Comprehensive DiabetesTreatment

Joshua L. Cohen, M.D., F.A.C.P.

Professor of Medicine

Interim Director, Division of Endocrinology &Metabolism

The George Washington University School ofMedicine

Diabetes Treatment Objectives

• Blood glucose control

» Improve patient wellbeing

» Prevent acute complications (DKA, infection,etc)

» Reduce the risk of chronic complications

• Cardiovascular disease risk reduction(lifestyle, lipids, blood pressure, smoking)

» Reduce risk of CAD, stroke and PVD

• Treat chronic complications

• Diabetes prevention

» Reduce future disease burden

Guidelines for Glycemic, BP, & Lipid Control

American Diabetes Assoc. Goals

HbA1C < 7.0% (Alternate goal for selected patients)

Blood pressure < 130/80 mmHg

Lipids

LDL: < 100 mg/dL (2.59 mmol/l)

< 70 mg/dL (1.81 mmol/l) (with overtCVD)

HDL: > 40 mg/dL (1.04 mmol/l) Men

> 50 mg/dL (1.30 mmol/l)Women

TG: < 150 mg/dL (1.69 mmol/l)

Statin therapy regardless of baseline lipids forpatients with overt CVD or multiple risk factors

ADA. Diabetes Care. 2013;36 (Suppl 1):S11-66

Effects of Early Glycemic Control: Long-Term Follow-up of Intervention Trials

Study Intervent.duration

Int.A1c

Observ.duration

Obs.A1c

Microvasc.comps

CV events anddeath

DCCT 6.5 yrs 7.4 (I)9.1(C)

11 yrs 8.0 (I)8.2 (C)

53-59%reduction inretinopathy

56% reduction inCV death, MI orCVA

UKPDS 10.0-10.7yrs

7.0 (I)7.9(C)

10 yrs 7.9 (I)8.5 (C

8.4 (I)8.9 (C)

24%reduction inaggregatemicrovasc.comps

15% reduction inMI27% reduction inall-cause death

STENO 2 7.8 yrs 7.9 (I)9.0(C)

5.5 yrs 7.7 (I)8.0 (C)

13% reduction inCV death20% reduction inall-cause death

Nathan DM, et al. N Engl J Med. 2005; 353:2643-53Holman RR, et al. N Engl J Med. 2008; 359:1577-89

Gaede P, et al. N Engl J Med. 2008; 358:580-91

Steno-2 Study: CardiometabolicControl During Follow-up

Gaede P, et al. NEngl J Med. 2008;358:580-91

Steno-2 Study Long-TermOutcomes

Any CardiovascularEvent

Individual CardiovascularEvents

Gaede P, et al. N Engl J Med. 2008; 358:580-91

Intervention Observation

Implications of Long-TermTrials

• Early treatment reduces complications

• Beneficial effects of early treatmentpersist

• Effects of poor metabolic control alsopersist

• Intensive interventions have risks aswell as benefits

HbA1C and Average Plasma Glucose

6597

126154

183212

240269

298

0

50

100

150

200

250

300

350

4 5 6 7 8 9 10 11 12

Avera

ge

Pla

sm

aG

luco

se

(mg

/dl)

HbA1C (%)

A 1% change in HbA1C equals a 29 mg/dl change inaverage plasma glucose

Glycemic Control Decision MakingElements

TargetHbA1C

Lower Higher

Inzucchi S et al. 2012;Diabetes Care. 35:1364-1379

Antihyperglycemic Agents:Major Sites of Action

SulfonylureasMeglitinidesNateglinide

InsulinLiver

Plasma glucose

Glitazones-Glucosidase

inhibitors

+

GI tract

Pancreas

Metformin

Muscle/Fat

–

(–) (+)

(–)

(+)

(+)

CarbohydrateAbsorption

GlucoseProduction

InsulinSecretion

GlucoseUptake

InsulinSecretion

GLP-1 agonist

DPP-4inhibitor

(–)

Kidney

Glycosuria

SGLT2inhibitor

(–)

Glucose-Lowering Therapy inType 2 Diabetes (1)

Inzucchi S et al. 2012; Diabetes Care. 35:1364-1379

Glucose-Lowering Therapy inType 2 Diabetes (2)

Inzucchi S et al. 2012; Diabetes Care. 35:1364-1379

Insulin Therapy

Intensive Insulin Therapy inType 1 Diabetes

• Goal: Mimic endogenous insulinsecretion in order to maintain fastingand post-prandial blood glucose withinnormal ranges

Physiologic Insulin Secretion

Insu

lin(µ

U/m

L)

Glu

cose

(mg/d

L) 150

100

50

08 10 12 2 4 6 8A.M. P.M.

