DIABETES MELLITUS
| CARING FOR DIABETIC PATIENTS —Marc Sandberg, MD, Medical Director, Diabetes Health Center, Hunterdon
Medical Center, Flemington, NJ
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| Health impact of diabetes: epidemic; children born in 2000 have 30% lifetime risk; preventable and treatable; untreated,
sixth leading cause of death and number one cause of blindness; Nurses Health Study—91% of diabetes prevented
by healthy weight, healthy diet, exercise, avoiding tobacco smoking, and limiting alcohol to one glass daily (one-
half glass for women); Diabetes Prevention Program—showed that diabetes preventable in individual with prediabetes or
high risk for diabetes; randomized participants into 3 groups; first group received metformin 850 mg; second group received
placebo; third group told to lose 7% of weight and perform 150 min of exercise weekly; half of participants from racial
or ethnic minority groups; followed for ≈3 yr; weight loss most significant in exercise group; metformin group reduced
risk for diabetes by >30%; those on intensive lifestyle modifications (most effective method) reduced risk by >60%; another
study using rosiglitazone showed risk reduction similar to that of metformin; even small changes in glycemic control
can have profound consequences for microvascular complications
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| Diagnosis: American Diabetes Association (ADA) criteria—fasting glucose (FG) >125 mg/dL, random plasma glucose
(PG) >199 mg/dL with symptoms, or 2-hr postprandial PG after glucose tolerance test (GTT) >199 mg/dL; recommended
that individuals ≥45 yr of age be screened every 3 yr using FG; screen earlier if individual overweight and has one additional
risk factor for diabetes
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| Risk factors: impaired glucose tolerance (IGT; GTT at 2 hr of 140-199 mg/dL) or impaired FG (IFG; 100-125 mg/dL);
family history of diabetes; habitual physical inactivity; certain races and/or ethnicities; hypertension; “bad” cholesterol;
gestational diabetes; polycystic ovary syndrome (PCOS); insulin resistance; vascular disease
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| Prevalence of complications at diagnosis: necessary to screen for all complications of type 2 diabetes at diagnosis
(50% incidence); for type 1 diabetes, screen at 3 to 5 yr after presentation; even small changes in HbA1c have profound
consequences in disease; United Kingdom Prospective Diabetes Study (UKPDS)—showed that 0.9% reduction in
HbA1c decreases risk for microvascular disease by 25% and risk for albuminuria by 34%; also looked at blood pressure
(BP) goal of 150/80 mm Hg; reduction to goal BP had profound consequences in reduction of micro- and macrovascular
disease; β-blockers not recommended as first-line therapy but as effective as angiotensin-converting enzyme (ACE) inhibitors
in reducing complications
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| Microalbuminuria: indicates destruction of vascular system of kidneys; patient probably also has retinopathy and at increased
risk for cardiovascular disease; test annually; screen with random microalbumin-to-creatinine ratio; if <30, recheck
in 1 yr; if ≥30, repeat (temporary elevations caused by, eg, infection, heart failure, exercise); if positive second
time, treat by glycemic control and hypertension control; even if patient not hypertensive, start medication; goal BP
<130/80 mm Hg; medications—ACE inhibitors and angiotensin receptor blockers (ARBs) equally effective; if ineffective,
add diuretic; if still ineffective, add β-blocker (speaker prefers cardioselective β-blockers, which have no negative
consequences on metabolic aspects of diabetes); if still ineffective, speaker adds nondihydropyridine calcium channel
blocker (eg, diltiazem, verapamil); dihydropyridine calcium channel blockers (eg, nifedipine, amlodipine) do not protect
kidneys; if still ineffective, refer to nephrologist (other instances include continued rise in creatinine, uncontrolled hypertension,
and hyperkalemia)
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| Risk for myocardial infarction (MI): if diabetic, risk of having first MI same as if not diabetic; if diabetic and had
previous MI, risk for second MI ≈10 times higher than if individual had neither; Heart Protection Study—substudy of
