ZACHARY T. BLOOMGARDEN, MD, Associate Clinical Professor, Medicine/Endocrinology, Mount Sinai School of Medicine, New York, NY.
RICHARD J. COMI, MD, Section Chief, Endocrinology, Diabetes & Metabolism, Dartmouth-Hitchcock Medical Center, Lebanon, NH. Dr Comi is a member
of the Patient Care Subspecialty Advisory Board.
DAVID M. KENDALL, MD, Chief of Clinical Services and Medical Director, International Diabetes Center, Minneapolis, Minn; and Associate Professor
of Medicine, University of Minnesota, Minneapolis. Dr Kendall currently is Executive Director, Medical Affairs, Amylin Pharmaceuticals,
Inc, San Diego, Calif
The statistics about diabetes mellitus are familiar to primary care physicians. It is estimated that one third of people with
diabetes have not been diagnosed and that, when they are diagnosed, it is often because they are experiencing complications.1 Moreover, in the past 10 years, the prevalence of the disease in the United States has increased about 30%, and more than
90% of these cases are type 2 diabetes mellitus (T2DM).2
ILLUSTRATIONS: SHARON AND JOEL HARRIS/www.illustrationOnLine.com
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The good news is that the number of classes of antihyperglycemic agents has grown from just 2 (insulin and insulin secretagogues)
to 5 (with the addition of biguanides, thiazolidinediones [TZDs], and alpha-glucosidase inhibitors [AGIs]), plus 2 new agents,
including an incretin mimetic and an amylinomimetic.3 Primary care physicians who optimize the use of this expanding armamentarium will be best equipped to help their patients
manage their diabetes long term.
Latest tools in the diabetes armamentarium
In 2005, 2 new and unique drugs were approved for the treatment of diabetes. The first, pramlintide (Symlin), is an amylinomimetic
agent, approved for the treatment of patients with type 1 diabetes (T1DM) and T2DM patients using meal-time insulin. The second
is exenatide (Byetta), an incretin mimetic agent for the treatment of T2DM. Besides improving glycemic control, both agents
significantly improve postprandial blood glucose and promote weight loss—benefits that are not available with most antihyperglycemic
agents.
Pramlintide is a synthetic analog of the hormone amylin, which is deficient in patients with diabetes. It acts by slowing
gastric emptying, curbing appetite, and suppressing postprandial plasma glucagons and hepatic glucose output. It is designed
to be an adjunct therapy for patients with T2DM who use mealtime insulin and have not maintained glycemic control despite
optimal insulin therapy, with or without a sulfonylurea and/or metformin.4,5 Clinical trials have shown the beneficial effect of amylin replacement on A1C levels in both T1DM and T2DM.5
As with many other hormone therapies, pramlintide must be injected—and these injections are done separately from insulin.
Pramlintide use is associated with a risk of severe hypoglycemia. Other side effects include nausea, vomiting, anorexia, and
headache. It is contraindicated in patients with gastroparesis or those taking medications affecting GI motility. The recommended
starting dosage is 15 mcg to 60 mcg tid before main meals, titrating up to 120 mcg tid for patients with T2DM as tolerated.
The second new agent, exenatide, is the first incretin mimetic approved for the treatment of T2DM. The drug works to mimic
the enhancement of glucose-dependent insulin secretion and several other glucoregulatory actions of naturally occurring incretins.
These actions suppress inappropriately elevated glucagon levels and slow the rate of gastric emptying. Patients taking either
metformin, sulfonylurea, or a combination of these drugs are candidates for exenatide. It is not approved for use with insulin.
Exenatide has been shown to be as effective as insulin glargine in improving glycemic control in patients, although they work
differently. Exenatide targets postprandial glucose levels, whereas glargine targets premeal glucose levels.6 Exenatide also has several advantages over glargine, in that it results in fewer nocturnal hypoglycemic episodes and promotes
weight loss. The use of glargine, however, produces lower fasting glucose concentrations and fewer daytime hypoglycemic episodes.7
Like pramlintide, exenatide must be injected. Side effects include nausea that abates over time, vomiting, diarrhea, and mild
to moderate hypoglycemia.4 The most common symptoms—nausea and vomiting—may lead to reduced acceptance by patients.6 Exenatide is administered within 1 hour before the morning and evening meals. The initial dose is 5 mcg bid. After a
month, the dosage is then increased to 10 mcg bid.
