advances in diabetes joseph a. aloi, md, facp, face associate professor of medicine clinical...
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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