DIABETES UPDATE
From Orlando Regional Healthcare’s 2007 Internal Medicine Conference: The Year in Review
David S.H. Bell, MD, Clinical Professor of Medicine, University of Alabama School of Medicine, Birmingham
| YEAR IN REVIEW IN DIABETES CARE
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| Type 1 diabetes: no “really dramatic advances” in management; some progress in defining genetics, pathogenesis, and natural
history; some hopeful immunotherapies; advances in therapy—continuous glucose monitoring devices (when used in
conjunction with insulin pump or basal-bolus therapy, produce “remarkable improvements” in diabetes control); better insulin
formulations (absorbed, act, and decrease blood glucose levels more quickly), including better long-acting insulins
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| Type 2 diabetes: improving patients’ lifestyles—no progress; rate of obesity in US population has risen from 15% in 1976
to 32% in 2006; vitamin D deficiency—seen in many Americans, especially elderly, obese, people with darker skin, and
those with insufficient sun exposure; leads to neuromuscular problems, eg, vitamin D–deficient elderly shown to have
more falls; may be related to development of type 1 and type 2 diabetes; known that vitamin D deficiency leads to insulin
resistance associated with type 2 diabetes, and, therefore, also may be associated with increased risk for cardiovascular
events; testosterone—recently discovered that decreased level in men also leads to increased insulin resistance, metabolic
syndrome, increased risk for diabetes, and possibly more cardiovascular events; “biggest news” in type 2 diabetes
care—advent of incretin mimetics and increasing evidence that type 2 diabetes is major risk factor for cardiovascular
events
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| MANAGEMENT OF TYPE 2 DIABETES
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| Natural history: starts with insulin resistance; initially, patients overcome resistance by increased insulin production in pancreas;
only one-third of insulin-resistant patients who have metabolic syndrome develop type 2 diabetes; other two-thirds
at increased risk for cardiovascular events; impaired glucose tolerance—postprandial glucose becomes elevated (>200
mg/dL; gold standard for type 2 diabetes) 2 yr before fasting glucose increases; for diagnosis—speaker advocates use of 1
serum specimen taken 2 hr after 75 g of glucose; if >200 mg/dL, patient has diabetes; if 140 to 200 mg/dL, patient has
impaired glucose tolerance; if <140 mg/dL, patient euglycemic; in genesis of cardiovascular disease, postprandial glucose
probably much more important than preprandial or fasting glucose; United Kingdom Prospective Diabetes Study
(UKPDS)—shows that at time of diagnosis, patients with type 2 diabetes have only 50% pancreatic β-cell function (decreases
to 25% 6 yr out, <10% 10 yr out, which is when patients require insulin); estimated that last time patient with type
2 diabetes has 100% pancreatic function 12 yr before diagnosis
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| Drug therapy: 10 to 12 yr ago, treatment options sulfonylureas (SUs) and insulin; still use SUs; new tools include other
secretagogues (repaglinide [Prandin], nateglinide [Starlix]); biguanides (metformin); thiazolidinediones (TZDs); incretin-like
drugs (exenatide [Byetta; injectable]; dipeptidyl peptidase-4 [DPP-4] inhibitors [oral]); improved insulins
(glargine [Lantus], detemir [Levemir; long acting]; lispro [Humalog], aspart [Novolog], glulisine [Apidra; fast acting];
inhaled insulin [difficult to deliver])
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| Secretagogues: SUs block energy-sensor potassium channel in wall of pancreatic β-cell; this leads to depolarization of β-
cell, influx of calcium, and increased release of insulin; work within 24 to 48 hr (metformin takes 1-2 wk; TZDs take 6
wk to 3 mo); in fact, speaker often starts with secretagogue in conjunction with other drugs and removes it later;
disadvantages—weight gain; hypoglycemia (secretagogues only group of oral agents used for treating type 2 diabetes
that causes hypoglycemia); studies show increase in cardiac events in patients taking SUs; SU associated with lowest
rates of hypoglycemia is glimepiride (also has cardiac safety, ie, does not block potassium channels in myocardium);
nateglinide also “perfectly safe as far as the heart is concerned”
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| Biguanides: metformin only one currently available; major effect suppression of hepatic glucose production; lowers fasting
and preprandial (but not postprandial) glucose; anorectic drug (especially at higher levels), ie, produces weight loss; 33%
of patients get diarrhea (worse at higher doses); contraindicated in patients with renal insufficiency (creatinine >1.5 mg/
dL), hepatic insufficiency, or congestive heart failure (CHF) because of risk for lactic acidosis; highly effective in treatment
of polycystic ovary syndrome (PCOS); cardioprotective (increases levels of 5-adenosine monophosphate-activated
protein kinase [5-AMPK]); in UKPDS, metformin decreased any diabetes-related end point by 32%, diabetes-related
mortality by 42%, all-cause mortality by 36%, and incidence of myocardial infarction (MI) by 39%; not associated with
hypoglycemia; lowers insulin resistance
