Achieving A1C and Glycemic Targets with Insulin What to Do When Oral Agents Fail New Paradigms,...

Achieving A1C and Achieving A1C and Glycemic Targets with InsulinGlycemic Targets with Insulin

What to Do When Oral Agents FailWhat to Do When Oral Agents Fail

New Paradigms, Guidelines, New Paradigms, Guidelines, and Evolving Strategiesand Evolving Strategies

JUAN P. FRIAS, M.D., FACEAssistant Clinical Professor of Medicine

University of California San DiegoSan Diego, CA

Healthy Eating, Increased Physical Activity, Weight Control

MetforminHighLow riskNeutral/lossGI/lactic acidosisLow

Efficacy (A1C)Hypoglycemia

WeightSide effects

Cost

Initial Initial MonotherapMonotherap

yy

A1C target not achieved after 3 months, proceed to 2-drug combo.

Metformin + (order does not denote specific preference)Insulin

(usually basal)GLP-1 RADPP-4 Inhib.TZDSFU

Efficacy (A1C)Hypoglycemia

WeightSide effects

Cost

HighMod. riskGainHypo.Low

HighLow riskGainEdema, HF, fxHigh

IntermediateLow riskNeutralRareHigh

HighLow riskLossGIHigh

HighestHigh riskGainHypo.Variable

Two Drug Two Drug Combo.Combo.

A1C target not met after 3 months, proceed to 3-drug combo.(order does not denote specific preference)

Three Drug Three Drug Combo.Combo.

Adapted from, Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

ADA/EASD: Managing ADA/EASD: Managing Hyperglycemia in Type 2 Hyperglycemia in Type 2

DiabetesDiabetes


Insulin (usually basal)

+ •TZD or•DPP-4-I, or•GLP-1 RA

GLP-1 RA +

•SFU, or•TZD, or•Insulin

DPP-4 Inh. +

•SFU, or

•TZD, or•Insulin

TZD +

•SFU or•DPP-4-I, or•GLP-1 RA, or•Insulin

SFU +

•TZD, or•DPP-4-I, or•GLP-1 RA, or•Insulin

MET + MET + MET + MET + MET +


Three Drug Three Drug Combo.Combo.

If combination therapy that includes basal insulin has failed to achieve A1C target after 3-6 months, proceed to a more complex

insulin strategy, usually in combination with 1-2 non-insulin agents

InsulinMultiple daily doses

More More Complex Complex Insulin Insulin

StrategiesStrategies


DiabetesDiabetes

Case #1Case #1

► 55 year old woman with 8-year history of type 2 55 year old woman with 8-year history of type 2 diabetesdiabetes

► For last 2 years, has taken metformin 1000 mg bid, For last 2 years, has taken metformin 1000 mg bid, pioglitazone 45 mg qd, and glimepiride 4 mg qdpioglitazone 45 mg qd, and glimepiride 4 mg qd● Seen 4 months ago: A1C 8.0%, BP 130/80, and Seen 4 months ago: A1C 8.0%, BP 130/80, and

LDL Cholesterol 125 mg/dL LDL Cholesterol 125 mg/dL

● Added atorvastatin 20 mg qd, told to intensify diet and Added atorvastatin 20 mg qd, told to intensify diet and exerciseexercise

► Weight 215 lbs (6 lb gain since last visit), height 5’ Weight 215 lbs (6 lb gain since last visit), height 5’ 55””, BMI 36 kg/m, BMI 36 kg/m22

► Fasting plasma glucose in the office = 196 mg/dLFasting plasma glucose in the office = 196 mg/dL

► Current A1C = 8.8%Current A1C = 8.8%

Question #1Question #1

What do you do now?What do you do now?

1)1) Start a GLP-1 receptor agonistStart a GLP-1 receptor agonist

2)2) Start a DPP-4 inhibitorStart a DPP-4 inhibitor

3)3) Add insulinAdd insulin

4)4) Reinforce efforts at better nutrition and Reinforce efforts at better nutrition and increased physical activityincreased physical activity

0:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00

Plasma Insulin Concentration

Time

Regular insulin

Rapid-acting: lispro, aspart, glulisine

Rosenstock J. Goldstein BJ et al, eds. Textbook of Type 2 Diabetes. Martin Dunitz;2003:131-154.Plank J et al. Diabetes Care. 2005;28:1107-1112.

Idealized Profiles of Human InsulinIdealized Profiles of Human Insulinand Insulin Analogs and Insulin Analogs

NPH

Insulin glargine

Insulin detemir

Consistent Results Using the Treat-to-Consistent Results Using the Treat-to-TargetTarget

Method with Glargine as Basal InsulinMethod with Glargine as Basal Insulin

1. Riddle M et al. Diabetes Care 2003;26:30802. Gerstein HC et al. Diabetes Med 2006;23:736 3. Bretzel RG et al. Lancet 2008;371:10734. Yki-Järvinen H et al. Diabetes Care 2007;30:13645. Schreiber SA et al. Diabetes Obes Metab 2007;9:31

Baseline Study end

5.5

6.0

6.5

7.0

7.5

8.0

8.5

9.0

9.5

T-T-T1

n = 367INSIGHT2

n = 206APOLLO3

n = 174INITIATE4

n = 58

A1C %

8.6 8.6 8.7 8.78.8

7.0 7.0 7.06.8

7.0

∆ -1.6 ∆ -1.6 ∆ -1.7 ∆ -2.0 ∆ -1.7

Schreiber5

n = 12,216

Insulin Dosage and FPG During StudyInsulin Dosage and FPG During Study(Both Treatment Groups)(Both Treatment Groups)

*Week 0 based on a starting dose of 10 unitsRiddle M, Rosenstock J, and Gerich, J. Diabetes Care. 2003;26(11)3080-3086.

