Updates in Diabetes Updates in Diabetes ManagementManagement

Kim Tartaglia, MDKim Tartaglia, MD

August 22, 2007August 22, 2007

ObjectivesObjectives

Review medications used to achieve Review medications used to achieve glycemic controlglycemic control

Review recent trials regarding Review recent trials regarding diabetic medicationsdiabetic medications

Provide general guidelines for Provide general guidelines for managing diabetesmanaging diabetes

Review the management of specific Review the management of specific patient profilespatient profiles

Glycemic ControlGlycemic Control

Goal of ADA is HbA1C <7%Goal of ADA is HbA1C <7%For each 1% decrease in A1C, 25% reduction of For each 1% decrease in A1C, 25% reduction of

microvascular eventsmicrovascular events

DCCT/EDIC TrialsDCCT/EDIC TrialsDecreased micro and macrovascular Decreased micro and macrovascular

complications in DM1 w/ intensive therapycomplications in DM1 w/ intensive therapy

UKPDS/Kumamoto TrialsUKPDS/Kumamoto TrialsDecreased microvascular complications in DM2 Decreased microvascular complications in DM2

with intensive therapywith intensive therapy

Types of InsulinTypes 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 InsulinInhaled 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 PumpInsulin Pump

Diabetes Care (2001)Diabetes Care (2001)– Compared continuous Compared continuous

insulin infusion (CSII) vs insulin infusion (CSII) vs mutiple insulin injections mutiple insulin injections (MDI)(MDI)

– No change in hypoglycemic No change in hypoglycemic evens or AICevens or AIC

– This contrasted trial w/ This contrasted trial w/ regular insulin that showed regular insulin that showed CSII had improved controlCSII had improved control

– QOL was the sameQOL was the same

Insulin PumpInsulin Pump

Pump BasicsPump BasicsBasalBasalInsulin:Carb ratioInsulin:Carb ratioCorrection factorCorrection factor

A word about DM1A word about DM1

Conventional vs Intensive Insulin Conventional vs Intensive Insulin therapytherapyIntensive: Intensive: >>3 shots per day or insulin pump3 shots per day or insulin pumpDrawback of intensive: Increased Drawback of intensive: Increased

hypoglycemia, weight gain, and costhypoglycemia, weight gain, and cost Starting doses for new DM1 patientsStarting doses for new DM1 patients

0.2-0.4unit/kg/day, divided b/w basal and 0.2-0.4unit/kg/day, divided b/w basal and bolusbolus

Most patients will require ~0.6unit/kg/day Most patients will require ~0.6unit/kg/day (more during puberty)(more during puberty)

Injectable Alternatives - Injectable Alternatives - ExenatideExenatide Mechanism of ActionMechanism of Action

– GLP-1 mimetic (synthetic form of extendin-4)GLP-1 mimetic (synthetic form of extendin-4)– Triggers secretion of insulin, suppresses glucagon Triggers secretion of insulin, suppresses glucagon

secretion, delays gastric emptying, improves secretion, delays gastric emptying, improves satietysatiety

IndicationIndication– DM2 who have failed oral therapyDM2 who have failed oral therapy– Cannot by used with insulin; contraindicated in Cannot by used with insulin; contraindicated in

DM1DM1

DoseDose– Starting: 5mcg BID; Target: 10mcg BIDStarting: 5mcg BID; Target: 10mcg BID

ExenatideExenatide

Side effectsSide effects– Nausea (44%), diarrhea/vomiting (13%), h/aNausea (44%), diarrhea/vomiting (13%), h/a

General considerationsGeneral considerations– Associated with significant weight loss Associated with significant weight loss

(~5lb)(~5lb)– Less hypoglycemia than Lantus Less hypoglycemia than Lantus – If using w/ sulfonylurea, decrease doseIf using w/ sulfonylurea, decrease dose– Give other meds at least 1hr before b/c of Give other meds at least 1hr before b/c of

delayed gastric emptyingdelayed gastric emptying

Injectable Alternatives- Injectable Alternatives- PramlintidePramlintide

Mechanism of ActionMechanism of Action– Analogue of human amylin (beta cells)Analogue of human amylin (beta cells)– Inhibits release of insulin and delays gastric Inhibits release of insulin and delays gastric

emptyingemptying

Can be used w/ DM1 or DM2Can be used w/ DM1 or DM2 Must be used with insulinMust be used with insulin Severe hypoglycemic episodes – 8%Severe hypoglycemic episodes – 8%

– Must decrease mealtime insulin 50% when Must decrease mealtime insulin 50% when starting Pramlintidestarting Pramlintide