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| Thiazolidinediones: improve mitochondrial function; decrease tissue triglycerides; improve insulin resistance and pancreatic
β-cell function; extremely effective in treatment of nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis
(NASH), and PCOS; decrease cardiac risk factors; decrease markers for atherosclerosis, eg, carotid intima-
media thickening; unknown whether they decrease cardiac events or whether they can be used in CHF
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| Insulin resistance: inflammatory state; leads to production of superoxides that quench nitric oxide; this causes endothelial
dysfunction that, in glomerulus of kidney, leads to microalbuminuria (secretion of albumin part of insulin-resistance syndrome
[IRS]); insulin salt- and water-retaining hormone working in distal tubule, also stimulates sympathetic nervous
system; insulin resistance associated with hypertension and diabetes; low levels of high-density lipoprotein (HDL) and
high levels of triglycerides classic symptoms of IRS; patient probably has insulin resistance if triglyceride-to-HDL ratio
>3.5; insulin resistance leads to high levels of plasminogen activator inhibitor-1 (PAI-1), which inhibits tissue plasminogen
activator (tPA), which slows breakdown of fibrin, resulting in more clotting and more thromboembolic phenomena;
TZDs most powerful drugs for reducing insulin resistance; decrease inflammation and clotting, and improve lipid profile,
glucose, and blood pressure (BP); some studies show 6-mm Hg decrease in systolic BP in patients taking TZDs; in patient
with diabetes, 4-mm Hg decrease in systolic BP can result in 51% decrease in cardiac events
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| Effect of TZDs on cardiac events: known that TZDs decrease cardiac risk factors and intima-media thickness of carotid
artery (surrogate marker for atherosclerosis); unclear whether they actually reduce cardiac events; in PROspective pioglitAzone
Clinical Trial In macroVascular Events (ProACTIVE) study, pioglitazone did not significantly reduce primary
composite end point (which measured cardiac events) over placebo; however, drug did significantly reduce risk
for MI, stroke, and premature death (principal secondary end point); in subsidiary study, pioglitazone reduced rate of
reinfarction by 30%; another study of patients with previous stroke found pioglitazone decreased recurrent strokes by
47% (however, patients also on statin or β-blocker showed virtually no effect); these studies questioned, and still controversial
whether TZDs (even pioglitazone) actually decrease cardiac events
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 | Rosiglitazone: major controversy whether rosiglitazone actually increases cardiac events in diabetes, instead of decreasing
them; cardiologist (Nissen) reviewed all clinical trials on rosiglitazone; hypothesized that rosiglitazone increases
low-density lipoproteins (LDL) and apolipoprotein B [apoB], and that this slight increase, despite other effects of lowering
insulin resistance, would result in increase in cardiac events; Nissen reviewed trials over Internet; because he did
not have original data, some have questioned study and its statistical analysis; trials of 6 to 12 mo found 43% early increase
in cardiac events with rosiglitazone; manufacturer of rosiglitazone submitted report to Food and Drug Administration
(FDA) showing 31% increase in cardiac events; however, results of 3-yr prospective Rosiglitazone Evaluated
for Cardiac Outcomes and Regulation of Glycaemia in Diabetes (RECORD) study found no increased risk for cardiac
events; controversy continues
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| Other side effects of TZDs: fluid retention; increased incidence of CHF; anemia; greater incidence of osteoporosis (documented
that TZDs cause conversion of osteoblasts into adipocytes); increase in upper limb fractures in women
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| Rimonabant: turned down for approval by FDA in 2007; blocks cannabinoid receptors, decreasing appetite and causing
12- to 15-lb weight loss; also decreases insulin resistance; not approved for safety reasons (blockade of cannabinoid receptors
thought to be associated with increased incidence of depression); approved in 30 other countries
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| Alpha-glucosidase inhibitors: inhibit α-glucosidase in brush border of small intestine; decrease breakdown of starch to sucrose
and of sucrose to glucose; reduce postprandial glucose but have no effect on preprandial or fasting glucose; as result,
have little effect on lowering hemoglobin A1c (HbA1c ); because of side effect profile, seldom used; adverse effects
include flatus; while these drugs lower only postprandial glucose, in patients with HbA1c <7.5%, most of contribution to
HbA1c level from postprandial glucose; more importantly, postprandial hyperglycemia and hyperlipidemia (ie, postprandial
dysmetabolism) associated with increased cardiac events
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| Postprandial dyslipidemia: when individuals eat, they get postprandial hyperglycemia and hyperlipidemia (high free fatty
acids and triglycerides); these increase production of superoxides and increase oxidative stress (free radical production),
which leads to endothelial dysfunction, decreased fibrinolysis, sympathetic hyperactivity, atherosclerosis, to inflammation