To

tal D

aily

Do

se, U

nit

s (

± SE

)

373633

3128

25

16

3941

43 44

10

0

10

20

30

40

50

0 2 4 6 8 10 12 14 16 24

Weeks in Study

*100

150

200

Mea

n F

PG

mg

/dL

(±

SE

)

206

125128135135

142153

175

121 118 117 116

Mean insulin dose 0.45 U/kg

Hypoglycaemia defined as plasma glucose 72 mg/dL*P<0.05 vs insulin glargineAdapted from Riddle M, et al. Diabetes Care. 2003;26:3080-3086. Used with permission.

0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

20 22 24 2 4 6 8 10 12 14 16 18

Time of day (h)

*

*

*

*

*

*

*Insulin glargineNPH

Basal insulin

Breakfast Lunch Dinner

Eve

nts

per

pat

ien

t ex

po

sure

–yea

rSymptomatic Hypoglycemic EventsSymptomatic Hypoglycemic Events

Detemir vs NPH Insulin in Type 2 Detemir vs NPH Insulin in Type 2 Diabetes Diabetes (n=476)(n=476)

*All reported events, including symptoms only.

Hermansen K et al. Diabetes Care. 2006;29:1269-1274.

Hyp

og

lyce

mia

Eve

nts

*

10.0

9.0

8.0

7.0

6.0

-2 0 4 8 12 16 20 24

DetemirNPH

A1C (%)

Study Week20 4 8 12 16 20 24

Study Week

400

350

300

250

200

150

100

50

0

DetemirNPH

Percentage of Patients Reaching Percentage of Patients Reaching Target A1C Target A1C at Week 24at Week 24 by Baseline by Baseline

A1CA1C

581 436 360 327 608

7.6 8.2 8.7 9.2 10.2

Baseline A1C Group

n

Mean Baseline A1C

Riddle M et al. ADA abstract 468-P. Diabetes. 2009;58(suppl 1):A125.

Exenatide QW Resulted in Superior Exenatide QW Resulted in Superior A1C Reduction vs. Insulin Glargine A1C Reduction vs. Insulin Glargine

ITT Population, N=456. *p<0.05Diamant M, et al. Lancet. 2010;375:2234-43.

0 8 14 18 22 26-1.8

-1.6

-1.4

-1.2

-1.0

-0.8

-0.6

-0.4

-0.2

0.0

Time (weeks)

Ch

an

ge in

A1C

(%

)

*

* * * *

-1.3%

-1.5%

Exenatide QW, N=233; baseline A1C=8.3%

Insulin glargine, N=223; baseline A1C=8.3%

Exenatide QW Resulted in Superior Exenatide QW Resulted in Superior Body Weight Reduction vs. Insulin Body Weight Reduction vs. Insulin

GlargineGlargine

Exenatide QW Resulted in Superior Exenatide QW Resulted in Superior Body Weight Reduction vs. Insulin Body Weight Reduction vs. Insulin

GlargineGlargine

Time (weeks)

Ch

an

ge in

Bod

y W

eig

ht

(kg

)

0 1 2 4 8 14 18 22 26-3

-2

-1

0

1

2

-2.6 kg

+1.4 kg

Exenatide QW, N=233; baseline weight=91 kg

Insulin glargine, N=223; baseline weight=91 kg

*

*

**

**

ITT Population, N=456. *p<0.05Diamant M, et al. Lancet. 2010;375:2234-43.

Case #1 Case #1 (cont.)(cont.)

► 20 U insulin glargine (~0.2 U/kg) is added to 20 U insulin glargine (~0.2 U/kg) is added to her oral agentsher oral agents

► Sent home with instructions to increase dose Sent home with instructions to increase dose by 2U every 3 days until FBG in 100-120 by 2U every 3 days until FBG in 100-120 mg/dL rangemg/dL range

► Call if any hypoglycemia and follow-up by Call if any hypoglycemia and follow-up by phone or in clinic in 1 weekphone or in clinic in 1 week

Riddle MC et al. Diabetes Care. 2003;26:3080-3086.Hermansen K et al. Diabetes Care. 2006;29:1259-1271.Nathan DM, et al. Diabetes Care 2009;32:193–203.

Should you reduce or stop one of Should you reduce or stop one of

the oral agents?the oral agents?

► Patient is up to 52 U with fasting blood Patient is up to 52 U with fasting blood glucose controlled (100-110 mg/dL range) glucose controlled (100-110 mg/dL range) since her last visit 4 months agosince her last visit 4 months ago

► A1C = 6.7%, monitoring occasional A1C = 6.7%, monitoring occasional postprandial blood glucosepostprandial blood glucose

► Patient finds insulin injections painless and Patient finds insulin injections painless and after working with diabetes educator, feels after working with diabetes educator, feels that she is now a that she is now a partnerpartner in her own therapy in her own therapy


““Fix the Fasting FirstFix the Fasting First””

► Even if you are not certain basal insulin alone Even if you are not certain basal insulin alone will achieve target A1C (e.g. patient with A1C will achieve target A1C (e.g. patient with A1C >10%), it is generally preferable to begin >10%), it is generally preferable to begin with it & add a rapid-acting analog with the with it & add a rapid-acting analog with the largest meal, if needed. largest meal, if needed.

