NEW DIRECTIONS IN DIABETES
| TOWARD EARLIER RECOGNITION AND TREATMENT OF DIABETES —George E. Dailey III, MD, Clinical
Professor of Medicine, University of California, San Diego, School of Medicine, and Head, Division of Diabetes and
Endocrinology, Scripps Clinic, La Jolla, CA
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| Pre-diabetes: American Diabetes Association (ADA) lowered upper limit of normal for fasting blood glucose (BG)
from 110 mg/dL to 100 mg/dL; motivation for change—in Diabetes Prevention Program (DPP), significant number
of people with fasting BG of 110 mg/dL found to have diabetes after glucose tolerance test (GTT)
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| Meaning of test results: fasting BG test—normal (<100 mg/dL); impaired fasting glucose (110-125 mg/dL); diabetes
(≥126 mg/dL); oral GTT—normal (<140 mg/dL); impaired glucose tolerance (140-199 mg/dL); diabetes
(≥200 mg/dL); same BG values used to evaluate postprandial glucose levels (suspect diabetes in any patient with
BG >140 mg/dL)
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| Patients with impaired glucose tolerance: cardiovascular risk elevated at least 2-fold; oxidative damage associated
with even brief periods of postprandial hyperglycemia; evaluate blood pressure and lipid levels; ≈10% per
year progress to frank diabetes; therapeutic measures—aspirin; weight loss (losing 5%-10% of body weight significantly
reduces risk for diabetes); exercise (independent beneficial effect); metformin (used in DPP; rate of progression
to diabetes reduced ≈31%)
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| Beta cell loss: already ≈50% in newly diagnosed patients in United Kingdom Prospective Diabetes Study (UKPDS);
rate of loss 3% to 4% per year in all treatment groups, suggesting loss begins 10 to 12 yr before diagnosis
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| Postprandial BG: begins rising 4 to 5 yr before fasting BG; in pregnant women with normal fasting BG but post-
challenge BG >140 mg/dL, GTT indicated; focus on postprandial hyperglycemia facilitates earlier diagnosis of diabetes;
hemoglobin [Hb]A1C —population studies show most people with HbA1C of 6% to 7% have postprandial
hyperglycemia; helpful in clarifying meaning of single BG value; rationale for earlier diagnosis—more beta cells
mean patient has chance of normalizing BG with diet and exercise (little chance of normalization once fasting BG
elevated); single agent likely to work well at this stage; in UKPDS, ≈50% of patients had complications ascribable
to diabetes at time of diagnosis (substantial number had retinopathy); microvascular complications begin when average
BG 110 mg/dL (HbA1C ≈5.8%)
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| Initial therapy metformin: begin as first drug after diagnosis and maybe in pre-diabetes; ≈5% of patients cannot
take (some have renal dysfunction); cardioprotective in UKPDS; long safety record (since 1952 in Europe); continue
after starting insulin (reduces total insulin dose and makes control easier); does not increase risk for hypoglycemia
because it does not stimulate insulin release; only oral agent not associated with weight gain, and sometimes
associated with weight loss
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| New ADA recommendations: most cost-effective approach to usual patient; at diagnosis—provide education on
nutrition therapy; begin metformin; next step—if HbA1C >7% after ≈2 mo, add thiazolidinedione (TZD); if
HbA1C >8%, consider sulfonylurea; if HbA1C >9%, insulin indicated; primary care physicians need to become
comfortable starting insulin therapy
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 | Speaker’s approach: adds sulfonylurea as next drug after metformin; if HbA1c ≈8%, starts TZD or exenatide
(Byetta)
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| Sulfonylureas: rarely appropriate as monotherapy; fastest acting oral agents; can titrate to maximal dose in 2 to 4
wk; all benefits apparent within 1 mo (no need to wait longer before adding additional agent); glipizide GITS (Glucotrol
XL) dose of 5 to 10 mg/dL provides maximal clinical benefit (higher doses of sulfonylureas unnecessary)
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| Oral drugs after starting insulin: continue insulin sensitizers (metformin [offsets weight gain]; TZDs [cause
weight gain]); sulfonylureas—to reduce weight gain and hypoglycemia, cut dose ≥50% when approaching target
fasting BG (100 mg/dL); when giving rapid-acting insulin bid, discontinue sulfonylurea
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| Long-acting insulin analogues (glargine; detemir): reduce weight gain and hypoglycemia, compared to NPH;
