Advances in Diabetes Joseph A. Aloi, MD, FACP, FACE - PowerPoint Presentation

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Advances in Diabetes

Joseph A. Aloi, MD, FACP, FACE

Associate Professor of MedicineClinical Director: Strelitz Diabetes CenterEastern Virginia Medical School

Drugs, devices, and practice

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DISCLOSURESServed as a consultant to Sanofi-AventisPI on 2 clinical Trials (DPP4 – Takeda, SGLT2 – BI)Acknowledge Dr. David Lieb and The National Diabetes Education Initiative (NDEI.org)

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GoalsDiscuss approach to patients with pre-diabetesHighlight new drugs in use and on the horizon?How do you initiate insulin therapy?What about non-insulin injectables (pramlintide, GLP agonists)

Devices/Technology

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Pre-Diabetes

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Frederick: A Case30 years old, worried about diabetes Obese (BMI 39 kg/m

2), HTN, LIPIDS, (+) FHXNot much exercise; no Tobacco; On HCTZ 12.5 mg daily

Comes to health screening HbA1c = 6.0 %, BP= 142/89 mmHg, TC=256, HDL= 29; decr mono-filament? intervention

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Is this important?At what FPG does your risk for retinopathy increase?

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Is this important?At what FPG does your risk for retinopathy increase?Approximately 106

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Is this important?What % of patients at diagnosis of DM have evidence of complications?Retinopathy 15%Nephropathy 20-25%Neuropathy

30%

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Diabetes Increases

Overall Cardiovascular Mortality

Krolewski AS et al. AJM. 1991;90(Supp 2A):56S-61S

Diabetes

No Diabetes

60

Two-fold in

Men

0-3

Duration of Follow-up (Years)

50

40

30

20

10

0

Four-fold in Women

4-7

8-11

12-15

16-19

20-23

60

0-3

Duration of Follow-up (Years)

50

40

30

20

10

0

4-7

8-11

12-15

16-19

20-23

Mortality Rate Per 1000

Mortality Rate Per 1000

2x

4-5x

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Cardiovascular Disease Mortality Increased in the Metabolic Syndrome:

Kuopio Ischaemic Heart Disease Risk Factor Study

Lakka HM et al. JAMA 2002;288:2709-2716.

Cumulative Hazard, %

0

2

6

8

12

Follow-up, y

YES

Metabolic

Syndrome:

NO

Cardiovascular Disease Mortality

RR (95% CI), 3.55 (1.98

–

6.43)

4

10

0

5

10

15

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Adler AI et al.

BMJ 2000;321:412-419. | Stratton IM et al.

BMJ 2000;321:405-412.

Updated mean HbA

1c

concentration (%)

0

20

40

60

80

Adjusted incidence

per 1000 person-years (%)

5

6

7

8

9

10

11

Microvascular

end points

MI

MI and Microvascular End Points:

Incidence by HbA

1c

Concentration in UKPDS

As A1c increases from 5.5% to 11%, MI increases 2-fold while

microvascular

events increase 10-fold.

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Estimated Prevalence of All Types of Diabetes and Prediabetes in Virginia, 2005

Potentially modifiable

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A1c (%) to eAG (mg/dl)

6.0% = 126 mg/dl

6.5% = 140 mg/dl

7.0% = 154 mg/dl

7.5% = 169 mg/dl

8.0% = 183 mg/dl

8.5% = 197 mg/dl

9.0% = 212 mg/dl

9.5% = 226 mg/dl

10.0% = 240 mg/dl

A1C = Estimated Average Glucose

Nathan DM, et al. Diabetes Care August 2008 vol. 31 no. 8 1473-1478

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1. A1C should be considered an additional optional diagnostic criterion, not the primary criterion for diagnosis of diabetes.

2. AACE/ACE suggest using traditional glucose criteria for diagnosis of diabetes when feasible.

3. A1C is not recommended for diagnosing type 1 diabetes.

4. A1C is not recommended for diagnosing gestational Diabetes.

AACE recommendations

:

ENDOCRINE PRACTICE Vol 16 No. 2 March/April 2010 155-6

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5. A1C may be misleading in several ethnic populations (for example, African American patients).

