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Volume 78 • Number 11 Commentary Managing Patients With Diabetes: First, Do No Harm Brian L. Mealey* O ne of the great hopes of mankind is the continuous advancement of scientific knowledge and the implementation of that knowledge to improve quality of life. Medicine and dentistry continue to make leaps that would have been unimaginable just 20 years ago. As clinicians, we must persistently evaluate the evidence base and integrate new information into our practices. The medical management of diabetes mellitus has changed markedly in the past decade. Publication of the Diabetes Control and Complications Trial (DCCT)1 in 1993 and the United Kingdom Prospective Diabetes Study (UKPDS)2 in 1998 forever altered the world of diabetes care. Prior to the publication of these landmark studies, people with diabetes did not know the answer to the basic question, ‘‘If I try to control my diabetes really well by intensive management regimens, will that make any difference in my risk for complications of diabetes?’’ Such a basic question needs an answer because diabetes is a difficult and costly disease to manage. If more intensive management regimens make no difference in eventual outcomes of the disease, there is little point in the added cost and effort. In the DCCT,1 patients were assigned randomly to one of two groups: 1) intensive insulin therapy in which subjects took three or more injections of insulin per day or used a subcutaneous insulin infusion pump; or 2) conventional therapy using one or two daily insulin injections. The results of the DCCT provided strong evidence that improved glycemic control resulting from intensive insulin treatment (hemoglobin A1c [HbA1c] of 7.2% in the intensive treatment group compared to 8.9% in the conventional treatment group) dramatically decreased the risk for diabetic complications. The prevalence of retinopathy was reduced by 76% in intensively treated patients compared to conventional therapy, and the progression of existing retinopathy decreased by 54%. Albuminuria, a sign of nephropathy, was reduced by 54%, and clinical neuropathy decreased by 60%. Thus, a change from conventional insulin treatment regimens to more frequent injection and more intensely monitored therapy resulted in improvement in glycemic control and dramatic reductions in the risk for diabetes-induced diseases of the eye, kidney, and nerves. The UKPDS evaluated conventional versus intensive treatment of patients newly diagnosed with type 2 diabetes. This study also showed a marked reduction in the complications of diabetes in the intensive treatment group when blood glucose levels were improved compared to the conventional treatment group. Since the DCCT and UKPDS were published, physicians have completely changed the way in which they manage diabetes based on the results of these studies and the availability of new oral and injectable agents and insulin analogs that more closely mimic endogenous insulin secretion.3 Gone are the days of type 1 patients coming into the dental office taking one or two injections of intermediate- or long-acting insulin each day. Instead, they are taking three or four injections of short-acting insulin each day plus a longacting (basal) insulin, or they are using an insulin pump. Likewise, it is much more common to see patients with type 2 diabetes come to the dental office taking multiple oral medications, often in combination with insulin injections, than it is to see type 2 patients taking just one oral medication. These intensive diabetes management regimens are a boon to people with diabetes because they reduce the risk for major complications. There also is evidence that better glycemic control decreases the risk and/or severity of periodontal diseases and that diabetic patients with periodontal disease respond more favorably to periodontal treatment when their glycemic control is good.4 However, the intensive regimens are not without their disadvantages, especially as they relate to treatment in the dental office. The most common complication of insulin therapy is hypoglycemia, a medical emergency with significant potential for negative outcomes. Hypoglycemia can and does occur in patients using oral agents such as sulfonylureas; however, its incidence is higher in those injecting insulin. In the DCCT, the incidence of severe hypoglycemia was three times greater in the intensive insulin group compared to those on conventional therapy.5 Severe hypoglycemia was defined as hypoglycemia in which neurologic impairment was * Department of Periodontics, University of Texas Health Science Center at San Antonio, San Antonio, TX. doi: 10.1902/jop.2007.070362 2072 Mealey J Periodontol • November 2007 severe enough that the patient required the assistance of another person. Remarkably, one-third of all severe hypoglycemic episodes in the DCCT led to seizures or coma. Thus, the risk for hypoglycemia should be recognized by dental practitioners as they treat patients with diabetes, especially those who are taking insulin, with the caveat that this risk is higher in patients with type 1 diabetes than in those with type 2 diabetes. Perhaps even more significant, in the DCCT, 36% of severe hypoglycemic reactions occurred without warning symptoms for the patient, and in another 51%, warning symptoms occurred but were not recognized as such by the patients. Therefore, we must be constantly vigilant in our practices for the signs and symptoms of hypoglycemia because many patients will have this complication without any warning given to us. Many practitioners I have met and discussed diabetes with seem to have an attitude that says, ‘‘I have been a dentist for 30 years, and I’ve never had a patient experience a severe hypoglycemic event in my practice.’’ My answer to that sentiment is two-fold: 1) be thankful that your past experience has been uneventful; and 2) your past experience with this disease has little relevance to today’s risk. The world of diabetes management is changing every year, and those changes consistently aim to bring blood glucose levels closer and closer to the normal range one would see in people without diabetes. As glycemic control improves, the risk for hypoglycemia increases. Therefore, we should all expect the incidence of acute complications such as hypoglycemia to increase in our practices in the future. The old cliché of ‘‘prevention is the best treatment’’ has never been truer than in managing today’s diabetic dental patient. There are two major means by which clinicians can assess a patient’s risk for hypoglycemia in the dental office. First, to gain an overall risk assessment, dentists should have documented evidence of the patient’s glycemic control in the recent past. The only currently available way to garner this information is to know the patient’s HbA1c values. The HbA1c test allows determination of blood glucose status during the 30 to 90 days prior to collection of the blood sample.3,6 As glucose circulates in the bloodstream, it becomes attached to a portion of the hemoglobin molecule on red blood cells. The higher the plasma glucose levels over time, the greater the percentage of hemoglobin that becomes glycated, and that percentage is measured using the HbA1c test. The normal HbA1c value is <6%. The American Diabetes Association (ADA) guidelines3 recommend that people with diabetes try to maintain glucose levels close to normal and to keep the HbA1c value <7%. If the HbA1c is >8%, the ADA recommends physician intervention in the patient’s management regimen to improve glycemic Table 1. Correlation Between HbA1c Levels and Mean Plasma Glucose Levels HbA1c (%) Mean Plasma Glucose (mg/dl) 6 135 7 170 8 205 9 240 10 275 11 310 12 345 control. Table 1 shows how the HbA1c values correlate with average plasma glucose levels.6 As patients’ HbA1c values decrease, their risk for diabetic complications generally decreases as well. However, it is important to recognize that the risk for in-office hypoglycemia is greater in patients with good glycemic control than it is in those with poor glycemic control. The lower the HbA1c, the greater the risk for hypoglycemia. Some patients with poor glycemic control have wide variability of their glucose levels and can have swings into the hypoglycemic range, especially if they take insulin before a dental appointment or do not eat when they take their usual insulin dose. This underscores the importance of dentists determining the true level of glycemic control by obtaining HbA1c values rather than relying on the patient’s self-report of their glycemic control. A consult should be sent to the diabetic patient’s physician to determine the degree of glycemic control. The most objective means of making this determination is to request the last 2 years of HbA1c values, so one can evaluate not just a single value but a series of values. The returned consult from the physician with the HbA1c values from the past 2 years can be placed in the patient’s dental chart for reference. Questions I ask myself when I receive the HbA1c values include the following: Does the patient have consistently elevated HbA1c values (>8%) and, thus, a lower risk for hypoglycemia (but a higher risk for long-term diabetic complications)? Does the patient have HbA1c values consistently closer to the recommended range (<7%) and, thus, a higher risk for hypoglycemia in my office? Does the patient have HbA1c values that fluctuate widely over time, perhaps indicating patient difficulty in managing glycemia and a potential for elevated risk 2073 Managing Dental Patients With Diabetes Volume 78 • Number 11 for hypoglycemia during periods when glucose levels are being kept at lower levels? The second way that clinicians can assess risk for an acute hypoglycemic event is to determine the patient’s capillary blood glucose levels prior to beginning dental treatment. Almost all diabetic patients have glucometers for home use. These devices allow patients to determine their glucose level in a matter of seconds from a small drop of blood taken after a finger stick. My office policy is to have all patients with diabetes bring their glucometers with them to each dental appointment. This becomes a matter of routine for the patient, and my experience has been that patients appreciate my interest in their diabetes management. Before dental treatment begins, patients check their blood sugar levels using their own glucometer. I document the glucose in the patient’s chart with an entry, such as ‘‘Preop glucose = 114 mg/dl by patient glucometer.’’ A normal fasting glucose level is <100 mg/dl. After a meal, people without diabetes will have a 2-hour postprandial glucose level <140 mg/dl.3 Symptoms of hypoglycemia usually are not seen in people without diabetes until the glucose level decreases to <60 mg/ dl.6 However, symptoms of hypoglycemia may occur in people with diabetes at glucose levels >60 mg/dl. After assessing pretreatment glucose levels using the patient’s glucometer, the clinician must decide what to do with that information. In general, if the patient is going to undergo a short procedure (<1 hour) in my office, and the glucose level is ;100 mg/dl, I proceed with treatment. If the procedure is going to last several hours, and the pretreatment glucometer reading is £100 mg/dl, I give the patient a small amount of oral carbohydrate before I begin, such as 4 ounces of fruit juice. This increases glucose levels 30 to 40 mg/ dl in most patients and can help to prevent hypoglycemia from occurring during the procedure. In all cases, the clinician must remain aware of the potential for hypoglycemia and be ready to manage that emergency should it arise. If a clinician wishes to keep a glucometer in the dental office, it is important to know that doing so requires compliance with the Clinical Laboratory Improvement Amendments of 1988 and their subsequent amended provisions. This act is known as CLIA, and it governs medical laboratories in the United States, including inoffice laboratories. If a dentist elects to keep an office glucometer, that dentist’s office is considered a medical laboratory under CLIA. The same is true for any other in-office medical test a dentist may wish to perform, such as an in-office C-reactive protein test or international normalized ratio. Glucometer testing for the purposes described above is considered a CLIAexempt procedure, meaning that a dental office using an office glucometer is considered a CLIA-waived medical laboratory. The office still must register with the government and receive a registration certificate. The added administrative burden of this process is why most dental offices prefer to allow patients to test their glucose level using the patient’s own glucometer. More information on CLIA may be found at www.cms.hhs.gov/ clia. The registration form is CMS Form 116. Another key factor in assessing an individual patient’s risk for hypoglycemia is to have an intimate knowledge of the diabetes medications each patient takes. The number of diabetes medications on the market has exploded in the past decade. Some medications carry very little added risk for hypoglycemia, whereas others are associated with high risk. Insulin directly lowers blood glucose levels; therefore, it carries a high risk for hypoglycemia.6 The Table 2. Types of Insulin, Listed in Order of Descending Peak Activity Times Type of Insulin Insulin Classification Onset of Activity Peak Activity Duration of Activity Glargine Long-acting 6 to 8 hours Peakless (has no peak in activity) >24 hours Detemir Long-acting 1 to 2 hours Relatively flat (minimal peak) £24 hours Ultralente Long-acting 6 to 10 hours 12 to 16 hours 20 to 30 hours Lente Intermediate-acting 3 to 4 hours 4 to 12 hours 16 to 20 hours NPH Intermediate-acting 2 to 4 hours 4 to 10 hours 14 to 18 hours Regular Short-acting 2 to 3 hours 4 to 12 hours Lispro Aspart Glulisine Rapid-acting NPH = neutral protamine Hagedorn. 2074 30 to 60 min 15 min 30 to 90 min <5 hours J Periodontol • November 2007 Mealey various insulins available today Table 3. have distinct pharmacodynamOral Agents for Diabetes Management ics, and the dentist must be aware of the time of peak activity Risk for for the insulins a given patient is Agent Hypoglycemia Action using (Table 2). For example, if a patient has a 9:00 am dental Sulfonylureas Stimulate pancreatic insulin secretion appointment and she injects a Glyburide High short-acting insulin, such as lisGlipizide High pro or aspart, at 8:00 am, peak Glimepiride Moderate insulin activity will take place at Meglitinides Stimulate rapid pancreatic insulin secretion the same time as dental treatRepaglinide Moderate ment when blood glucose levels Nateglinide Moderate are becoming lower. This increases the potential for in-office Biguanides Block production of glucose by liver, improve hypoglycemia. With the multiple Metformin Low tissue sensitivity to insulin injection regimens many diabetic Thiazolidinediones Improve tissue sensitivity to insulin patients use today, it may be difRosiglitazone Low ficult to avoid a time of peak Pioglitazone Low activity to provide dental treatment. That is fine, so long as a-Glucosidase inhibitors Slow absorption of carbohydrate from gut; the dental office personnel know Acarbose Low decrease post-prandial peaks in glycemia how to recognize and treat a Miglitol Low hypoglycemic event. Having paDDP-4 inhibitors (called ‘‘gliptins’’) Stimulate pancreatic insulin secretion only tients check their blood glucose after an increase in glucose level following Sitagliptin Low levels with their glucometers just a meal; block hepatic glucose production Vildagliptin