within atheromatous plaque, and more cardiac events; thus, postprandial dyslipidemia important cardiovascular risk
factor (much more important than fasting glucose)
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| Data from Study to Prevent Non-Insulin-Dependent Diabetes Mellitus (STOP-NIDDM trial): found that patients on
the α-glucosidase inhibitor acarbose had 64% decrease in MIs, 35% decrease in cardiovascular events, and 50% reduction
in intima-media thickness (went back to baseline when they came off drug); demonstrates that not only drugs that decrease
preprandial glucose, but also those that reduce postprandial glucose, should be utilized
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| Incretins: hormones secreted from gastrointestinal (GI) tract in direct proportion to meal size; stimulate insulin secretion; 2
incretins, most important one being glucagon-like peptide-1 (GLP-1); broken down by DPP-4 inhibitors; plasma half-life
<5 min; act on pancreatic β-cell receptor; stimulate glucose-dependent release of insulin; release decreases with onset of
type 2 diabetes; incretins not only improve insulin secretion, but also suppress glucagon (lowers postprandial glucose and
has effect on β-cells to suppress apoptosis, which preserves (and perhaps even improves) β-cell mass, and may also increase
proliferation); effect of incretin seen in patients who have had bariatric surgery—gastric bypass surgery found to
cure type 2 diabetes in 70% of patients; improvement not from weight loss and reduction in insulin resistance, but due to
alteration in GI tract; production of grehlin bypassed, resulting in satiety and weight loss; GLP-1 increases to very high
levels, which in turn increases number of β-cells and insulin production; GLP-1 receptors in pancreas and throughout
body; shown that patients with heart failure given injection of GLP-1 have marked improvement in ejection fraction;
problematic that incretins are broken down quickly by DPP-4; thus, drugs resistant to DPP-4 now used
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| Exenatide: synthetic version of component of Gila monster (lizard) saliva; has GLP-1 activity resistant to breakdown by
DPP-4; improves postprandial and fasting glucose; also improves HbA1c levels; can cause weight loss (either due to nausea
associated with drug or because it decreases gastric emptying and produces early satiety); administered by injection
bid; prolonged form (taken once weekly) in development
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| Liraglutide: long-acting DPP-4-resistant GLP-1 receptor agonist; may be released in 2008; given qd; much more powerful
than exenatide
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| DPP-4 inhibitors: sitagliptin (Januvia) currently available; vildagliptin and another drug in development and may be available
next year; these drugs increase GLP-1 levels by suppressing activity of DPP-4
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| Managing glycemia: conservative management of glycemia (eg, diet and exercise; oral antidiabetic [OAD] monotherapy)
ineffective once patient diagnosed with diabetes; be aggressive in lowering HbA1c to goal levels (6.5% in patients with
type 2 diabetes) and maintaining it at that level by adding more medicines, combination therapy, and finally, insulin
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| Oral combination therapy: benefits—lower HbA1c ; less hypoglycemia; better compliance; fewer side effects; lower cost;
would like HbA1c level as low as possible to lower risk for cardiac event; in population study from England, for every 1%
that HbA1c above 5%, cardiovascular risk increased by 26%, and for every 1% above 8%, risk increased by 40%; get
HbA1c to goal by using drugs that do not cause hypoglycemia; speaker’s experience that starting off with combination
therapy enables almost 92% of patients to attain American Diabetes Association (ADA) HbA1c goal of <7%, 78% to attain
<6.5%, and 42% to attain <6%; in future, expect to use drugs that will improve pancreatic function (TZDs do so in
minor way; speaker thinks incretin-like drugs will prove much more effective in increasing β-cell function and activity);
triple therapy—can offer improved glycemic control; in speaker’s study, SU/metformin/TZD therapy has proven effective
in bringing patients’ HbA1c into range of ADA goal and maintaining it for prolonged period; 51% of patients still at
<7% after 6 yr, probably because TZD improved β-cell function; patients gained weight but weight plateaued after 3 yr
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| Insulin therapy: when oral therapy fails, add insulin; in patients with HbA1c >7%, add 1 injection of basal insulin to oral
therapy; if HBA1C >8%, lower postprandial glucose with premixed insulins; can start with 1 injection at evening meal;
then go to morning and lunchtime injections; in combination with oral agents, can get >70% of patients to HbA1c goal
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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. Cite developments in diabetes care that have occurred during the last year.
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| 2. Describe the mechanisms of action, benefits, and possible adverse effects of the oral medications currently used to
treat type 2 diabetes.
