Insulin 201:Insulin 201:Moving beyond basal insulinMoving beyond basal insulin

in type 2 diabetes

Dr. Sara Stafford, MDCM FRCPCFraser Health Division of Endocrinology

DisclosureDisclosure

• Honoraria for CME: Honoraria for CME: – Eli Lilly, Boehringer Ingelheim, Novo Eli Lilly, Boehringer Ingelheim, Novo

Nordisk, Animas, Sanofi Aventis, MerckNordisk, Animas, Sanofi Aventis, Merck

• This program was developed by This program was developed by – Dr. Alice YY ChengDr. Alice YY Cheng

• This program was supported by an This program was supported by an unrestricted educational grant from unrestricted educational grant from Sanofi DiabetesSanofi Diabetes

Learning objectivesLearning objectivesBy the end of this program, you will be able to :By the end of this program, you will be able to :

1.1. Name the 3 types of insulin, 3 insulin regimens and Name the 3 types of insulin, 3 insulin regimens and pros/cons of eachpros/cons of each

2.2. Discuss the evidence comparing regimensDiscuss the evidence comparing regimens

3.3. Identify the patient who needs to move beyond basal Identify the patient who needs to move beyond basal insulin aloneinsulin alone

4.4. Select the regimen best suited for a particular patientSelect the regimen best suited for a particular patient

5.5. Pick a starting dose and titratePick a starting dose and titrate

In your practice, what is the most In your practice, what is the most common starting regimen for common starting regimen for

your pts with T2DM?your pts with T2DM?

1.1. Basal aloneBasal alone

2.2. Basal plus one BolusBasal plus one Bolus

3.3. Basal BolusBasal Bolus

4.4. Premixed BIDPremixed BID

5.5. Premixed TIDPremixed TID

In your opinion, what is the best In your opinion, what is the best insulin regimen for T2DM?insulin regimen for T2DM?

1.1. Basal aloneBasal alone

2.2. Basal BolusBasal Bolus

3.3. Premixed BIDPremixed BID

4.4. Premixed TIDPremixed TID

5.5. Dumb question! CanDumb question! Can’’t t answer that.answer that.

The Rules of 3The Rules of 3’’ss

3 Types of insulins3 Types of insulinsBOLUSBOLUS

• Regular or TorontoRegular or Toronto• Apidra (glulisine)Apidra (glulisine)• Humalog (lispro)Humalog (lispro)

• Novorapid (aspart)Novorapid (aspart)

BASALBASAL• NPHNPH

• Lantus (glargine)Lantus (glargine)• Levemir (detemir)Levemir (detemir)

PRE-MIXEDPRE-MIXED• 30/7030/70

• Humalog Mix25, Mix50 Humalog Mix25, Mix50 (insulin lispro/lispro protamine)(insulin lispro/lispro protamine)

• Novomix 30 Novomix 30 (biphasic insulin aspart)(biphasic insulin aspart)

Canadian Diabetes Association Clinical Practice Guidelines. Can J Diabetes 2008;32(Suppl 1).

PRE-MIXED: 30/70, Humalog Mix25, Mix50, Novomix 30

McMahon GT, Dluhy RG. NEJM 2007;357:1759.McMahon GT, Dluhy RG. NEJM 2007;357:1759.

0 12 24

Rel

ativ

e G

lyce

mic

Eff

ect

Duration in Hours

NPH

Detemir

Glargine

Human Regular

LisproAspartglulisine

B DL HS

Insu

lin e

ffe

ct

Bolus Insulin

Basal Insulin

Endogenous Insulin

B = breakfast; L = lunch; D = dinner; HS = bedtime.1. Leahy JL. In: Leahy JL, Cefalu WT (eds). Insulin Therapy. Marcel Dekker Inc., New York, 2002.2. Bolli GB, et al. Diabetologia 1999; 42:1151-67.

Normal Insulin Secretion: Normal Insulin Secretion: The Basal-Bolus Insulin ConceptThe Basal-Bolus Insulin Concept

Time of administration

3 Insulin Regimens3 Insulin Regimens

B DL HS

Insu

lin e

ffe

ct

Bolus Insulin

Basal Insulin

Endogenous Insulin

B = breakfast; L = lunch; D = dinner; HS = bedtime.