Tailor therapy to the patient
The current and primary goal of treatment for T2DM is to achieve hemoglobin A1C levels as near normal as possible to minimize
the risk of diabetes-related complications, such as blindness, nerve damage, and the risk of lower extremity amputation, renal
disease, and cardiovascular disease. The American Diabetes Association suggests that the A1C target should be less than 7%,
whereas the American Association of Clinical Endocrinologists aims for a target of less than 6.5%.2,8
When a patient is first diagnosed with T2DM, weight management and regular physical activity may effectively achieve glycemic
control. Lifestyle interventions have been shown to produce a 58% reduction in the incidence of diabetes in individuals at
high risk for the disease.9 However, because of the progressive decline of beta-cell function leading to worsening disease, adding pharmacotherapy to
lifestyle interventions often becomes necessary.
Most oral antihyperglycemic agents can reduce A1C levels on average from 0.8% to 2% from a baseline of 8.5% to 9.5%.3 An observational analysis of data from the United Kingdom Prospective Diabetes Study (UKPDS) showed that even a 1% decline
in A1C levels was associated with a 37% decrease in risk for microvascular complications and a 21% decrease in the risk of
any end point or death related to diabetes.10
Table 1: Oral agents for type 2 diabetes mellitus
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There are numerous options for initial monotherapy to lower serum glucose levels: with several sulfonylureas, a biguanide,
2 TZDs, and 2 AGIs (see Table 1). The selection of the most appropriate agent to meet patient needs takes into account individual
personal and medical characteristics and possibly financial concerns (see Table 2).
Table 2: Cost of selected oral medications for type 2 diabetes mellitus: Online US pharmacies
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As one of the first available therapies for diabetes, the first-generation sulfonylureas—chlorpropamide (Diabinase), tolazamide
(Tolinase), and tolbutamide (Orinase)—stimulate beta-cells to increase insulin secretion. The second-generation sulfonylureas
(glimepiride [Amaryl], glipizide [Glucotrol], and glyburide [DiaBeta, Glynase PresTab, Micronase]) are prescribed more frequently
today and are more potent.
Sulfonylureas have a rapid onset of action—making them good choices for those with A1C levels greater than 8%. However, these
drugs can cause hypoglycemia and mild weight gain.3,4 They are also labeled with a black box warning of a possible increase in cardiovascular risk. However, more recent data
suggest that sulfonylurea therapy is not associated with a substantial increase in the risk of CVD. Sulfonylureas are generally
taken once or twice a day, depending on the specific medication.
Metformin, the only biguanide approved in the United States for the treatment of T2DM, is the most widely prescribed oral
treatment for the management of T2DM. Metformin lowers blood glucose levels by decreasing hepatic glucose production and increasing
insulin sensitivity. The UKPDS found that metformin reduced the risk of diabetes-related complications in overweight patients.
In contrast to sulfonylureas, metformin has been shown to cause fewer hypoglycemic attacks and does not encourage weight gain.11
Patients with lower (than 8% baseline) A1C levels may be ideal candidates for metformin.3 Patients should beware of GI side effects, such as nausea, diarrhea, and abdominal pain—all of which can be minimized by
taking the drug with food. Lactic acidosis is a rare complication. Contraindications include impaired renal function, alcohol
abuse, and pregnancy.4 Metformin is most effective at a dosage of 2000 mg/d bid; however, a significant number of patients cannot tolerate this
dosage, and the drug is titrated down to a maximally tolerated dosage (usually between 1500 and 2000 mg/d).
The TZDs are another effective therapy. These drugs—pioglitazone (Actos) and rosiglitazone (Avandia)—act by binding to the
peroxisome proliferator-activated receptor-gamma (PPAR-gamma), thereby increasing the insulin sensitivity of adipose tissue,
muscle, and the liver. They also have the potential to treat conditions associated with insulin resistance. Insulin resistance
is associated with hypertension, low levels of HDL cholesterol, and higher levels of triglycerides, all of which increase
the risk of cardiovascular disease.2,12
While approved as monotherapy, TZDs are used more often in combination with other antihyperglycemic medications.12 They provide consistent improvement in glycemic control when used in combination with agents with complimentary action.
