Transcript Document

HYPOGLYCEMIA IN
TYPE 1 DM
Presented By:
Alaa Monjed
OUTLINE
• Definition of Hypoglycemia in T1DM, incidence
and Impact of on DM management
• How to maintain Glucose Homeostasis and
Counterregulaton of Hypoglycemia
• Counterregulatory failure and hypoglycemia
unawareness in T1DM
• How to Prevent and treat?
• Different insulin regimens, MDI and CSII
Case #1
• 49 year old male, T1DM for 20 years, on Lantus qhs
and NR ac meals.
• He used to have a tight glycemic control with HbA1c 66.5%.
• Recently had a hypoglycemia coma resulting in brain
injury.
• Now, runs BG between 9-20 mmol/L.
• HbA1c > 9.5%.
Case#2
• 45 year old lady, T1DM for 30 years.
• HbA1c 5.4- 6.5% with no evidence of microvascular DM
complications.
• On NR premaels and NPH twice daily +/- 4 am NR.
• Has hypoglycemia unawareness and recurrent severe
hypoglycemia.
• Over the last year she had at least 5 – 6 episodes of
hypoglycemia induced Seizures.
• This fear of hypoglycemia influences an individual’s ability
to adhere to optimal insulin replacement regimens and to
put in place those measures required to achieve nearnormal glucose control
• In this way, hypoglycemia has emerged as a major obstacle
to achieving the goals of intensive insulin therapy in
everyday clinical practice
Hypoglycemia in Type 1 Diabetes
DIABETES, VOL. 59, OCTOBER 2010
Definition of Hypoglycemia
1. The development of autonomic or neuroglycopenic
symptoms
2. A low plasma glucose level (<4.0 mmol/L for
patients treated with insulin or an insulin
secretagogue)
3. Symptoms responding to the administration of
carbohydrate
ADA Definition of
Hypoglycemia
• All episodes of an abnormally low plasma glucose
concentration (with or without symptoms) that expose the
individual to harm.
• The workgroup recommended that people with diabetes
become concerned about the possibility of hypoglycemia at
a SMBG level ≤3.9 mmol/L.
ADA Workgroup on Hypoglycemia
(2005)
Symptoms of Hypoglycemia
Severity of Hypoglycemia
INCIDENCE OF
HYPOGLYCEMIA
• Hypoglycemia is a fact of life for most people with
type 1 diabetes
• The average individual with type 1 DM experiences
about 2 episodes of symptomatic
hypoglycemia/week, a figure that has not changed
substantially in the last 20 years
• Severe hypoglycemia has
 annual prevalence of 30–40% and
 annual incidence of 1.0 – 1.7 episodes per patient per year
Frier BM. The incidence and impact of hypoglycemia in type 1 and type 2
diabetes. International Diabetes Monitor 2009;21:210–218
Hypoglycemia in T1DM
It occurs as a consequence of 3 factors:
• Bahavioral issues
 Too much insulin
 Alcohol on an empty stomach
 Exercise-related
 Individuals who stack their insulin
• Impaired counterregulatory system
• Diabetes complications
 Autonomic neuropathy
 gastroparesis
 Renal failure
NOCTURNAL
HYPOGLYCEMIA
• It can lead to disruption of sleep and delays in
correction of the hypoglycemia
• Nighttime is typically the longest period between
self-monitoring of plasma glucose, between food
ingestion, and the time of maximum sensitivity to
insulin
• It becomes less common using rapid acting insulin
analogs before meals and using long acting insulin
analogs rather than NPH as the basal insulin
IMPACT OF
HYPOGLYCEMIA
• An estimated 2–4% of people with T1DM die from
hypoglycemia
• Prolonged, profound hypoglycemia can cause neurological
damage and brain death
• Hypoglycemia causes a transiently prolonged corrected QT
interval
• It is reasonable to suggest that a fatal arrhythmia triggered by
hypoglycemia might explain the “dead in bed syndrome”
• It is preventing the maintenance of euglycemia over a lifetime
GLUCOSE HOMEOSTASIS
• Insulin acts to restore normoglycemia through:
decreasing hepatic glucose production
increasing glucose uptake by skeletal muscle and adipose
tissue
