DIABETES MELLITUS
| DIABETES UPDATE —John Bantle, MD, Professor of Medicine, Division of Endocrinology and Diabetes, University of
Minnesota Medical School, Minneapolis
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| Prevalence: continuing to increase in United States; >12% of people >40 yr of age have diabetes; diabetes mortality rate increasing
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| Diabetes prevention: Diabetes Prevention Program—involved ≈3200 people at high risk for type 2 diabetes; concluded diabetes
preventable; patients randomized to 3 interventions (standard lifestyle plus placebo; standard lifestyle plus metformin;
intensive lifestyle modification); intensive lifestyle measures included low-calorie, low-fat diet, at least 150 min/
wk of intensive physical activity, and 16-lesson one-on-one course on diet, exercise, and behavior modification; those in
intensive lifestyle group had greatest weight loss and 58% risk reduction for developing diabetes (risk reduction in metformin
group 61%)
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| Type 1 diabetes: Diabetes Control and Complications Trial (DCCT)—concluded that tight control of blood glucose (BG) in
type 1 diabetics reduces risk for retinopathy, nephropathy, and neuropathy; involved 1441 type 1 diabetic volunteers randomly
assigned to conventional or intensive therapy; after 7 yr, study stopped because benefits of intensive therapy so compelling; Epidemiology
of Diabetes Intervention and Complications (EDIC) trial—continuation of DCCT; hemoglobin (Hb) A1C values
among patients in 2 previous treatment groups merged, but those previously treated conventionally showed significant increase
in albuminuria (not seen among those previously treated intensively); therefore, start intensive therapy as early as
possible after onset of type 1 diabetes and probably also for type 2 diabetes; target Hb A1C ≤7%; EDIC also found intensive
diabetes therapy protects against macrovascular events (eg, myocardial infarction [MI], stroke) and peripheral vascular disease;
first demonstration that control of glucose retards atherosclerosis
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| Type 2 diabetes: United Kingdom Prospective Diabetes Study (UKPDS)—concluded treating type 2 diabetes protects
against microvascular complications; 4200 patients, assigned to conventional or intensive therapy with sulfonylureas or
insulin; demonstrated type 2 diabetes is progressive disease, and that good glycemic control requires stepwise addition of
proven agents; also concluded controlling blood pressure (BP) important in reducing microvascular complications,
strokes, heart failure (HF), and diabetes-related deaths; progressiveness of type 2 diabetes— ≈50% of β cell function already
lost at start of study, and continued decline correlated with loss of responsiveness to oral agents and need to add insulin
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| Diabetes and atherosclerosis: Finnish study—concluded diabetes is coronary artery disease (CAD) risk equivalent; involved
people 45 to 64 yr of age; found that diabetics without previous MI had slightly higher rate (20%) of MI than
nondiabetics with previous MI (19%), and among diabetics with previous MI, 45% had another MI
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 | Heart Protection Study: involved 20 500 high-risk people in Great Britain between 40 and 80 yr of age who had coronary
heart disease (CHD), noncoronary vascular disease, or diabetes; patients randomized to placebo and simvastatin 40 mg
daily, then further randomized to receive antioxidant vitamins or placebo; findings—antioxidant vitamins not effective;
simvastatin reduced risk for overall mortality, CHD mortality, nonfatal MI, need for coronary revascularization, and
stroke, regardless of low-density lipoprotein (LDL) value at start of study
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| Diabetes treatment goals: American Diabetes Association (ADA) goals—preprandial BG 90 to 130 mg/dL; peak postprandial
BG <180 mg/dL; Hb A1C <7.0% (strive for Hb A1C <6.0% in selected patients who do not have trouble recognizing
symptoms of hypoglycemia); goals for controlling macrovascular disease risk factors—BP <130/80 mm Hg, LDL <100
mg/dL (<70 mg/dL with history of CAD); high-density lipoprotein (HDL) >40 mg/dL in men and >50 mg/dL in women;
