ADVANCES IN DIABETES CARE
Educational Objectives
| The goal of this program is to improve the management of type 2 diabetes. After hearing and assimilating this program,
the clinician will be better able to:
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 | 1. Diagnose type 2 diabetes and prescribe initial therapy.
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| 2. Explain the role of incretins in normal physiologic blood glucose control.
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| 3. Discuss the use of newer agents such as exenatide and sitagliptin.
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| 4. Select appropriate combination therapy for optimal blood glucose control.
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| 5. Describe newer approaches to diabetes control, such as incretin therapy and endocannabinoids.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the
planning committee 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. Leahy is a consultant and on the Speakers’ Bureaus for Merck and Sanofi-Aventis. Dr. Prescott and the
planning committee reported nothing to disclose.
Acknowledgments
Dr. Leahy spoke in South Burlington, VT, at the 33rd Annual Family Medicine Review Course, presented June 5-8,
2007, by the University of Vermont College of Medicine. Dr. Prescott was recorded in Napa, CA, at Clinical Pharmacology
2007: Drug Therapy Management, presented April 27-29, 2007, by the University of California, Davis, Health
System. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of
this program.
| APPROACH TO MANAGING TYPE 2 DIABETES —John L. Leahy, MD, Professor, Department of Medicine, and
Chief, Division of Endocrinology, Diabetes, and Metabolism, University of Vermont College of Medicine; and
Director, Regional Diabetes Center and Attending Physician at Medicine Health Care Service, Fletcher Allen
Health Care/University of Vermont, Burlington
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| Diabetes in United States: statistics worsening; nearly 21 million Americans have diabetes, 40 million have prediabetes,
and 60 million have metabolic syndrome
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| Standards of care: updated every January by American Diabetes Association; based on proven outcomes; hemoglobin
(Hb) A1C <7.0%; systolic blood pressure (BP) <130 mm Hg; low-density lipoprotein (LDL) <100 mg/dL; triglycerides
<150 mg/dL; in patients with type 2 diabetes, studies show that LDL of 70 mg/dL better than 100 mg/dL for primary prevention
of cardiac disease and stroke; in patients with no preexisting vascular disease, LDL <100 mg/dL acceptable
(many require statin therapy); in patients with history of, eg, myocardial infarction (MI), coronary artery bypass grafting
(CABG), angioplasty, transient ischemic attack (TIA), or peripheral vascular disease, increase dose of statin to further decrease
LDL; use sufficient dosage to attain lipid goals (eg, 10 mg of atorvastatin [Lipitor] probably insufficient in many
patients); use of combination therapy increasing; study found BP control affects microvascular and macrovascular complications
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| Drugs and glucose control: drugs available to target β-cell dysfunction, excess glucose production by liver, and insulin
resistance (ie, problem of glucose uptake by skeletal muscle); drugs that slow carbohydrate absorption from gut; many
drugs available, but Hb A1C control still difficult; no perfect drug; in average patient, drugs reduce Hb A1C by 1.0% to
1.5%; barriers to glucose control—progressive nature of disease (failure may be due to biologic reason, rather than patient
compliance); decision to use insulin (most patients eventually require insulin); treatment inertia by patients (“don’t
give me another drug, I’m already on 10 drugs”) or physicians (“if I put my patient on insulin, I’m going to ruin their
life”); insurance systems and high cost
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| International consensus statement: published August 2006; diagnosis of type 2 diabetes—fasting blood glucose
(FBG) ≥126 mg/dL (confirmed by repeating test); oral glucose tolerance testing; random blood glucose (BG) of ≥200
mg/dL with symptoms (eg, polyuria, polydipsia, unexplained weight loss); after diagnosis, patient should be started on
lifestyle modification and metformin (chance of reaching and maintaining goal with lifestyle modification alone poor)
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| A Diabetes Outcome Progression Trial (ADOPT): patients with recently diagnosed type 2 diabetes given sulfonylurea
(glyburide), metformin, or thiazolidinedione (TZD; rosiglitazone [Avandia]) as initial therapy; 4-yr study (extended