Basal aloneBasal alone

Time of administration

B DL HS

Insu

lin e

ffe

ct

Bolus Insulin

Basal Insulin

Endogenous Insulin

B = breakfast; L = lunch; D = dinner; HS = bedtime.1. Leahy JL. In: Leahy JL, Cefalu WT (eds). Insulin Therapy. Marcel Dekker Inc., New York, 2002.

Basal-BolusBasal-Bolus

Time of administration

B DL HS

Insu

lin e

ffe

ct

Endogenous Insulin

Time of administration

Basal Plus Bolus (main meal)Basal Plus Bolus (main meal)

Bolus Insulin

Basal Insulin

B DL HS

Insu

lin e

ffe

ct

Endogenous Insulin

Time of administration

BID PremixedBID Premixed

B DL HS

Insu

lin e

ffe

ct

Endogenous Insulin

Time of administration

TID PremixedTID Premixed

What are the pros and cons?What are the pros and cons?

Basal aloneBasal alone

PROSPROS• One injectionOne injection• One type of insulinOne type of insulin• ConvenientConvenient• Control fastingControl fasting• One SMBGOne SMBG

CONSCONS• No targeted No targeted

postprandial controlpostprandial control• Need functioning Need functioning

pancreas to provide pancreas to provide bolus insulinbolus insulin

Basal BolusBasal Bolus

PROSPROS• Flexibility in timingFlexibility in timing• Flexibility in quantityFlexibility in quantity• Physiologic Physiologic • Do not need a Do not need a

pancreaspancreas

CONSCONS• 2-4 injections2-4 injections• 2-4 SMBG2-4 SMBG• HypoglycemiaHypoglycemia

Premixed BID or TIDPremixed BID or TID

PROSPROS• 2-3 injections2-3 injections• 1 insulin1 insulin

CONSCONS• No flexibility in dosingNo flexibility in dosing• No flexibility in timingNo flexibility in timing

How do the regimens compare? How do the regimens compare? What do the studies say?What do the studies say?

Basal vs PremixedBasal vs Premixed

Basal vs Human premixedBasal vs Human premixed

Janka HU et al. Diab Care 2005;29:254-259.Janka HU et al. J Am Geriatr Soc 2005;55:182-188.

Favours premixed Favours basal

Qayyum R et al. Ann Intern Med 2008;149:549-559

Basal vs Premixed analogueBasal vs Premixed analogue

Favours premixed Favours basal

Qayyum R et al. Ann Intern Med 2008;149:549-559

Basal Bolus vs PremixedBasal Bolus vs Premixed

-1.6 (60%)-1.2 (50%)*

-4.2 (NR)

-1.9 (NR)

–4.0

–3.0

–2.0

–1.0

0

Miyashita et al,

2008

Masuda et al,

2008

Liebl et al,

2009

-2.0 (NR)P=0.0052

Mea

n Δ

A1C

Fro

m B

asel

ine

(%)

0.5Hirao et al,

2008

-2.6(32%) -2.6 (33%)

P=NS

-4.4 (NR)

–5.0

P=0.32

P=NS

NovoMix 30 BID

Humalog Mix50 BID

Basal-Bolus

Fritsche et al,

2010

-0.7 (28%)

-1.3 (47%)

P=0.0009

Liebl A et al. Diabetes Obes Metab 2009;11:45-52. Hirao K et al. Diabetes Res Clin Pract 2008;79:171-176. Miyashita Y et al. Cardiovasc Diabetol 2008;7:16-24. Fritsche A et al. Diabetes Obes Metab 2010;12:115-123. Masuda H et al. Diabetes Obes Metab 2008;10:1261-1265.

A1C Comparison Between Analogue Premix BID vs Basal-Bolus Therapy in Type 2 Diabetes

(*Number in brackets indicates the % achieving A1C <7%; NR=Not reported)

-1.2-1.3

-1.9

–4.0

–3.0

–2.0

–1.0

0

Rosenstock et al, 2008Ligthelm et al, 2006

P=NS Non-inferior

Mea

n Δ

A1C

Fro

m B

asel

ine

(%)

0.5

-2.1

–5.0

NovoMix TID

Humalog Mix50 TID

Basal-BolusP= 0.021

Not Non-inferior

Ligthelm RJ et al. Exp Clin Endocrinol Diabetes 2006;114:511-519. Rosenstock J et al. Diabetes Care 2008;31:20-25.