► It is easier for the HCP & patient to see which It is easier for the HCP & patient to see which insulin needs to be adjustedinsulin needs to be adjusted

Basal Insulin TherapyBasal Insulin Therapy

► Usual first step in beginning insulin therapyUsual first step in beginning insulin therapy

► Continue oral agents and add basal insulin to Continue oral agents and add basal insulin to optimize FPGoptimize FPG

► A1C of up to 9.0% usually brought to goal (7%) by A1C of up to 9.0% usually brought to goal (7%) by addition of basal insulin therapy to oral agentsaddition of basal insulin therapy to oral agents

► Easy and generally safe: patient-directed treatment Easy and generally safe: patient-directed treatment algorithms with small risk of serious hypoglycemiaalgorithms with small risk of serious hypoglycemia

► ADA and EASD: ADA and EASD: ””If triple combination therapy If triple combination therapy exclusive of insulin is tried, the patient should be exclusive of insulin is tried, the patient should be monitored closely, with the approach promptly monitored closely, with the approach promptly reconsidered if it proves unsuccessfulreconsidered if it proves unsuccessful””

ADA=American Diabetes Association; EASD=European Association for the Study of Diabetes.ADA/EASD Management of hyperglycemia in type 2 diabetes: A patient-centered approach. 19 April 2012 [Epub ahead of print]

Case Presentation #2: Case Presentation #2: Strategies for Advancing Strategies for Advancing to Postprandial Glucose to Postprandial Glucose

ControlControl


If combination therapy that includes basal insulin has failed to achieve A1C target after 3-6 months, proceed to a more complex

insulin strategy, usually in combination with 1-2 non-insulin agents


Insulin (usually basal)

+ •TZD or•DPP-4-I, or•GLP-1 RA

GLP-1 RA +

•SFU, or•TZD, or•Insulin

DPP-4 Inh. +

•SFU, or

•TZD, or•Insulin

TZD +

•SFU or•DPP-4-I, or•GLP-1 RA, or•Insulin

SFU +

•TZD, or•DPP-4-I, or•GLP-1 RA, or•Insulin

MET + MET + MET + MET + MET +


Three Drug Combo.

InsulinMultiple daily doses

More Complex Insulin

Strategies


DiabetesDiabetes

Non-Insulin Regimen

Basal Insulin only (usually with oral

agents)

Basal insulin + 1 (mealtime) rapid-acting insulin injection

Pre-mixed insulin twice daily

Basal insulin + ≥2 (mealtime) rapid-acting insulin injection

More Flexible Less Flexible

1

2

3+

Low

Mod

High

Number of

injections

Complexity of

regimen

Sequential Insulin Strategies Sequential Insulin Strategies in in

Type 2 DiabetesType 2 Diabetes


Case #2Case #2

► 50-year-old man with 6-year history of type 2 50-year-old man with 6-year history of type 2 diabetesdiabetes

► 295 lb, 6’ 1295 lb, 6’ 1””, BMI 39 kg/m, BMI 39 kg/m22

► For last 2 years, has taken metformin 1000 mg For last 2 years, has taken metformin 1000 mg bid and glimepiride 8 mg qdbid and glimepiride 8 mg qd

► 3 months ago, A1C 9.2%3 months ago, A1C 9.2%

► Started a twice-daily premixed analog insulin Started a twice-daily premixed analog insulin (70/30); current dose 40 U bid(70/30); current dose 40 U bid


► Current A1C 7.5% and random plasma Current A1C 7.5% and random plasma glucose in the office 185 mg/dLglucose in the office 185 mg/dL

► Patient experiencing nighttime hypoglycemia Patient experiencing nighttime hypoglycemia (reports middle-of-night sweating)(reports middle-of-night sweating)

► SMBG diary focused on fasting glucoseSMBG diary focused on fasting glucose

► Patient instructed to measure glucose before Patient instructed to measure glucose before meals, at bedtime, and during night for a meals, at bedtime, and during night for a weekweek


PatientPatient’’s A1C is 7.5% and SMBG diary reveals s A1C is 7.5% and SMBG diary reveals high fasting and post-dinner glucose, and high fasting and post-dinner glucose, and nocturnal hypoglycemia. The next step for this nocturnal hypoglycemia. The next step for this patient to gain control is to:patient to gain control is to:

1)1) Continue with the twice-daily premix and Continue with the twice-daily premix and increase doseincrease dose

2)2) Continue with premixed and discontinue Continue with premixed and discontinue glimepirideglimepiride

3)3) Switch to a long-acting insulin analog aloneSwitch to a long-acting insulin analog alone

4)4) Basal insulin + GLP-1 receptor agonistBasal insulin + GLP-1 receptor agonist

5)5) Switch to a basal-bolus insulin regimenSwitch to a basal-bolus insulin regimen

4:00 16:00 20:00 24:00 4:00

Breakfast Lunch Dinner

8:0012:008:00

Time

GlargineGlargineoror

DetemirDetemir

Basal/Bolus Treatment Program Basal/Bolus Treatment Program WithWith

Rapid-acting and Long-acting Rapid-acting and Long-acting AnalogsAnalogs

LisproLispro

AspartAspartoror

GlulisineGlulisineororPlasma

Insulin

LisproLispro

AspartAspartoror

GlulisineGlulisineoror

LisproLispro

AspartAspartoror

GlulisineGlulisineoror

““All to Target” TrialAll to Target” TrialInsulin Glargine + Glulisine on to Background OralsInsulin Glargine + Glulisine on to Background Orals

