Advances in Diabetes

Joseph A. Aloi, MD, FACP, FACEAssociate Professor of Medicine

Clinical Director: Strelitz Diabetes CenterEastern Virginia Medical School

Drugs, devices, and practice

DISCLOSURES

Served as a consultant to Sanofi-Aventis PI on 2 clinical Trials (DPP4 – Takeda,

SGLT2 – BI) Acknowledge Dr. David Lieb and The

National Diabetes Education Initiative (NDEI.org)

Goals Discuss approach to patients with pre-

diabetes Highlight new drugs in use and on the

horizon? How do you initiate insulin therapy? What about non-insulin injectables

(pramlintide, GLP agonists) Devices/Technology

Pre-Diabetes

Frederick: A Case 30 years old, worried about diabetes Obese (BMI 39 kg/m2), HTN, LIPIDS, (+) FHX Not 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

Is this important?

At what FPG does your risk for retinopathy increase?

Is this important?

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

Is this important?

What % of patients at diagnosis of DM have evidence of complications? Retinopathy 15% Nephropathy 20-25% Neuropathy 30%

Diabetes IncreasesOverall Cardiovascular Mortality

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

DiabetesNo Diabetes

60

Two-fold inMen

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

04-7 8-11 12-15 16-19 20-23

Mor

talit

y R

ate

Per 1

000

Mor

talit

y R

ate

Per 1

000

2x

4-5x

Cardiovascular Disease Mortality Increased in the Metabolic Syndrome: Kuopio Ischaemic Heart Disease Risk Factor Study

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

Cum

ulat

ive

Haz

ard,

%

0 2 6 8 12Follow-up, y

YES

Metabolic Syndrome:

NO

Cardiovascular Disease Mortality

RR (95% CI), 3.55 (1.98–6.43)

4 100

5

10

15

Adler AI et al. BMJ 2000;321:412-419. | Stratton IM et al. BMJ 2000;321:405-412.

Updated mean HbA1c concentration (%)

0

20

40

60

80

Ad

just

ed in

ciden

ce

per

10

00

pers

on

-years

(%

)

5 6 7 8 9 10 11

Microvascular end points

MI

MI and Microvascular End Points: Incidence by HbA1c Concentration in UKPDS

As A1c increases from 5.5% to 11%, MI increases 2-fold while microvascular events increase 10-fold.

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

396,260Diagnosed

198,130Undiagnosed

4,479 Children (<20) yo

112,339Gestational

1,208,841Prediabetes(IFG and IGT)

Potentially modifiable

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

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

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

DRUGS

DPP-4 Inhibitors• Mechanism: insulin secretion (BG-dependent),

glucagon secretionLowers 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

Renal glucose handling SGLT2 mediates 90% of filtered glucose

reabsorption in the convoluted segment of the proximal renal tubule

SGLT1 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 exceeded

Hyperglycaemia increases SGLT2 and maximal capacity; excess glucose returns to the bloodstream

Safety of SGLT2 inhibition

Long-term safety not yet studied Short-term studies show

Minimally increased urine volume No excessive losses of fluid, sodium, or potassium Few instances of hypoglycemia Increased urinary tract infections and vaginitis Modest weight loss

Individuals with familial renal glycosuria are asymptomatic

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 practice

With an increase in longevity DM complications such as retinopathy also increase

Shortened life expectancy persists until the 1940s

Insulin is an anabolic protein hormone necessary for life;

Before & After

IM Isletin

Type 1 Diabetes

Why Insulin Therapy in Diabetes?

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

InsulinDeficiency(Relative)

InsulinResistance

InsulinDeficiency(Absolute)

Type 2 Diabetes

+

* 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-

Cel

l F

un

ctio

n (

%)*

Years from Diagnosis

25 –

100 –

75 –

0 –

50 –

l-12

l-10

l-6

l-2

l0

l2

l6

l10

l14

50 % -Cell Function at Diagnosis

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

hypoglycemia 45% worried they would need insulin forever More 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.

More Patient Perceptions

Many patients know someone (often a family member) who has been on insulin

Often 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.

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 care

Belief 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.

Basal vs. Meal-time Insulin

Basal insulin: Insulin required to

maintain normal blood glucose while fasting

Offsets hepatic glucose production

NPH, glargine, detemir

www.iheartguts.com

Meal-time insulin: Also called prandial,

nutritional Insulin required to

manage rise in glucose after a meal is eaten

Regular, aspart, glulisine, lispro

Insulin Analogues

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

Insulin Analogues Closely Match the Physiologic Insulin Profile

Basal insulin analogues Slow and steady rate of absorption Protracted actions Low within-subject variability in actions

Meal-time insulin analogues Rapid 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.

