Transcript Hypoglycaemia in Type1Diabetes Mellitus

In the name of GOD
1
1
Hypoglycaemia in Type1Diabetes Mellitus
&
Glycaemic Variablity
F.Sarvghadi M.D
Endocrinologist.
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. JAMA
1979;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)
Intensive group
Retinopathy
Severe hypoglycemia
(per 100 patient-years)
80
14
12
10
60
8
Conventional
group
40
Retinopathy
(per 100 patient-years)
16
100
6
4
20
2
0
5
6
7
8
9
10
11
12
13
0
14
HbA1c (%)
DCCT, Diabetes Control and Complications Trial
DCCT Research Group. N Engl J Med 1993;329:977–86
ADA / EASD consensus
“The selection of glycaemic targets and glucoselowering 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”
Diabetes care 2015; 35:1364 -1379
ADA, American Diabetes Association; EASD, European Association for the Study of
Diabetes
ADA/EASD. Position statement. 2012. http://care.diabetesjournals.org/content/early/2012/04/17/dc12-0413.full.pdf
Glucose variability
Characterizing Hyperglycemia/Hypoglycemia and
Oscillations
A
C
B
D
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 glucoselowering 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)
Mild – Moderate
Sever
Asymptomatic
Probable
Symptomatic
Relative
hypoglycemia
Alsahli M et al .Endocrinol Metab Clin N Am 42 (2013) 657–676
Frequency
• Event rates for severe hypoglycemia for patients with
type 1 diabetes range from 62 to 320 per 100 patientyears.
• 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 Frequently
Unrecognized by Patients
• Many episodes are asymptomatic; CGMS data show that
unrecognized hypoglycemia is common in people with insulintreated 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
74% of all events occurred at night
CGMS, continuous glucose monitoring system
Chico et al. Diabetes Care 2003;26(4):1153–7
Defense against hypoglycemia
B.S < 80
< 65
< 48
< 40
< 30
< 20
< 10
Insulin
Glucagon
Epinephrine
G.H - Cortisol
Neuradrenergic
Glu.auto regulation
Lethargy
Coma, Convulsion
Permanent damage
Death
Neuroglycopenic
Symptoms of Hypoglycemia
Pathophysiology of glucose counter-regulation
TIDM
Absolute insulin deficiency
Insulin -
Glucagon Insulin therapy
Hypoglycemia
Hypoglycemia
unawareness
defective glucose
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 25fold 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 treatmentinduced hypoglycemia reverses hypoglycemia unawareness,
and improves the reduced epinephrine component of
defective glucose counterregulation in most affected
patients.
Diabetes,1994, 43:1426–1434
Lancet , 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, bblockers)
• 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
74.2% used insulin
32.1% had several
NSNHE events
The rest took monotherapy
with oral agents
The rest did not report experiencing several NSNHE events
• Impact on well-being
10.4%
79.3%
60.7%
63.7%
43.7%
woke up from the NSNHE and did not go back to sleep
said the event impacted their functioning the following day
reported moderate to severe impact on next day functioning
said emotional functioning was impacted
said social functioning was impacted
Brod M et al. Diabetes Obes Metab. 2013;15:546-557
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
Hypoglycemia – Key Message
• 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
Examples of Carbohydrate for Treatment of Mild to Moderate
Hypoglycemia
<15 kg
15 to 30 kg
>30 kg
5g
10 g
15 g
Glucose tablet (4 g)
1
2 or 3
4
Dextrose tablet (3 g)
Apple or orange juice;
regular soft drink; sweet
beverage (cocktails)
2
3
5
40 ml
85 ml
125 ml
Patient Weight
Amount of carbohydrate
Carbohydrate Source
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 24hour coverage, flexibility and that reduces the burden of hypoglycemia.
Thank you