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| 3. Identify and manage the risk factors in type 2 diabetes for increased cardiac events and cardiovascular disease.
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| 4. Explain the effects of incretin hormones and their role in the management of type 2 diabetes.
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| 5. Discuss the evidence supporting combination oral therapy over more conservative management.
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Suggested Reading
Abbasi F et al: Effect of metformin treatment on multiple cardiovascular disease risk factors in patients with type 2 diabetes
mellitus. Metabolism 53:159, 2004; Bell DS: Advances in diabetes for the millennium: the heart and diabetes.
MedGenMed 6(3 Suppl):7, 2004; Bell DS: Do sulfonylurea drugs increase the risk of cardiac events? CMAJ 174:185, 2006;
Bell DS: Importance of postprandial glucose control. South Med J 94:804, 2001; Bell DS: The case for combination therapy
as first-line treatment for the type 2 diabetic patient. Treat Endocrinol 5:131, 2006; Bell DS, Ovalle F: Long-term efficacy
of triple oral therapy for type 2 diabetes mellitus. Endocr Pract 8:271, 2002; Bell DS, Ovalle F: Outcomes of
initiation of therapy with once-daily combination of a thiazolidinedione and a biguanide at an early stage of type 2 diabetes.
Diabetes Obes Metab 6:363, 2004; Chiasson JL et al: Acarbose treatment and the risk of cardiovascular disease and hypertension
in patients with impaired glucose tolerance: the STOP-NIDDM trial. JAMA 290:486, 2003; Dormandy JA et al:
Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone
Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet 366:1279, 2005; Effect of intensive
blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective
Diabetes Study (UKPDS) Group. Lancet 52:854, 1998; Janka HU et al: Comparison of basal insulin added to oral
agents versus twice-daily premixed insulin as initial insulin therapy for type 2 diabetes. Diabetes Care 28:254, 2005; Manley
S: Haemoglobin A1c--a marker for complications of type 2 diabetes: the experience from the UK Prospective Diabetes
Study (UKPDS). Clin Chem Lab Med 41:1182, 2003; McIntosh CH et al: Applications of dipeptidyl peptidase IV inhibitors
in diabetes mellitus. Int J Biochem Cell Biol 38:860, 2006; McIntosh CH et al: Dipeptidyl peptidase IV inhibitors:
how do they work as new antidiabetic agents? Regul Pept 128:159, 2005; 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; O'Keefe JH, Bell DS: Postprandial hyperglycemia/hyperlipidemia
(postprandial dysmetabolism) is a cardiovascular risk factor. Am J Cardiol 100:899, 2007; Ovalle F, Bell DS:
Clinical evidence of thiazolidinedione-induced improvement of pancreatic beta-cell function in patients with type 2 diabetes
mellitus. Diabetes Obes Metab 4:56, 2002; Ovalle F, Bell DS: Effect of rosiglitazone versus insulin on the pancreatic
beta-cell function of subjects with type 2 diabetes. Diabetes Care 27:2585, 2004; Riddle MC: Glycemic management of
type 2 diabetes: an emerging strategy with oral agents, insulins, and combinations. Endocrinol Metab Clin North Am 34:77,
2005; Riddle MC et al: Exenatide elicits sustained glycaemic control and progressive reduction of body weight in patients
with type 2 diabetes inadequately controlled by sulphonylureas with or without metformin. Diabetes Metab Res Rev
22:483, 2006; Riddle MC, Drucker DJ: Emerging therapies mimicking the effects of amylin and glucagon-like peptide 1.
Diabetes Care 29:435, 2006; Salehi M, D'Alessio DA: New therapies for type 2 diabetes based on glucagon-like peptide 1.
Cleve Clin J Med 73:382, 2006; Sidhu JS et al: Effect of rosiglitazone on common carotid intima-media thickness progression
in coronary artery disease patients without diabetes mellitus. Arterioscler Thromb Vasc Biol 24:930, 2004; Sidhu JS et
al: Effects of rosiglitazone on endothelial function in men with coronary artery disease without diabetes mellitus. Am J Cardiol
94:151, 2004; Wyne KL et al: Constructing an algorithm for managing type 2 diabetes. Focus on role of the thiazolidinediones.
Postgrad Med Spec No:63, 2003.
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. Bell has been a speaker and consultant for
GlaxoSmithKline, Novo Nordisk, Novartis, and Takedo.
Acknowledgements
Dr. Bell was recorded at the 2007 Internal Medicine Conference: The Year in Review, held July 16-20, 2007, in Lake Buena
Vista, FL, and sponsored by Orlando Regional Healthcare. The Audio-Digest Foundation thanks Dr. Bell and Orlando Regional
Healthcare for their cooperation in the production of this program.
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