Transcript Updates in Diabetes Managment

Updates in Diabetes Management
Kim Tartaglia, MD
August 22, 2007
Objectives
 Review medications used to achieve
glycemic control
 Review recent trials regarding diabetic
medications
 Provide general guidelines for managing
diabetes
 Review the management of specific
patient profiles
Glycemic Control
 Goal of ADA is HbA1C <7%
 For each 1% decrease in A1C, 25% reduction of
microvascular events
 DCCT/EDIC Trials
 Decreased micro and macrovascular complications in
DM1 w/ intensive therapy
 UKPDS/Kumamoto Trials
 Decreased microvascular complications in DM2 with
intensive therapy
Types of Insulin
McEvoy GK, ed. Insulin human and insulin analogue. In: American Hospital Formulary Service. Bethesda,
MD: American Society of Health-System Pharmacists; 2005: 2970-2980.
Inhaled Insulin
 Brand Name: Exubera
 Onset of Action: rapid acting
 Considerations: contraindicated in
smokers as absorption unpredictable
 Monitoring: PFTs at outset and every 6
months
 Meta-analysis in Annals of Int Med (2006)
–Same number of patients reached
target A1C
–Slightly higher A1Cs
–Slight higher patient satisfaction
Insulin Pump
 Diabetes Care (2001)
– Compared continuous insulin
infusion (CSII) vs mutiple
insulin injections (MDI)
– No change in hypoglycemic
evens or AIC
– This contrasted trial w/
regular insulin that showed
CSII had improved control
– QOL was the same
Insulin Pump
 Pump Basics
Basal
Insulin:Carb ratio
Correction factor
A word about DM1
 Conventional vs Intensive Insulin therapy
Intensive: >3 shots per day or insulin pump
Drawback of intensive: Increased
hypoglycemia, weight gain, and cost
 Starting doses for new DM1 patients
0.2-0.4unit/kg/day, divided b/w basal and
bolus
Most patients will require ~0.6unit/kg/day
(more during puberty)
Injectable Alternatives - Exenatide
 Mechanism of Action
– GLP-1 mimetic (synthetic form of extendin-4)
– Triggers secretion of insulin, suppresses glucagon
secretion, delays gastric emptying, improves satiety
 Indication
– DM2 who have failed oral therapy
– Cannot by used with insulin; contraindicated in DM1
 Dose
– Starting: 5mcg BID; Target: 10mcg BID
Exenatide
 Side effects
– Nausea (44%), diarrhea/vomiting (13%), h/a
 General considerations
– Associated with significant weight loss (~5lb)
– Less hypoglycemia than Lantus
– If using w/ sulfonylurea, decrease dose
– Give other meds at least 1hr before b/c of
delayed gastric emptying
Injectable Alternatives- Pramlintide
 Mechanism of Action
– Analogue of human amylin (beta cells)
– Inhibits release of insulin and delays gastric emptying
 Can be used w/ DM1 or DM2
 Must be used with insulin
 Severe hypoglycemic episodes – 8%
– Must decrease mealtime insulin 50% when starting
Pramlintide
Pramlintide
 Dose: Given TID (before major meals)
– DM1: Start at 15mcg w/ goal of 60mcg
– DM2: Start at 60mcg w/ target of 120mcg
 Cannot be mixed w/ insulin (incompatible)
 Side effects –nausea, h/a, vomiting
 Assoc w/ ~3lb weight loss at highest dose
 Safety not determined in kids
Oral agents - Secretagogues
 Meglitinides – Repaglinide and Nateglinide
 Mechanism of Action: Stimulate insulin
secretion
 Side effects: hypoglycemia, weight gain
 General considerations
– Nateglinide only decreases A1C 0.5-1%
Oral agents - Sulfonylureas
 Glipizide, Glyburide, Glimepiride
 Mechanism: Stimulates insulin secretion
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(glucose-dep when used chronically)
Side effects: hypoglycemia, weight gain
General considerations
– Glyburide has highest hypoglycemia episodes
and concern for ischemic heart dz (UGDP
study)
– Glipizide is generic; for XL, get full efficacy at
5-10mg daily (no benefit for going higher).
Glipizide
Table 2. FPG and
HbA1c in all patients
at randomization and
at final visit in the two
studies
Efficacy, Safety, and Dose-Response
Characteristics of Glipizide
Gastrointestinal Therapeutic System
on Glycemic Control and Insulin
Secretion in NIDDM: Results
of two multicenter, randomized,
placebo-controlled clinical trials.