6. A1C may be misleading in the setting of various hemoglobinopathies, iron deficiency, hemolytic anemias, thalassemias, spherocytosis, and severe hepatic and renal disease.

7. AACE/ACE endorse the use of only standardized, validated assays for A1C testing.

AACE recommendations

cont’

ENDOCRINE PRACTICE Vol 16 No. 2 March/April 2010 155-6

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DRUGS

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DPP-4 Inhibitors

• Mechanism:

 insulin secretion (BG-dependent),  glucagon secretion

Lowers PPG more than FPG

• Efficacy: modest (  HbA1c 0.6-0.8%)

•

Advantages:

weight neutral,

no hypoglycemia,

?



-cell preservation

•

Disadvantages:

cost, ? Urticaria/rash

meta-analysis suggests no increase in CV events

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Renal glucose handling

SGLT2 mediates 90% of filtered glucose reabsorption in the convoluted segment of the proximal renal tubuleSGLT1 mediates 10% of reabsorption in the distal straight segment In individuals without diabetes, all filtered glucose is reabsorbed

Glycosuria results when maximal reabsorptive capacity is exceededHyperglycaemia increases SGLT2 and maximal capacity; excess glucose returns to the bloodstream

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Safety of SGLT2 inhibitionLong-term safety not yet studiedShort-term studies showMinimally increased urine volume

No excessive losses of fluid, sodium, or potassiumFew instances of hypoglycemiaIncreased urinary tract infections and vaginitis

Modest weight lossIndividuals with familial renal glycosuria are asymptomatic

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1920s:

Diabetes is known to be a function of blood glucose Longevity is short in many Type 1 DM

Mortality is from acidosis/infection (pulmonary)In less than 2 years Insulin is isolated and begins to appear in clinical practiceWith an increase in longevity DM complications such as retinopathy also increaseShortened life expectancy persists until the 1940s

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Insulin is an anabolic protein hormone necessary for life;

Before & After

IM Isletin

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Type 1 Diabetes

Why Insulin Therapy in Diabetes?

Central role in both Type 1 and Type 2 diabetesGreatest potency of all available therapies

Insulin

Deficiency(Relative)

Insulin

Resistance

Insulin

Deficiency

(Absolute)

Type 2 Diabetes

+

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* Extrapolation from years 0 to 6 from diagnosis based on Homeostasis Model Assessment (HOMA) data from UKPDS. The data points for the time of diagnosis (0) and the subsequent 6 years are taken from the obese subset of the UKPDS population.

Lebovitz HE. Diabetes Rev.

1999;7:139-153.

UKPDS:

-Cell Function Declines Over Time-Cell Function (%)

*

Years from Diagnosis

25 –

100 –

75 –

0 –

50 –

l

-12

l

-10

l

-6

l

-2

l

0

l

2

l

6

l

10

l

14

50 %



-Cell Function at Diagnosis

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What do patients worry about?In a survey of over 700 pts with T2DM not yet on insulin:45% of patients worried insulin would restrict their lifestyle

43% worried they would have problems with hypoglycemia45% worried they would need insulin foreverMore than half felt that they had ‘

failed’Peragallo-Dittko V. Diab Educ. 2007. 33(3), 60S-65S.

Polonsky WH et al. Diab Care 2005. 28:2543-2545.

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More Patient PerceptionsMany patients know someone (often a family member) who has been on insulinOften these people were started late in the course of their diabetes, and insulin is linked with kidney failure, blindness, and death

When discussing insulin with patients, ask “What does insulin mean to you and to your family?”

Peragallo-Dittko V. Diab Educ. 2007. 33(3), 60S-65S.

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What About Providers?In the Diabetes Attitudes, Wishes and Needs (DAWN) study providers reported negative attitudes toward insulin—about half felt it could have a positive impact on patient careBelief in the benefit of insulin was also low among specialists

Clinicians sometimes use insulin as a threat—You’ll need insulin soon if you don’t start exercising!Insulin is seen as too difficult to initiate, and too time-consuming (for the provider and the patient)

Peragallo-Dittko V. Diab Educ. 2007. 33(3), 60S-65S.