most HbA1C lowering achieved at fasting BG of 100 mg/dL (HbA1C <7%); effective dose provides 0.5 units of insulin
per kg body weight; raise dose until fasting BG 80 to 120 mg/dL; safe to increase dose 2 units every 3 to 4
days; glargine reduced nighttime hypoglycemia almost 50%, compared to NPH; insulin detemir—newly available;
fatty acid added to end of beta chain; bound to albumin in blood and interstitial spaces, and released slowly; duration
of action for average dose ≈20 hr; morning dose may be required if BG elevated at nighttime meal; may be better
than glargine (requires more study)
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| Postprandial glucose control: becomes more important as target BG level approached; when HbA1C <7%, postprandial
BG contributed 66% to daily average; get fasting BG down first
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| Rapid-acting insulin analogues (lispro; aspart; glulisine [Apidra]): peak in ≈2 hr; eliminated in 3 to 4 hr
(lowering risk of hypoglycemia); can be given ≤20 min after start of meal (regular insulin should be given 45-60
min before meal; “virtually never occurs”); switching amino acid on end of beta chain increased absorption of
lispro and aspart; glulisine—new agent; substituting lysine at other end of beta chain stabilized insulin molecule,
eliminating need to add zinc, which slows peak and duration of action; somewhat faster acting; clinical advantage
not established
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| Postprandial glucose monitoring: aim to reduce rise in BG to <40 mg/dL (normal BG ≈100-140 mg/dL); if BG
above target (eg, 160 or 180 mg/dL) after eating each typical meal, increase dose 1 to 2 units before eating that
meal again; patients eventually establish proper doses, which become intuitive for each typical meal
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| New inhaled insulin: human insulin (recombinant DNA origin) injection powder (Exubera); rapid acting; onset
similar to lispro (not eliminated as quickly); patients who try it prefer inhalation to injections, but cost 2 to 2.5
times higher; slight decline in forced expiratory volume in 1 sec (FEV1 ; investigators found patients with diabetes
lose lung function at rate slightly higher than normal); contraindicated in patients with significant asthma and in
smokers; requires baseline pulmonary function studies, repeated at 6 mo; may be useful in getting more patients on
insulin therapy
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| Incretin mimetics: exenatide first on market; based on observation that when equal amounts of insulin given orally
and intravenously (IV), peak insulin level ≈2.5 times higher after oral route; upon ingestion of food, glucagon-
like peptide (GLP)-1 released from neuroendocrine cells in gut; GLP-1 causes early insulin secretion from beta
cells; in pre-diabetes, levels of GLP-1 lower than normal; early insulin signals liver and peripheral tissues to prepare
to store glucose; loss of early insulin secretion hallmark of unhealthy beta cell (begins in pre-diabetes when
fasting BG >100 mg/dL); exenatide—restores early insulin secretion; suppresses glucagon (hormone that opposes
effect of insulin; elevated in diabetes); reduces production of glucose in liver; delays gastric emptying; acts in
brain to affect satiety; associated with weight loss; approved for use in patients with BG uncontrolled with metformin
or sulfonylurea; side effect—nausea in ≤30% of patients (tends to decrease with time); 5% to 8% discontinued
drug in studies; weight loss—mainly due to effect on satiety center in brain; unlike other therapies,
benefits not overridden by compensatory mechanisms at 2 yr; average weight loss 11 to 12 lb (loss minimal or
absent in 25% of patients)
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| Incretin drugs not yet released: another GLP agonist—liraglutide; employs albumin-binding technology used in
detemir insulin; 2 oral drugs—vildagliptin (Galvus); sitagliptin (Januvia); block enzyme that degrades GLP;
lower HbA1C <1%; no risk of hypoglycemia; restore early insulin secretion; no effect on weight; useful in early
diabetes, eg, with metformin
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| Questions and answers: short-acting secretagogues—low risk of hypoglycemia; useful in patients who develop
hypoglycemia on sulfonylurea; insulin pump—indicated in patients with type 1 diabetes; enables varying basal insulin
dose; absorption more reliable because rapid-acting insulins used; consider when BG uncontrolled with 2 to 3
injections; referral to endocrinologist recommended
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| WHAT TO EXPECT FROM THE NEW DRUGS FOR DIABETES —Michael D. Whitaker, MD, Assistant Professor