to 5 yr in some patients); Hb A1C <7% used as secondary outcome; FBG >180 mg/dL used as primary outcome
(“I don’t think any of us would ever think of that as a true clinical parameter for failure of therapy”); based on secondary
outcome data, metformin started to deviate, with more failure at ≈4 yr; no significant difference between metformin and
TZD; based on primary outcome data, study concluded that TZD superior to metformin; speaker suggests TZD or metformin
may be used as first drug; study saw higher failure rate in patients who received sulfonylurea (based on study, difficult
to support use of sulfonylurea as first drug)
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| Additional therapy: for patients not reaching goal of Hb A1C <7%, can add TZD (no hypoglycemia), sulfonylurea
(least expensive), or basal insulin (most effective); mix and match therapies to reach goal; if patient on 2 drugs (eg, sulfonylurea
and metformin), adding third drug (eg, TZD) likely to lower Hb A1C 1.0% to 1.5%; if patient on therapy and
Hb A1C >8.5%, consider insulin therapy
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| Normal physiologic BG control: with ingestion of food, “not a lot happens to blood sugars” due to increase in insulin
and decrease in glucagon (patients with type 2 diabetes [postprandial hyperglycemia] have loss of insulin response [ie, β-
cell dysfunction], and failure to decrease glucagon); incretins—gut-derived hormones secreted in response to nutrient
ingestion; potentiate insulin response to meal; rise in insulin not due to increase in glucose; signal β cells; glucose-dependent
insulinotropic peptide (GIP); glucagon-like peptide-1 (GLP-1; newer agent)
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| Studies about incretin effect: 1) oral or intravenous (IV) glucose given to patients without diabetes; effects of oral
and IV glucose identical, but insulin response 3-fold higher with oral glucose (incretin effect; stimulus for insulin response
to meal); 2) patients with glucose intolerance given meal and infused with GLP-1; postprandial hyperglycemia
controlled profoundly and glucagon turned off
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| Dipeptidyl peptidase-4 (DPP-4): after eating, GLP-1 and GIP enter vascular system; DPP-4 metabolizes and inactivates
GLP-1 and GIP in 1 to 2 min
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| Summary of glucose homeostasis: healthy people—food ingested; gut receives signal from brain to release GLP-1
and GIP to improve insulin secretion and to turn off glucagon secretion, with downstream effects of preventing liver from
“being a factory for glucose” and causing food to be taken up in target tissues; results in small change in glucose after
meals; patients with type 2 diabetes—compared to IV glucose, ability of oral glucose to potentiate response attenuated
(ie, GLP-1 not secreted in normal way); type 2 diabetes “is somewhat a disease of GLP-1 deficiency”; study measured
BG every hour from 10:00 PM to 4:00 PM ; in patients with type 2 diabetes, infusion of GLP-1 shown to normalize BG
within 2 hr and remained normal all night
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| Approaches to incretin therapy: IV GLP-1 must be infused continuously (impractical); 1) give drug that looks like
GLP-1 or binds to GLP-1 receptors, but can be used practically, ie, not metabolized quickly like native GLP-1; exenatide
(Byetta; injected) currently available; 2) develop drugs that inhibit activity of DPP-4; sitagliptin (Januvia; taken orally)
currently on market
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| Exenatide: on market since June 2005; naturally occurring peptide that occurs in saliva of Gila monsters; subcutaneous
(SC) injections bid; original indications—can be used with metformin, or sulfonylurea, or both (more recently, used
with TZD); in 30-wk trials of patients with Hb A1C levels of ≈8.5%, exenatide lowered Hb A1C levels by ≈1% (regardless
of background drug); patients interested in drug because of 1) sustainability of effect on Hb A1C and 2) weight loss (with
side effect of nausea); study showed 100-kg patients lost 5 to 6 kg after 2 yr
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| Sitagliptin: efficacy in lowering Hb A1C similar to exenatide; indicated to be used only with metformin or TZD (not with
combination of two); no weight loss; once-daily oral dosing; standard dose (100 mg/day) must be reduced for patients
with renal dysfunction; if creatinine clearance <50 mL/min, give 50 mg/day (if <30 mL/min, give 25 mg/day); no side effects
or problems with hypoglycemia; weight neutrality, not weight loss