6000 participants with diabetes; 50% had no heart disease, with mean cholesterol 220 mg/dL; randomized to simvastatin
40 mg or placebo; patients followed for 5 yr; major coronary events significantly reduced (27%); strokes reduced 24%;
revascularizations reduced 17%; major vascular events reduced 22%; reductions seen regardless of patients’ initial cholesterol
levels; Collaborative AtoRvastatin Diabetes Study (CARDS; atorvastatin 10 mg) showed similar results;
statins—recommended in almost all patients, especially those >40 yr of age, and with total cholesterol >135 mg/dL; goal
low-density lipoproteins <100 mg/dL (<70 mg/dL if patient has vascular disease); if patient <40 yr of age, still consider
statin if high risk; statins category X (not for use in patients who could possibly become pregnant, unless using birth control),
but otherwise recommended for younger-aged patients at high risk for cardiovascular disease (above and beyond diabetes);
aspirin—necessary in all patients as secondary prevention, and as primary prevention if other cardiovascular
risk factors present (eg, family history, smoking, hypertension, microalbuminuria, dyslipidemia) and if >40 yr of age; if
<30 yr of age, aspirin should not be used (risk for Reye’s syndrome); if high risk and between 30 and 40 yr of age, consider
aspirin; cardiac testing—controversial; no guidelines; of patients tested, 1 in 5 have abnormal result, and 1 in 15
have major abnormality on exercise stress test; annual electrocardiography (ECG) recommended; if patient sedentary and
wants to perform vigorous exercise, stress test recommended
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| Retinopathy: screen (by ophthalmologist or optometrist) on yearly basis; if type 2 diabetes, begin screening at diagnosis;
if type 1, begin screening after 3 to 4 yr; gestational diabetes (unless with preexisting diabetes) does not lead to increased
risk
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| Foot care: best screening instrument tuning fork; examining feet at each visit prevents amputations by 50%; if no pulses
found, perform ankle-brachial index (ABI) testing; if abnormalities present (eg, anatomic deformity), lesions or cuts not
healing, or patient experiencing deficits in sensation, refer to podiatrist
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| Hyperglycemia in intensive care unit (ICU): higher PG in hospital leads to longer hospital stay and increase in
morbidity and mortality; maintain PG between 80 and 110 mg/dL in ICU and between 110 and 180 mg/dL in general
ward; difficult to maintain recommended levels once patient discharged
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| Summary of treatment: goal—HbA1c <7% (according to ADA); <6.5% according to American Association of Clinical
Endocrinologists; <6% in certain patients (according to ADA); BP <130/80 mm Hg; total cholesterol <135 mg/dL;
LDL <100 mg/dL or <70 mg/dL with cardiovascular disease; triglycerides <150 mg/dL; high-density lipoprotein >40
mg/dL for men and >50 mg/dL for women
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| Pathophysiology: insulin resistance; β cells compensate by making more insulin (superphysiologic amounts); at some
point, β cells begin to fail; newer medications preserve β-cell function but probably do not reverse β-cell dysfunction; treatment
goal to imitate normal pancreatic function
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| Insulin: pancreas constantly produces small amount of insulin (ie, basal insulin; prevents ketosis) and insulin for each meal
(ie, bolus or mealtime insulin); using regular and neutral protamine Hagedorn (NPH) insulin not effective in mimicking insulin
produced by pancreas; today choices include inhaled insulin; NPH and Lente insulin not true basal insulins (peak at
≈48 hr); insulin glargine and insulin detemir truer basal insulins; regular insulin takes 30 to 60 min for onset of action
(must give 45 min before meal); insulin lispro, aspartate, and glulisine given within 5 min of eating and even after eating
(good for finicky eaters in pediatric population); more hypoglycemia with old premixed insulin than with new ones; insulin
detemir and glargine “flat” basal insulins; inhaled insulin (Exubera)—can obtain ≈27 units/session (3 puffs) per meal; kinetics