of Medicine, Mayo Clinic College of Medicine, and Consultant, Department of Endocrinology, Mayo Clinic
Scottsdale, Scottsdale, AZ
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| What to know about inhaled insulin: lungs offer alternative to injection—large surface area; extensive circulation;
permeable membranes; fast-acting insulin—duration of action falls between regular insulin and rapid-acting
insulin analogues; in type 1 diabetes—equivalent to regular insulin in patients on long or intermediate basal
bolus insulin program; in type 2 diabetes—effective when BG no longer controlled by diet and exercise or oral
agents; same as considerations for initiating any other insulin
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| Dosing problematic: provided in foil blister packets containing 1 mg (equals 3 units of regular insulin) or 3 mg (8
units); mix and match—for other doses; eg, for 11 units of insulin, 1 mg packet and 3 mg packet; for 16 units of
insulin, two 3-mg packets; correct dosing poses difficulties for patients on higher doses of insulin, eg, 40, 50, or
60 units of regular insulin
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| Hypoglycemia: rates equivalent to those in patients taking regular insulin or oral agents combined with regular insulin
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| Lung disease: available data show slight decline in FEV1 and diffusion capacity, but stable over 2 yr (longer-term
data lacking); consequences unknown for taking drug directly into lung for 5 to 10 yr or longer; effect unknown
on undiagnosed asthma or chronic obstructive pulmonary disease; patients must stop smoking 6 mo before starting
therapy; pulmonary function studies required before starting drug and at 6 and 12 mo; insurance reimbursement
uncertain for pulmonary function studies linked to diabetes
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| Requires unwieldy device: blister packets placed in bottom of large device before inhaling; education on proper use
of device needed for physicians, patients, and educators
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| Concluding observation: speaker suspects therapy may be destined for same fate as jet injector for insulin (“fell by
wayside”); “subset of patients will be desperately interested... I don’t think we should withhold it, but keep in
mind the shortfalls”
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| What to know about incretins: gut hormones that enhance insulin secretion in response to food; GLP-1 degraded
in <2 min by dipeptidyl-peptidase IV (DPP-IV) enzyme
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| How to enhance incretin effects: first option—decrease DDP-IV to prolong GLP-1 viability; second option—give
incretin mimetic (exenatide, GLP-1 analogue; comes from gila monster saliva)
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| Effect on pancreas: exenatide restores first-phase insulin secretion; improves glucose-dependent insulin secretion;
stimulates synthesis of insulin; evidence in animal studies that it may cause formation of new beta cells (effect in
humans would alter natural history of type 2 diabetes)
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| Effect on gut: exenatide slows gastric emptying in diabetes; postprandial glucose rises faster when stomach empties
more quickly; GLP-1 responds by slowing stomach emptying; reduced GLP-1 levels in diabetes leads to accelerated
gastric emptying
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| Effect on appetite: patients taking exenatide feel fullness in stomach, leading to weight loss
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| Effects of exenatide therapy on patients: reduces weight, HbA1C levels, and BG; side effects—mainly nausea; also
vomiting and diarrhea; start at low dose (5 µg exenatide bid); after ≈1 mo, move to full dose (10 µg bid)
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| Potential drawbacks: hypoglycemia—not seen in patients on metformin, but may be problem in those on sulfonylureas;
requires injection—in morning and evening; cost—expensive; carried by most formularies
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| Candidates for therapy: obese patients with type 2 diabetes and inadequately controlled BG; “probably the brunt of
your practice”; helps control weight in patients failing metformin therapy
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Educational Objectives
| The goal of this program is to educate the listener about current therapies for diabetes. After hearing and assimilating
this program, the clinician will be better able to:
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| 1. Recognize pre-diabetes in patients.
