Use of Metformin in Adolescents with

Insulin Resistance

presented by

Krista Dahl-Koehler

Insulin Resistance Impaired biologic response to insulin Characterized by:

Decreased insulin-stimulated glucose transport Decreased

metabolism of glucose in skeletal muscle and adipocytes

Diminished ability to suppress hepatic glucose production (gluconeogenesis and glycogenolysis)

Insulin Resistance Causes:

Genetics: Specific genes isolated that increase likelihood of developing insulin resistance and diabetes

Obesity [?]

Risk Factors IR exacerbated by:

Obesity esp. abdominal

High carb diet Sedentary lifestyle Aging Ethnicity Increased levels of certain hormones

Glucocorticoids Androgens

Signs/Symptoms Often asymptomatic

Acanthosis nigricans Hyperpigmentated patches

of skin, velvety texture Typically on back of neck May be seen on elbows,

knees, knuckles, armpits

Diagnosis of Insulin Resistance Measuring insulin resistance

Hyperinsulinemic euglycemic clamp – gold standard – invasive, expensive

Minimal model – based on glycemic response to endogenous and exogenous insulin

HOMA model – calculated based on fasting levels of glucose and insulin

Not practical or affordable for clinical use – only used in research

Clinical diagnosis of IR based on clinical findings

Prediabetes Elevated glucose levels, but doesn’t meet criteria for DM More practical to test for prediabetes than IR Clinical markers of worsening IR and rising CVD risk

Testing for Prediabetes

Fasting Plasma Glucose Test: abnormal readings mean pt has Impaired Fasting Glucose

The preferred test

Oral Glucose Tolerance Test: abnormal readings mean pt has Impaired Glucose Tolerance

Prediabetes Precedes diabetes

57 million US citizens 2 million US adolescents

between ages of 12-19

1 of 10 (10%) progress to T2DM each year

Most develop T2DM within 10 years unless they lose 5-7% of body weight

Cost of T2DM Economic:

Average per capita medical expenditures: Pt with DM: $13,243 Pt w/o DM: $ 2,560

Total cost DM/year: $132 billion

Quality of Life Increased risk of heart dz, CVA, HTN,

retinopathy, blindness, kidney failure, neuropathy, amputations

Significant morbidity and mortality

American Diabetes Association:

Criteria Overweight (BMI >85th percentile for age and sex, weight for

height >85th percentile, or weight >120% of ideal for height) Plus any two of the following risk factors:

Family history of type 2 diabetes in first- or second-degree relative

Race/ethnicity (e.g., Native American, African American, Latino, Asian American, and Pacific Islander)

Signs of insulin resistance or conditions associated with insulin resistance (e.g., acanthosis nigricans, hypertension, dyslipidemia, or PCOS)

Maternal history of diabetes or GDM

Age of initiation: age 10 years or at onset of puberty, if puberty occurs at a younger age

Frequency: every 2 years Test: FPG preferred

Table 4: Testing for type 2 diabetes in

asymptomatic children

Treatment PlanRecommendations for Managing

Body Weight in Youths with or at Risk of Type 2 Diabetes

Food modification Physical activity Psychosocial support

Importance of Prevention

When pt diagnosed with T2DM, approximately 50% of β-cell function already lost

Do lifestyle modifications work?

Yes!!! Losing 5-7% of weight prevents or delays onset of diabetes by ~60%

But…

<10% of youth with T2DM are successfully treated with exercise and diet

Purpose What else can we do to stop progression

to T2DM?