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Basal vs. Meal-time InsulinBasal insulin:

Insulin required to maintain normal blood glucose while fastingOffsets hepatic glucose production

NPH, glargine, detemir

www.iheartguts.com

Meal-time insulin: Also called prandial, nutritionalInsulin required to manage rise in glucose after a meal is eaten

Regular, aspart, glulisine, lispro

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Insulin Analogues

Owens DR. Nat Rev Drug Discov. 2002 Jul; 1(7):529-40.

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Insulin Analogues Closely Match the Physiologic Insulin Profile

Basal insulin analogues Slow and steady rate of absorption Protracted actions

Low within-subject variability in actionsMeal-time insulin analoguesRapid absorption Peak actions coincide with peak carbohydrate absorption Can be given within 20 min of a meal (including after)

Rodbard HW et al

. Endocrine Practice. Vol 15, No. 6, 2009.

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Klein O, et al. Diabetes Obes Metab. 2007;9(3):290-9.

Plank J, et al. Diabetes Care

. 2005;28:1107–1112.Rave K, et al. Diabetes Care. 2005;28:1077–1082.

Insulin Profiles

0

2

4

6

8

10

12

14

16

18

20

22

24

Plasma Insulin Levels

Time (hours)

Long-acting analogues

NPH

Regular insulin

Rapid-acting analogues

24

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Long-Acting Insulin Analogues vs NPH in Type 2 Diabetes: A Meta-AnalysisAnalogues provide comparable glycemic control to NPH Analogues are associated with reduced risks of nocturnal and symptomatic hypoglycemia

Detemir may be associated with less weight gain

Monami M, et al. Diabetes Res Clin Pract. 2008;81:184-9.

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Mean A1c

(%)

Weeks

Insulin glargine

NPH insulin

Riddle MC, Rosenstock J.

Diabetes.

2002;51(suppl 2):A113.



60% reach target A1C < 7%

Treat-to-Target Study:

Insulin Glargine vs NPH Insulin

Added to Oral Therapy

6

7

8

9

0

4

8

12

16

20

24

TARGET

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NPH + OAD

Detemir + OAD

Hypoglycemic events per patient per year

Detemir vs NPH:

Risk of

Hypoglycemia

0

2

4

6

8

10

12

14

16

18

Overall

Nocturnal

Hermansen K et al.

Diabetes Care.

2006;29:1269-1274.

p < 0.001

p < 0.001

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Long-Acting Insulin Analogues and concentrated insulin on the horizon

FDA Panel Endorses Insulin DegludecNov 09, 2012Novo Nordisk's insulin degludec (abbreviated IDeg, brand name Tresiba) is a long-acting basal insulin that forms soluble multihexamers on subcutaneous injection. It has a half-life of 25 hours, which is twice as long as currently available basal insulin products, with a 42-hour duration of effect.

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Long-Acting Insulin Analogues and concentrated insulin on the horizon

Euglycemic Clamp Dose-response Study Comparing Insulin Glargine U300 With Lantus® U100 [Recruiting]

U500

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Insulin and Weight GainInsulin initiation does lead to weight gainBut it’s modest (1.7 kg (about 4 lbs) over 10 yrs in UKPDS)

Those gaining the most weight tend to have lost weight prior to insulin, or to have been under poor controlSuggests that some of the weight is ‘catch up’ weight

Still, intensifying diet, exercise is criticalLarger E. Diab Metab 2005. 31 (4, part 2); 4S51-56.