Time of Day:

50

25

0

Breakfast Lunch Supper

10 12 2 4 6 8

Insulin PharmacodynamicsClassification Generic

NamesOnset ofAction

Peak Duration ofAction

Rapid-actinganalog

Lispro

Aspart

Glulisine

5-15 min 0.5-2hours

3-5 hours

Short-acting Regular 30-60 min 2-4 hours 4-8 hours

Intermediate NPH 1-3 hours 4-10hours

10-20hours

Long-acting Glargine

Detemir

2-4 hours Broad

“peakless”

16-24hours

Insulins: Brand and Generic Names

• “Basal” formulations» Lantus glargine

» Levemir detemir

» Humulin N, Novolin N NPH

• “Bolus” formulations» Humalog lispro

» Novolog aspart

» Apidra glulisine

» Humulin R, Novolin R regular

• Pre-mixed» NPH – regular (“70 – 30”) 70% NPH/30% reg

» Novolog mix (“75/25”) 75% int/25% aspart

» Humalog mix (“70/30”) 70% int/30% lispro

Implementation of Basal BolusTherapy

NPH at AM and HS+ Aspart AC

Glargine HS or AM+ Aspart AC

6-29

Insu

lin

Eff

ect

B SL HS B

Aspart

NPH

Insu

lin

Eff

ect

B SL HS B

Aspart

Glargine

Insulin Therapy in Type 2 Diabetes• Effective...can lower hyperglycemia by a

greater amount than any other therapeuticoption

• For recently diagnosed patients, insulinsensitivity and endogenous insulin secretionmay improve as a result of reducedglucotoxicity.

• UKPDS: Cardiovascular risk declines withHbA1C. CV risk in insulin treatment group notworsened.

• May be less expensive and simpler thanmulti-drug combination therapy

Insulin Therapy in Type 2Diabetes

• Who should be started on insulin?

• When should insulin therapy be initiated?

• What are the barriers to using insulin?

• How should insulin be initiated and titrated?

• How can initial insulin therapy be intensified?

• What are the safety considerations in usinginsulin?

Fear of self-injection

Perception that insulin userepresents a personalfailure

Fear that insulin will causediabetic complications

Lack of resources andsupport for patient education

Lack of knowledge aboutappropriate insulin use

Perception of complexity ininitiation and dose titration

Concerns about long-termconsequences of insulintherapy

Hypoglycemia

Weight gain

Cost

Patient Provider

Concerns About Insulin

Indications for Insulin in Type 2Diabetes

• Severe insulin deficiency (ex DKA)

• Symptomatic hyperglycemia

• Uncontrolled hyperglycemia despite oralagents

» Fasting glucose >250 mg/dl or randomglucose frequently >300 mg/dl

» Hb A1C ≥10%

• Inadequately controlled glucose (Hb A1C

target) on non-insulin therapy

EASIE: Addition of Glargine Insulin orSitagliptin in Patients Not Controlled

on Metformin

• 6 month, randomized open label trial

• 515 patients randomized to glargineinsulin or sitagliptin

• Insulin dose titrated twice weekly toachieve fasting glucose target range of95-140 mg/dl