Diabetes Care 1997
Oral agents - Metformin
 Mech of Action: decreases hepatic glucose
production and ↓ insulin resistance
 Side effects: abdominal pain, diarrhea,
lactic acidosis
 General considerations
Should quickly titrate up to 1000mg BID
Decrease dose by half if CrCl=50-70 and do
not use if CrCl<50 (Cr>1.4)
No role for extended release
Oral agents - TZDs
 Rosiglitazone, Pioglitazone
 Mech of Action: increased insulin senstivity
in adipose, liver, muscle
 Side effects: edema, CHF, weight gain
 General considerations
Contraindicated in CHF (can worsen)
Recent NEJM: ↑ risk of MI and CV mortality in
meta-analysis, another trial: ↑ risk of CHF
Alpha-glucosidase inhibitors
 Acarbose and Miglitol
 Mech of Action: impairs enzymes to digest
complex carbs, delaying their absorption
 Side effects: flatulence, diarrhea
 General considerations
Most effective at ↓ post-prandial glucose (PPG)
Only decreases A1C 0.5-1%
Management of DM2
 Physicians start pharmacotherapy late and
do not titrate aggressively
 Beta cell decline is the natural progression
of DM2; therefore, you will have to stepup therapy
 Most oral agents decrease A1c 1.5-2%;
insulin will decrease A1C by >2%
Management of DM2
 Rapidity of glycemic effect
Insulin is most rapid (starts within minutes)
Secretagogues work within hours; full effect
in 1-2 weeks
Metformin, AGIs take month for full efficacy
(need to titrate weekly to decrease GI effects)
TZDs do not reach full effect until months
after starting
DM2: Specific Considerations
 48yo man found to have hyperglycemia on
screening; A1C=8.4%. How do you treat?
– Lifestyle only?
– Monotherapy? With what?
If A1C>8, consider SFU as has faster action and
less side effects
If A1C=7-8 or obese, consider metformin (no
hypoglycemia, no weight gain)
– Starting dose?
Glipizide XL 2.5-5mg daily
Metformin 500mg QD-BID, titrate weekly
Management of DM2
 Same patient, good control x2 years but
on most recent check, A1C 7.8 persistently
– What happened?
– What do you do?
Add second agent (metformin or SFU)
Do not substitute
DM2 Management
 51yo woman on maximum doses of
metformin and glipizide, A1C=8.9%
– What’s next?
TZDs possibly if A1c<8% but given recent
concerns would be hesitant
Start insulin: single injection of Lantus
(glargine) while continuing oral therapy
Start exenatide at 5mcg BID and titrate
DM2 Management
 36yo obese woman w/ polyuria, polydipsia
BG-338. A1C pending
– What do you predict her A1C to be?
A1C usually >10% in setting of overt symptoms
– What is your first step in management?
Insulin. Studies have shown glucose aggravates
insulinopenia and insulin insenstivity.
– Is she relegated to a life of insulin?
No. Once she has improved control, oral therapy
can be started
References
 Diabetes Control and Complications Trial. The effect of intensive treatment of
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diabetes on the development and progression of long-term complications in insulindependent diabetes mellitus. NEJM 1993; 329: 977.
Diabetes Control and Complications Trial. Intensive Diabetes Treatment and
Cardiovascular disease in patients with type 1 diabetes. NEJM 2005; 353: 2643.
Ceglia L, et al. Meta-analysis: Efficacy and safety of inhaled insulin therapy in adults
with diabetes mellitus. Ann Intern Med 2006; 145: 665-675.
Jones MC. Therapies for Diabetes. American Family Physician 2007; 75: 1831.
Mooradian AD, et al. Narrative Review: A Rational Approach to Starting Insulin
Therapy. Ann Intern Med 2006; 145: 125-134.
Ohkubo Y, et al. Intensive insulin therapy prevents the progression of diabetic
microvascular complications in Japanese patients with non-insulin dependent diabetes
mellitus: a randomnzed prospective 6-year study. Diabetes Res Clin Pract 1995; 28:
103.
Ryan EA, et al. Diabetes Care 2004; 27: 1028.
Simonson DC, et al. Efficacy, Safety, and Dose-Response Characteristics of
Glipizide Gastrointestinal Therapeutic System on Glycemic Control and
Insulin Secretion in NIDDM: Results of two multicenter randomized,placebocontrolled clinical trials Diabetes Care 1997; 20: 597.
References
 Prospective Diabetes Study UK Group. Intensive blood-glucose control with
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sulphonylureas or insulin compared with conventional treatment and risk of
complications in patients with type 2 diabetes. Lancet 1998; 352: 837.
Prospective Diabetes Study UK Group. Effect of intensive blood-glucose
control with metformin on complications in overweight patients with type 2
diabetes. Lancet 1998; 353: 854.
Riddle MC, et al. Glycemic Management of Type 2 Diabetes: An Emerging
Stratey with Oral Agents, Insulins, and Combinations. Endocrin Metab Clin
2005; 34: 77.
Tsui E, et al. Intensive insulin therapy with insulin lispro. Diabetes Care
2001; 24: 1722.