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| Insulin therapy: 3 rapid-acting insulin analogues available (appear more physiologically correct, compared to regular
insulin); long-acting insulin analogues include insulin glargine (Lantus) and insulin detemir (Levemir); pulmonary
insulin—complicated therapy; no longer on market; starting insulin therapy—start with 1 insulin injection/day in
combination with oral agents; insulin glargine vs insulin suspension, isophane (NPH)—once-daily insulin glargine
compared to bedtime NPH and oral agents; both excellent at improving Hb A1C (8.6% to 6.9%); no difference in efficacy
between insulin glargine and NPH; insulin glargine may be slightly safer (ie, less middle-of-night lows); effective basal
insulin therapy—do not stop drugs (eg, sulfonylurea or secretagogue); stopping secretagogue lowers chance for Hb A1C
control; give sufficient amount of insulin (average dose for NPH or insulin glargine, 45-50 U/day; instruct patients about
adjusting dose by 1 U/day until BG reaches 110-115 mg/dL); when basal insulin not enough—address postmeal BG
control; many patients do well with 1 injection of prandial insulin at largest meal, along with basal insulin
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| Summary of step therapy: 1) diet, exercise, and metformin; 2) drug therapy; 3) address FBG with basal insulin; 4) 1
injection of short-acting insulin at dinnertime; if ineffective, use 2 injections; eventually use full basal-bolus regimen (not
required by every patient); prandial insulin—use rapid-acting analogues; start with small dose (4 U) and adjust weekly
to reach bedtime BG of <130 mg/dL
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| DRUGS FOR TREATING DIABETES —Pamela T. Prescott, MD, MPH, Professor, Department of Internal Medicine,
Division of Endocrinology, Clinical Nutrition, and Vascular Medicine, and Director, Student Programs, University
of California, Davis, School of Medicine, Sacramento, CA
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| High glucose levels: abnormal; elevated levels lasting 10 to 20 yr cause remarkable cardiovascular, central nervous system
(CNS), gastrointestinal (GI), and muscle changes and abnormalities; greater reductions in glucose levels require
greater number of drugs (eg, reducing patient’s Hb A1C from 10% to 8% may require 1 drug, reducing Hb A1C to 6%
may require 4 drugs and insulin); with each additional drug, cost and complications increase, and interactions between
drugs become more complex
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| Glucose modulation: involves liver and muscles; control of abnormalities involves pancreas, fat cells, and brain; fat
cells—leptin signals brain to “turn off so we stop eating”; ghrelin produced in stomach and helps with satiety; adiponectin
produced in fat cells (decreases appetite; increases muscle sensitivity for better glucose uptake; affects GI tract); pancreas
and fat cells signal CNS to recognize and respond to hormones so that glucose levels decrease
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| Treatment goals: stabilize β cells to prevent development of type 2 diabetes; reduce insulin resistance; increase insulin
secretion; maintain effects; increase β cells (in 80%-95% of patients with type 2 diabetes, insulin secretion stops because
β cells die)
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| Lifestyle modifications: diet and exercise effective, but effects plateau over time; study found metformin not as effective
as diet and exercise in preventing diabetes (as single agent, lifestyle modification did better); obese patients—decrease
fat mass; give medications to decrease obesity and progression of diabetes; thin patients—Asians and South
Pacific Islanders (eg, Fijians) have problems with β cells; therapies that increase insulin secretion (eg, TZDs, metformin,
secretagogues) ineffective
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| Newer medications: incretins—help pancreas to be better conductor for glucose; limit effect of fat cells on glucose
levels; endocannabinoids—help brain; at start of meal, brain sends out hormonal messages to pancreas to stimulate insulin
secretion and to fat cells to take up or release glucose; whether obese or thin, patients with type 2 diabetes have
same problem with signaling between pancreas and brain, and between fat cells and brain; helpful for broader group of
patients
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| Glucagon: made in β cells; in type 2 diabetes, mismanagement and miscommunication between insulin and glucagon
(signal to decrease glucagon when glucose ingested dysfunctional; adds to ineffectiveness of insulin); over time, excess