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| 2. Institute and manage initial therapy for diabetes.
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| 3. Administer insulin therapies, including the long-acting insulin analogues and the rapid-acting insulin analogues.
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| 4. Evaluate the role of the new inhaled insulin in the management of diabetes.
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| 5. Explain the therapeutic benefits of the new incretin mimetics and include these agents as indicated in managing
diabetes
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Discussed on This Program
Exenatide [Byetta]
Glipizide GITS (Glucotrol XL)
Insulin aspart (rDNA origin) [NovoLog, Novolog Mix 70/30]
Insulin detemir (rDNA origin) [Levemir]
Insulin glargine [Lantus]
Insulin glulisine (rDNA origin) [Apidra]
Insulin human (rDNA origin) injection powder [Exubera]
Insulin lispro, human (rDNA) [Humalog, Humalog Mix 75/25]
Insulin suspension, isophane (NPH) [several trade names]
Liraglutide (investigational)
Metformin HCl [several trade names]
Sitagliptin [Januvia] (investigational)
Vildagliptin [Galvus] (investigational)
Suggested Reading
Becker RH et al: A comparison of the steady-state pharmacokinetics and pharmacodynamics of a novel rapid-acting
insulin analog, insulin glulisine, and regular human insulin in healthy volunteers using the euglycemic clamp
technique. Exp Clin Endocrinol Diabetes 113:292, 2005; Becker RH et al: Insulin glulisine, a new rapid-acting insulin
analogue, displays a rapid time-action profile in obese non-diabetic subjects. Exp Clin Endocrinol Diabetes
113:435, 2005; Dailey GE 3rd et al: Glycemic control with glyburide/metformin tablets in combination with
rosiglitazone in patients with type 2 diabetes: a randomized, double-blind trial. Am J Med 116:223, 2004; Dailey GE
3rd: Early insulin: an important therapeutic strategy. Diabetes Care 28:220, 2005; Dailey GE 3rd: Improving oral
pharmacologic treatment and management of type 2 diabetes. Manag Care 13:41, 2004; Drucker DJ: Glucagon-
like peptides. Diabetes 47:159, 1998; Heine RJ et al: Exenatide versus insulin glargine in patients with suboptimally
controlled type 2 diabetes: a randomized trial. Ann Intern Med 143:559, 2005; Heise T et al: Lower within-
subject variability of insulin detemir in comparison to NPH insulin and insulin glargine in people with type 1 diabetes.
Diabetes 53:1614, 2004; Nauck MA et al: Five weeks of treatment with the GLP-1 analogue liraglutide improves
glycaemic control and lowers body weight in subjects with type 2 diabetes. Exp Clin Endocrinol Diabetes
114:417, 2006; 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; Strowig SM et al: Comparison of insulin monotherapy
and combination therapy with insulin and metformin or insulin and troglitazone in type 2 diabetes. Diabetes
Care 25:1691, 2002.
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. Dailey—Sanofi-Avantis, Eli Lilly-Amylin, GSK, Merck, Novartis (investigator; speaker; occasional
consultant); Dr. Whitaker—Eli Lilly (research support)
Dr. Dailey was recorded at 28th Annual Primary Care Medicine: A Practical Approach, sponsored by the Scripps
Clinic and held in San Diego, CA, August 11-13, 2006; Dr. Whitaker, at Primary Care Update 2006, sponsored by
the Mayo Clinic College of Medicine and Mercy Medical Center, and held in Durango, CO, September 15-16, 2006.
The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.
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