Download DIABETES COMPLICATIONS AND THERAPEUTICS

DIABETES
COMPLICATIONS
AND
THERAPEUTICS
Robert Zimmerman, MD
A 19 yo f has a 1 year hx of type 1 DM.
Which of the following statements is true regarding
her evaluation?
A. She should be referred to an ophthalmologist to
screen for diabetic retinopathy
B. She should have a urine screen for albumin.
C. She should have screening lipids.
D. She should have a creatinine clearance.
E. All of the above
Screening Guidelines for Diabetes Mellitus
Type 1 DM Type 2 DM
Retinopathy
5 years
baseline
Nephropathy
5 years
baseline
HgbA1c
baseline
baseline
Lipids
baseline
baseline
Foot exam
baseline
baseline
A 50 y/o male presents with chest pain
– Pt. developed chest pain walking to his seat at at the
Cleveland Dew Tour.
– Pain was substernal, radiating to the left arm.
– The pain resolved after sitting in his seat. The pain
returned after a biker nearly fell off his bike while
soaring over Terminal Tower. The pain resolved 2
minutes later.
– During the Dew Tour the patient drank 8 large cokes
and missed much of the acrobatics due to frequent
stops in the bathroom.
50 y/o family history/PE
–
Patient’s father had type 2 diabetes and died of a heart
attack at age 57. Patient’s brother has hypertension,
diabetes, hyperlipidemia
Physical Exam
–
–
–
WD/WN WM NAD BP 156/92 P84 R12
–
Abd benign No edema
Head NC/AT Eyes No retinopathy
Lungs clear Heart sounds normal
LAB
–
–
–
EKG NS ST-TW changes
Glucose 250, Na 130, K 4.0,
CBC normal
–
–
–
–
–
A. Insulin
B. Sulfonylurea
C Metformin
D Thiozolidinedione
E Nateglanide
UKPDS: Glycemic Control Study in
Type 2 Diabetes
Effect of Metformin
0
Any
DiabetesRelated
Endpoint
DiabetesRelated
Death
All-Cause
Mortality
Myocardial
Infarction
Fatal MI
-10
-20
Risk
Reduction-30
(%)
-40
-50
-32
-36
-42
-39
-50
-60
UKPDS Report 34. Lancet 1998.
50 y/o
– Patient treated with metformin 1000 bid initially with
good response
– Also treated with atenolol 50 q am for chest pain and
hypertension
– After 1 year he gained 10 pounds and was having
blood sugars in the 200’s
– Patient developed chest pain during rib burn-off at
the lakefront.
– Patient to be admitted for cath and possible
angioplasty
–
The patient was found to have a 90 % occlusion in the LAD, and
underwent angioplasty after being treated with glimeperide for
his elevated blood sugar and atorvastatin 10 mg for LDL
cholesterol of 130 mg/dl.
–
Prior to his next office visit he was found to have the following
labs
–
–
–
–
–
TG 160
Cholesterol 190
LDL Cholesterol 98
HbA1c 7.2
FBS 130
Which of the following would be the most
appropriate management for this patient?
A Increase atorvastatin to 80 mg/d
B Improve glycemic control to a goal
HbA1c of 6.0
C Add fenofibrate
D Add ezetimibe
ACCORD
– A comprehensive, customized, therapeutic strategy
targeting glycated hemoglobin levels below 6.0%
increased the rate of death from any cause after a
mean of 3.5 years, as compared with a strategy
targeting levels of 7.0 to 7.9% in patients with a
median glycated hemoglobin level of 8.1% and either
previous cardiovascular events or multiple
cardiovascular risk factors.
– As compared with the standard-therapy group, the
intensive-therapy group had a relative increase in
mortality of 22% and an absolute increase of 1.0%
during this follow-up period, with similar differences in
death from cardiovascular causes
Gerstein HC et al N Engl J Med 2008; 358: 2545-2559
Effects of Combination Lipid Therapy
in Type 2 Diabetes Mellitus ACCORD
n engl j med 362;17, 2010
Effect of Simvastatin with or without Ezetimibe
in Familial Hypercholesterolemia on carotid intimal
thickness
Simvastatin
LDL cholesterol
192.7±60.3 mg/dl
Combined-therapy group
141.3±52.6 mg/dl
n engl j med 358, 1431, 2008
Intensive Lipid Lowering with Atorvastatin
in Patients with Stable Coronary Disease
La Rosa et al n engl j med 352, 1426, 2005
– PROVE IT–TIMI 22
- Randomized, double-blind
- N=4162; ACS <10 d
- Atorvastatin 80 mg/d,
pravastatin 40 mg/d
- Design: equivalence
– Primary endpoint: composite CV
events
– LDL-C
- Baseline: 106 mg/dL
- Study: 95 mg/dL vs 62 mg/dL
Death or Major
Cardiovascular Event (%)
Is Very Low LDL-C the Answer?
