. ORIGIN Investigators. Eur Heart J. 2013;34:3137-44

SAGLB.DIA.14.06.0065a / 2014.06

Treatment

Treatment of hypoglycemia in non hospitalized patients

Alsahli M et al .Endocrinol Metab Clin N Am 42 (2013) 657–676

Treatment of hypoglycemia in hospitalized patients

Alsahli M et al .Endocrinol Metab Clin N Am 42 (2013) 657–676

• Frequent use of continuous glucose monitoring in a

clinical care setting may reduce episodes of hypoglycemia

• In children, the use of mini-doses of glucagon has been

shown to be useful in the home management of mild or

impending hypoglycemia associated with inability or

refusal to take oral carbohydrate

• Dose = 10 mcg x (years of age)

• Dose range 20 – 150 mcg

Hypoglycemia – Key Message

Examples of Carbohydrate for Treatment of Mild to Moderate Hypoglycemia

Patient Weight <15 kg 15 to 30 kg >30 kg

Amount of carbohydrate 5g 10 g 15 g

Carbohydrate Source

Glucose tablet (4 g) 1 2 or 3 4

Dextrose tablet (3 g) 2 3 5Apple or orange juice; regular soft drink; sweet beverage (cocktails)

40 ml 85 ml 125 ml

Glucagon Kit

Prevention of hypoglycemia

Alsahli M et al .Endocrinol Metab Clin N Am 42 (2013) 657–676

Conclusion• Hypoglycemia is a frequent occurrence for many patients with type 1 or type

2 diabetes treated with insulin or insulin secretagogues and those with renal insufficiency.

• Episodes of hypoglycemia have significant morbidity and mortality and are the main limiting factor for achieving near optimal glycemic control.

• Management and prevention of hypoglycemia should focus on reducing risk factors through patient education, individualization of glycemic targets, and judicious use of antidiabetic regimens.

• There remains an important need for a new insulin with improved 24-hour coverage, flexibility and that reduces the burden of hypoglycemia.

Thank you