similar to regular insulin or insulin lispro (Humalog); short-acting; mealtime insulin; does not replace long-acting insulin;
contraindications include previous smoking for ≥6 mo, significant lung disease, chronic obstructive pulmonary
disease, asthma, and pregnancy; monitor with pulmonary function tests
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| Sulfonylureas: inexpensive; cause hypoglycemia; speaker thinks glimepiride (Amaryl) most useful; maximum dose 8
mg (90% of effect at 4 mg); glyburide shown to affect heart negatively (unlike glimepiride); principle in diabetes care
never to substitute one medication for another, but instead add medication (unless not tolerated)
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| Metformin (eg, Glucophage): safe if used properly; first-line therapy; not used in conditions that predispose to lactic
acidosis; harmful to kidneys when used with contrast (contrast harmful element); recommend stopping metformin on day
of study and repeat creatinine reading 2 days later to ensure kidneys not harmed by contrast; renally excreted
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| Thiazolidinediones (TZDs): troglitazone discontinued few years ago for rare side effect of liver failure; rosiglitazone
and pioglitazone not shown to affect liver (in fact, reverse fatty liver disease); anti-inflammatory effects (help in vascular
remodeling and preserving stent patency); adding rosiglitazone to metformin enables good glucose control for ≥30 mo; β-
cell-preserving effects of glitazones lead to less need for insulin; study—participants newly diagnosed with diabetes randomized
to glyburide, metformin, or rosiglitazone; time to reach FG >180 mg/dL significantly shorter with glyburide and
longest with rosiglitazone (possibly because of β-cell preservation); TZDs may cause weight gain (on average, 4-5 lb);
perform liver function tests at diagnosis and annually thereafter; congestive heart failure (CHF) precautions; contrainidicated
in CHF classes III and IV (can cause some fluid retention); edema reversible by lowering dose (those treated with
insulin especially prone); expensive
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| Incretin effect: basis of new medications; insulin effect different (ie, less) with intravenous (IV) glucose than with oral
glucose; true regardless of whether patient diabetic; enteroinsular axis involved; glucagon-like peptide-1 (GLP-1)—main
hormone; accounts for 50% of stimulus of insulin secretion when person eats; quickly metabolized by dipeptidyl peptidase-4
(DPP-4); inhibiting DPP-4 indirectly increases GLP-1; leads to stimulation of insulin secretion, suppression of
glucagon secretion, increase in β-cell mass and function, improvement of insulin sensitivity, and enhancement of glucose
disposal; inhibitors of DPP-4 (eg, sitagliptin [Januvia]) not shown to decrease gastric emptying and do not reduce food
intake and weight; when person eats, GLP-1 increased but rapidly broken down by DPP-4; GLP-1 particles that do not
get broken down stimulate β cells to release insulin and inhibit α cells from releasing glucagon; in type 2 diabetes, glucagon
released uncontrollably (contributes to postprandial hyperglycemia); preventing release of glucagon maintains euglycemia
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| Exenatide (Byetta): appears like GLP-1 to body but not readily broken down by DPP-4; protein (cannot be ingested);
given subcutaneously bid at dose of 5 to 10 µg; major side effect transient nausea and vomiting; decreases HbA1c over
time and maintains it for >110 wk; similar to TZDs ( β-cell preservation); causes significant weight loss
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| Sitagliptin (Januvia): DPP-4 inhibitor, thereby raises GLP-1 levels; used in combination with metformin or TZDs, or
as monotherapy; decreases HbA1c , FG, and 2-hr postprandial PG; no effect on weight; relatively lipid-neutral
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| Amylin: same mechanism of action as exenatide, but does not increase insulin secretion; shuts off glucagon, decreases appetite,
and normalizes gastric motility; indicated for type 1 and type 2 diabetes; injectable (tid); ideal for patients with