Metformin Oral Biguanide Lowers both basal and postprandial

glucose levels Decreases hepatic gluconeogenesis Reduces intestinal glucose absorption Increases insulin sensitivity (improved

glucose uptake and utilization by skeletal muscle and adipose tissue)

Metformin Reduces HA1C by 1.5 - 2.0%

Not associated with hypoglycemia

Other beneficial effects: Modest weight reduction Improved lipid parameters

Metformin: Dosage First line pharmacologic therapy for

T2DM uncontrolled by diet and exercise Adult (>17 y/o):

Initially: 500mg PO BID or 850 PO QD with meals

Increase daily dosage by 500mg/24hr in weekly increments or 850 mg/24hr in 2 week intervals

Maximum dose: 2550mg/24hr (TID) Adolescents and Children (10-16 y/o)

Initially: 500 mg PO BID with meals Increase in dosage by 500mg/24hr in weekly

increments Maximum dose: 2000mg/24hr

Metformin - Contraindications Absolute

Contraindications: CHF Metabolic acidosis During radiology

studies with iodinated contrast media

Renal impairment/dz Surgery Hepatic dz

Relative Contraindications: Excessive ETOH intake Dehydration Anemia Thyroid dz Pregnancy Breast-feeding

Metformin Side Effects Most common: GI discomfort (30-50%)

Nausea/Vomiting Dyspepsia Flatulence Diarrhea Dysgeusia (Metallic taste) Short term abdominal discomfort and diarrhea – 40% pediatric pts

Anorexia, Weight loss Vitamin B12 deficiency anemia Most Serious: Lactic Acidosis (rare; 50% of cases fatal –

medical emergency) – onset subtle, nonspecific symptoms Diarrhea Severe muscle pain Cramping Unusual weakness Sleepiness Respiratory distress

Metformin – use in Prediabetes Diabetes Prevention Program - 2002

Large RCT of adult pts with IGT Incidence of DM reduced:

by 58% with intensive lifestyle modification by 31% by metformin alone

Least effective for participants > 60 y/o Most effective for participants ages 25-44 (youngest in study)

and those with BMI >35 Not FDA approved for use in prediabetes, but

often used successfully in adults American Diabetic Association recommends that

metformin be considered (in addition to lifestyle counseling) for adults at very high risk of DM and < 60 y/o.

So… If metformin can be used successfully in

adults and adolescences with T2DM, and adults with prediabetes, and metformin was most effective with the

youngest population of adults in the DPP study?

Can it be used successfully in adolescences with prediabets?

Evidence Based Medicine QuestionIn adolescents with insulin resistance, does the

addition of metformin to lifestyle intervention improve body composition and indicators of insulin sensitivity?

Patient: Adolescents ages 9-19 with insulin resistance

Interventions: metformin added to lifestyle intervention (modifications in exercise and diet)

Comparison: lifestyle intervention alone Outcome: improved body composition (BMI,

weight) and indicators of insulin sensitivity (fasting insulin, fasting glucose)

Significant improvements in: Body composition:

Weight: 1, 3, 4, 5, 6 BMI: 1, 2 (mild improvement), 3, 5 Body fat: 4

Insulin sensitivity: Fasting insulin: 1, 6 Insulin sensitivity models: 2, 4 Response to OGTT: 4 Fasting blood glucose: 1

Past Research on Metformin and Adolescents with Prediabetes/IR

University of Colorado RCT “Addition of Metformin to a Lifestyle

Modification Program in Adolescents with Insulin Resistance” (2008)

Randomized double-blind placebo controlled trial 6 month study 85 adolescents with insulin resistance ages 12-19

University of Colorado RCT Selection Criteria:

Fasting insulin level >25 μU/mL /or/ HOMA >3.5

2 of 3 risk factors1. Acanthosis nigricans2. Obesity (BMI>95% for age)3. Family hx of T2DM

University of Colorado RCT 70% received metformin, 30% received placebo

500mg QD X 1 month 500mg BID X 1 month 850mg BID X 4 months (If GI side effects occurred for > 2 weeks, the patient as

lowered to the previous dose tolerated.)