Low before treatment begins allows the dentist to get a better idea Combination agents Combine actions from two different of the risk for the glucose level drug classes; level of risk for hypoglycemia Metformin + glyburide High reaching a critically low point depends on individual drugs in the Metformin + glipizide High during therapy. A very common combination agent Metformin + rosiglitazone Low insulin regimen in the United Metformin + pioglitazone Low States today for people with type Glimepiride + rosiglitazone Moderate 1 diabetes is an injection of rapid-acting insulin before each DDP-4 = dipeptidyl peptidase-4. meal (lispro, aspart, or glulisine) and an injection of long-acting the drug is taken alone or in combination with oral insulin once a day (ultralente, detemir, or glargine).3 agents that do not themselves cause hypoglycemia Oral agents are used commonly in type 2 diabetes because the drug stimulates insulin production only (Table 3). Many of these agents stimulate an increase when the body needs more insulin after a meal. Exein pancreatic insulin secretion, which increases the natide can increase the risk for hypoglycemia associrisk for hypoglycemia. Prior to dental treatment, it is ated with the use of agents that directly stimulate important for the dentist to make sure that a diabetic insulin secretion, such as the sulfonylureas and patient taking one of these agents has eaten. Conmeglitinides. Exenatide also slows gastric emptying, versely, there are a number of oral medications that which prevents a sudden increase in blood glucose pose very little risk for hypoglycemia. after a meal, and it decreases hepatic glucose proFinally, several newer injected agents have been induction. troduced since 2005 to improve glycemic control. ExPramlintide is an injected agent taken only by type enatide is a synthetic version of an incretin hormone 1 and type 2 patients who use insulin. Pramlintide called exendin-4 and is used by people with type 2 dislows down absorption of carbohydrate from the gut abetes who also take oral agents. The drug is injected and decreases hepatic glucose production. Unlike exin the morning before breakfast and in the evening beenatide, pramlintide does not adjust its action to the fore dinner. Exenatide stimulates insulin secretion, amount of glucose in the bloodstream. Thus, pramlinbut only in response to increased glucose in the bloodtide has a very high risk for hypoglycemia and, in fact, stream that follows a meal. This makes it a relatively carries a ‘‘black box warning’’ from the United States safe drug with a low incidence of hypoglycemia when 2075 Managing Dental Patients With Diabetes Food and Drug Administration because of this serious potential side effect. It is clear that the medical management of diabetes has changed. It is equally clear that our management of these patients in the dental office has not changed nearly enough. A recent study of general dentists and periodontists revealed that 77% of periodontists and 44% of generalists always ask patients with diabetes what type of diabetes they have, and ;80% of periodontists and 56% of generalists ask these patients about their medical management regimen or about how well their diabetes is controlled.7 However, only 35% of periodontists and 14% of generalists consistently communicate with the physicians who treat their dental patients with diabetes, and only 28% of periodontists and 14% of generalists objectively evaluate glycemic control by consulting the physician about laboratory values, such as the HbA1c. As diabetes management becomes more complex, as the number and types of medications increase, and as physicians continue to stress maintaining glucose levels at or near the normal range for their patients with diabetes, it is incumbent upon dentists to recognize the increased risk for medical emergencies in the office and to be ready to treat those emergencies when they arise. ‘‘I’ve been a dentist for 30 years and I’ve never had that happen to me,’’ goes out the window as soon as the first patient seizes or becomes unconscious in your dental chair. 2076 Volume 78 • Number 11 REFERENCES 1. Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329:977-986. 2. U.K. Prospective Diabetes Study (UKPDS) Group. 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. 3. American Diabetes Association. Standards of medical care in diabetes – 2007 (position statement). Diabetes Care 2007;30(Suppl. 1):S4-S41. 4. Mealey BL, Oates TW. Diabetes mellitus and periodontal diseases. J Periodontol 2006;77:12891303. 5. Diabetes Control and Complications Trial Research Group. Hypoglycemia in the Diabetes Control and Complications Trial. Diabetes 1997;46:271-286. 6. Mealey BL, Ocampo G. Diabetes mellitus and periodontal disease. Periodontol 2000 2007;44:127153. 7. Kunzel C, Lalla E, Lamster IB. Management of the patient who smokes and the diabetic patient in the dental office. J Periodontol 2006;77:331-340. Correspondence: Dr. Brian L. Mealey, Department of Periodontics, University of Texas Health Science Center at San Antonio, Mail Code 7894, 7703 Floyd Curl Dr., San Antonio, TX 78248. E-mail: [email protected]. Submitted June 27, 2007; accepted for publication July 3, 2007.