► 572 patients with type 2 diabetes uncontrolled on oral 572 patients with type 2 diabetes uncontrolled on oral agentsagents

● PREMIX: n=192PREMIX: n=192

● GLARG+1: n=189GLARG+1: n=189

● GLARG+0-3: n=191GLARG+0-3: n=191

► Mean baseline parameters: Mean baseline parameters:

● A1C 9.4%A1C 9.4%

● Age 54 yearsAge 54 years

● Diabetes duration 9 yearsDiabetes duration 9 years

● BMI 33 kg/mBMI 33 kg/m22

“All to Target” study, Diabetes. 2011;60(suppl 1), 409-P, 073-OR

Insulin Glargine + Glulisine: Insulin Glargine + Glulisine: A1C and Hypoglycemia A1C and Hypoglycemia

c d

a

b

a p < 0.025 versus PREMIX c p < 0.05 versus PREMIX

b p < 0.05 versus PREMI d p < 0.01 versus PREMIX

“All to Target” study, Diabetes. 2011;60(suppl 1), 409-P, 073-OR

► Patient to switch to basal-bolus insulin Patient to switch to basal-bolus insulin therapy:therapy:● First step, patient starts with 40 U insulin First step, patient starts with 40 U insulin

glargineglargine

► After 3 months, patient remains on metformin After 3 months, patient remains on metformin + glimepiride, and is using 62 U glargine daily+ glimepiride, and is using 62 U glargine daily● A1C now 7.2%A1C now 7.2%

► Asked to repeat SMBG profiles prior to next Asked to repeat SMBG profiles prior to next visitvisit


Case #2 Case #2 (cont)(cont)


PatientPatient’’s A1C is approaching target, but not s A1C is approaching target, but not fully there. What is next for this patient?fully there. What is next for this patient?

1)1) Continue basal insulin and increase doseContinue basal insulin and increase dose

2)2) Continue basal insulin and initiate prandial Continue basal insulin and initiate prandial insulininsulin

3)3) Add GLP-1 receptor agonist to basal insulinAdd GLP-1 receptor agonist to basal insulin

4)4) Return to twice-daily premix at lower doseReturn to twice-daily premix at lower dose

5)5) Continue basal insulin and recommend Continue basal insulin and recommend diabetes education to advise on diabetes education to advise on controlling dietcontrolling diet

Mealtime Insulin: Rapid-Acting Mealtime Insulin: Rapid-Acting Analogs Analogs

(Lispro, Aspart, Glulisine) vs Regular(Lispro, Aspart, Glulisine) vs Regular

Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.

Hours

10

8

6

4

2

0

0 1 2 3 4 5 6 7 8 9 10 11 12

Insu

lin

Act

ivit

y

Human regular

Timing offood

absorbed

Analog insulin

Insulin Glargine + ExenatideInsulin Glargine + Exenatide

Buse,JB Ann Int Med 154:103, 2011


How do you start dosing a short-acting How do you start dosing a short-acting analog at dinner?analog at dinner?

1)1)Up to 4-6 U pre-mealUp to 4-6 U pre-meal

2)2)Use sliding scaleUse sliding scale

3)3)By body weight: 0.1 U/kgBy body weight: 0.1 U/kg

4)4)By carbohydrate countingBy carbohydrate counting

► At 6-month follow-up patient is doing well At 6-month follow-up patient is doing well with 56 U glargine and 14-18 U glulisine with 56 U glargine and 14-18 U glulisine at dinnerat dinner

► Mealtime dose occasionally adjusted Mealtime dose occasionally adjusted based on:based on:● Meal carbohydrate contentMeal carbohydrate content● ActivityActivity

► A1C = 6.3%A1C = 6.3%

► He feels well, has infrequent He feels well, has infrequent ““hyposhypos””, and , and is pleased with his BG controlis pleased with his BG control


► Continue follow-up with patientContinue follow-up with patient

► Over time, if postprandial glucose becomes Over time, if postprandial glucose becomes elevated at meals other than dinner, add elevated at meals other than dinner, add pre-meal insulin at that mealpre-meal insulin at that meal


Basal-Bolus Insulin Replacement: Basal-Bolus Insulin Replacement: SummarySummary

► An effective insulin treatment strategy An effective insulin treatment strategy provides both basal and prandial insulin provides both basal and prandial insulin coveragecoverage

► Initially, prandial insulin may be needed Initially, prandial insulin may be needed only at the largest meal of the day, with only at the largest meal of the day, with coverage at other meals added based on coverage at other meals added based on postprandial glucose concentrationspostprandial glucose concentrations

► Rapid-acting insulin analogs more closely Rapid-acting insulin analogs more closely match post-meal carbohydrate absorptionmatch post-meal carbohydrate absorption

Insulin Therapy in Type 2 Insulin Therapy in Type 2 Diabetes: ConclusionsDiabetes: Conclusions

► Most patients will ultimately need insulin therapy Most patients will ultimately need insulin therapy alone or in combination with other agents to alone or in combination with other agents to maintain glycemic controlmaintain glycemic control

► The most convenient strategy for initiating insulin The most convenient strategy for initiating insulin is starting with a single dose of basal insulinis starting with a single dose of basal insulin