PramlintidePramlintide

Dose: Given TID (before major meals)Dose: Given TID (before major meals)– DM1: Start at 15mcg w/ goal of 60mcg DM1: Start at 15mcg w/ goal of 60mcg – DM2: Start at 60mcg w/ target of 120mcgDM2: Start at 60mcg w/ target of 120mcg

Cannot be mixed w/ insulin (incompatible)Cannot be mixed w/ insulin (incompatible) Side effects –nausea, h/a, vomitingSide effects –nausea, h/a, vomiting Assoc w/ ~3lb weight loss at highest doseAssoc w/ ~3lb weight loss at highest dose Safety not determined in kidsSafety not determined in kids

Oral agents - SecretagoguesOral agents - Secretagogues

Meglitinides – Repaglinide and Meglitinides – Repaglinide and NateglinideNateglinide

Mechanism of Action: Stimulate insulin Mechanism of Action: Stimulate insulin secretionsecretion

Side effects: hypoglycemia, weight Side effects: hypoglycemia, weight gaingain

General considerationsGeneral considerations– Nateglinide only decreases A1C 0.5-1%Nateglinide only decreases A1C 0.5-1%

Oral agents - SulfonylureasOral agents - Sulfonylureas

Glipizide, Glyburide, GlimepirideGlipizide, Glyburide, Glimepiride Mechanism: Stimulates insulin secretion Mechanism: Stimulates insulin secretion

(glucose-dep when used chronically)(glucose-dep when used chronically) Side effects: hypoglycemia, weight gainSide effects: hypoglycemia, weight gain General considerationsGeneral considerations

– Glyburide has highest hypoglycemia Glyburide has highest hypoglycemia episodes and concern for ischemic heart episodes and concern for ischemic heart dz (UGDP dz (UGDP study)study)

– Glipizide is generic; for XL, get full efficacy Glipizide is generic; for XL, get full efficacy at 5-10mg daily (no benefit for going at 5-10mg daily (no benefit for going higher).higher).

GlipizideGlipizideTable 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: Resultsof two multicenter, randomized, placebo-controlled clinical trials.Diabetes Care 1997

Oral agents - MetforminOral agents - Metformin Mech of Action: decreases hepatic Mech of Action: decreases hepatic

glucose production and glucose production and ↓ ↓ insulin insulin resistanceresistance

Side effects: abdominal pain, diarrhea, Side effects: abdominal pain, diarrhea, lactic acidosislactic acidosis

General considerationsGeneral considerationsShould quickly titrate up to 1000mg BIDShould quickly titrate up to 1000mg BIDDecrease dose by half if CrCl=50-70 and Decrease dose by half if CrCl=50-70 and

do not use if CrCl<50 (Cr>1.4)do not use if CrCl<50 (Cr>1.4)No role for extended releaseNo role for extended release

Oral agents - TZDsOral agents - TZDs

Rosiglitazone, PioglitazoneRosiglitazone, Pioglitazone Mech of Action: increased insulin Mech of Action: increased insulin

senstivity in adipose, liver, musclesenstivity in adipose, liver, muscle Side effects: edema, CHF, weight gainSide effects: edema, CHF, weight gain General considerationsGeneral considerations

Contraindicated in CHF (can worsen)Contraindicated in CHF (can worsen)Recent NEJM: Recent NEJM: ↑↑ risk of MI and CV mortality risk of MI and CV mortality

in meta-analysis, another trial: in meta-analysis, another trial: ↑↑ risk of risk of CHFCHF

Alpha-glucosidase inhibitorsAlpha-glucosidase inhibitors

Acarbose and MiglitolAcarbose and Miglitol Mech of Action: impairs enzymes to Mech of Action: impairs enzymes to

digest complex carbs, delaying their digest complex carbs, delaying their absorptionabsorption

Side effects: flatulence, diarrheaSide effects: flatulence, diarrhea General considerationsGeneral considerations

Most effective at Most effective at ↓↓ post-prandial glucose post-prandial glucose (PPG)(PPG)

Only decreases A1C 0.5-1%Only decreases A1C 0.5-1%

Management of DM2Management of DM2

Physicians start pharmacotherapy Physicians start pharmacotherapy late and do not titrate aggressivelylate and do not titrate aggressively

Beta cell decline is the natural Beta cell decline is the natural progression of DM2; therefore, you progression of DM2; therefore, you will have to step-up therapywill have to step-up therapy

Most oral agents decrease A1c 1.5-Most oral agents decrease A1c 1.5-2%; insulin will decrease A1C by 2%; insulin will decrease A1C by >>2%2%