The typical dosage for pioglitazone is 15 to 45 mg/d qd, and the typical dosage for rosiglitazone is 4 to 8 mg/d, given either
once or twice daily. Side effects for both drugs include weight gain, fluid retention, and mild anemia, and they are contraindicated
in patients with congestive heart failure because of the possibility that edema could exacerbate their condition.3,12
AGIs are among the least potent oral agents for diabetes, lowering A1C levels by up to only 1% via blockade of the breakdown
of carbohydrates and delaying the absorption of glucose.3 Given along with either a sulfonylurea or insulin, they may increase the risk of hypoglycemia, though neither does alone.
Thus, the 2 AGIs—acarbose (Precose) and miglitol (Glyset)—are used only infrequently and rarely in combination with sulfonylureas.
Their adverse effects—abdominal pain, diarrhea, and flatulence—may influence patient compliance to the prescribed drug regimen.4
Disease progression calls for combination therapy
Combination therapy is recommended whenever efforts to achieve target goals with any single therapy is unsuccessful. A fasting
plasma glucose (FPG) or A1C that is consistently over 150 mg/dL or 7%, respectively, indicates inadequate glycemic control
and should prompt a review of the patient's medication and raise the possibility that a change in the drug regimen is appropriate.
The combinations of a sulfonylurea plus metformin or metformin plus a sulfonylurea are commonly used and are effective in
achieving glycemic control.3 TZDs are also approved for use in dual therapy combined with a sulfonylurea, metformin, or insulin.
Another possible combination is the addition of a nonsulfonylurea secretagogue with metformin or a TZD.4 Nonsulfonylurea secretagogues—including nateglinide (Starlix) and repaglinide (Prandin)—are rapidly absorbed and cleared
mainly by hepatic metabolism. This may make these drugs useful before meals. Potential adverse effects for both include weight
gain and hypoglycemia.
The effectiveness of dual therapy in improving A1C levels begs the question of whether to use 2 agents as separate agents,
or in a combination tablet. There are now several combination antihyperglycemic tablets available, including metformin/glipizide
(Metaglip), metformin/glyburide (Glucovance), metformin/pioglitazone (Actosplus Met), and metformin/rosiglitazone (Avandamet).
While these combination tablets help to minimize the number of medications that a patient is prescribed and potentially improves
adherence with the drug regimen, there are disadvantages to consider. For example, the combination tablet cannot be adjusted
to address a side effect specific to one agent, and the patient may have to take more pills to obtain maximum efficacy than
they would taking separate medications.3
In time, a third agent to achieve target A1C levels may be necessary. One option is to add a third oral antihyperglycemic
medication, such as the addition of a TZD to dual therapy of metformin and a sulfonylurea. A recent study of patients receiving
glimepiride, 6 mg/d, metformin, 2.5 mg/d, and rosiglitazone, 4 or 8 mg/d, showed significant reductions in A1C levels and
FPG.12 Another option is to add insulin to oral dual therapy.
Insulin: A staple in diabetes management
The UKPDS showed that a greater percentage of patients receiving insulin therapy when compared with lifestyle intervention
or sulfonylurea therapy were able to maintain glycemic control as measured by FPG or A1C levels, underscoring a role for early
insulin use.2 While concern remains about the risks of weight gain, hypoglycemia, or cardiovascular effects associated with insulin use,
the beneficial effect of intensive glycemic control outweighs the risks.2,13 A growing body of evidence suggests that initiating insulin therapy earlier in the disease is safe and effective.14,15 With newer insulin analogs now available, it is easier to achieve glycemic control while reducing the risks.
A decade ago, regular insulin, neutral protamine Hagedorn (NPH; Humulin N, Novolin N) , and ultralente (Humulin U) were the
standard insulin therapies. Today, the more commonly used insulins include long-acting insulin glargine (Lantus) and the short-acting
insulins lyspro (Humalog), glulisine (Apidra), and aspart (NovoLog). Another long-acting insulin analog that was recently
approved is insulin detemir (Levemir).