A1C Comparison for Analogue Premix TID vs Basal-Bolus Therapy in Type 2 Diabetes

Basal Bolus vs Basal PlusBasal Bolus vs Basal Plus

31

1-2-3 Study: 1 vs 2 vs 3 bolus + basal + OADs

Population: 785 T2DM on OHA, HbA1c >8% Main objective: Non-inferiority HbA1c of bolus administered w/ 1 vs 2 vs 3 meals/d

Basal insulin + sensitiser(s) D/C SU + bolus insulin 2x/day

Basal insulin + sensitiser(s) D/C SU + Bolus insulin 3x/day

basal insulin + 2 oral agents

Visit

Weeks

Run-in phase Treatment phase

2 oral agents

Basal insulin HbA1c >7%

Screening

Ibasal insulin + sensitiser(s) D/C SU + bolus insulin 1x/day

−16 −15 −13 −8 −1 0 2 8 16 24 25

1 2 3 4 5 6 7 8 9 10 11

D/C=discontinued; SU=sulphonylurea

32

1-2-3 Study

Davidson et al ADA 09

Run in Baseline Week 8 Week 16 Week 24

6

7

8

9

10

11

Glulisine 1x

Glulisine 2x

Glulisine 3xH

bA

1c (

%)

10.19

10.19

10.16

7.44

7.29

7.40

Randomized patients (HbA1c>7% at baseline) n= 343

Pat

ien

ts (

%)

wit

h H

bA

1C <

7.0%

37%

29.7%

0

20

40

60

80

Patients who achieved

HbA1c <7.0% with basal

during run in

Additional patients who

achieved HbA1c <7.0% with 1 bolus

added to basal

Whole population n= 785 T2D pts failing OHAs

-0.44%

More hypo

But we donBut we don’’t treat people for t treat people for only 24-52 weeks!!only 24-52 weeks!!

LM 75/25 G

45% 40%

24 months

A1c < 7%43% of maintenance*

19% of original

A1c < 7%37% of maintenance

14% of original

16.8 months * 14.4 months

5.4 ± 5.8kg*

3.7 ± 5.6kg

N Engl J Med 2009:361:1736-47

N Engl J Med 2009;361:1736-47

Transition to a Complex Insulin Regimen

* Intensify to a complex insulin regimen in year one if unacceptable hyperglycaemia

708 T2DMon dual

oral agents

Add biphasic insulin*twice a day

Add prandial insulin*three times a day

R

First Phase

Add basal insulin*once (or twice) daily

Add prandial insulinat midday

Add basal insulinbefore bed

Second Phase

Add prandial insulinthree times a day

From one year onwards, if HbA1c levels were >6.5%, sulfonylurea therapy was stopped and a second type of insulin was added

N Engl J Med 2009;361:1736-47

Primary Outcome: HbA1c at 3 Years

Median±95% confidence interval

N Engl J Med 2009;361:1736-47

Increase in Body Weight Over 3 Years

N Engl J Med 2009;361:1736-47

Grade 2 or 3 Hypoglycemia Over 3 Years

Allpatients

Patients withHbA1c ≤6.5%

N Engl J Med 2009;361:1736-47

Complex Insulin Regimens

Proportion eligible for a second type of insulin per protocol

Proportion taking two types of insulin

Therefore …Therefore …

• Diabetes is PROGRESSIVEDiabetes is PROGRESSIVE

• The regimen must change over timeThe regimen must change over time

• All roads lead to Basal Bolus conceptAll roads lead to Basal Bolus concept

• If youIf you’’re not going to titrate – donre not going to titrate – don’’t startt start

When should we consider When should we consider moving from Basal Alone to moving from Basal Alone to

another regimen?another regimen?

When to progress?When to progress?

• Fasting glucose at target YET the A1C Fasting glucose at target YET the A1C remains above targetremains above target

• Fasting glucose CLOSE to target BUT Fasting glucose CLOSE to target BUT the postprandial readings are very high the postprandial readings are very high

How to dose?How to dose?