30
40 mg of
pravastatin
25
20
80 mg of
atorvastatin
15
10
5
0
P = 0.005
0
No.
at Risk
Prav 2063
Atorv 2099
3
6
9 12 15 18 21 24 27 30
Months of Follow-up
1688
1736
– 25% relative risk reduction of
outcomes
Cannon CP et al. N Engl J Med 2004;350:1495-1504. Copyright 2004
Massachusetts Medical Society. All rights reserved.
1536
1591
1423
1485
810
842
138
133
52 y/o B/M with diabetes following a
kidney transplant
– Patient developed end stage renal disease
secondary to hypertension
– Doing well after transplant but now has increased
urination due to prednisone 10 mg/d
– Found to have high blood sugar on random afternoon
check of 300.
–
–
–
–
Patient has Cr of 1.6
Patient treated with glipizide 10 mg q AM
Blood sugars AM 100, L118, D 110 HS 300
How would you treat this patient at this time?
– A Add metformin
– B Add a second dose of glipizide at
supper
– C Add a dose of repaglinide at supper
– D Stop prednisone
– E Start glucovance
Insulin Response to Repaglinide
100
80
Insulin
60
(U/mL)
40
Repaglinide
20
Placebo
0
100
80
Repaglinide Doses
Repaglinide
60
Blood Levels
(mg/mL) 40
20
0
0
2
4
6
1
1
1
1
8
0
2
4
6
Hours After First Dose
1
8
2
0
2
2
2
4
Strange P, Diabetes Technol Ther 1999.
40 y/o W/F who presents with acanthosis
nigracans, hirsutism, and diabetes
–
–
–
–
She has been having irregular periods since age 12
She has been struggling with facial hair since age 14
Physical Exam is notable for BP 150/93 Ht 5’2”,
weight 130 lbs, acanthosis nigricans around her
neck, hair above her lip
– Labs notable for glucose 250, Testosterone 95 (2080), Hb A1c 9.0, Cr 1.6
Which of the following agents would be
most appropriate to start in this patient?
–
–
–
–
–
A. Insulin
B. Glyburide
C Repaglinide
D Thiazolidinedione
E Metformin
52 y/o obese male c/o nocturia 2 x/night, 10 lb
weight loss, and blurred vision. You screen the
patient for diabetes. Which of the following is
diagnostic of diabetes
A. 3+ glucose on urine dip stick
B. HbA1c 6.5
C. FBS 125
D. 2 Hr post prandial blood sugar 199
E. Evidence of proliferative diabetic
retinopathy
New Diabetes Classifications
Increased Risk for Diabetes
– IFG FPG >100 <126
– IGT 2 hour p 75 g glucose dissolved in water PG >
140 <200
– HbA1c 5.7-6.4%
Diabetes
– Diabetes FPG >126 , 2 hour p 75 g glucose load
PG> 200, casual glucose > 200 with symptoms
– HbA1c > 6.5%
23 y/o w/f with Type 1 Diabetes presents with
difficult to control blood sugars , frequent
nightmares, and a wet pillow case. She is
currently taking 20 N 10 R AM , 10N 10 R PM
Breakfast
Lunch
Dinner
Bedtime
254
95
115
178
300
120
98
110
285
110
89
95
You check a 3 am blood sugar and it is
30. The most apporpriate action is to
A Decrease the PM NPH insulin due to the Dawn
phenomenon
B Decrease the PM NPH due to the Somogyi
effect
C Increase the PM NPH due to high blood
sugars in the AM
D Decrease the bedtime snack due to high blood
sugars in the AM
Which of the following has been
shown to be the most effective
treatment to prevent diabetes in a
patient with IFG or IGT?
– A Exenatide
– B Insulin
– C Exercise
– D Metformin
3234 subjects
with IFG or IGT
Which of the following is not a criteria for
the metabolic syndrome?
– A Waist circumference > 102 cm in
men
– B Evidence of Coronary Artery Disease
– C Triglyceride level greater than 150
– D BP > 130/85
– E Fasting glucose > 110
Which of the following is associated
with the greatest weight reduction?