triglycerides <150 mg/dL; smoking cessation; use of aspirin in diabetics ≥40 yr of age; “fine print” recommendations—
BP regimen should include use of angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB)
because of evidence they protect against progression of nephropathy; consider statin therapy in diabetic patients >40 yr of
age with total cholesterol >135 mg/dL
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| How diabetics did (1999-2000 data): ≈37% achieved Hb A1C goal; 36% got BP <130/80 mm Hg, and 48% got total cholesterol
<200 mg/dL; only 7% achieved all goals
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| Case of 49 yr old woman: presents with fatigue and weight gain; on no medications; has hypertension; body mass index
(BMI) 40.2 kg/m2 , fasting BG 162 mg/dL, Hb A1C 6.7%, low HDL, high triglycerides, and no signs of nephropathy;
diagnosis type 2 diabetes
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| Possible treatment options: 1) lifestyle modification; 2) lifestyle modification plus meal replacements or use of sibutramine
or orlistat; 3) lifestyle plus metformin; 4) gastric bypass surgery; 5) use of metformin, lisinopril, and fenofibrate;
remarks—all options reasonable; Hb A1C decreases with weight reduction
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| Rimonabant (Accomplia): selective endocannabinoid receptor antagonist in final stages of clinical trials; appears promising
in reducing appetite and weight in diabetic patients; mean weight loss in 1 yr in trials ≈8.6 kg
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| Gastric bypass surgery: average weight loss ≈100 lb; probably takes away diabetes; reduces lipids and BP, and reduces
chances of developing osteoarthritis (OA) of hips and knees (speaker likes this option for patient)
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| Case of 58 yr old man with diabetes for 8 yr: complains of fatigue and blurred vision; has hypertension; already on glyburide,
metformin, amlodipine, and aspirin; BMI 32.6 kg/m2 ; has pretibial edema and decreased perception of light touch
and vibration in both feet; fasting BG ≈200 mg/dL, Hb A1C 9.1%, LDL high, and microalbuminuria present;
recommendations—use of glargine (Lantus) insulin, NovoLog Mix 70/30 (70% NPH, 30% aspart) premixed insulin, or
Humalog Mix 75/25 (75% NPH, 25% lispro) premixed insulin; also use ACE inhibitor or ARB and statin; stop amlodipine
(can cause peripheral edema; generally, avoid calcium channel blockers in diabetic patients with hypertension)
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| Insulin: 2 basic types—basal insulin (necessary to regulate hepatic glucose production and normalize fasting BG) and bolus
insulin (controls postprandial BG); fast-acting agents—lispro (Humalog), aspart (NovoLog), and glulisine
(Apidra); rapid onset; peak in 1 to 2 hr; preferred bolus insulins for use at mealtime; glargine (Lantus)—does not peak;
has 24-hr duration of action; regular and NPH insulins—will probably disappear over next few years
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| Advice on treating patient: consider starting with Lantus 10 units at bedtime, then titrate; if BG before breakfast >180
mg/dL, increase by 8 units; if 140 to 180 mg/dL, go up 4 units; if BG 120 to 140 mg/dL, go up 2 units until goal of 90
to 120 mg/dL reached; takes 4 or 5 telephone calls over 1 mo; use nurse educator if available
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| Treat to Target study: compared bedtime Lantus to bedtime NPH insulin in forced titration scheme; involved 750 people
with type 2 diabetes; at 18 wk, no difference in Hb A1C in 2 groups, but those in Lantus group had less hypoglycemia;
Lantus and NovoLog 70/30 Mix—study involved 230 type 2 diabetics placed on insulin because they were not adequately
controlled on oral agents; at 28 wk, average Hb A1C 6.9% in NovoLog group and 7.4% in Lantus group; those
in NovoLog Mix group experienced more hypoglycemia (not serious) and weight gain
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| Exenatide (Byetta): first in series of receptor agonists for glucagon-like peptide 1 (GLP-1; incretin hormone secreted by
cells in small intestine); enhances glucose-dependent insulin secretion, suppresses hepatic glucagon production, slows
gastric emptying, and enhances satiety; given twice daily subcutaneously (SQ), typically before breakfast and supper; reduces