postprandial hyperglycemia who need to lose weight; higher the dose, lower the postprandial hyperglycemia excursion;
60 µg maximum dose for type 1 (120 µg maximum, type 2)
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| Summary: after diagnosis, check urine ketones; if present, start insulin; if symptomatic, insulin or sulfonylureas; if asymptomatic
and not ketotic, ADA recommends metformin in addition to lifestyle modification; if metformin fails, add basal insulin;
can also add sulfonylurea or TZD; if metformin plus other therapy fails and patient already on insulin, increase insulin; if on
sulfonylurea, add insulin or TZD; if on TZD, add sulfonylurea or insulin; if still ineffective, endocrine consultation indicated;
early aggressive management using medications (first line) or early use of insulin recommended
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| EVALUATION OF DRUGS FOR TREATING DIABETES AND PREDIABETES —Michael A. Bush, MD, Clinical Associate
Professor of Medicine, the David Geffen School of Medicine at the University of California, Los Angeles, and
former Clinical Chief, Division of Endocrinology, Cedars-Sinai Medical Center, Los Angeles, CA
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| Introduction: postchallenge PG—best for determining prediabetes biochemically; 75 g glucose given; measured at 0
and 2 hr; may show IGT; ADA revised defintition of normal PG to <100 mg/dL; definition of diabetes same (126 mg/
dL); 100 to 125 mg/dL defined as IFG; must perform GTT to define IGT
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| Studies: Diabetes Prevention Program—followed participants who had IGT; 11% per year developed diabetes; in patients
given metformin 850 mg bid (once daily for those with gastrointestinal distress), 7.8% developed diabetes each
year; other group of patients randomized to lifestyle modifications, with goal of losing 7% of weight (achieved mean of
6% weight loss); after 3 yr, only one-third of participants maintained weight loss; even so, they still obtained benefit; lifestyle
modification best method (confirmed by other studies); Troglitazone In Prevention Of Diabetes (TRIPOD)
study—Hispanic overweight women with history of gestational diabetes; 12% developed diabetes annually (reduced to
<50% by troglitazone); had protective value, but troglitazone discontinued several years ago due to rare side effect; Pioglitazone
In Prevention Of Diabetes (PIPOD) study—proposed that reduction in incidence of diabetes in patients given
TZD in TRIPOD study dependent on whether pancreas reduced insulin secretion; reduction appeared to improve development
of diabetes; results similar to TRIPOD study; showed that ACE inhibitors and ARBs significantly reduced development
of diabetes; Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication (DREAM) study—
compared to placebo, rosiglitazone significantly reduced progression to type 2 diabetes (diabetes possibly being
masked); 4 mo after withdrawal of rosiglitazone, rate of development of new diabetes same as in placebo group; no lasting
preservation benefit to pancreas; ramipril showed no significant benefit for preventing transition to diabetes (although
more patients returned to normoglycemia); all medications for prevention off-label; study—individual with IFG has 10-
fold increased risk of becoming diabetic over 6.5 yr, compared to individual with normal postload glucose (also true for
IGT); individual with IFG and IGT has 40-fold increased risk
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| Algorithm for management of diabetes and prediabetes: start with metformin and lifestyle modification; sulfonylurea
added if HbA1c still uncontrolled, or TZD if concerned about hypoglycemia; other option to start insulin early;
basal insulin and metformin effective and complementary; A Diabetes Outcome Progression Trial (ADOPT)—4000 participants
given rosiglitazone, metformin, or glyburide; goal to maintain FG at <140 mg/dL; FG >180 mg/dL considered
failure; twice as many failures with glyburide as with rosiglitazone and metformin; speaker favors combination therapy;
with higher initial HbA1c , success more likely with combination therapy
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| Hormones: GLP-1 and gastric inhibitory polypeptide (GIP) in intestine enhances insulin secretion; glucagon brings
