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Disclaimer: CME certification for these activities has expired. All information is pertinent to the timeframe in which it was released.


Demystifying The Complexities Of Insulin Use In The Patient With Diabetes


GOAL
To provide primary care physicians with up-to-date information on the treatment and management of patients with type 2 diabetes mellitus.

TARGET AUDIENCE
This activity is designed for primary care physicians. No prerequisites required.

LEARNING OBJECTIVES
The Johns Hopkins University School of Medicine takes responsibility for the content, quality, and scientific integrity of this CME activity. At the conclusion of this activity, the participant should be able to:

  • Organize the difficulties in achieving optimal glucose control.
  • Summarize the major clinical recommendations for the care of type 2 diabetes mellitus (T2DM).
  • Compare and contrast the pharmacokinetic and pharmacodynamic parameters of human insulin and insulin analogs.
  • Identify the efficacy of fast-acting insulin analogs in the management of T2DM.
  • Express the rationale for earlier initiation of physiologic insulin in the
     management of patients with T2DM.
  • Describe insulin therapy treatment options currently available for the management of newly diagnosed patients with T2DM.

ACCREDITATION STATEMENT
The Johns Hopkins University School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. 

CREDIT DESIGNATION STATEMENT
The Johns Hopkins University School of Medicine designates this educational activity for a maximum of 2 AMA PRA Category 1 Credit(s)TM. Physicians should only claim credit commensurate with the extent of their participation in the activity.

The estimated time to complete this educational activity: 2 hours.
Release date: July 15, 2006. Expiration date: July 15, 2008.

DISCLAIMER STATEMENT
The opinions and recommendations expressed by faculty and other experts whose input is included in this program are their own. This enduring material is produced for educational purposes only. Use of The Johns Hopkins University School of Medicine name implies review of educational format, design, and approach. Please review the complete prescribing information of specific drugs or combinations of drugs, including indications, contraindications, warnings, and adverse effects, before administering pharmacologic therapy to patients.

This program is supported by an educational grant from Eli Lilly and Company.

Full Disclosure Policy Affecting CME Activities:
As a provider accredited by the Accreditation Council for Continuing Medical Education (ACCME), it is the policy of the Johns Hopkins University School of Medicine to require the disclosure of the existence of any significant financial interest or any other relationship a faculty member or a sponsor has with the manufacturer(s) of any commercial product(s) discussed in an educational presentation. The Program Director and Participating Faculty reported the following:

PROGRAM DIRECTOR

Christopher D. Saudek, MD
Hugh P. McCormick Family Professor
of Endocrinology and Metabolism
Director, The Johns Hopkins Diabetes Center
Program Director, General Clinical Research Center
Johns Hopkins University School of Medicine
Baltimore, Maryland
Dr Saudek reports receiving sponsored research support from DexCom; receiving in kind research support from Medtronic/MiniMed; serving as a speaker for Lifescan, Inc.; and serving on medical advisory boards for Aventis, DexCom, Eli Lilly and Company, Lifescan, Inc., Novartis, Novo Nordisk, and XL Health.

PARTICIPATING FACULTY

Neil Brooks, MD
Medical Director
Vernon Manor Health Care Center
Vernon, Connecticut
Dr Brooks reports serving as a consultant for Eli Lily and Company, EyeTel Imaging, Pfizer Inc, and Sepracor Inc.

Vivian Fonesca, MD
Professor of Medicine
Director, Diabetes Program
Tullis-Tulane Alumni Chair in Diabetes
Tulane University Medical Center
New Orleans, Louisiana
Dr Fonesca reports receiving grants/research support from and serving as a consultant for AstraZeneca, Aventis, Eli Lilly and Company, GlaxoSmithKline, Pfizer Inc, and Takeda Pharmaceuticals North America.

Notice: Faculty have indicated that they have not referenced unlabeled/unapproved uses of drugs or devices.

Collective Clinical Forum provides disclosure information from contributing authors, lead presenters, and participating faculty. Collective Clinical Forum does not provide disclosure information from authors of abstracts and poster presentations. The reader shall be advised that these contributors may or may not maintain financial relationships with pharmaceutical companies.

Demystifying The Complexities Of Insulin Use In The Patient With Type 2 Diabetes Mellitus
Christopher D. Saudek, MD

It is now well known that the incidence and prevalence of obesity and diabetes has reached epidemic proportions in the United States. Unfortunately, the consequences of these epidemics are not received, not understood, or not accepted by the general population. The vast majority (ie, >95%) of patients with diabetes have type 2 diabetes, a disease that is largely preventable because it is strongly associated with obesity.