► Addition of prandial insulin should be considered Addition of prandial insulin should be considered when significant postprandial glucose excursions when significant postprandial glucose excursions occur (e.g., >180 mg/dL), staring with the meal occur (e.g., >180 mg/dL), staring with the meal with the largest postprandial glucose excursionwith the largest postprandial glucose excursion

► Side effects (risk of hypoglycemia and weight gain) Side effects (risk of hypoglycemia and weight gain) must be addressed with patient, and appropriate must be addressed with patient, and appropriate follow-up scheduledfollow-up scheduled

Case Studies, Clinical Dilemmas, Case Studies, Clinical Dilemmas, and 2012 ADA/EASD Guidelines forand 2012 ADA/EASD Guidelines for

Diabetes ManagementDiabetes Management

Focus On Insulin-based Focus On Insulin-based ApproachesApproaches

Workshop Interactive, ARS SessionWorkshop Interactive, ARS Session


VIVIAN A. FONSECA, MD, FRCPVIVIAN A. FONSECA, MD, FRCPProgram ChairmanProgram Chairman

Professor of Medicine and Pharmacology | Tulis-TulaneProfessor of Medicine and Pharmacology | Tulis-TulaneAlumni Chair in Diabetes | Chief, Section of Alumni Chair in Diabetes | Chief, Section of

Endocrinology | Tulane University Health Sciences Endocrinology | Tulane University Health Sciences CenterCenter

Case Studies and Clinical DilemmasCase Studies and Clinical Dilemmas

1. 1. Less stringent A1c goals may be appropriate Less stringent A1c goals may be appropriate for which of the following patients?for which of the following patients? 1)1)Patients with advanced microvascular complicationsPatients with advanced microvascular complications

2)2)Patients with advanced macrovascular complicationsPatients with advanced macrovascular complications

3)3)Patients with extensive comorbid conditionsPatients with extensive comorbid conditions

4)4)All of the above patients may qualify for less stringent All of the above patients may qualify for less stringent A1c goalsA1c goals

5)5)None of the above patients qualify for less stringent None of the above patients qualify for less stringent A1c goalsA1c goals


2. 2. With respect to recommendations contained With respect to recommendations contained in the new ADA/EASD Guidelines issued on April in the new ADA/EASD Guidelines issued on April 19, 2012, all of the following are true for 19, 2012, all of the following are true for managing older patients with T2D, EXCEPT:managing older patients with T2D, EXCEPT: 1)1)The focus should be on achieving specific glycemic The focus should be on achieving specific glycemic targetstargets2)2)The focus should be on drug safetyThe focus should be on drug safety3)3)The patient should be invited to participate in the The patient should be invited to participate in the treatment decisionstreatment decisions4)4)Less ambitious glycemic targets can be considered in Less ambitious glycemic targets can be considered in the older patientthe older patient5)5)Glycemic targets less than 7.5%-8.0% can be Glycemic targets less than 7.5%-8.0% can be considered if tighter control is not easily achievedconsidered if tighter control is not easily achieved

ADA-EASD Position Statement: ADA-EASD Position Statement: Management of Hyperglycemia in Management of Hyperglycemia in

T2DMT2DM

OTHER CONSIDERATIONSOTHER CONSIDERATIONSAge: Older adults

Reduced life expectancy Higher CVD burden Reduced GFR At risk for adverse events from

polypharmacy More likely to be compromised from

hypoglycemiaLess ambitious targetsHbA1c <7.5–8.0% if tighter

targets not easily achievedFocus on drug safety

Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

Case Studies and Clinical DilemmasCase Studies and Clinical Dilemmas 3. 3. Which of the following statements regarding Which of the following statements regarding key considerations in the management of type 2 key considerations in the management of type 2 diabetes is FALSE?diabetes is FALSE? 1)1)The mechanisms driving hyperglycemia change with The mechanisms driving hyperglycemia change with duration of the diseaseduration of the disease2)2)The loss of beta cell function drives the full expression The loss of beta cell function drives the full expression of the diseaseof the disease3)3)Clinical inertia often results in prolonged exposure to Clinical inertia often results in prolonged exposure to hyperglycemia, thereby leading to increased risk of hyperglycemia, thereby leading to increased risk of complicationscomplications4)4)Maximizing doses of first- and second-line agents Maximizing doses of first- and second-line agents before introducing additional therapies will always before introducing additional therapies will always improve adherence and clinical outcomes improve adherence and clinical outcomes


4. 4. AJ is a 58-year old man with a recent history AJ is a 58-year old man with a recent history of type 2 diabetes. After being well controlled of type 2 diabetes. After being well controlled on metformin (2000 mg per day) treatment on metformin (2000 mg per day) treatment alone for 1 year, his latest A1c is 8.2%. Which of alone for 1 year, his latest A1c is 8.2%. Which of the following treatment options would be LEAST the following treatment options would be LEAST appropriate for AJ?appropriate for AJ? 1)1)Increase his dose of metforminIncrease his dose of metformin

2)2)Add a sulfonylurea to his treatment regimenAdd a sulfonylurea to his treatment regimen

3)3)Add basal insulin to his treatment regimenAdd basal insulin to his treatment regimen

4)4)Add a GLP-1 agonist to his treatment regimenAdd a GLP-1 agonist to his treatment regimen

T2DM Antihyperglycemic Therapy: General RecommendationsDiabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

Progressive Platform Approach (PPA) to Glycemic Control

A Practice-Oriented Analysis of 2012 ADA/EASD 2012 Guidelines

Platform 1: Lifestyle Changes Plus Oral Foundation Agents

Most patients will be started on the oral agent metformin, and if individualized target goals are not met promptly, an additional oral agent may be tried; or alternatively, a basal insulin is "usually" employed as the starting insulin.