““Whatever you pick will be Whatever you pick will be WRONG … and thatWRONG … and that’’s okay!s okay!””

• You will inject ______ units of insulin each nightYou will inject ______ units of insulin each night

• You will continue to increase by 1 unit every night until You will continue to increase by 1 unit every night until

your blood sugar level is _______ mmol/L before your blood sugar level is _______ mmol/L before

breakfastbreakfast

• Do not increase your insulin when your fasting blood Do not increase your insulin when your fasting blood

sugar is _______ mmol/Lsugar is _______ mmol/L

Basal insulin self-titration tool

10

4-7

4-7

Basal Bolus (MDI)Basal Bolus (MDI)

• 0.5 u/kg = TDI0.5 u/kg = TDI

• 50% bolus, 50% basal50% bolus, 50% basal

• Add 10% of basal dose as bolus insulin Add 10% of basal dose as bolus insulin with each mealwith each meal

• Add 5-10 units at each mealAdd 5-10 units at each meal

PremixedPremixed

• 0.5 units / kg = TDI0.5 units / kg = TDI

• 2/3 in the AM + 1/3 in the PM2/3 in the AM + 1/3 in the PM

• 5-10 units BID5-10 units BID

What about the orals?What about the orals?• METFORMINMETFORMIN• METFORMIN METFORMIN • METFORMINMETFORMIN

• Secretagogues only if basal aloneSecretagogues only if basal alone• TZD – stopTZD – stop• DPP-4 – benefit but cost DPP-4 – benefit but cost • GLP-1 receptor agonist – benefit (dose & weight) GLP-1 receptor agonist – benefit (dose & weight)

but cost (off-label) but cost (off-label)

The LOGBOOKThe LOGBOOK

Breakfast Lunch Supper

Before After Before After Before After Bedtime

Sunday 9.7 9.2 7.5

Monday 9.4 10 6.9

Tuesday 9.0 8.9 8.6 7.8

Wednesday 9.1 8.5 7.5

Thursday 8.8

How do I approach it?How do I approach titration?

How to approach logbook?How to approach logbook?

1.1. Where are the lows / highs?Where are the lows / highs?

2.2. Why are there lows / highs?Why are there lows / highs?

3.3. Do I adjust / switch or add?Do I adjust / switch or add?

a)a) Titrate to avoid hypoglycemia firstTitrate to avoid hypoglycemia first

b)b) Titrate to reduce hyperglycemiaTitrate to reduce hyperglycemia

Where are the lows / highs?Where are the lows / highs?

• Look for pattern of timingLook for pattern of timing

• AC meals?AC meals?

• PC meals?PC meals?

• Bedtime?Bedtime?

• Nocturnal?Nocturnal?

Why are there lows / highs?Why are there lows / highs?

• Too much / little foodToo much / little food

• Too much / little activityToo much / little activity

• Too much / little insulin activityToo much / little insulin activity

• What did you EAT?What did you EAT?

• What did you DO?What did you DO?

• What did you TAKE?What did you TAKE?

Patterns to look for …Patterns to look for …

Breakfast Lunch Supper

Before After Before After Before After Bedtime

Sunday

Monday

Tuesday

Wednesday

Thursday

If high fasting …Too little insulin overnight OR

Nocturnal hypoglycemia

Patterns to look for …Patterns to look for …

Breakfast Lunch Supper

Before After Before After Before After Bedtime

Sunday

Monday

Tuesday

Wednesday

Thursday

Reflects the bolus insulin from the meal prior

Patterns to look for …Patterns to look for …

Breakfast Lunch Supper

Before After Before After Before After Bedtime

Sunday

Monday

Tuesday

Wednesday

Thursday

2h pc meal sugar reflects the bolus insulin from the meal

If on premixed …If on premixed …

Breakfast Lunch Supper

Before After Before After Before After Bedtime

Sunday

Monday

Tuesday

Wednesday

Thursday

Reflects the bolus portion of the premixed injection at breakfast / dinner

If on premixed…If on premixed…

Breakfast Lunch Supper

Before After Before After Before After Bedtime

Sunday

Monday

Tuesday

Wednesday

Thursday

Reflects the intermediate portion of the premixed injected the night before /

breakfast

Adjust / Switch / Add?Adjust / Switch / Add?