Diabetes is an independent risk factor for coronary heart disease, to the point that the risk of a cardiovascular event in a patient with diabetes is the same as for someone without diabetes who has already had a myocardial infarction. Patients need to understand this link, although a survey of people with diabetes, commissioned by the American Diabetes Association and the American College of Cardiology, found that 68% of patients did not know of this link and approximately 50% said their healthcare provider never discussed ways that they could reduce their risks for heart disease and stroke.1 Also, 75% of individuals surveyed reported having risk factors associated with cardiovascular disease (eg, high blood pressure or high cholesterol) but failed to relate these problems to their diabetes.1

The growing rate of diabetes impacts primary care. As many more patients are affected by this disease, primary care physicians will find themselves not only diagnosing diabetes, but also participating and perhaps leading the long-term management of these patients.

Diagnosing Diabetes
There are several ways to distinguish type 1 diabetes from type 2 diabetes, as summarized in Table 1. Of particular note, in type 1 diabetes blood sugars vary widely throughout the day; in type 2 diabetes the blood sugar levels are usually more stable. Also, whereas diabetic ketoacidosis was formerly considered to be associated only with type 1 diabetes, we are seeing it more frequently in individuals with type 2 diabetes. The presence of diabetic ketoacidosis would therefore not exclude a diagnosis of type 2 diabetes, although it is more strongly associated with type 1. The other most characteristic features of type 2 diabetes include its strong association with being overweight, having a positive family history of diabetes, and developing diabetes after approximately 40 years of age. However, presence or absence of any one of these features is not diagnostic of either type of diabetes; thus, the whole clinical picture must be taken into consideration.

It is important to distinguish type 1 from type 2 diabetes for several reasons. First, patients with type 1 diabetes depend on exogenous of insulin for survival because, at least after the Òhoneymoon period,Ó they have virtually no pancreatic insulin secretion. In the absence of insulin therapy, the patient with type 1 diabetes will eventually develop diabetic ketoacidosis. Patients with type 2 diabetes, on the other hand, may do very well with diet and exercise alone for a period of time and progress at highly variable rates (months to years to decades) in their requirement for the various oral agents and then insulin.

The Consequences of Diabetes
Poorly managed diabetes–whether type 1 or type 2–results over the years in a series of long-term complications, categorized as macrovascular and microvascular. The macrovascular complications manifest as heart disease, peripheral vascular disease, and stroke. Microvascular complications include diabetic retinopathy, diabetic peripheral neuropathy (DPN), and diabetic nephropathy.

Diabetic retinopathy is usually asymptomatic (hyperglycemia can cause blurred vision as a result of lens stiffening, but this is an acute complication, not retinopathy, and is reversible when the diabetes is well controlled). Diabetic retinopathy is evident to the examining ophthalmologist by the presence of microaneurysms, exudates, and other changes in the retina. These changes can progress to proliferative diabetic retinopathy, in which bleeding into the vitreous occurs, frequently causing visual impairment. However, the progression of diabetic retinopathy is significantly slowed or avoided altogether by properly timed laser photocoagulation. Therefore, regular examinations by an ophthalmologist are necessary to detect, follow, and treat retinopathy appropriately.

By contrast, DPN generally presents symptomatically–as pain, dysesthesia, and/or "pins and needles." It is almost always distal (ie, toes and feet) and proceeds proximally, thus symptoms that start in the hands or shoulders would not typically be DPN. Sometimes the presenting symptom is not pain but numbness, which puts the patient at significant risk of foot injury. The management is to control the bothersome symptoms, if present, and, particularly, to avoid traumatic foot damage by very good foot care.

Nephropathy presents with asymptomatic proteinuria (microalbuminuria); therefore, a spot urine test for microalbumin is recommended annually. It is unclear whether the frequent comorbidity of hypertension is causing the nephropathy or caused by it, but probably both. At any rate, hypertension is frequently present in patients with diabetes and nephropathy and greatly increases the risk for heart disease. Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers are usually first-line treatment for hypertension in patients with diabetes. However, most people with diabetes require more than one antihypertensive medication, and the most important rule is to control the blood pressure with whatever it takes.