glucagon decreases amount of insulin that can be secreted
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| Incretin effect: at start of meal, food hits stomach and hormones (ie, incretins) released, signaling pancreas to increase
insulin production; GLP-1—only incretin available for therapy; compared to oral glucose, IV glucose does not cause as
rapid rise in insulin; GLP-1 may help maintain insulin secretion over time and may slow steady decline and death of pancreatic
β cells; slows absorption of food and stomach emptying; affects brain, decreases glucose production by liver, and
may increase insulin sensitivity; may keep brain on task to “tell us when finished eating”; incretins cleared through system
rapidly (≤2 min; even more rapid with defects in DPP); exenatide resistant to effects of DPP and remains in system
longer (several hours); sitagliptin blocks effects of DPP to keep GLP available longer
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| Exenatide: lowers glucose; increases insulin secretion; decreases glucagon; causes weight loss (5-15 lb); effect appears
continuous (United Kingdom Prospective Diabetes Study [UKPDS] showed that over time, every other agent [eg, metformin,
insulin] stopped working); can be used as single agent, but currently marketed for combination use; can be used
in combination with metformin or sulfonylureas; ongoing studies with TZDs (not yet approved by Food and Drug Administration
to be used with TZDs or insulin); given SC bid; half-life long enough to bridge middle meal; start with 5 µg
bid and increase over time
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| Cannabinoid receptors: in hypothalamus, increase appetite; in limbus, increase motivation to eat and to smoke tobacco;
in adipose tissue, increase release of adiponectin from fat cells; in stomach, increase absorption and decrease in
peptides; in skeletal muscle, slow absorption of glucose; effects of blocking receptors—decreased appetite; increased
adiponectin (released from fat cells; decreases insulin resistance when absent; in diabetes, adiponectin decreased); in
muscle, increased glucose uptake; in liver, decreased lipogenesis; in GI tract and brain, increased satiety; weight loss; increased
high-density lipoprotein (HDL); decreased triglycerides; improved metabolic syndrome
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| Pramlintide (Symlin): can be added when patient unresponsive to insulin; synthetic amylin; amylin cosecreted with insulin
in pancreas; over time, amylin secretion lost; involved in modulation of how quickly food passes through stomach;
used to slow absorption of food; marketed for weight loss; may decrease appetite
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Suggested Reading
American Diabetes Association: Standards of medical care in diabetes. Diabetes Care 28 Suppl 1:S4, 2005;
Crotty S et al: The new insulins. Pediatr Emerg Care 23:903, 2007; Edelman SV: Does addition of pramlintide
to basal insulin improve glycemic control in type 2 diabetes mellitus? Nat Clin Pract Endocrinol Metab 4:194, 2008;
Hoogwerf BJ: Exenatide and pramlintide: new glucose-lowering agents for treating diabetes mellitus. Cleve Clin J
Med 73:477, 2006; Kahn SE et al: Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N
Engl J Med 355:2427, 2006; Mack GS: Pfizer dumps Exubera. Nat Biotechnol 25:1331, 2007; Monnier L et al:
Contributions of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycemia of type 2
diabetic patients: variations with increasing levels of HbA(1c). Diabetes Care 26:881, 2003; Nathan DM et al:
Management of hyperglycemia in type 2 diabetes: A consensus algorithm for the initiation and adjustment of therapy:
a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes.
Diabetes Care 29:1963, 2006; Nauck MA et al: Effects of subcutaneous glucagon-like peptide 1 (GLP-1 [7-36
amide]) in patients with NIDDM. Diabetologia 39:1546, 1996; Nauck MA et al: Incretin effects of increasing glucose
loads in man calculated from venous insulin and C-peptide responses. J Clin Endocrinol Metab 63:492, 1986;
Rachman J et al: Near-normalisation of diurnal glucose concentrations by continuous administration of glucagon-
like peptide-1 (GLP-1) in subjects with NIDDM. Diabetologia 40:205, 1997; Siminerio LM: Approaches to help
people with diabetes overcome barriers for improved health outcomes. Diabetes Educ 34 Suppl 1:18S, 2008; Yale
JF et al: The effect of a thiazolidinedione drug, troglitazone, on glycemia in patients with type 2 diabetes mellitus
poorly controlled with sulfonylurea and metformin. A multicenter, randomized, double-blind, placebo-controlled
trial. Ann Intern Med 134:737, 2001.
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