Aschner P, et al. Lancet. 2012; 379:2262-69

EASIE Study: HbA1c Results

Aschner P, et al. Lancet.2012; 379:2262-69

Initiation of Insulin in Type 2Diabetes

• Basal insulin only

» Glargine or detemir insulin: QD

» Intermediate insulin: HS or BID

• Intermediate/short-acting premix

» 70/30 or 75/25: BID

• Mealtime rapid-acting insulin

Starting With Basal Insulin

• 1 injection with no mixing

• Slow, safe, and simple titration

• Low dosage

• Limited weight gain

• Does not alter pre- to post-prandial glucose

increment

Basal Insulin in Type 2 Diabetes

• Start with basal insulin» Glargine

» Detemir

» NPH hs

• Initial dose:» 10 units

» 0.2-0.3 units/kg

• Titrate based on fasting blood glucose

• Add premeal short-acting insulin ifnecessary

Basal Insulin Titration

8 units180 mg/dl or higher

6 units140 – 179 mg/dl

4 units120 – 139 mg/dl

2 units100 - 119 mg/dl

Basal insulinincrement

Fasting blood glucose

Adjust weekly based on averagefasting glucose

Treat to Target Study: Glargine or NPH

Insulin Added to Oral Therapy

Patients inadequatelycontrolled on OHAs

A1C 7.5%–10%

Continue OHAs+

NPH insulin at bedtime

Continue OHAs+

Insulin glargine at bedtime

24-wk treatment

Target FPG 100 mg/dL

Riddle et al. Diabetes Care. 2003;26:3080-3086.

Mean A1C Levels During Study

6

7

8

9

0 4 8 12 16 20 24

Mean

A1C

(%)

Time (wk)

Insulin glargine

NPH insulin

Target A1C (%)

Treat to Target Study

Riddle et al. Diabetes Care. 2003;26:3080.

By week 18, the percentage of patients with HbA1C < 7.0%increased from 2.5% to 66.2%

Rosenstock J, et al. Diabetes. 2001; 50(suppl 2):A520.

Treat to Target Study

Week 18Week 12Week 8Week 0

100

80

60

40

20

02.5

27.7

69.8

32.3

47.7

19.9

48.843.0

8.3

66.2

28.4

5.4Per

cent

ofP

atie

nts

Graph based on preliminary data available as of 13December 2000.

HbA1c 7.0% HbA1c > 7.0%, 8.0) HbA1c > 8.0%

Per Cent Achieving HbA1c Goal

Treat to Target Study: Risk ofHypoglycemia

0

0.2

0.4

0.6

0.8

1

1.2

1.4

Time / 24 hour clock

GlargineNPH

B L D

Insulininjection

Events per patient exposureyear

( 72 mg/dL, 4.0 mM)(%)

B L D

Insulininjection

Proportion of patients withhypoglycemia 72 mg/dL (4.0 mM)

Risk of Hypoglycemia

0

5

10

15

20

25

30

20212223241 2 3 4 5 6 7 8 9 10111213141516171819

Time / 24 hourclock

GlargineNPH

Treat to Target Study

Riddle et al. Diabetes Care. 2003; 26:3080.

Basal Insulin Titration

• Increase glargine insulin dose by 2 unitsif fasting blood glucose is >120 mg/dl(6.6 mM)

• Adjust insulin dose no more often thanevery 3-4 days

• Decrease insulin dose if nocturnalhypoglycemic reactions occur

Patient Instructions

Comparison of Clinic-Directed BasalInsulin Dose Algorithm with Patient-

Directed Algorithm

Clinic Patient

Comparison of Clinic-DirectedBasal Insulin Dose Algorithm with

Patient-Directed Algorithm

Hypoglycemia

Comparison of Glargine withOnce or Twice Daily Detemir

HbA1C

Pre- and Post-meal glucose

Rosenstock J, et al. Diabetologia. 2008; 51:408-416

Initiation of Pre-Mixed Insulin

• May be advantageous in patients with post-prandial hyperglycemia

• Increased risk of hypoglycemia if patient takesinsulin dose and does not eat usual meal

• Formulations:

» 70% NPH + 30% Regular

» 75% NPL + 30% Lyspro

» 70% Protamine-Aspart + 30% Aspart

• Initial dose: 10 units bid before breakfast anddinner

Adjustment of Pre-Mixed Insulin

• Adjust once or twiceweekly

» Adjust pre-breakfastdose based on pre-dinner capillary bloodglucose

» Adjust pre-dinner dosebased on pre-breakfast capillaryblood glucose

» 2 hour post-mealglucose levels canalso be used to adjust

3 dayaverageglucose

(mg/dl)

Insulin doseadjustment(change inunits ofinsulin)

<80 - 2

80-109 No Change

110-139 + 2

140-179 + 4

180 + 6

Comparison of basal only withpre-mix

• Comparable efficacy

• Greater risk of hypoglycemia with pre-mix

• Slightly greater weight gain with pre-mix

• Intensification of therapy may be morecumbersome if starting with pre-mix

Should Oral Agents Be ContinuedWhen Insulin is Started?

