Advances in Diabetes
Drugs, devices, and practice
Joseph A. Aloi, MD, FACP, FACE
Associate Professor of Medicine
Clinical Director: Strelitz Diabetes Center
Eastern Virginia Medical School
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 prediabetes
 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 Increases
Overall Cardiovascular Mortality
Four-fold in Women
Two-fold in
Men
60
Diabetes
No Diabetes
50
40
2x
30
20
10
0
0-3
4-7 8-11 12-15 16-19 20-23
Duration of Follow-up (Years)
Krolewski AS et al. AJM. 1991;90(Supp 2A):56S-61S
Mortality Rate Per 1000
Mortality Rate Per 1000
60
50
40
4-5x
30
20
10
0
0-3
4-7 8-11 12-15 16-19 20-23
Duration of Follow-up (Years)
Cardiovascular Disease Mortality Increased
in the Metabolic Syndrome: Kuopio
Ischaemic Heart Disease Risk Factor Study
15
Cumulative Hazard, %
Cardiovascular Disease Mortality
Metabolic
Syndrome:
RR (95% CI), 3.55 (1.98–6.43)
10
YES
5
NO
0
0
2
4
6
Follow-up, y
Lakka HM et al. JAMA 2002;288:2709-2716.
8
10
12
Adjusted incidence
per 1000 person-years (%)
MI and Microvascular End Points: Incidence
by HbA1c Concentration in UKPDS
80
60
40
MI
As A1c increases
from 5.5% to 11%, MI
increases 2-fold while
microvascular events
increase 10-fold.
20
0
Microvascular
end points
5
6
7
8
9
10 11
Updated mean HbA1c concentration (%)
Adler AI et al. BMJ 2000;321:412-419. | Stratton IM et al. BMJ 2000;321:405-412.
Estimated Prevalence of All Types of Diabetes and
Prediabetes in Virginia, 2005
396,260
Diagnosed
1,208,841
Prediabetes
(IFG and IGT)
198,130
Undiagnosed
4,479 Children
(<20) yo
Potentially modifiable
112,339
Gestational
A1C = Estimated Average Glucose
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
Nathan DM, et al. Diabetes Care August 2008 vol. 31 no. 8 1473-1478
AACE recommendations:
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.
ENDOCRINE PRACTICE Vol 16 No. 2 March/April 2010 155-6
AACE recommendations cont’
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.
ENDOCRINE PRACTICE Vol 16 No. 2 March/April 2010 155-6
DRUGS
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
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
Why Insulin Therapy in Diabetes?
 Central
role in both Type 1 and Type 2
diabetes

Greatest potency of all available therapies
Insulin
Deficiency
(Absolute)
Type 1 Diabetes
Insulin
Resistance
+
Insulin
Deficiency
(Relative)
Type 2 Diabetes
UKPDS: -Cell Function Declines Over Time
-Cell Function (%)*
100 –
75 –
50 % -Cell Function at Diagnosis
50 –
25 –
0 –l
l
-12 -10
l
-6
l
l
l
l
-2
0
2
6
Years from Diagnosis
l
10
l
14
* 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.
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

Meal-time insulin:



Also called prandial,
nutritional
Insulin required to
manage rise in glucose
after a meal is eaten
Regular, aspart, glulisine,
lispro
www.iheartguts.com
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.
Insulin Profiles
Rapid-acting analogues
Plasma Insulin Levels
Regular insulin
NPH
Long-acting analogues
0
2
4
6
8
10
12
14
16
18
20
22
24
24
Time (hours)
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.
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.
Treat-to-Target Study:
Insulin Glargine vs NPH Insulin
Added to Oral Therapy
9
Insulin glargine
NPH insulin
8
Mean A1c
(%)
7
60% reach target A1C < 7%
TARGET
6
0
4
8
12
16
20
24
Weeks
Riddle MC, Rosenstock J. Diabetes. 2002;51(suppl 2):A113.
Detemir vs NPH:
Risk of Hypoglycemia
p < 0.001
Hypoglycemic
events per
patient per year
18
16
14
12
10
8
6
4
2
0
Detemir + OAD
NPH + OAD
p < 0.001
Overall
Nocturnal
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
Long-Acting Insulin Analogues and
concentrated insulin on the horizon
FDA Panel Endorses Insulin Degludec
Nov 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 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
Antihyperglycemic Monotherapy:
Maximum Therapeutic Effect on A1c
Acarbose
Nateglinide
Sitagliptin
Liraglutide
Exenatide
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C Level (%)
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.
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 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
Physiology of the Incretin System : A Key Regulator
of Post-Prandial Glucose Metabolism
gastric
emptying
insulin
secretion
GLP-1
GLP-1
GIP
GIP
DPP-4
Inhibitor
hepatic
glucose
production
glucagon
secretion
peripheral
glucose
uptake
*
*
*
*
Incretin Effect
*
*
*
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
Effects of Exenatide LAR on A1C in
Patients With Type 2 Diabetes
Placebo LAR (n=14)
Exenatide LAR 0.8 mg (n=16)
Exenatide LAR 2.0 mg (n=15)
Mean A1C (%)
10
Mean :
+0.4 ± 0.3%
9
8
-1.4 ± 0.3%*
7
-1.7 ± 0.3%*
6
0
3
*P<0.0001 compared with placebo LAR.
LAR=long-acting release.
6
9
Weeks
12
15
Kim D et al. Diabetes Care. 2007;30(6):1487-1493.
Mean Change in Weight
(kg)
Effects of Exenatide LAR on Weight in
Patients With Type 2 Diabetes
Placebo LAR (n=14)
Exenatide LAR 0.8 mg (n=16)
Exenatide LAR 2.0 mg (n=15)
2
1
0
-1
-2
Mean :
-0.04 ± 0.7 kg
-0.03 ± 0.7 kg
-3
4
-5
-6
-3.8 ± 1.4 kg*
0
3
*P<0.05 compared with placebo LAR.
LAR=long-acting release.
6
9
Weeks
12
15
Kim D et al. Diabetes Care. 2007;30(6):1487-1493.
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
Albumin:creatinine >300:
HR 1.74
(95% CI:1.37-2.21)
African American:
HR 1.43
(95% CI: 1.20- 1.71)
Long Duration
>12-15 y of Diabetes:
Every 1 yr increase in age:
HR 1.03
(95% CI: 1.02, 1.05)
Women:
HR 1.21
(95% CI: 1.02- 1.43)
BMI > 30:
HR 0.65
(95% CI: 0.50-0.85)
Autonomic Nerve
Dysfunction:
HR 4.43
Numb feet:
HR 2.8
Coronary Artery Disease
or calcification
HR Risk =2-4 X :
Vinik, Maser, Ziegler
Autonomic Imbalance: Prophet of Doom or Hope. Diabetic Medicine 2010; 28; 643-651
Previous Hypoglycemic
Event:
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 Alert
11
mmol
3.5
mmol
Glucose is trending at a rate
≥ .2 mmol/min
1:33P
RISE
RATE
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