• Based on the patterns and the reasons, Based on the patterns and the reasons, one can decide whether to one can decide whether to – Adjust existing dosesAdjust existing doses– Switch to different treatmentSwitch to different treatment– Add a treatmentAdd a treatment

How much to titrate by?How much to titrate by?

2 units OR 10%2 units OR 10%

““Not an exact science … trial and error!Not an exact science … trial and error!””

Future considerationsFuture considerations

Does early insulin replacement therapy strategy with basal insulin…

• Reduce macrovascular events?• Delay progression of microvascular complications?• Prevent progression to diabetes in individuals with

IFG/IGT by restoring beta cell function?

SummarySummary

• Diabetes is PROGRESSIVEDiabetes is PROGRESSIVE

• Regimens need to CHANGE over timeRegimens need to CHANGE over time

• Understand the time-action profilesUnderstand the time-action profiles

In In high-riskhigh-risk people with IFG, IGT or early people with IFG, IGT or early diabetes: diabetes:

a)a) Does insulin replacement therapy targeting fasting Does insulin replacement therapy targeting fasting normoglycemia (≤ 5.3 mmol/L) with insulin glargine normoglycemia (≤ 5.3 mmol/L) with insulin glargine reduce CV outcomes more than standard reduce CV outcomes more than standard approaches to dysglycemia?approaches to dysglycemia?

b)b) Does adding omega-3 fatty acids reduce CV Does adding omega-3 fatty acids reduce CV death?death?

ORIGIN: Research questions

The ORIGIN Trial Investigators. N Engl J Med 2012. DOI: 10.1056/NEJMoa1203858.The ORIGIN Trial Investigators. N Engl J Med 2012. DOI: 10.1056/NEJMoa1203859. The ORIGIN Trial Investigators. N Engl J Med 2012. DOI: 10.1056/NEJMoa1203858.

The ORIGIN Trial Investigators. N Engl J Med 2012. DOI: 10.1056/NEJMoa1203859.

IFG: impaired fasting glucoseIGT: impaired glucose toleranceCV: cardiovascular

IFG: impaired fasting glucoseIGT: impaired glucose toleranceCV: cardiovascular

ORIGIN: Trial Design

IFG: impaired fasting glucose; IGT: impaired glucose tolerance; T2D: type 2 diabetes; PUFA: polyunsaturated fatty acidIFG: impaired fasting glucose; IGT: impaired glucose tolerance; T2D: type 2 diabetes; PUFA: polyunsaturated fatty acid

The ORIGIN Trial Investigators. N Engl J Med 2012. DOI: 10.1056/NEJMoa1203858.The ORIGIN Trial Investigators. N Engl J Med 2012. DOI: 10.1056/NEJMoa1203859. The ORIGIN Trial Investigators. N Engl J Med 2012. DOI: 10.1056/NEJMoa1203858.

The ORIGIN Trial Investigators. N Engl J Med 2012. DOI: 10.1056/NEJMoa1203859.

*Placebo of omega-3 PUFA

Omega n=6319

Placebo n=6292

Median 6.2 years

Median 6.2 years

Participants with high CV risk

and

IFG or IGT or newly detected or early T2D

(on 0 or 1 oral agent)N=12,537

Omega-3 PUFA

Placebo*

R

Omega-3 PUFA

Placebo*

R

R

Standard glycemic care

N=6273

Titrated insulin glargine to FPG

goal ≤ 5.3 mmol/L N=6264

N %

Prior Diabetes (for ~ 5.4 y) 10321 82

New Diabetes 760 6

IFG &IFG &/or /or IGTIGT 14521452 1212

Smoking 12

Hypertension 80

Any Albuminuria 15

Previous CVD 59

Median FPG 125 mg/dl 6.9 mM

Median A1C 6.4%

Baseline Characteristics (n=12,537)Mean Age = 63.5 yrs; Females = 35%

Median Glargine Dose & IQR (U/kg)

Median (IQR) 28 (19-39) U/d in 70 Kg Person

Median FPG (SI Units)Median FPG (SI Units)