As a general rule, the use of more than two oral agents may not be optimal, and consideration to insulin or a GLP-1 agonist should be given if target goals are not reached with intensification of oral therapy.

Treatment choices, at least in part, will depend on how far from goal the patient is.

Inadequate Treatment Inadequate Treatment ResponseResponse

Progress to Next Progress to Next PlatformPlatform

Platform 2: Oral Foundation Agents Plus Basal Insulin If individualized target goal attainment fails with one or two oral agents, typically the management plan will focus on a combined oral-insulin based regimen, or the addition of a GLP-1 agonist. Usually, the foundation insulin for beginning therapy for platform 2 will be a basal insulin.

Glycemic control with oral agents individualized to patient's needs plus a basal insulin will frequently be a sustainable regimen for many patients with T2D.

Treatment choices, at least in part, will depend on how far from goal the patient is.

Inadequate Treatment Inadequate Treatment ResponseResponse

Progress to Next Progress to Next PlatformPlatform



Platform 3: Multi-Insulin Regimen If individualized glycemic targets cannot be maintained on the combination of oral agents plus basal insulin or GLP-1 agonist, shorter-acting insulin formulations may need to be added to basal insulin to address post-prandial glycemic control. Insulin sensitizers may need to be continued. Platform 3 therapy will generally require titration of multi-insulin regimens to achieve glycemic control in patients who have progressive T2D and have failed a combined oral agent-basal insulin +/- GLP-1 agonist regimen.

Bariatric surgery may be considered as an option, particularly when medical therapy is clearly failing in obese patients.




5. 5. Which of the following statements about recent Which of the following statements about recent clinical trial findings related to the use of insulin in clinical trial findings related to the use of insulin in patients with type 2 diabetes is FALSE?patients with type 2 diabetes is FALSE? 1)1)In a substudy of the UKPDS, patients with newly diagnosed type In a substudy of the UKPDS, patients with newly diagnosed type 2 diabetes demonstrated that early addition of insulin to oral agent 2 diabetes demonstrated that early addition of insulin to oral agent monotherapy maintained glucose levels below target for 6 yearsmonotherapy maintained glucose levels below target for 6 years2)2)In the Treat-to-Target trial, glargine and NPH insulin In the Treat-to-Target trial, glargine and NPH insulin demonstrated equivalent efficacy when added to 1 or 2 oral agents demonstrated equivalent efficacy when added to 1 or 2 oral agents in type 2 diabetesin type 2 diabetes3)3)In the Treat-to-Target trial, rates of hypoglycemia were In the Treat-to-Target trial, rates of hypoglycemia were significantly lower with glargine than with NPHsignificantly lower with glargine than with NPH4)4)In a recent study that examined the strategy of adding basal In a recent study that examined the strategy of adding basal insulin versus a third oral agent to oral combination therapy with insulin versus a third oral agent to oral combination therapy with metformin and sulfonylurea, it was demonstrated that overall A1c metformin and sulfonylurea, it was demonstrated that overall A1c reductions were significantly better with a maximal dose of reductions were significantly better with a maximal dose of rosiglitazone than with a low dose of insulin glarginerosiglitazone than with a low dose of insulin glargine


6. 6. BP is a 42-year old man who was diagnosed with BP is a 42-year old man who was diagnosed with diabetes and started on metformin therapy 4 diabetes and started on metformin therapy 4 months ago. His current HbA1c is 8.2%. According months ago. His current HbA1c is 8.2%. According to the ADA/EASD consensus algorithm, which of the to the ADA/EASD consensus algorithm, which of the following would be the LEAST appropriate next step following would be the LEAST appropriate next step in therapy for BP?in therapy for BP? 1)1)Add a sulfonylureaAdd a sulfonylurea

2)2)Add basal insulin glargineAdd basal insulin glargine

3)3)Add a glitazoneAdd a glitazone

4)4)Add postprandial insulinAdd postprandial insulin


7. 7. Which of the following statements about the Which of the following statements about the pharmacokinetic characteristics of insulin pharmacokinetic characteristics of insulin glargine is FALSE?glargine is FALSE? 1)1)Peak action occurs at approximately 5-7 hours from Peak action occurs at approximately 5-7 hours from administrationadministration

2)2)Duration of action is approximately 24 hoursDuration of action is approximately 24 hours

3)3)Glargine produces a flat action profile similar to that if Glargine produces a flat action profile similar to that if continuous subcutaneous insulin infusioncontinuous subcutaneous insulin infusion

4)4)Onset of action is approximately 2 hoursOnset of action is approximately 2 hours


8. 8. When the goal is to “minimize costs,” the When the goal is to “minimize costs,” the new ADA/EASD Guidelines issued on April 19, new ADA/EASD Guidelines issued on April 19, 2012 for management of T2D suggest:2012 for management of T2D suggest: 1)1)The combination of metformin plus a DPP-4 inhibitorThe combination of metformin plus a DPP-4 inhibitor

2)2)The combination of metformin plus a GLP-1 receptor The combination of metformin plus a GLP-1 receptor agonistagonist

