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