PenultimateIQR 4.4 – 5.8

IQR 5.7 – 7.9

Median A1C LevelsMedian A1C Levels

IQR 5.5 – 6.5

IQR 5.8 – 6.9

Years of Follow-up

Pro

po

rtio

n w

ith e

ven

ts

0.0

0.1

0.2

0.3

0.4

0.5

0 1 2 3 4 5 6 7

Glargine

Standard Care

# at Risk 1 2 3 4 5 6 7

G

SC

6264 6057 5850 5619 5379 5151 3611 766

6273 6043 5847 5632 5415 5156 3639 800

Time to Adjudicated Primary Outcome 1 - CV Death MI Stroke

Adj. HR 1.02 (0.94, 1.11)Log Rank P = 0.63

1st Co-primary: MI, Stroke, or CV Death

Years of Follow-up

Pro

po

rtio

n w

ith e

ven

ts

0.0

0.1

0.2

0.3

0.4

0.5

0 1 2 3 4 5 6 7

Glargine

Standard Care

# at Risk 1 2 3 4 5 6 7

G

SC

6264 5827 5474 5153 4835 4523 3076 631

6273 5833 5493 5186 4880 4555 3142 663

Time to Adjudicated Primary Outcome 2 - CV Death-MI-Stroke-HF Hosp-Revasc

Adj. HR 1.04 (0.97, 1.11)Log Rank P = 0.27

2nd Co-Primary: MI, Stroke, CV Death, Revascularization, Heart Failure

Years of Follow-up

Pro

po

rtio

n w

ith e

ven

ts

0.0

0.1

0.2

0.3

0.4

0.5

0 1 2 3 4 5 6 7

Glargine

Standard Care

# at Risk 1 2 3 4 5 6 7

G

SC

6264 6150 6024 5857 5687 5508 3906 847

6273 6159 6029 5878 5710 5501 3931 878

Time to Adjudicated All Death

Adj. HR 0.98 (0.90, 1.08)Log Rank P = 0.70

All-cause Death

Cancers Overall & by Type Cancers Overall & by Type (N=953)(N=953)

HR (95%CI) P  Glargine Standard N (%) Rate N (%) RateCancer Death 0.94 (0.77, 1.15) 0.52 189 (3.0) 0.51 201 (3.2) 0.54

Any Cancer 1.00 (0.88, 1.13) 0.97 476 (7.6) 1.32 477 (7.6) 1.32

Lung 1.21 (0.87, 1.67) 0.27 80 (1.3) 0.22 66 (1.1) 0.18

Colon 1.09 (0.79, 1.51) 0.61 76 (1.2) 0.21 70 (1.1) 0.19

Breast 1.01 (0.60, 1.71) 0.95 28 (0.4) 0.08 28 (0.4) 0.08

Prostate 0.94 (0.70, 1.26) 0.70 88 (2.1) 0.36 89 (2.2) 0.38

Melanoma 0.88 (0.44, 1.75) 0.71 15 (0.2) 0.04 17 (0.3) 0.05

Other 0.95 (0.80, 1.14) 0.59 233 (3.7) 0.64 245 (3.9) 0.67

Any Skin 1.02 (0.78, 1.33) 0.88 110 (1.8) 0.30 108 (1.7) 0.29HR

Favors Insulin Favors Standard

The ORIGIN Trial Investigators. N Engl J Med 2012. DOI: 10.1056/NEJMoa1203858.The ORIGIN Trial Investigators. N Engl J Med 2012. DOI: 10.1056/NEJMoa1203858.

ORIGIN: Effect on new diabetes among 1456 ORIGIN: Effect on new diabetes among 1456 participants with no diabetes at study entryparticipants with no diabetes at study entry

• 11stst OGTT: a median of 24 days after last visit OGTT: a median of 24 days after last visit• 22ndnd OGTT: a median of 100 days after the last visit OGTT: a median of 100 days after the last visit• “ “Uncertain diabetes”: cases of diabetes that could not be confirmed Uncertain diabetes”: cases of diabetes that could not be confirmed

by the predefined adjudication criteriaby the predefined adjudication criteria

Favours Insulin Favours Standard

OR (95% CI) P Insulin glargine

Standard care

  N (%) N (%)

After 1st OGTT 0.72 (0.58 - 0.91)

0.006 182 (24.7) 224 (31.2)

After 2nd OGTT 0.80 (0.64 - 1.00)

0.050 219 (29.7) 248 (34.5)