fasting and postprandial BG, reduces Hb A1C (≈0.8% in 30 wk), and causes weight loss (≈5 lb in 30 wk, no plateau
out to 80 wk); main adverse effect nausea (usually transitory)
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| NEWER DEVELOPMENTS IN THE CARE OF DIABETIC PATIENTS —Daniel Einhorn, MD, Clinical Professor of
Medicine, University of California, San Diego, School of Medicine, and Medical Director, Scripps-Whittier Institute for
Diabetes, La Jolla
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| Issues in glucose control: Hb A1C—at best, rough guide for BG control (not very sensitive; can easily hide BG fluctuations;
patient with Hb A1C of 5.7% to 5.8% can have diabetes); high BG and fluctuations symptomatic; ratio of Hb
A1C to fructosamine provides general sense of trends in patient’s BG; points—have patient wear Holter monitor for 3
days if in doubt about BG status; daily BG checks no longer necessary once patient stable on oral agents; with very
high Hb A1C fasting BG overrepresented; 70% of hyperglycemia in diabetics seen in postprandial phase; interaction
exists between chronic hyperglycemia and spikes (“spikes matter”)
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| Barriers to achieving BG goal: wearing off of medications; hypoglycemia; weight gain; edema; gastrointestinal (GI) side
effects; cardiac and renal contraindications
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| Exenatide (Byetta): antidiabetic drug derived from incretin gut hormones (GLP-1); GLP-1 hormones—released in gut when
food ingested; stimulate β-cells to release insulin in proportion to amount of glucose, and affect how hard body has to
work to do this; suppress glucagon production in liver, particularly after meals (in diabetics, glucagon high and does not
suppress normally with eating, so hepatic glucose production stays high; glucagon is major agent of insulin resistance; diabetes
may be redefined as hyperglucagon disease); suppress gastric emptying (in type 2 diabetes, emptying accelerated);
promote satiety in brain (many people in clinical trials who claimed they had nausea really had satiety)
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| Comments: effects of exenatide on Hb A1C appear not to wear off; exenatide appears to preserve β-cells; people lose weight
with this drug because they eat less (weight gain of 8.7 kg typical with intensive insulin therapy); exenatide not indicated for
type 1 diabetes; since this drug slows gastric emptying, it may affect some drugs that need to be absorbed quickly; nausea
usually transient, occurs at start of therapy, and resolves permanently
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| Administration: Byetta available in prefilled pens; give 10 µg twice daily (consider giving half dosage during first month to
minimize nausea); points—simple to give (“just follow the arrows”); each pen lasts 1 mo (contains 60 doses); generally give
1 hr before breakfast and supper; drug requires refrigeration
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| Problems with exenatide: experience with drug lacking; use requires injections (once-a-month version being developed); mild
nausea; advantages—normalizes glucose fluctuations; actions physiologic; associated with weight loss; well tolerated; does
not cause hypoglycemia; compatible with other therapies; may preserve β-cells; price about same as other therapies
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| Observations: other GLP-1 agents being studied, along with dipeptidyl peptidase (DPP)-IV inhibitors (same actions, but
taken orally once daily, not associated with weight loss, and may show some tachyphylaxis)
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| Sleep deprivation: contributes to obesity, diabetes, and other health problems; can influence decisions about food and exercise;
aggravates insulin resistance
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| Sleep apnea: present in ≈10% of adults; prevalence as high as 15% among older overweight people; predisposing factors
similar to those for diabetes; independently associated with insulin resistance and glucose intolerance; continuous positive
airway pressure (CPAP) improves insulin sensitivity and type 2 diabetes
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| Comments: loud snoring independent risk factor for type 2 diabetes; hormonal changes associated with sleep deprivation contribute