Pharmacotherapy Options of Hyperglycemia
In type 2 diabetes, there are several metabolic defects and, therefore, many therapeutic targets (Table 2). First, insulin secretory capacity is not able to overcome insulin resistance. The secretion of insulin can be enhanced by sulfonylureas and the glinides. The increased insulin secretion can cause hypoglycemia and, sometimes, weight gain. Improving responsiveness to endogenous insulin (overcoming insulin resistance) is accomplished by the thiazolidinediones (glitazones). Rosiglitazone and pioglitazone, however, frequently cause weight gain, peripheral edema, and can worsen heart failure. Metformin acts more specifically on the liver, reducing hepatic glucose output, although it also has side effects (mainly gastrointestinal–bloating or diarrhea) and is contraindicated in conditions with increased lactic acid production or decreased clearance, such as renal insufficiency, congestive heart failure, or elective surgery. Finally, digestion and absorption of dietary carbohydrate can be slowed by the a-glucosidase inhibitors, acarbose or miglitol. They may be considered in patients who have predominantly postprandial hyperglycemia, but are associated with increased flatus and other gastrointestinal side effects.

Two types of newer agents are under investigation or recently approved by the US Food and Drug Administration: incretin mimetics and glucagon analogs. Incretins are insulinotropic hormones produced by the gastrointestinal tract. They are secreted in response to nutrient ingestion and stimulate insulin secretion. They also slow gastric emptying, which tends to reduce postprandial hyperglycemia. Glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide are 2 examples of incretin hormones. Exenatide and pramlintide, 2 incretin mimetics, are a GLP-1–receptor agonist and amylin analog, respectively. They are given parenterally by injection twice a day. Importantly, incretin mimetics also suppress appetite, so they may be useful in overweight/obese patients because they can cause weight loss. Exenatide has been shown to improve insulin secretion and decrease glycosylated hemoglobin (HbA1c) in patients on glyburide, metformin, or glyburide plus metformin.2-5 Pramlintide in addition to insulin in patients with type 1 and type 2 diabetes was associated with modest reductions in HbA1c.6,7 Alternatively, glucagon secretion may be increased, which can be suppressed with GLP-1Ðlike analogs and other new drugs in development.

The Monograph
This issue of Collective Clinical Forum was developed to present some of the most common challenges in diagnosing and managing patients with diabetes. I, along with a leading endocrinologist/diabetologist, Vivian Fonseca, MD, and a prominent family practice physician, Neil Brooks, MD, present 5 case studies. The challenges these case studies highlight include making the diagnosis of diabetes and differentiating type 1 from type 2 diabetes, patient motivation and sociodemographic limitations that can impact adherence and treatment options, elderly and adolescent patients, patient education, and treatment options in the setting of poor glucose control (short-term and long-term). These case studies are meant to serve as a reference for primary care physicians as they find increasing numbers of patients with diabetes in their practices.

TABLES

REFERENCES

1. American Diabetes Association Web site. Awareness of link between diabetes, heart disease and stroke critically lacking, American Diabetes Association and American College of Cardiology survey finds [press release]. Available at: http://www.diabetes.org/uedocuments/marketresearch.pdf. Accessed April 20, 2006.
2. Poon T, Nelson P, Shen L, et al. Exenatide improves glycemic control and reduces body weight in subjects with type 2 diabetes: a dose-ranging study. Diabetes Technol Ther. 2005;7:467-477.
3. De Fronzo RA, Ratner RE, Han J, et al. Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care. 2005;28:1092-1100.
4. Kendall DM, Riddle MC, Rosenstock J, et al. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in patients with type 2 diabetes treated with metformin and a sulfonylurea. Diabetes Care. 2005;28:1083-1091.
5. Buse JB, Henry RR, Han J, et al. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes. Diabetes Care. 2004;27:2628-2635.
6. Ryan GJ, Jobe LJ, Martin R. Pramlintide in the treatment of type 1 and type 2 diabetes mellitus. Clin Ther. 2005;27:1500-1512.
7. Ratner R, Whitehouse F, Fineman MS, et al. Adjunctive therapy with pramlintide lowers HbA1c without concomitant weight gain and increased risk of severe hypoglycemia in patients with type 1 diabetes approaching glycemic targets. Exp Clin Endocrinol Diabetes. 2005;113:199-204.


*Hugh P. McCormick Family Professor of Endocrinology and Metabolism, Director, The Johns Hopkins Diabetes Center, Program Director, General Clinical Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Address correspondence to: Christopher D. Saudek, MD, Osler 576-Endocrinology, 600 North Wolfe Street, Baltimore, MD 21287. E-mail: csaudek@jhu.edu.

The content in this monograph was developed with the assistance of a staff medical writer. Each author had final approval of his/her article and all its contents.





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