inhibiting glucagon secretion
Response to Hypoglycemia in
Normal Subjects
• The mechanisms that normally prevent or rapidly
correct hypoglycemia:
 decreased pancreatic islet βcell insulin secretion
 increased pancreatic islet αcell glucagon secretion
 increased adrenomedullary epinephrine secretion
 the ingestion of food prompted by symptoms of
hypoglycemia
 Cortisol and GH contribute only if the hypoglycemia
persists for several hours
RESPONSE TO
HYPOGLYCEMIA IN
DIABETES
INSULIN
• The first defense, the ability to suppress insulin release,
cannot occur in patients with absolute beta-cell failure
(type 1 diabetes and long-standing type 2 diabetes)
• Thus, the main defense against hypoglycemia is
increased release of counterregulatory hormones ,
which raise BG concentrations by stimulating glucose
production and by antagonizing the insulin-induced
increase in glucose utilization
GLUCAGON
• The glucagon response to hypoglycemia, although
normal at the onset of diabetes, is lost in parallel with
that of insulin in type 1 diabetes and more slowly in
type 2 diabetes
• This may be the result of beta-cell failure and
subsequent loss of the hypoglycemia-induced decline
in intraislet insulin that normally signals increased
glucagon secretion during hypoglycemia
EPINEPHRINE
• The epinephrine response to hypoglycemia also becomes
attenuated in many patients, at least in part because of
recent antecedent hypoglycemia
• An attenuated epinephrine response causes defective
glucose counterregulation, which is associated with a 25fold or greater increased risk of severe hypoglycemia
Hypoglycemia-Associated
Autonomic Failure
• The concept of hypoglycemia-associated autonomic failure
(HAAF) in T1DM and advanced T2DM posits that recent
antecedent iatrogenic hypoglycemia causes both
defective glucose counterregulation
 hypoglycemia unawareness
and, thus, a vicious cycle of recurrent hypoglycemia
Mechanisms of sympathoadrenal failure and hypoglycemia in diabetes.
Cryer PE. J Clin Invest. 2006 Jun;116(6):1470-3.
Mechanisms of sympathoadrenal failure and hypoglycemia in diabetes.
Cryer PE. J Clin Invest. 2006 Jun;116(6):1470-3.
HYPOGLYCEMIA
UNAWARENESS
• With recurrent hypoglycemia, the nervous system
adapts to low BG levels and maintains glucose
uptake despite hypoglycemia (by upregulating
GLUT1 transporters at the BBB) without adrenergic
effects, resulting in unawarness to hypoglycemia
• It is associated with a 6-fold increased risk for severe
hypoglycemia
Long-term recovery from unawareness, deficient
counterregulation and lack of cognitive dysfunction
during hypoglycaemia, following institution of rational,
intensive insulin therapy in IDDM
Diabetologia. 1994 Dec;37(12):1265-76.
• Fanelli CS et al.
 21 T1DM pts with hypoglycemia unawareness and
frequent mild/severe hypoglycemia episodes while on
"conventional" insulin therapy
 intensive insulin therapy which meticulously prevented
hypoglycemia (based on physiologic insulin replacement
and continuous education, EXP, n = 16), or maintenance
of the original "conventional" therapy (CON, n = 5)
 An increase in glycated Hb by 1% over 1 yr and a
significant reduction in the hypoglycemia frequency
Avoidance of hypoglycemia restores
hypoglycemia awareness by increasing betaadrenergic sensitivity in type 1 diabetes.
• PATIENTS: 10 men with T1DM and hypoglycemia
unawareness (mean age [+/-SD], 46 +/- 16 years; mean
duration of diabetes, 20 +/- 10 years).
• INTERVENTION: Strict avoidance of hypoglycemia.
• MEASUREMENTS: beta-Adrenergic sensitivity was
measured by isoproterenol testing before and at 2 and 4
months after strict avoidance of hypoglycemia.
Hypoglycemia awareness and catecholamine response
were measured by performing hypoglycemic clamp
(glucose level, 3 mmol/L) before and after 4 months of
avoidance of hypoglycemia.