to illness and behavorial problems; in 1 study, ≈33% of people with type 2 diabetes had sleep apnea (among men,
prevalence ≈50%); people ≥65 yr of age have 2 in 3 chance of having sleep apnea (assume patients have it until proven otherwise);
urge diabetic patients to sleep 1 hr more daily
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| Rimonabant: blocks cannaboid receptors in brain; once-a-day pill safe; helps negotiate food intake in variety of ways and
helps reduce insulin resistance (mainly by reducing abdominal adiposity); study—50% of people lost 5% body weight,
≈20 lost >10% body weight; Hb A1C reduced ≈1.7% (>50% of reduction not explained by weight loss; this drug appears
to have independent effect on insulin resistance and metabolic rate); triglycerides improved slightly, and BP decreased;
some dysphoria only adverse effect reported; waist circumference decreased (on average) ≈2 in
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| Pramlintide (Symlin): generally reserved for type 1 diabetics and type 2 diabetic patients who require tight control; adjunct
to mealtime insulin; requires cutback in insulin use; helps smooth out postprandial BG highs; given bid; start low to
avoid nausea, and gradually increase to therapeutic dose; benefits include weight loss, decreased postprandial glucose,
and less hypoglycemia
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| Newer developments: tight glucose control helps prevent cardiovascular events; insertion of pacemaker into stomach
helpful in treating diabetes and decreasing appetite (done laparoscopically; creates reverse peristalsis); glucose meters
helpful in managing diet
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| Therapeutic goals: BP control most important target, followed by LDL cholesterol, triglycerides, HDL cholesterol, then
BG; presence of microalbuminuria denotes high-risk patient; develop understanding with patient on use of multiple drugs
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| Critical therapies in diabetic patients: aspirin 325 mg/day; ACE inhibitors or ARBs; statins (regardless of cholesterol); almost
always begin BG control with metformin and thiazolidinediones (TZDs; metformin-rosiglitazone [Avandamet] coming
back); add Byetta if patient not well controlled, then add Lantus insulin if fasting glucose still up; bottom line—strive for
normal glycemic control, Hb A1C ≈6.0%, and control BP and lipids
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| Questions and answers: cost of Byetta—≈$130 monthly; use of Byetta in treating obesity in nondiabetic patients—currently
not approved; Byetta as first-line therapy—speaker likes its early use for BG control, but still uses metformin and TZD
first because of cardiovascular issues; Byetta in glucose intolerance—being studied, but currently not approved; how long
to continue Byetta if weight loss occurs and Hb A1C drops significantly—consider Byetta maintenance therapy; how gastric
bypass affects gut hormones—diabetes resolves in 1 to 2 days after bypass; BG significantly lower (probably involves
early delivery of nutrients to ileum)
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Educational Objectives
| The goal of this program is to educate the listener about the diagnosis and treatment of diabetes. After hearing and assimilating
this program, the clinician will be better able to:
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| 1. Work toward current American Diabetes Association goals for controlling blood glucose (BG) in diabetic patients.
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| 2. Recognize the importance of tight glycemic control in diabetic patients for the prevention of microvascular and macrovascular
complications.
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| 3. Manage blood pressure (BP) and treat lipid problems in diabetic patients.
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| 4. Utilize insulin preparations in type 2 diabetics who fail to lower their BG on oral agents.
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| 5. Consider using newly developed agents for treating diabetic patients, including Exenetide (Byetta), pramlintide
(Symlin), and probably soon rimonabant (Accomplia).
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Discussed on This Program
Amlodipine [AmVaz, Norvasc]
Aspirin (acetylsalicylic acid; ASA) [many trade names]
Exenatide [Byetta]
Fenofibrate [Tricor, Antara, Lofibra]