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Cost of Insulin

INSULIN

ONE VIAL (1,000 U)/FIVE-PACK PENS (1,500 U)

NPH

$45/$135

Detemir

$95/$190

Glargine

$95/$190

Regular

$45/$135

Aspart

$105/$200

Glulisine

$95/$180

Lispro

$105/$200

70/30 (regular)

$45/$135

70/30 (aspart)

$105/$200

75/25 (lispro)

$105/$200

Adapted from “Premixed Insulin for Type 2 Diabetes”, AHRQ, March 2009

http://www.effectivehealthcare.ahrq.gov/ehc/products/18/125/Insulin_Consumer_Web.pdf

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Antihyperglycemic Monotherapy:Maximum Therapeutic Effect on A1c

Precose [PI]. West Haven, CT: Bayer; 2003; Aronoff S, et al.

Diabetes Care. 2000;23:1605–1611; Garber AJ, et al. Am J Med. 1997;102:491–497; Goldberg RB, et al. Diabetes Care. 1996;19:849–856; Hanefeld M, et al.

Diabetes Care. 2000;23:202–207; Lebovitz HE, et al.

J Clin Endocrinol Metab. 2001;86:280–288; Simonson DC, et al. Diabetes Care. 1997;20:597–606; Wolfenbuttel BH, van Haeften TW. Drugs. 1995;50:263–288; Nelson P, et al. Diabetes Technol Ther

. 2007;9:317–326.

Garber AJ, et al. American Diabetes Association. 2008; 07

–

LB

.

Glipizide GITS

Insulin

-0.5

0

-1.0

-1.5

-2.0

Reduction in A1C Level (%)

Metformin

Nateglinide

Glimepiride

Repaglinide

Pioglitazone

Acarbose

Rosiglitazone

Sitagliptin

Exenatide

Liraglutide

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What About Other Medications with Insulin?GLP-1 agonists are generally FDA approved for combination use with insulin (updated monthly)

Colesevelam: one study (n=287) showed a significant reduction (0.4%) in A1c when added to pts taking insulin (but also a 20% increase in triglycerides)Acarbose: may see further reduction in A1c when used with insulin (may see more hypoglycemia)

Sulfonylureas/glinides: increased risk for hypoglycemia; some continue, especially if pt only on basal insulinTZDs: increased weight gain, fluid retention Metformin: safe to continue

Rodbard HW

et al. Endocrine Practice. Vol 15, No. 6, 2009.Brunetti L et al. Ann Pharmacother. 44(7-8), 1196-206, 2010.http://www.univgraph.com/bayer/inserts/precose.pdf

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peripheral

glucose uptake

hepatic

glucose

production

insulin

secretion

GLP-1

GIP

glucagon

secretion

gastric

emptying

DPP-4

GLP-1

GIP

Inhibitor

Physiology of the Incretin System :

A Key Regulator of Post-Prandial Glucose Metabolism

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The Incretin Effect

Beta-Cell Response to Oral vs IV Glucose

Incretin Effect

*

*

*

*

*

*

*

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GLP-1 Effects in Humans

Understanding the Natural Role of Incretins

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Glucagon-Like Peptide-1

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Exenatide: Clinical Pharmacology

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Frequent Adverse Events in Diabetic Patients Treated With GLP-1 Analogues

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Change in Body Weight Following 82 Weeks of Exenatide Treatment

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Kim D et al.

Diabetes Care. 2007;30(6):1487-1493.

*P<0.0001 compared with placebo LAR.LAR=long-acting release.

Effects of Exenatide LAR on A1C in Patients With Type 2 Diabetes

Weeks3

6

9

12

15

Mean A1C (%)

6

7

8

9

10

0

Placebo LAR (n=14)

Exenatide LAR 0.8 mg (n=16)

Exenatide LAR 2.0 mg (n=15)

+0.4 ± 0.3%

-1.4 ± 0.3%*

-1.7 ± 0.3%*

Mean :

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Kim D et al.

Diabetes Care

. 2007;30(6):1487-1493.

*

P

<0.05 compared with placebo LAR.

LAR=long-acting release.