–
–
–
–
–
A Metformin
B Exenatide/Liraglutide
C Acarbose
D Pramlintide
E Nateglanide
Mechanism of Incretins
Incretin
Incretin
Mimetic
Mimetic
Ingestion
of food
GI tract
DPP-4
inhibitor


Glucose
dependent
 Insulin
(GLP-1and
GIP)
Pancreas
Release of
active incretins
GLP-1 and GIP
X
Inactive
GLP-1
DPP-4
enzyme
Beta cells
 Blood glucose
in fasting and
postprandial
states
Alpha cells
Glucosedependent
 Glucagon
(GLP-1)
Inactive
GIP
 Glucose
uptake by
peripheral
tissue
 Hepatic
glucose
production
Incretin hormones GLP-1 and GIP are released by the intestine throughout the day, and their levels 
in response to a meal.
Incretin Mimetics are resistant to DPP-4 inactivation
Concentrations of the active intact hormones are increased by DPP-4 inhibition, thereby increasing
and prolonging the actions of these hormones.
GLP-1=glucagon-like peptide-1; GIP=glucose-dependent insulinotropic polypeptide.
Matching Pharmacology to Pathophysiology
Glucose Influx
 Glucagon
Secretion
-Glucosidase
Inhibitors
 Hepatic
Glucose
Output
Metformin
(Glitazones)
Plasma
Glucose
Insulin
SU
Meglitinides
Nateglinide
Glitazones
(Metformin)
 Peripheral
Glucose Uptake
Source: DeFronzo R, Ann Intern Med 1999;131:281-303
 Insulin
Secretion
Which of the following is not approved
for treating diabetes in the United States?
–A
–B
–C
–D
–E
Rosiglitizone
Bromocriptine
Colesevelam
Pramlintide
Carbergoline
Pramlintide Reduces Postprandial
Glucose Excursions
– Suppresses postprandial glucagon
secretion
– Slows gastric emptying
– Reduces food intake
– Decreases weight
– Reduces HbA1c up to 0.7%
– Requires 3 injections/day
Bromocriptine: Proposed
mechanism of action
Morning
administration
(within 2 hours
of waking) of
CYCLOSET
Corrects
Low dopaminergic tone in
hypothalamus in early
morning in diabetes
Restoration of morning
peak in dopaminergic
activity (via D2 receptormediated activity)
Sympathetic tone
HPA axis tone
 Hepatic gluconeogenesis
 FFA and TG
 Insulin resistance
 Inflammation/hypercoagulation
Impaired glucose metabolism,
hyperglycemia and insulin resistance
Adverse cardiovascular pathology
Sympathetic tone
HPA axis tone
 Hepatic gluconeogenesis
 FFA and TG
 Insulin resistance
 Inflammation/hypercoagulation
Decreased postprandial glucose levels
Reduction in insulin resistance
Day-long reduction in plasma glucose,
TGs and FFAs
Fonseca. Use of Dopamine agonists in Type-2-Diabetes. Oxford American Pocket Cards. OUP, 2010
Cincotta. Hypothalamic role in Insulin Resistance and insulin Resistance Syndrome. Frontiers in Animal39
Diabetes
Research Series. Taylor and Francis, Eds Hansen,
B Shafrir, E London, pp 271-312, 2002
39
CYCLOSET® (bromocriptine mesylate) Tablets
A unique formulation of bromocriptine
CYCLOSET®
4.8 mg tablets
•
Traditional formulations of
bromocriptine were not designed to
provide the same pharmacokinetic/
pharmacodynamic profile as
CYCLOSET at equivalent dosing
•
CYCLOSET is a novel quick-release
formulation of bromocriptine that
increases CNS dopaminergic activity
•
CYCLOSET has no AB-rated equivalent
Novartis Parlodel®
5 mg tablets
Mylan bromocriptine
5 mg tablets
*AB is the FDA therapeutic equivalence rating that indicates
bioequivalence has been studied and demonstrated
40
confidential
Data on file, Santarus, Inc
Cycloset® Safety Trial:
Evaluation of A1c Reduction of
Cycloset in a 24-week Efficacy Period
0.6% to 0.9% HbA1c reductions vs. placebo when CYCLOSET
added to other oral antidiabetics (OAD)
0.4
Failing Any OAD
(n=412)
Failing Metformin
± OAD
(n=282)
Failing Metformin
+ Sulfonylurea
(n=192)
Failing TZD ± OAD
(n=81)
Placebo
0.2
CYCLOSET
0
Average baseline
HbA1c 8.3%
-0.2
-0.4
-0.6
- 0.57
P<.0001
-0.8
- 0.69
P<.0001
- 0.69
P=.0002
- 0.91
P=.0026
HbA1c changes from
baseline vs. placebo in
patients completing 24
weeks of treatment (per
protocol population) (%)
Efficacy data in combination with thiazolidinediones are limited. Efficacy has not been
confirmed in combination with insulin.