Glyburide (glibenclamide) [DiaBeta, Glynase PresTab, Micronase]
Insulin aspart (rDNA origin) [NovoLog; NovoLog Mix 70/30]
Insulin glargine [Lantus]
Insulin glulisine (rDNA origin) [Apidra]
Insulin injection, regular (several trade names)
Insulin lispro, human (rDNA) [Humalog, Humalog Mix 75/25, Humalog Mix 50/50]
Insulin suspension, isophane (NPH; several trade names)
Insulin zinc suspension (lente) [Humulin L, Lente Iletin II, Novalin L]
Insulin zinc suspension, extended (ultralente) [Humulin U Ultralente]
Lisinopril [Prinivil, Zestril]
Metformin HCl [Fortamet, Glucophage, Glucophage XR]
Metformin-rosiglitazone [Avandamet]
Orlistat [Xenical]
Pramlintide acetate [Symlin]
Rimonabant (SR 141716) [Accomplia; investigational]
Sibutramine HCl [Meridia]
Simvastatin [Zocor]
Suggested Reading
Ahren B, Schmitz O: GLP-1 receptor agonists and DPP-IV inhibitors in the treatment of type 2 diabetes. Horm Metab Res
36:867, 2004; Amsterdam EA: Rimonabant: unique and promising. Prev Cardiol 8:140, 2005; Anderson DC Jr: Pharmacologic
prevention or delay of type 2 diabetes mellitus. Ann Pharmacother 39:102, 2005; Aring AM: Evaluation and prevention
of diabetic neuropathy. Am Fam Physician 71:2123, 2005; Chalasani N et al: Effect of rosiglitazone on serum liver
biochemistries in diabetic patients with normal and elevated baseline liver enzymes. Am J Gastroenterol 100:1317, 2005;
Colquitt JL et al: Clinical and cost-effectiveness of continuous subcutaneous insulin infusion for diabetes. Health Technol
Assess 8:1, 2004; Demuth HU et al: Type 2 diabetes—therapy with dipeptidyl peptidase IV inhibitors. Biochim Biophys
Acta 1751:33, 2005; Exenatide (Byetta) for type 2 diabetes. Med Lett Drugs Ther 47:45, 2005; Frykberg RG: Diabetic foot
ulcers: pathogenesis and management. Am Fam Physician 66:1655, 2002; Goldman-Levine JD, Lee KW: Insulin detemir
—a new basal insulin analog. Ann Pharmacother 39:502, 2005; Hirschel B: Effect of rimonabant on weight reduction
and cardiovascular risk. Lancet 366:369, 2005; Joy SV et al: Incretin mimetics as emerging treatments for type 2 diabetes.
Ann Pharmacother 39:110, 2005; Konzem SI et al: Controlling hypertension in patients with diabetes. Am Fam Physician
66:1209, 2002; Luna B, Feinglos MN: Oral agents in the management of type 2 diabetes mellitus. Am Fam Physician
63:1747, 2001; Mayfield JA, White RD: Insulin therapy for type 2 diabetes: rescue, augmentation, and replacement of
beta-cell function. Am Fam Physician 70:489, 2004; Meriden T: Progress with thiazolidinediones in the management of
type 2 diabetes. Clin Ther 26:177, 2004; Moore H et al: Dietary advice for treatment of type 2 diabetes mellitus in adults.
Cochrane Database Syst Rev CD004097, 2004; Negro R et al: Rosiglitazone effects on blood pressure and metabolic parameters
in nondipper diabetic patients. Diabetes Res Clin Prac 70:20, 2005; Ruilope LM, Segura J: Losartan and other
angiotensin II antagonists for nephropathy in type 2 diabetes mellitus: a review of the clinical trial evidence. Clin Ther
25:3044, 2003; Setter SM et al: Metformin hydrochloride in the treatment of type 2 diabetes mellitus: a clinical review
with a focus on dual therapy. Clin Ther 25:2291, 2003; Thorp ML: Diabetic nephropathy: common questions. Am Fam
Physician 72:97, 2005; Trachtenbarg DE: Diabetic ketoacidosis. Am Fam Physician 71:1705, 2005; Turok DK et al:
Management of gestational diabetes mellitus. Am Fam Physician 68:1767, 2003; Zhao HL: An update on the management
of nephropathy in type 2 diabetes. J Clin Med Assoc 66:627, 2003.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial
relationship with the manufacturer or provider of any commercial product or service discussed. The following has been disclosed:
Dr. Bantle owns stock in Amylin Pharmaceuticals Inc. Dr. Einhorn has various relationships with Medtronic Neuro,
Eli Lilly and Co, Amylin Pharmaceuticals, Merck and Co, Takeda Pharmaceuticals, Sanofi-Aventis, Sankyo Co, and GlaxoSmithKlein,
among others.
Dr. Bantle was recorded May 23, 2005, at the annual Family Medicine Review Update, sponsored by the University of
Minnesota Medical School, Minneapolis. Dr. Einhorn spoke June 24, 2005, at Family Medicine Update: 2005, sponsored
by the San Diego Academy of Family Physicians and held in Coronado, California. The Audio-Digest Foundation
thanks the speakers and the sponsors for making this program possible.
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