• Study acknowledged that intensive lifestyle interventions of many studies not realistic• Incorporated monthly goal setting and

standardized information: for diet and exercise

University of Colorado RCT: Results Metformin did not lead to significant change in lab values

Metformin did not improve glucose metabolism Monthly goal setting alone did not lead to significant weight loss Metformin did not lead to significant change in overall weight loss

>5% change in BMI for 23% of participants receiving metformin (p=0.001)

University of Colorado RCT

Decreased portion size plus metformin adherence led to: significant BMI decrease (BMI −1.3 kg/m2, p = .005) 60% were also seen to have an improvement or

resolution of impaired fasting glucose (IFG), impaired glucose tolerance (IGT) or IFG/IGT

Weight loss in 70% of subjects in this group (vs. 20% in placebo adherent group)

University of Colorado RCT

Girls overall were twice as likely than boys to decrease BMI by 5% (p = 0.002)

Metformin did not lead to significant weight loss overall, but it did lead to significant weight loss among females (p=0.02)

BMI Change by Gender

Metformin Placebo P value

Females −0.40 kg/m2 ± 1.60

(n = 33)

1.04 kg/m2 ± 1.19

(n = 9),

(P = .02)

Males −0.35 kg/m2 ± 2.69

(n = 15)

0.34 kg/m2 ± 1.20

(n = 7)

(NS)

University of Colorado RCT: Conclusions Disappointing results in terms of glucose

metabolism and insulin levels Metformin beneficial in subset of

participants Linear relationship between weight loss

and metformin adherence Reduced portion size important goal

University of Colorado RCT: DiscussionMetformin found to be more effective in

Caucasian subjects in other studies – consideration for future, more diverse studies

Concerns that greater changes in weight initially might lead to more compliance and better results

The Children’s Hospital at Westmead RTC “Randomized, Controlled Trial of Metformin for

Obesity and Insulin Resistance in Children and Adolescents: Improvement in Body Composition and Fasting Insulin” (2006)

Cross-over, randomized double-blind placebo controlled trial 12 month study 28 adolescents with insulin resistance ages 9-18 No lifestyle intervention component –

metformin vs. placebo only

Selection criteria: Obesity Clinical suspicion of

insulin resistance: Fasting insulin to glucose

radio > 4.5 /or/

Presence of acanthosis nigricans

The Children’s Hospital at Westmead RTC

The Children’s Hospital at Westmead RTC Dosage:

1g of metformin or placebo BID X 6 months, two week wash-out period, then 6 months of the other

Dosage built up for 3 week period ending with 1 g

Standardized information on healthy eating and exercise given to all pts

The Children’s Hospital at Westmead RTC: Results Metformin led to

significant changes in body composition as raw scores and z-scores: Weight (p=0.02; 0.009) BMI (p=0.002; 0.005) Waist circumference

(p=0.003; 0.005)

The Children’s Hospital at Westmead RTC: Results Metformin led to significant changes some

indicators of insulin sensitivity: Fasting insulin (p=0.011) Fasting glucose (p=0.48)

But not others: Insulin sensitivity measured by minimal model, including

acute insulin response, disposition index, glucose disposal, glucose effectiveness (p=0.506)

The Children’s Hospital at Westmead RTC: Discussion Results showed that weight loss was

primarily subcutaneous (p=0.002) rather than visceral (p=0.231) adipose tissue from abdomen

Visceral fat is implicated in insulin resistance

Could possibly be the reason for lack in significant improvement in insulin sensitivity measurements

Safety of Metformin Metformin is first line pharmacologic

therapy for T2DM and some cases of prediabetes because of its overall safety

2 participants (9 y/o) in Westmead study reduced from 1g BID to 750g QD due to nausea No difference found in LFTs, serum

creatinine, or lactate levels between metformin and placebo

Application for Practitioners Lifestyle management key

Weight loss and diet are still most important

Consider realistic goals: decrease portion size

Still little guidance / recommendations for practitioners besides lifestyle management

Metformin promising, but more research is needed in this area – esp. in terms of indicators of insulin sensitivity

Severe cases: Endocrine referral

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