3)3)The combination of metformin plus a insulin (usually The combination of metformin plus a insulin (usually basal)basal)

4)4)The combination of metformin plus a thiazolidine-The combination of metformin plus a thiazolidine-dionedione

5)5)All of the aboveAll of the above

6)6)None of the aboveNone of the above


9. 9. Which of the following statements regarding Which of the following statements regarding insulin glargine in type 2 diabetes is TRUE?insulin glargine in type 2 diabetes is TRUE? 1)1)Clinical trials have demonstrated significant intra-Clinical trials have demonstrated significant intra-patient variabilitypatient variability2)2)Studies demonstrate that once-daily insulin glargine Studies demonstrate that once-daily insulin glargine was less effective than NPH insulin given once or twice was less effective than NPH insulin given once or twice daily in reducing A1c levelsdaily in reducing A1c levels3)3)Clinical trials have demonstrated that nocturnal Clinical trials have demonstrated that nocturnal hypoglycemia was less frequent when using insulin hypoglycemia was less frequent when using insulin glargine than with NPH insulinglargine than with NPH insulin4)4)Studies show that when compared to NPH insulin, Studies show that when compared to NPH insulin, insulin glargine use resulted in more weight gaininsulin glargine use resulted in more weight gain


T2DMT2DM

ANTI-HYPERGLYCEMIC THERAPYANTI-HYPERGLYCEMIC THERAPY

Therapeutic options: Therapeutic options: InsulinInsulin

Neutral protamine Hagedorn (NPH)Neutral protamine Hagedorn (NPH)

RegularRegular

Basal analogues (glargine, detemir)Basal analogues (glargine, detemir)

Rapid analogues (lispro, aspart, glulisine)Rapid analogues (lispro, aspart, glulisine)

Pre-mixed varietiesPre-mixed varieties


Long (Detemir)

Rapid (Lispro, Aspart, Glulisine)

Long (Glargine)

0 2 4 6 8 10 12 14 16 18 20 22 24

Short (Regular)

Hours after injection

Insu

lin

level

ANTI-HYPERGLYCEMIC THERAPYANTI-HYPERGLYCEMIC THERAPY

Therapeutic options: Therapeutic options: InsulinInsulin

Intermediate (NPH)


T2DMT2DM


10. 10. The new ADA/EASD Guidelines issued on The new ADA/EASD Guidelines issued on April 19, 2012 for management of T2D April 19, 2012 for management of T2D recommend or indicate all of the following recommend or indicate all of the following EXCEPT:EXCEPT: 1)1)Unless it is contraindicated, metformin is the optimal first-Unless it is contraindicated, metformin is the optimal first-line drugline drug

2)2)Comprehensive CV risk reduction is a major focus of Comprehensive CV risk reduction is a major focus of therapytherapy

3)3)The combination of metformin, plus the addition of at least The combination of metformin, plus the addition of at least two other appropriately selected oral agents, should precede two other appropriately selected oral agents, should precede use of insulinuse of insulin

4)4)The combination of metformin plus insulin (usually basal) is The combination of metformin plus insulin (usually basal) is an appropriate second step in patients not achieving targets an appropriate second step in patients not achieving targets on on

5)5)None of the above is correctNone of the above is correct


11. 11. Which of the following options is the LEAST Which of the following options is the LEAST appropriate way to initiate basal insulin in a appropriate way to initiate basal insulin in a patient with type 2 diabetes?patient with type 2 diabetes? 1)1)Start with 10 units of bedtime insulin glargineStart with 10 units of bedtime insulin glargine

2)2)Start with 10 units of morning NPH insulinStart with 10 units of morning NPH insulin

3)3)Start with 10 units of morning insulin glargineStart with 10 units of morning insulin glargine

4)4)Start with 10 units of bedtime insulin detemirStart with 10 units of bedtime insulin detemir


12. 12. Which of the following statements regarding the Which of the following statements regarding the early initiation, addition, or intensification of insulin early initiation, addition, or intensification of insulin therapy in type 2 diabetes is FALSE?therapy in type 2 diabetes is FALSE? 1)1)Early insulin therapy has been shown to have Early insulin therapy has been shown to have beneficial effects on short-term glycemic control but beneficial effects on short-term glycemic control but little effect on long-term controllittle effect on long-term control2)2)Short-term positive effects of early insulin initiation is Short-term positive effects of early insulin initiation is explained by rapid reduction of glucotoxicityexplained by rapid reduction of glucotoxicity3)3)Early initiation of insulin therapy may lead to Early initiation of insulin therapy may lead to immediate improvement in beta-cell function immediate improvement in beta-cell function 4)4)Initiation of insulin therapy, after failure of lifestyle Initiation of insulin therapy, after failure of lifestyle modification and an oral agent, is one option modification and an oral agent, is one option recommended in the ADA guidelinesrecommended in the ADA guidelines

Sequential Insulin Strategies in T2DM Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]


13. 13. All of the following are potential barriers All of the following are potential barriers associated with insulin initiation in diabetes, associated with insulin initiation in diabetes, EXCEPT:EXCEPT: 1)1)Potential for hypoglycemiaPotential for hypoglycemia

2)2)Weight gainWeight gain

3)3)Potential for unpredictable action of long-acting Potential for unpredictable action of long-acting formulationsformulations

4)4)Improved cognitive function with oral agentsImproved cognitive function with oral agents


14. 14. When initiating insulin therapy in patients When initiating insulin therapy in patients with type 2 diabetes, patients should be advised with type 2 diabetes, patients should be advised to maintain regular eating habits and exercise to maintain regular eating habits and exercise schedules, centered around their insulin schedules, centered around their insulin treatment regimen.treatment regimen. 1)1)TrueTrue

2)2)FalseFalse


15. 15. TK is a 64-year old woman with a 3-year history of TK is a 64-year old woman with a 3-year history of type 2 diabetes. Despite losing 10 pounds in the past type 2 diabetes. Despite losing 10 pounds in the past year, her most recent A1c is 7.9%. year, her most recent A1c is 7.9%.