glucose out of liver; effects potentiated by GLP-1 and GIP; intestinal hormones metabolized quickly by DPP-4;
sitagliptin—inhibits DPP-4; increases GLP-1 and GIP levels 2- to 3-fold; net effect reduction of FG, with more significant
effect on postprandial control; exenatide—identical to substance in saliva of Gila monster; has 50% homology
to GLP-1, binds to GLP-1 receptors, and not broken down by DPP-4; affects satiety signal and slows stomach
emptying; speaker suggests it has stronger effect on fasting and postprandial glucose than sitagliptin; causes slow and
steady weight loss
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Suggested Reading
Baggio LL et al: Biology of incretins: GLP-1 and GIP. Gastroenterology 132:2131, 2007; Campos C: Treating the
whole patient for optimal management of type 2 diabetes: considerations for insulin therapy. South Med J 100:804, 2007;
Eddy DM et al: Clinical outcomes and cost-effectiveness of strategies for managing people at high risk for diabetes. Ann
Intern Med 143:251, 2005; Herman WH et al: The cost-effectiveness of lifestyle modification or metformin in preventing
type 2 diabetes in adults with impaired glucose tolerance. Ann Intern Med 142:323, 2005; Mikhail N: Exenatide: a
novel approach for treatment of type 2 diabetes. South Med J 99:1271, 2006; Orchard TJ et al: The effect of metformin
and intensive lifestyle intervention on the metabolic syndrome: the Diabetes Prevention Program randomized trial. Ann Intern
Med 142:611, 2005; Schmitz O et al: Amylin agonists: a novel approach in the treatment of diabetes. Diabetes 53
Suppl 3:S233, 2004; Schou JH et al: Normal secretion and action of the gut incretin hormones glucagon-like peptide-1
and glucose-dependent insulinotropic polypeptide in young men with low birth weight. J Clin Endocrinol Metab 90:4912,
2005; Stancoven A et al: Preventing macrovascular complications in type 2 diabetes mellitus: glucose control and beyond.
Am J Cardiol 99:5H, 2007; Stenstrom G et al: Latent autoimmune diabetes in adults: definition, prevalence, beta-
cell function, and treatment. Diabetes 54 Suppl 2:S68, 2005; Turina M et al: Diabetes and hyperglycemia: strict glycemic
control. Crit Care Med 34:S291, 2006; Wylie-Rosett J et al: 2006-2007 American Diabetes Association Nutrition
Recommendations: issues for practice translation. J Am Diet Assoc 107:1296, 2007.
Educational Objectives
The goal of this program is to improve the management of type 2 diabetes and prediabetes. After hearing and assimilating
this program, the clinician will be better able to:
 | 1. Recommend tests to determine presence of complications and measures for prevention.
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| 2. Utilize the new criteria of the American Diabetes Association for the diagnosis of diabetes.
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| 3. Describe the mechanisms of action of new drugs for diabetes and their relation to the pathophysiology of diabetes.
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| 4. Summarize the results of the major diabetes studies.
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| 5. Explain the role of hormones involved in diabetes.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty members to disclose relevant
financial relationships within the past 12 months that might create any personal conflicts of interest. Any identified
conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business
or commercial interest. For this program, the following has been disclosed: Dr. Sandberg is on the Speakers’ Bureaus of
Merck, NovoNordisk, and Amylin, and is a clinical investigator for Merck and Eli Lilly. Dr. Bush is on the Speakers’ Bureaus
of NovoNordisk, Eli Lilly, Sanofi-Aventis, Pfizer, Merck, and Amylin, and is a consultant for NovoNordisk and
Takeda.
Acknowledgements
Dr. Sandberg was recorded at the 31st Semi-Annual Family Practice Review, held March 25-30, 2007, in Lancaster, PA,
and sponsored by the Temple University School of Medicine and Lancaster General Hospital. Dr. Bush was recorded at the
34th Annual Family Practice Refresher Course, held May 29 to June 2, 2007, in Los Angeles, CA. The Audio-Digest Foundation
thanks the speakers and the sponsors for their cooperation in the production of this program.
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