• Metformin: Yes

» Better glucose control

» Less weight gain

• DPP4 Inhibitor: ?

» Better post-prandial glucose control

• Pioglitazone: ?

» May result in lower insulin dose requirement

» Fluid retention

» Weight gain

• Sulfonylurea: ?

» More weight gain

» Higher risk of hypoglycemia

• Initial dose of insulin glargine should equal

approximately 80% of the total daily dose of

intermediate acting insulin.

• For example if patient was on NPH 40 units am

and 50 units pm...the total dose is 90 units and

estimated initial dose of glargine is 65 - 75 units

to control nocturnal and fasting hyperglycemia

Switching from NPH Insulin to GlargineInsulin

Insulin ”Pen”

Weight Gain with InsulinTreatment

• In controlled studies, weight gain attributable toinsulin therapy is generally modest

• In patients with poorly controlled diabetes, weightgain may be due to re-establishment of usualbasal weight

• Recurrent hypoglycemia may exacerbate weightgain because of additional calories consumed totreat hypoglycemia

• Weight gain can be minimized by concurrent useof metformin

Insulin Safety Concerns

• Hypoglycemia

• Cardiovascular disease risk

• Cancer

Risk Factors for Hypoglycemia inBasal-Insulin Treated Patients

• Lower HbA1C target

• Concomitant use of sulfonylurea

• Renal or hepatic impairment

• Advanced age

• NPH or pre-mix insulin before evening meal

• Hypoglycemic unawareness

• Missed meals (especially if basal insulindose is too high)

Diabetes and Cancer• Epidemiologic studies suggest diabetes may

be associated with increased risk of certaincancers

» Pancreas (pooled OR 1.8)

» Liver

» Colorectal (pooled RR 1.3)

» Breast (pooled RR 1.2)

» Bladder (pooled RR 1.2)

» Endometrium (pooled RR 2.1)

• It is not known to what extent this associationis due to common risk factors (diet, activity,etc) or to a causal link (insulin signaling, etc.)

Insulin Treatment and Cancer• Recently, a series of epidemiologic studies reported

a possible association between glargine insulin useand increased risk of cancer

• These studies have been extensively debated.Potential confounding variables such as duration ofdiabetes, comorbidities and other confounders maynot have been fully controlled.

• Additional retrospective epidemiologic analyses haveyielded conflicting results.

• Large, randomized, prospective trials, have not foundevidence that glargine insulin is associated withincreased cancer risk

• “Cancer risk should not be a major factor whenchoosing between available diabetes therapies…”

ADA/ACS Consensus Report

ORIGIN Trial• Randomized trial, compared titrated basal

insulin with standard care in patients withdiabetes, impaired glucose tolerance orimpaired fasting glucose

• 12,537 study subjects followed for median 6.2years

• Co-primary outcomes:

» Cardiovascular death, nonfatal MI, nonfatal stroke

» Above plus revascularization or hospitalization forheart failure

Gerstein HC. et al. N Engl J Med. 2012; 367:319-27

ORIGIN Trial Outcomes

Gerstein HC. et al. N Engl J Med. 2012; 367:319-27

Summary

1. The worldwide prevalence of diabetes is projectedto continue increasing, especially in regionsundergoing rapid socioeconomic change anddevelopment

2. Early intensive glycemic control is associated withreduced long-term risk of microvascular andcardiovascular complications

3. Target HbA1C should be individualized based onmultiple factors including diabetes duration,presence of cardiovascular complications, risk ofhypoglycemia, etc.

Summary (2)

4. Insulin treatment in type 2 diabetes is highlyeffective in improving glycemic control

5. When starting a patient on basal insulin, aprogram to titrate the insulin dose totherapeutic goal should be followed

6. Large prospective trials have shown thatglargine insulin use is not associated withincreased cardiovascular or cancer risks