Ideally, insulin therapy should be initiated as oral therapy is continued.3 Starting conservatively, a single, 10 U dose of NPH or glargine can be given at bedtime or 70/30 insulin at the evening
meal. Both NPH and glargine are effective as basal insulins, although glargine has several more advantages. Glargine is given
once a day and provides a less pronounced peak and duration than NPH, which may be delivered twice a day.2,4,8 The Treat-to-Target Trial also demonstrated that a single bedtime injection of NPH or glargine added to oral therapy helped
patients achieve A1C levels less than or equal to 7%. Those given glargine were less likely to experience nocturnal hypoglycemia
than those given NPH.14 Insulin detemir seems to have similar effects as glargine.4
The dosage of basal insulin must be adjusted according to the patient's self-monitored FPG level. Typically, with an FPG great
than 140 mg/dL, the dose is increased by 4 U. An increase of 2 U is made when the FPG is between 120 mg/dL and 140 mg/dL.2
When basal insulin in combination with oral agents fails, the addition of short-acting insulins may be helpful in controlling
postprandial blood glucose levels. The short-acting insulins are more effective with their more rapid onset and shorter duration
of action.4 These characteristics provide patients with greater flexibility in terms of when they must administer their injections in
relation to their meals, whereas regular insulin required patients to adhere to a rigid injection-and-mealtime schedule.
Dr Bloomgarden discloses that he has served as a consultant and/or as an advisor for NovoNordisk, Amylin, and Eli Lilly.
Dr Comi discloses that he has no financial relationship with any manufacturer in this area of medicine.
Dr Kendall discloses that he has an equity position in Amylin.
REFERENCES
1. American Diabetes Association. Position statement: standards of medical care in diabetes. Diabetes Care. 2005;28(suppl):S4-S36.
2. Braunstein SN, White JR. Trends in the management of type 2 diabetes: An emerging role for insulin. J Manag Care Pharm. 2005;11(suppl):S2-S11.
3. Riddle MC. Glycemic management of type 2 diabetes: an emerging strategy with oral agents, insulins, and combinations. Endocrinol Metab Clin N Am. 2005;34:77-98.
4. Abramowicz M, ed. Drugs for diabetes. Treatment Guidelines from The Medical Letter. 2005;3:57-62.
5. Schmitz O, Brock B, Rungby J. Amylin agonists: a novel approach in the treatment of diabetes. Diabetes. 2004;53 (suppl):S233-S238.
6. Comi RJ. Treatment of type 2 diabetes mellitus: a weighty enigma (editorial). Ann Intern Med. 2005;143:609-610.
7. Heine RJ, Van Gaal LF, Johns D, et al. Exenatide versus insulin glargine in patients with suboptimally controlled type
2 diabetes. Ann Intern Med. 2005;143:559-569.
8. Hirsch IB. Intensifying insulin therapy in patients with type 2 diabetes mellitus. Am J Med. 2005;118:215-265.
9. Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or
metformin. N Engl J Med 2002;346:393-403.
10. Stratton IM, Adler AI, Neil HA, et al. Association of glycaemia with macrovascular and microvascular complications of
type 2 diabetes (UKPDS 35): prospective observational study. BMJ. 2000;8(suppl 1):405-412.
11. UKPDS Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type
2 diabetes (UKPDS 34). Lancet. 1998;352:854-865.
12. Meriden T. Progress with thiazolidinediones in the management of type 2 diabetes mellitus. Clin Ther. 2004;26:177-190.
13. UK Prospective Diabetes Study. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional
treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352:837-853.
14. Riddle MC. Timely initiation of basal insulin. Am J Med. 2004:116;3S-9S.
15. Riddle MC, Rosenstock J, Gerisch J. The Treat-to-Target Trial. Diabetes Care. 2003;26:3080-3086.
Clinical pearls
We have, over the past decade, had this tremendous increase in the ability to treat diabetes by giving insulin sensitizers,
with the recognition more and more that diabetes is a disease primarily of insulin resistance and secondly of insulin deficiency.
You can't get it without both.
Zachary T. Bloomgarden, MD
In the old days, you would put patients on a schedule to line up with their insulin. Now, we have the ability to line up their
insulin with the patient's schedule. And that's a huge difference for the patient.
Richard J. Comi, MD
Regular titration to achieve the lowest blood glucose as you can, as safely as possible, and as long as possible, really has
to be part and parcel in the treatment in every visit with a patient with diabetes.