Management of DM2Management of DM2

Rapidity of glycemic effectRapidity of glycemic effectInsulin is most rapid (starts within minutes)Insulin is most rapid (starts within minutes)Secretagogues work within hours; full Secretagogues work within hours; full

effect in 1-2 weekseffect in 1-2 weeksMetformin, AGIs take month for full efficacy Metformin, AGIs take month for full efficacy

(need to titrate weekly to decrease GI (need to titrate weekly to decrease GI effects)effects)

TZDs do not reach full effect until months TZDs do not reach full effect until months after startingafter starting

DM2: Specific DM2: Specific ConsiderationsConsiderations

48yo man found to have hyperglycemia 48yo man found to have hyperglycemia on screening; A1C=8.4%. How do you on screening; A1C=8.4%. How do you treat?treat?– Lifestyle only?Lifestyle only?– Monotherapy? With what?Monotherapy? With what?

If A1C>8, consider SFU as has faster action and If A1C>8, consider SFU as has faster action and less side effectsless side effects

If A1C=7-8 or obese, consider metformin (no If A1C=7-8 or obese, consider metformin (no hypoglycemia, no weight gain)hypoglycemia, no weight gain)

– Starting dose?Starting dose?Glipizide XL 2.5-5mg daily Glipizide XL 2.5-5mg daily Metformin 500mg QD-BID, titrate weeklyMetformin 500mg QD-BID, titrate weekly

Management of DM2Management of DM2

Same patient, good control x2 years Same patient, good control x2 years but on most recent check, A1C 7.8 but on most recent check, A1C 7.8 persistentlypersistently– What happened?What happened?– What do you do?What do you do?

Add second agent (metformin or SFU)Add second agent (metformin or SFU)Do not substitute Do not substitute

DM2 ManagementDM2 Management

51yo woman on maximum doses of 51yo woman on maximum doses of metformin and glipizide, A1C=8.9%metformin and glipizide, A1C=8.9%– What’s next?What’s next?

TZDs possibly if A1c<8% but given TZDs possibly if A1c<8% but given recent concerns would be hesitantrecent concerns would be hesitant

Start insulin: single injection of Lantus Start insulin: single injection of Lantus (glargine) while continuing oral therapy(glargine) while continuing oral therapy

Start exenatide at 5mcg BID and titrateStart exenatide at 5mcg BID and titrate

DM2 ManagementDM2 Management 36yo obese woman w/ polyuria, 36yo obese woman w/ polyuria,

polydipsia BG-338. A1C pendingpolydipsia BG-338. A1C pending– What do you predict her A1C to be?What do you predict her A1C to be?

A1C usually >10% in setting of overt symptomsA1C usually >10% in setting of overt symptoms

– What is your first step in management?What is your first step in management?Insulin. Studies have shown glucose Insulin. Studies have shown glucose

aggravates insulinopenia and insulin aggravates insulinopenia and insulin insenstivity.insenstivity.

– Is she relegated to a life of insulin?Is she relegated to a life of insulin?No. Once she has improved control, oral No. Once she has improved control, oral

therapy can be startedtherapy can be started

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Diabetes Control and Complications Trial. Intensive Diabetes Treatment and Diabetes Control and Complications Trial. Intensive Diabetes Treatment and Cardiovascular disease in patients with type 1 diabetes. NEJM 2005; 353: 2643.Cardiovascular disease in patients with type 1 diabetes. NEJM 2005; 353: 2643.

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Ryan EA, et al. Diabetes Care 2004; 27: 1028.Ryan EA, et al. Diabetes Care 2004; 27: 1028. Simonson DC, et al. Simonson DC, et al. Efficacy, Safety, and Dose-Response Characteristics Efficacy, Safety, and Dose-Response Characteristics

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ReferencesReferences

Prospective Diabetes Study UK Group. Intensive blood-glucose Prospective Diabetes Study UK Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 treatment and risk of complications in patients with type 2 diabetes. Lancet 1998; 352: 837.diabetes. Lancet 1998; 352: 837.

Prospective Diabetes Study UK Group. Effect of intensive blood-Prospective Diabetes Study UK Group. Effect of intensive blood-glucose control with metformin on complications in overweight glucose control with metformin on complications in overweight patients with type 2 diabetes. Lancet 1998; 353: 854.patients with type 2 diabetes. Lancet 1998; 353: 854.

Riddle MC, et al. Glycemic Management of Type 2 Diabetes: An Riddle MC, et al. Glycemic Management of Type 2 Diabetes: An Emerging Stratey with Oral Agents, Insulins, and Combinations. Emerging Stratey with Oral Agents, Insulins, and Combinations. Endocrin Metab Clin 2005; 34: 77.Endocrin Metab Clin 2005; 34: 77.

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