Data on file, Santarus, Inc
Scranton et al, Diabetologia 2008; 51 (Suppl. 1): S372-373. Poster, EASD 2008. Rome, Italy
Cincotta et al, Diabetologia 2008; 51 (Suppl. 1): S22. Poster, EASD 2008. Rome, Italy
KM Curve – Cycloset® Safety Trial
Cumulative Percent Composite CVD Endpoint
HR 0.58; 95% CI,
0.35-0.96
RRR=42
%
*MI, Stroke, hospitalization unstable angina, hospitalization CHF, or coronary revasc.
KM Curve: the separation in favor of Cycloset begins 3 months and persists through the end
of the study
42
Gaziano M. Diabetes Care 2010, March 23 online
Colesevelam
N=141
N=166
Fonseca, DIABETES CARE, VOLUME 31, NUMBER 8, AUGUST 2008
–
70-year-old man who has type 2 diabetes mellitus and severe
chronic broncho-pulmonary disease
–
Admitted to the intensive care unit (ICU) for treatment of TB. He
is mechanically ventilated.
–
On the second hospital day, the patient begins receiving enteral
feeding (Ensure 50cc/hr) through a nasogastric catheter.
–
He has had 3 recent hospitalizations for respiratory failure with
ICU stays of greater than 2 weeks.
–
His usual diabetes medications are insulin levemir, 30 units at
bedtime, and pioglitizone, 30 mg orally daily.
–
A recent hemoglobin A1C is 7.5% [4.0–6.1].
Which of the following is the best treatment plan to
manage this patient’s plasma glucose levels and
reduce mortality risk?
– (A) Regular Insulin infusion with a plasma glucose
goal of 80 to 110 mg/dL
– (B) Lispro Insulin infusion with a plasma glucose goal
of 80 to 220 mg/dL
– (C) Regular Insulin infusion with a plasma glucose
goal of 140 to 180 mg/dL
– (D) Insulin glargine, 20 units daily, and supplemental
insulin lispro every six hours with a plasma glucose
goal of 100-150 mg/dL
– (E) Insulin Levemir, 20 units daily, and supplemental
insulin Novolog every six hours with a plasma
glucose goal of 140 to 180 mg/dL
Intensive Insulin Therapy in Critically
Ill Patients
Conventional
Intensive
Mean AM BG
(mg/dL)
153
103
% Receiving insulin
39%
100%
6
39
BG <40 mg/dL
Conventional insulin treatment Rx insulin when blood glucose >215 mg/dL
Intensive insulin treatment Rx insulin when glucose >110 mg/dL; target range =
80–110 mg/dL N=1548
van den Berghe G, et al. N Engl J Med. 2001;345:1359–1367.
Leuven Study: Intensive Insulin Therapy in
Critically Ill Patients Improves Survival
Survival in ICU (%)
100
Intensive treatment
96
4.6% mortality
92
Conventional treatment
8% mortality
88
84
Risk reduction = 40%
80
0
0
20
40
60
80
100 120 140 160
Days After Admission
20 mg/dL  BG associated with 30%  risk of death
van den Berghe G, et al. N Engl J Med. 2001;345:1359–1367.
NICE - SUGAR
Intensive Control
90 day mortality
27.5%
24.9%
Severe hypoglycemia
6.8%
0.5%
Glucose control (median)
107
141 mg/dL
Insulin infusion
97%
69%
No difference – 30 day mortality, ICU days, hospital days,
days of mechanical ventilation, days of renal replacement,
organ failures
Critically Ill Patients
• Insulin therapy should be initiated for
treatment of persistent hyperglycemia,
starting at a threshold of no greater than 180
mg/dL (10.0 mmol/L).
• Once insulin therapy has been started, a
glucose range of 140 to 180 mg/dL (7.8 to
10.0 mmol/L) is recommended for the
majority of critically ill patients.
• Intravenous insulin infusions are the
preferred method for achieving and
maintaining glycemic control in critically ill
patients.