David M. Kendall, MD
ON THE HORIZON
More therapeutic options for type 2 diabetes mellitus
Unique pharmacologic therapies are becoming available for the treatment of type 2 diabetes (T2DM). One is muraglitazar
(Pargluva, brand name if approved). It is the first dual alpha/gamma peroxisome proliferator-activated receptor (PPAR) agonist
to undergo FDA review. Interest in this agent has been high because of its potential both to increase insulin sensitivity
by targeting PPAR-gamma and to decrease triglycerides and increase HDL cholesterol by targeting PPAR-alpha.
While the drug has been shown to be effective in treating hyperglycemia and dyslipidemia in patients with diabetes, its
side effects include weight gain and edema. An analysis and accompanying editorial in the Journal of the American Medical
Association also called into question the cardiovascular safety of the drug.1,2 Late in 2005, development of the drug appeared
to be on hold, and it is thought that it could take up to 5 years for the manufacturer to compile the additional safety data
requested by the FDA.
The other drug is the first inhaled insulin (Exubera). It was approved in January 2006 for the treatment of T2DM and type
1 diabetes. In an open-label, randomized control trial in 48 outpatient centers in the United States, inhaled insulin improved
overall glycemic control and A1C when added to or substituted for dual agent oral therapy.3 In a 12-week, randomized controlled
trial, inhaled insulin improved glycemic control more quickly than rosiglitazone, which may take more that 18 weeks to reach
peak glucose lowering.4
This inhaled insulin is not without side effects. Typical of most insulin therapy, it is associated with weight gain. Other
side effects include mild to moderate hypoglycemia and mild cough. Despite the unique delivery method, it is not likely to
eliminate the need for injected basal insulin. The use of inhaled insulin may also require greater patient education on how
to titrate and adjust dosages.
1. Nissen SE, Wolski K, Topol EJ. Effect of muraglitazar on death and major adverse cardiovascular events in patients with
type 3 diabetes mellitus. JAMA. 2005 Oct 20 (epub ahead of print);1-6.
2. Brophy JM. Selling safety—lessons from muraglitazar. JAMA. 2005 Oct 20 (epub ahead of print);1-3.
3. Rosenstock J, Zinman B, Murphy LJ, et al. Inhaled insulin improves glycemic control when substituted for or added to oral
combination therapy in type 2 diabetes. Ann Intern Med. 2005;143:549-558.
4. DeFronzo RA, Bergenstal RM, Cefalu WT, et al. Efficacy of inhaled insulin in patients with type 2 diabetes not controlled
with diet and exercise. Diabetes Care. 2005;28:1922-1928.
Drugs mentioned in this article
ALPHA-GLUCOSIDASE INHIBITORS
Acarbose (Precose)
Miglitol (Glyset)
BIGUANIDE
Metformin (Glucophage)
NONSULFONYLUREA SECRETAGOGUES
Nateglinide (Starlix)
Repaglinide (Prandin)
SULFONYLUREAS, FIRST-GENERATION
Chlorpropamide (Diabinese)
Tolazamide (Tolinase)
Tolbutamide (Orinase)
SULFONYLUREAS, SECOND-GENERATION
Glimepiride (Amaryl)
Glipizide (Glucotrol)
Glyburide (DiaBeta, Glynase Prestab, Micronase)
THIAZOLIDINEDIONES
Pioglitazone (Actos)
Rosiglitazone (Avandia)
OTHERS
Exenatide (Byetta)
Pramlintide (Symlin)
COMBINATION AGENTS
Metformin/glipizide (Metaglip)
Metformin/glyburide (Glucovance)
Metformin/pioglitazone (Actosplus Met)
Metformin/rosiglitazone (Avandamet)
RAPID-ACTING INSULINS
Aspart (NovoLog)
Glulisine (Apidra)
Lyspro (Humalog)
Regular insulin
LONG-ACTING INSULINS
Detemir (Levemir)
Glargine (Lantus)
Neutral protamine Hagedorn (NPH) (Humulin N, NPH Iletin, Novolin N)
Ultralente (Humulin U)
INVESTIGATIONAL
Muraglitazar (Pargluva)
Inhaled insulin (Exubera)