Adjudicated +

uncertain diabetes

0.69 (0.56 - 0.86)

0.001 254 (34.5) 310 (43.1)

0.5 1 2

Odds Ratio (OR)

ORIGIN: Hypoglycemia & weightORIGIN: Hypoglycemia & weight

 Glargine(N=6264)

Standard(N=6273) P

% no./100py  % no./100py

Any non-severe     ≥ 1 episode 57 17 25 5 <0.001Severe       ≥ 1 episode 6* 1.0 2 0.3 <0.001Participants with no hypoglycemia

43 75 <0.001

Glargine Standard P

Weight change since randomized

1.6 kg (3.5 lbs) -0.5 kg (1 lb) <0.001

*One death due to hypoglycemia in the glargine group

The ORIGIN Trial Investigators. N Engl J Med 2012. DOI: 10.1056/NEJMoa1203858.The ORIGIN Trial Investigators. N Engl J Med 2012. DOI: 10.1056/NEJMoa1203858.

Years of Follow-up

Pro

po

rtio

n w

ith

eve

nts

0.0

0.0

50

.10

0.1

50

.20

0.2

50

.30

0 1 2 3 4 5 6 7

n-3 fatty acids

Placebo

# at Risk 1 2 3 4 5 6 7

n-3

P

6281 6161 6034 5882 5706 5503 3896 879

6255 6143 6017 5848 5685 5492 3893 837

Time to Adjudicated CV Death

Primary Outcome: CV Death

HR 0.98; 95% CI, 0.87-1.10;P=0.72

Omega 3

Years of Follow-up

Pro

po

rtio

n w

ith

eve

nts

0.0

0.0

50

.10

0.1

50

.20

0.2

50

.30

0 1 2 3 4 5 6 7

n-3 fatty acids

Placebo

# at Risk 1 2 3 4 5 6 7

n-3

P

6281 6044 5843 5630 5403 5154 3601 791

6255 6051 5852 5616 5387 5140 3604 766

Time to Adjudicated Primary Outcome 1 - CV Death MI Stroke

HR 1.01; 95% CI, 0.93-1.10

MI, stroke or CV deathMI, stroke or CV death

Insulin - What can we tell our patients?Insulin - What can we tell our patients?

• Glargine insulin in type 2 diabetes (over 6 years):Glargine insulin in type 2 diabetes (over 6 years):

– Achieves near-normal glycemic controlAchieves near-normal glycemic control

– Neutral effect on CV outcomesNeutral effect on CV outcomes

– Does not increase cancerDoes not increase cancer

– Increases the risk of hypoglycemia (modest)Increases the risk of hypoglycemia (modest)

– Increase weight (modest)Increase weight (modest)

– Slows progression to diabetes BUT this must be Slows progression to diabetes BUT this must be balanced against the increase hypoglycemia and weight balanced against the increase hypoglycemia and weight gain and in the context of other oral therapies that have gain and in the context of other oral therapies that have also shown a reduction in progression to diabetesalso shown a reduction in progression to diabetes

Omega 3 - What can we tell our patients?Omega 3 - What can we tell our patients?

• The use of omega-3 fatty acids has a neutral effect on CV The use of omega-3 fatty acids has a neutral effect on CV outcomesoutcomes

• This is in keeping with findings from recent meta-analyses of This is in keeping with findings from recent meta-analyses of omega-3 fatty acids in the modern era of CV management omega-3 fatty acids in the modern era of CV management 1,21,2

• One more large-scale ongoing trial – ASCENDOne more large-scale ongoing trial – ASCEND33 – is evaluating – is evaluating the use of 1 g of omega-3 fatty acids in people with diabetes for the use of 1 g of omega-3 fatty acids in people with diabetes for primary prevention – 15,480 randomized – follow up to 2017primary prevention – 15,480 randomized – follow up to 2017

1. Kwak SM, et al. Arch Intern Med 2012;172:686-94.2. Chen Q, et al. Cardiovasc Drugs Ther 2011;25:259-65.

3. ASCEND: http://www.ctsu.ox.ac.uk/ascend Accessed June 21, 2012.

ASCEND: A Study of Cardiovascular Events iN DiabetesASCEND: A Study of Cardiovascular Events iN Diabetes