Fritsche A, Stefan N, Häring H, Gerich J, Stumvoll M
Ann Intern Med. 2001;134(9 Pt 1):729.
• RESULTS: After 4 months,
the mean number of episodes of hypoglycemia (glucose
level<3.9 mmol/L) decreased from 8.4 +/- 0.9 to 1.4
+/- 0.3 per week (P<0.001).
 Hemoglobin A(1c) values increased from 6.8% +/0.3% to 7.7% +/- 0.3% (P<0.001).
• CONCLUSIONS: Avoidance of hypoglycemia in
patients with type 1 diabetes who have hypoglycemia
unawareness seems to restore hypoglycemia awareness,
primarily by increasing beta-adrenergic sensitivity
• A two- to three-week period of scrupulous avoidance
of hypoglycemia is advisable since that often restores
awareness
Hypoglycemia in the
Diabetes Control and
Complications Trial
THE DCCT RESEARCH GROUP
DCCT Trial
Conventional Therapy
Intensive Therapy
•
1 or 2 daily injections of
insulin including mixed insulin
•
Insulin 3 or more times daily
by injection or pump
•
No daily adjustments of
insulin dosage
•
SMBG qid
•
Dosage adjustment according
to SMBG, diet, exercise
•
Goals of therapy:
•
Goals of therapy:
 Absence of symptoms due
to hyperglycemia or
hyperglycosuria
 Absence of ketonuria
 Maintenance of IBW
 No severe/frequent hypoBG
 Premeal BG 3.9-6.7
 Postprandial BG <10
• 65% in the intensive group vs 35% in the conventional
group had at least one episode of severe hypoglycemia over
6.5 years
• 30% in each group experienced a second episode within the
4 months following the first episode of severe hypoglycemia
• Within each treatment group, the number of prior episodes
of hypoglycemia was the strongest predictor of the risk of
future episodes, followed closely by the current HbA1c
value
Epidemiology of severe hypoglycemia in the
diabetes control and complications trial
The DCCT Research Group
• Severe hypoglycemia occurred more often during
sleep (55%); 43% of all episodes occurred between
midnight and 8 AM
• Of episodes that occurred while subjects were
awake, 36% were not accompanied by warning
symptoms
The American Journal of Medicine
Volume 90, Issue 4, April 1991, Pages 450–459
How to Treat Hypoglycemia?
STRATEGIES TO PREVENT
HYPOGLYCEMIA
• Patients at high risk for severe hypoglycemia should be
informed of their risk and counseled, along with their
significant others, on preventing and treating
hypoglycemia (including use of glucagon)
• Preventing driving and industrial accidents through selfblood glucose monitoring
• Taking appropriate precautions prior to the activity
• Documenting BG readings taken during sleeping hours
• Individuals may need to have their insulin regimen
adjusted appropriately to lower their risk
STRATEGIES TO PREVENT
HYPOGLYCEMIA
1. Diabetes self-management (supported by education and
empowerment)
2. Frequent self-monitoring of blood glucose (and perhaps
in some instances continuous glucose sensing)
3. Flexible and appropriate insulin (and other drug)
regimens
4. Individualized glycemic goals
5. Ongoing professional guidance and support
Insulin Regimens
• Use of long-acting insulin analogs (glargine,
detemir) as the basal insulin and rapid-acting insulin
analogs (lispro, aspart, glulisine) as the pre-meal
bolus insulin reduces the risk of hypoglycemia,
particularly nocturnal hypoglycemia.