Effects of Exenatide LAR on Weight in Patients With Type 2 Diabetes

Weeks

3

6

9

12

15

Mean Change in Weight (kg)

- 6

- 5

- 4

- 3

- 2

0

0

-0.04 ± 0.7 kg

-0.03 ± 0.7 kg

-3.8 ± 1.4 kg*

- 1

1

2

Placebo LAR (n=14)

Exenatide LAR 0.8 mg (n=16)

Exenatide LAR 2.0 mg (n=15)

Mean :

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Once-Weekly vs Twice-Daily Exenatide in Type 2 Diabetes: A1C

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Frederick: A Case60 years old, diabetes for 8 yearsObese (BMI 33, wt =100 kg) with

non-proliferative retinopathy, normal renal functionNot much exercise; not successful with dietary changes

Metformin 1g BID, glimepiride 4 mg daily Sitagliptin 100 mg dailyCurrent A1c = 9.4% Home glucose (checks 3-4 times per week)Fasting : 180-200 mg/dLPre-meal glucose : 200-250 mg/dL

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What Dose?Calculate total daily dose (TDD)0.5 units per kg body weightMore if obese, less if high-risk for hypoglycemia

Approximately ½ of TDD is basal insulin and ½ is meal-time insulin (divided by three meals)80 kg patient; TDD = 40 units

20 units basal insulin, 20 units meal-time (about 6 units per meal)

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Correction Insulin:The 1700 Rule

Once you know the total daily dose, you can determine how many mg/dL blood glucose 1 unit of rapid-acting insulin will cover1700/TDD = # mg/dL lowered by 1 unit

Example: 80 kg patient; TDD 0.5 x 80 kg40 units TDD 1700/40 = 42.5 (round to 40) mg/dL1 unit of rapid-acting insulin will lower the glucose by about 40 mg/dL

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Frederick was started on 22 units of basal insulin at bedtime He chose an insulin pen, and gave his first injection in the office before leaving

He was provided with a self-titration scheduleHe was seen within the month by a provider in the practice

At his 3 month visit:A1c = 7.1% FPG= 115-135 mg/dL

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Persons More likely to Have Events with Intensification of Treatment

Women: HR 1.21 (95% CI: 1.02- 1.43)

African American:

HR 1.43 (95% CI: 1.20- 1.71)

Albumin:creatinine >300: HR 1.74(95% CI:1.37-2.21)

BMI

>

30:

HR 0.65

(95% CI: 0.50-0.85)

Coronary Artery Disease

or calcification

HR Risk =2-4 X :

Every 1 yr increase in age:

HR 1.03

(95% CI: 1.02, 1.05)

Autonomic Nerve Dysfunction:

HR 4.43

Numb feet:

HR 2.8

Long Duration

>12-15 y of Diabetes:

Previous Hypoglycemic Event:

Vinik, Maser, Ziegler

Autonomic Imbalance: Prophet of Doom or Hope. Diabetic Medicine 2010; 28; 643-651

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Frederick was titrated with his basal insulin and did well for ~ 2yearsHe experienced little hypoglycemia; gained about 12

lbs; basal dose now 64 units daily, continues with metformin, SU and sitagliptin.He is frustrated by weight gain and worsening control

At his 30 month visit:A1c = 7.9% (avg. 180 mg/dL) FPG= 100-110 mg/dLPPG = 180-220 mg/dL

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What is next best step?Add meal time insulin ?

Add injectable incretin ?Bariatric Referral?

Transition to u-500 insulin?

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DEVICES

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First “Sliding Scale” Insulin

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The STAR 3 Study

1-Year Randomized Controlled Trial

Comparing Sensor-Augmented Pump (SAP) and Multiple Daily Injection (MDI) Therapies

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Rise Rate AlertRise Rate Alert

11 mmol

3.5 mmol

Glucose is trending at a rate

≥ .2 mmol/min

RISE

RATE

1:33P

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Frederick F.: A Case60 years old, diabetes for 15 yearsObese (BMI 30, wt =80 kg) with

(+) MAERuns 3 miles daily

Detemir insulin 40 units AM, Pre-meal analogue insulin 10 unitsCurrent A1c = 8.9% Home glucose checks Fasting and pre mealsFasting : 130 mg/dLPre-meal glucose : 140-170

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Lunch is largest meal

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SummaryMultiple strategies for controlaloija@evms.edu

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