Her current medication regimen includes metformin and Her current medication regimen includes metformin and a sulfonylurea. a sulfonylurea.

You decide to add insulin treatment to her regimen. You decide to add insulin treatment to her regimen. Which of the following is the MOST appropriate next Which of the following is the MOST appropriate next step in therapy for TK? step in therapy for TK?


1)1)Start with bedtime intermediate-acting insulin; check Start with bedtime intermediate-acting insulin; check fasting glucose weekly and increase dose until fasting fasting glucose weekly and increase dose until fasting levels are in target range; check A1c in 6 monthslevels are in target range; check A1c in 6 months

2)2)Start with morning basal insulin; check fasting Start with morning basal insulin; check fasting glucose daily and increase dose until fasting levels are glucose daily and increase dose until fasting levels are in target range; check A1c in 6 monthsin target range; check A1c in 6 months

3)3)Start with bedtime basal insulin; check fasting glucose Start with bedtime basal insulin; check fasting glucose daily and increase dose slowly until fasting levels are in daily and increase dose slowly until fasting levels are in target range; check A1c in 3 monthstarget range; check A1c in 3 months

4)4)Start with morning intermediate-acting insulin; check Start with morning intermediate-acting insulin; check fasting glucose daily until fasting levels are in target fasting glucose daily until fasting levels are in target range; check A1c in 3 monthsrange; check A1c in 3 months


16. 16. Rapid-acting insulin analogues control post-Rapid-acting insulin analogues control post-prandial glucose levels better than regular prandial glucose levels better than regular insulin, but cause more hypoglycemia.insulin, but cause more hypoglycemia. 1)1)TrueTrue

2)2)FalseFalse

Case Studies and Clinical DilemmasCase Studies and Clinical Dilemmas 17. 17. In which of the following patients with type 2 In which of the following patients with type 2 diabetes would it be MOST appropriate to initiate diabetes would it be MOST appropriate to initiate insulin therapy?insulin therapy? 1)1)A newly diagnosed 80-year old patient who is A newly diagnosed 80-year old patient who is treatment naïvetreatment naïve2)2)A patient who has been on metformin monotherapy A patient who has been on metformin monotherapy for 6 months with an A1c of 7%, who is prone to for 6 months with an A1c of 7%, who is prone to hypoglycemic episodeshypoglycemic episodes3)3)A newly diagnosed 58-year old patient with severe A newly diagnosed 58-year old patient with severe hyperglycemia at diagnosishyperglycemia at diagnosis4)4)All of the above would be good candidates for insulin All of the above would be good candidates for insulin therapytherapy5)5)None of the above would be good candidates for None of the above would be good candidates for insulin therapyinsulin therapy


18. 18. GG is a 68-year old woman with a 3-year history of GG is a 68-year old woman with a 3-year history of type 2 diabetes. Her A1c is 8.1% and she is currently on type 2 diabetes. Her A1c is 8.1% and she is currently on metformin, a sulfonylurea, and bedtime basal insulin. metformin, a sulfonylurea, and bedtime basal insulin. Her fasting plasma glucose levels are consistently Her fasting plasma glucose levels are consistently around 110 mg/dL and her postprandial levels are around 110 mg/dL and her postprandial levels are around 180 mg/dL. Which of the following is the MOST around 180 mg/dL. Which of the following is the MOST appropriate next step in therapy for GG?appropriate next step in therapy for GG? 1)1)Increase her dose of basal insulin by 4 units and Increase her dose of basal insulin by 4 units and continue to monitor her fasting glucose dailycontinue to monitor her fasting glucose daily2)2)Discontinue her basal insulin and initiate treatment Discontinue her basal insulin and initiate treatment with a GLP-1 receptor agonistwith a GLP-1 receptor agonist3)3)Increase her dose of basal insulin by 2 units and add a Increase her dose of basal insulin by 2 units and add a pre-meal rapid-acting insulinpre-meal rapid-acting insulin4)4)Add a rapid acting insulin before the largest meal with Add a rapid acting insulin before the largest meal with or without discontinuing her sulfonylurea or without discontinuing her sulfonylurea

KEY POINTSKEY POINTS

Glycemic targets & BG-lowering therapies must be individualized.

Diet, exercise, & education: foundation of any T2DM therapy program

Unless contraindicated, metformin = optimal 1st-line drug.

After metformin, data are limited. Combination therapy with 1-2 other oral / injectable agents is reasonable; minimize side effects.

Ultimately, many patients will require insulin therapy alone / in combination with other agents to maintain BG control.

All treatment decisions should be made in conjunction with the patient (focus on preferences, needs & values).

Comprehensive CV risk reduction - a major focus of therapy.



T2DMT2DM

Achieving A1C and Glycemic Targets with Insulin What to Do When Oral Agents Fail New Paradigms,...

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