•
Although many clinicians believe CSII is better, at
comparable A1C levels CSII has not been found to
consistently result in less hypoglycemia than a basalbolus regimen with insulin analogs
Glargine vs. NPH Pharmacology
Heinemann, L et al. Diabetes Care 2000; 23:644
Glargine vs. NPH
• Glargine possesses modest therapeutic advantage
over NPH in T1DM
• HbA1c weighted-mean difference - 0.11%
• In meta-analysis, no significant difference in any
type of hypoglycemia
Singh et al. CMAJ 2009; 180: 385
Insulin Detemir vs. NPH
• Similar glycemic control observed in T1DM
• T1DM - HbA1c weighted change of -0.06%
• Slightly lower risk of severe and nocturnal
hypoglycemia in T1DM but not in T2DM on MDI
• Severe hypoBG RR 0.74
• Nocturnal hypoBG RR 0.92
Singh et al. CMAJ 2009; 180: 385
weighted mean difference
between HbA1c values
was −0.12% (95% CI,
−0.17% to −0.07%)
for adult T1DM pts
Figure 3. Differences in overall hypoglycemic event rate. A, Standardized mean
differences (error bars indicate 95% confidence interval [CI]) in overall hypoglycemic
event rate during therapy with short-acting insulin (SAI) analogues compared with
structurally unchanged SAI in patients with type 1 diabetes mellitus.
• The standardized mean difference for overall
hypoglycemia (episodes per patient per month) was
−0.05 (95% CI, −0.22 to 0.11)
• Conclusion: the analysis suggests only a minor
benefit to HbA1c values in adult patients with type 1
diabetes mellitus but no benefit in the remaining
population with type 2 or gestational diabetes from
SAI analogue treatment
• RCTs and before/after studies of ≥ 6 months’ duration
CSII and with severe hypoglycemia frequency > 10
episodes/100 patient years on MDI
• Severe hypoglycemia was reduced during CSII compared
with MDI,
• with a rate ratio of 2.89 (95% CI 1.45 to 5.76) for RCTs
• 4.34 (2.87 to 6.56) for before/after studies [rate ratio 4.19
(2.86 to 6.13) for all studies]
• The reduction was greatest in those with the highest
initial severe hypoglycemia rates on MDI (P < 0.001)
• 1-year, multicenter, RCT study
• The efficacy of sensor-augmented pump therapy was compared
with that of a regimen of MDI in 485 patients (329 adults and
156 children) with inadequately controlled T1DM.
• Patients received recombinant insulin analogues and were
supervised by expert clinical teams.
• The primary endpoint was the change from the baseline
glycated hemoglobin level
• At 1 year, the baseline mean glycated hemoglobin level
(8.3% in the two study groups) had
 decreased to 7.5% in the SAP
 8.1% in the MDI group (P<0.001)
•
The proportion of patients who reached the glycated
hemoglobin target (<7%) was greater in the SAP group
than in the MDI group
• The rate of severe hypoglycemia in the SAP group
(13.31 cases per 100 person-years) did not differ
significantly from that in the MDI group (13.48 per 100
person-years, P = 0.58)
Severe hypoBG
SAP
N=247
MDI
N-248
P-value
No. of events
32
27
0.58
No. of patients
21
17
Rate per 100
Person-yr
13.31
13.48
0.84
Sensor-augmented CSII has been reported to achieve
lower A1C levels without an increase in hypoglycemia
Strength of Evidence
• High indicates high confidence that evidence reflects the true
effect; further research is unlikely to change confidence in the
estimate of the effect
• Moderate indicates moderate confidence that evidence reflects
the true effect; further research may change confidence in the
estimate of the effect and may change the estimate
• Low indicates low confidence that evidence reflects the true
effect; further research is likely to change confidence in the
estimate of the effect and is likely to change the estimate
• Insufficient indicates that evidence is unavailable, does not
permit a conclusion, or consists of only 1 study with high risk
of bias
• Limitation: Many studies were small, of short duration,
and limited to white persons with type 1 diabetes mellitus
• Conclusion: CSII and MDI have similar effects on
glycemic control and hypoglycemia, except CSII has a
favorable effect on glycemic control in adults with
T1DM.
• For glycemic control, rt-CGM is superior to SMBG and
sensor-augmented insulin pumps are superior to MDI
and SMBG without increasing the risk for hypoglycemia
TAKE HOME
MESSAGE
• Treatment-induced hypoglycemia is a common problem
• It has a significant impact on diabetic patient’s glycemic
control
• At each clinic visit, hypoglycemia and hypoglycemia
unawareness should be assessed and the
preventing/treating strategies should be discussed
• Glycemic control should be individualized based on the
microvascular complications, duration of DM, autonomic
neuropathy, hypoglycemia unawareness and hypoglycemia
fears
THANKS