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

Pla

sma

Insu

lin

Lev

els

Time (hours)

Long-acting analogues

NPH

Regular insulin

Rapid-acting analogues

24

Long-Acting Insulin Analogues vs NPH in Type 2 Diabetes: A Meta-Analysis

Analogues 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.

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

NPH + OAD

Detemir + OAD

Hypoglycemic events per

patient per year

Detemir vs NPH:

Risk of Hypoglycemia

02

4

6

8

10

12

1416

18

Overall Nocturnal

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

p < 0.001

p < 0.001

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.

Long-Acting Insulin Analogues and concentrated insulin on the horizon

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

U500

Insulin and Weight Gain

Insulin initiation does lead to weight gain But 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 control

Suggests that some of the weight is ‘catch up’ weight

Still, intensifying diet, exercise is critical

Larger E. Diab Metab 2005. 31 (4, part 2); 4S51-56.

Cost of InsulinINSULIN 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 2009http://www.effectivehealthcare.ahrq.gov/ehc/products/18/125/Insulin_Consumer_Web.pdf

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

-0.50 -1.0 -1.5 -2.0Reduction in A1C Level (%)

Metformin

Nateglinide

GlimepirideRepaglinidePioglitazone

Acarbose

Rosiglitazone

Sitagliptin

ExenatideLiraglutide

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 insulin

TZDs: increased weight gain, fluid retention

Metformin: safe to continueRodbard 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

peripheralglucose uptake hepatic

glucose production

insulin

secretionGLP-1

GIP

glucagonsecretion

gastric

emptying

DPP-4

GLP-1GIP

Inhibitor

Physiology of the Incretin System : A Key Regulator of Post-Prandial Glucose Metabolism

The Incretin Effect Beta-Cell Response to Oral vs IV Glucose

Incretin Effect*

*

*

*

**

*

GLP-1 Effects in HumansUnderstanding the Natural Role of Incretins

GLP-1 secreted upon the ingestion of food

Glucagon-Like Peptide-1

Exenatide: Clinical Pharmacology

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

Change in Body Weight Following 82 Weeks of Exenatide Treatment

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

Mea

n A

1C (

%)

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 :

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

Weeks3 6 9 12 15

Mea

n C

han

ge

in W

eig

ht

(kg

)

- 6

- 5

- 4

- 3

- 2

0

0

-0.04 ± 0.7 kg

-0.03 ± 0.7 kg

-3.8 ± 1.4 kg*

- 1

12

Placebo LAR (n=14)Exenatide LAR 0.8 mg (n=16)Exenatide LAR 2.0 mg (n=15)

Mean :

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

Frederick: A Case 60 years old, diabetes for 8 years Obese (BMI 33, wt =100 kg) with non-proliferative retinopathy, normal renal function Not much exercise; not successful

with dietary changes Metformin 1g BID, glimepiride 4 mg daily Sitagliptin 100 mg daily Current A1c = 9.4% Home glucose (checks 3-4 times per week)

Fasting : 180-200 mg/dL Pre-meal glucose : 200-250 mg/dL

What Dose?

Calculate total daily dose (TDD) 0.5 units per kg body weight More 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)

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 cover

1700/TDD = # mg/dL lowered by 1 unit Example: 80 kg patient; TDD 0.5 x 80 kg 40 units TDD 1700/40 = 42.5 (round to 40) mg/dL 1 unit of rapid-acting insulin will lower the

glucose by about 40 mg/dL

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 schedule

He was seen within the month by a provider in the practice

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

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

Frederick was titrated with his basal insulin and did well for ~ 2years

He 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/dL PPG = 180-220 mg/dL

What is next best step?

Add meal time insulin ? Add injectable incretin ? Bariatric Referral? Transition to u-500 insulin?

DEVICES

First “Sliding Scale” Insulin

The STAR 3 Study

1-Year Randomized Controlled Trial Comparing Sensor-Augmented Pump (SAP) and Multiple Daily Injection (MDI) Therapies

Rise Rate Alert

Rise Rate Alert11

mmol

3.5 mmol

Glucose is trending at a rate ≥ .2 mmol/min

RISERATE

1:33P

Frederick F.: A Case 60 years old, diabetes for 15 years Obese (BMI 30, wt =80 kg) with (+) MAE Runs 3 miles daily Detemir insulin 40 units AM, Pre-meal analogue

insulin 10 units Current A1c = 8.9% Home glucose checks Fasting and pre meals

Fasting : 130 mg/dL Pre-meal glucose : 140-170

Lunch is largest meal

Summary Multiple strategies for control

aloija@evms.edu