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 6-6.5%.

• 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 near-normal 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 ofHypoglycemia

• 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 OFHYPOGLYCEMIA

• 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 25-fold 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 hypoglycemiaMechanisms 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.

HYPOGLYCEMIAUNAWARENESS

• 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

• 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

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.

Avoidance of hypoglycemia restores hypoglycemia awareness

by increasing beta-adrenergic 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 MAnn 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 TrialConventional

Therapy• 1 or 2 daily injections of

insulin including mixed insulin

• No daily adjustments of insulin dosage

• Goals of therapy: Absence of symptoms

due to hyperglycemia or hyperglycosuria

Absence of ketonuria Maintenance of IBW No severe/frequent

hypoBG

Intensive Therapy

• Insulin 3 or more times daily by injection or pump

• SMBG qid

• Dosage adjustment according to SMBG, diet, exercise

• Goals of therapy: 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 MedicineVolume 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 self-blood 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

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

STRATEGIES TO PREVENT HYPOGLYCEMIA 

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 basal-bolus 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

Drag picture to placeholder or click icon to add

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

SAPN=247

MDIN-248

P-value

No. of events 32 27 0.58

No. of patients

21 17

Rate per 100Person-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