• Validated insulin infusion protocols with 49
demonstrated safety and efficacy, and with
l
t
f
fh
l
i
Severe Diabetic Complications
Overview
Microvascular Complications
Macrovascular Complications
Diabetic Retinopathy
Stroke
Diabetic Nephropathy
Heart
Disease
Diabetic Neuropathy
Peripheral
Vascular Disease
Harris MI. Clin Invest Med 1995;18:231-239
Nelson RG et al. Adv Nephrol Necker Hosp
1995;24:145-156
World Health Organization, 2002;Fact Sheet N° 138
50
Which of the following is not true regarding
diabetic retinopathy?
A. Glycemic control predicts the risk for onset of
diabetic retinopathy
B. Glycemic control predicts the risk for
progression of diabetic retinopathy
C. Laser therapy reduces risk of visual loss
D. Office ophthalmoscopy is adequate for
detection of significant retinopathy
E. PKC inhibitor trials show regression of
proliferative retinopathy
51
Retinopathy
52
DCCT: Glycemic Control Study in
Type 1 Diabetes
Effect on Cumulative Incidence of Complications
60.0
50.0
40.0
55.0
64%
Risk
Reduction
Cumulative
Incidence 30.0
(%)
20.0
59%
Risk
Reduction
29.8
Conventional
Intensive
39%
Risk
Reduction
64%
23.9
16.4
13.0
10.0
7.9
0.0
Retinopathy
Progression
54%
Risk
Reduction
5.1
2.5
Laser Rx Microalbuminuria Albuminuria
Risk
Reduction
13.4
5.0
Clinical
Neuropathy
DCCT. Ann Intern Med 1995.
DCCT. Kidney Int 1995.
DCCT. Ophthalmology 1995.
A 65 yo m has new onset type 2 DM.
Which of the following statements is/are likely true?
A. His WHR ratio is <0.65
B. His HDL cholesterol is low.
C. His LDL-C particle size is larger than his non
diabetic counterpart
D. His HgbA1c is normal at diagnosis
E. He will not develop renal disease
Which of the following is not true of 55 yo f
with a 20 yr hx of DM?
A. Her CHD risk is 5x her non DM female counterpart
B. An ulcer on her metatarsal is more likely secondary to
neuropathy than PVD.
C. Her risk for PVD is increased by smoking
D. Ischemic CHD symptoms are similar to her male
counterpart with DM
Cardiovascular Events in DCCT/EDIC
Cumulative Incidence
Cumulative Incidence of First of Any Event
0.12
0.10
Risk reduction 42%
95% CI: 19, 63
Log-rank P = 0.016
0.08
0.06
Conventional
0.04
Intensive
0.02
0.00
0
1
2
3
4
5
Number at Risk
Intensive: 705
Conventional: 714
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
Years from Study Entry
683
688
629
618
113
92
Lipid Lowering Trials in DM
– Summary of Lipid lowering trials with diabetic
patients shows favorable effects of LDL cholesterol
lowering
(Snow, Ann Int Med, 2004;140:650)
– Large subset of diabetic subjects in Heart Protection
Study (simva) got RR that was the same as nondiabetic subjects
– CARDs trial (atorva) had a RR 37%
– ASPEN trial (atorva) had a RR 10% (P = NS)
Use of Fibrates in Diabetes Mellitus
– Diabetic patients with/without CHD: focus on LDL
strategies
– Fibrate use or Niacin should be considered in pts
with
↑ triglycerides (↑ non-HDL cholesterol)
Complications of Type 1 DM
Neuropathy
- Peripheral
 Altered
Sensation (Numbness, Pain,
Dysesthesias)
- Autonomic
 Gastroparesis
 Impaired
bladder emptying
 Orthostatic
 Resting
hypotension
tachycardia
 Hypoglycemic
unawareness
A 55 yo m with 30 yr hx of type 1 DM presents with diarrhea and
fecal incontinence.
Which one of the following is not likely to be associated?
A. Resting tachycardia
B. Orthostatic hypotension
C. Impotence
D. Heme positive stools
E. Gustatory sweating
Which of the following statements is not true
about complications of diabetes mellitus?
A. ACE-inhibitor and ARB therapy have both shown
favorable reduction in nephropathy risk
B. Vitamin B12 deficiency may be associated with
glucophage use
C. Onset and progression of peripheral neuropathy are
related to duration of diabetes mellitus, but not to
glycemic control
D
Coronary heart disease risk in diabetic patients is 25 higher than in non-diabetic patients
E
Onset and progression of diabetic retinopathy are
favorably affected by intensive glycemic control
– Treatment of Diabetes now has more
therapeutic options
– Choice of Agents is often determined by
pathophysiology and side effects
– Improved control can prevent or delay the
long term complications of diabetes
– Preservation of Beta Cell Function is
emerging as a potential target of therapy