Module 10. Troubleshooting Glucose Fluctuations: Impact of Concomitant Medications on Glycemic Control
Even the most seasoned health care providers (HCPs) have found diabetes to be among the most challenging diseases to manage. The difficulties arise from the dynamic nature of this disease state, the lack of patient knowledge about the potential side effects of treatment, and the challenges people with diabetes face with adhering to an often complex medication regimen. Type 2 diabetes mellitus (T2D), in particular, is progressive and, as the disease advances, patients are forced to evolve with it or risk long-term adverse patient outcomes. Even when the appropriate therapy is chosen, there is still risk of medication side effects and interactions. Pharmacists are acutely attuned to the risks of medication use; but, with dozens of possible medications and even more supplements, sometimes choosing from this seemingly overwhelming sea of treatment options can be intimidating. The purpose of this module is to provide education to help you understand how multiple medications can affect blood glucose (BG) control in people with diabetes.
Prescription-drug use among adults has risen substantially in the United States (U.S.) since 1999. In a 2013 report, the most substantial increases in prescription-drug use were seen in patients 40 to 65 years of age and those aged 65 years and older.1 The most commonly prescribed medications, not surprisingly, were for hypertension, hyperlipidemia, diabetes, and depression. With so many new interventions and so many drugs coming off patent, polypharmacy (i.e., a patient on 5 or more clinically relevant agents) among those affected is now the new normal and it is part of the pharmacist’s role as a HCP to ensure that the combination of medications does not lead to negative outcomes.
There are multiple ways in which medications can impact diabetes control. Some medications may alter BG test results, creating false high or low blood-sugar readings. The detriment in this is obvious and could be quite serious. Other agents can cause substantial weight gain, leading to greater insulin resistance and subsequently higher BG levels. Drug interactions that might make the medications used for diabetes control more or less effective are also possible. The more medications a patient takes, the more likely he or she is to experience drug interactions that could cause harm. This point may seem intuitive, but it is something we should not forget or take lightly. One study suggested that senior patients who were taking 10 or more medications had over a 90% chance of experiencing one or more drug interactions of clinical significance.2 This percentage may seem alarming, but it reinforces the concept that pharmacists must remain vigilant and well-educated while managing medication use, especially for frail and older adult patients. Pharmacists are well suited to review existing and new medications and intervene with patients and providers when medications are potentially contributing to glycemic fluctuations in people with diabetes. Before reviewing specific medications and medication classes that can impact glucose control, a brief review of the physiology of blood glucose metabolism will be provided.
THE PHYSIOLOGY OF BG METABOLISM
The first step toward a better understanding of diabetes and the medications that might affect control is to better understand the physiology of BG metabolism. This will allow for better recognition of the effects medications can have on BG control. Insulin is the main hormone involved in glucose regulation and homeostasis. It is released from the pancreatic beta cells in response to elevations in BG and in response to signaling by incretin hormones (such as GLP-1), thereby helping glucose become properly stored in the liver in the form of glycogen, which may be used when required. In addition, insulin allows the cells in the body to obtain energy by assisting carbohydrates and fats in becoming absorbed and used effectively. Increased body fat can interfere with insulin action, causing resistance to the action of the hormone, making it more difficult to properly keep BG in balance. Glucagon is the opposing hormone to insulin and is also produced in the pancreas, thereby inducing gluconeogenesis and other mechanisms to raise BG in response to hypoglycemia.
It is not possible in the scope of this activity to cover every medication that may affect BG metabolism. This activity, though, will highlight some of the more common medications traditionally used in practice. Keep in mind that medications and/or factors that can alter BG metabolism and raise blood sugars may have the potential to affect patients with existing diabetes and may also create conditions that lead to new-onset diabetes in certain at-risk individuals.
Before discussing specific medications that can affect blood glucose control, conditions and factors that can affect glucose monitoring will be discussed, followed by a brief review of drug interaction principles.
CONDITIONS THAT AFFECT TESTS TO MONITOR DIABETES
Hemoglobin A1c (A1C)
The blood test for glycosylated hemoglobin (A1C) allows HCPs to have an indicator of glycemic control over a period of approximately 3 months and has become the standard-of-care measure for how well patients are controlling their diabetes. A1C is a stable glycoprotein formed when glucose binds to hemoglobin in the blood. The average life span of a red blood cell (RBC) is approximately 3 months, which is why A1C is a measure indicative of an approximate 3-month period.3 This test is also used to help confirm a diagnosis of diabetes, to screen for prediabetes, as well as assess a patient with diabetes to determine response to treatment. The American Diabetes Association (ADA) has stated that an A1C level of 7 or lower is a basic target for adult patients with diabetes, although they also state that A1C goals should be individualized with higher or lower goals appropriate depending on patient-specific considerations.4 Given the central role of A1C monitoring in diabetes management, it is important to consider factors that may impact or alter measured A1C levels, and thus, how clinicians interpret the results. If such factors are not considered, the patient is at risk for over- or under-treatment and associated negative consequences.
The ADA notes that as an indirect measure of average glucose control, there are multiple limitations to A1C testing.4 For example, conditions that affect red blood cell lifespan (such as hemolytic and other anemias, glucose-6-phosphate dehydrogenase deficiency, recent blood transfusion, use of drugs that stimulate erythropoiesis, end-stage kidney disease, and pregnancy) can result in discrepancies between average glucose levels and the measured A1C.4 In the case of patients with end-stage renal disease who are using drugs that stimulate erythropoiesis, a relatively younger pool of erythrocytes is created, thus biasing the A1C measurement to the low. Hemolysis is another condition that can reduce the RBC life span, which increases the proportion of younger, less mature RBCs.5 If that life span is reduced, the resultant A1C value can be falsely lowered. Drug-induced immune-mediated hemolysis is rare, but should not be overlooked. Common drugs, which range from penicillin to methyldopa (Aldomet) have been associated with this reaction. Even more common medications—ibuprofen (Motrin), diclofenac (Zorvolex, Voltaren), and cephalosporins—have also been implicated. Importantly, take a closer look at a patient profile if a sudden and unexpected change in A1C level is noted. If this occurs, a practitioner has to be aware that hemolysis may be contributory, so further work-up should be considered.6-8 Drugs that are commonly associated with bleeding include nonsteroidal anti-inflammatory drugs (NSAIDs) and aspirin, meaning that patients on these medications who have changes in their bowel habits and A1C levels also warrant further evaluation.9
Self-Monitoring of Blood Glucose (SMBG)
Like A1C, SMBG is also central to diabetes self-management – particularly for patients on insulin therapy. The ADA includes a specific section on glucose meter accuracy and a discussion of factors that can limit SMBG accuracy within the Standards of Medical Care for Diabetes.10 The ADA lists the following as factors that can limit SMBG accuracy:
- Use of Counterfeit Strips: Patients should be counseled against purchase of preowned or second-hand test strips as use may provide incorrect SMBG results.
- Oxygen: Some monitors (those that utilize glucose oxidase, such as Glucocard meters) should only be used in patients with normal oxygen saturation. If used in patients with higher oxygen tensions (i.e., those on oxygen therapy), artificially low glucose readings could result and vice versa. Monitors that utilize glucose dehydrogenase (such as Freestyle Mini, Accu-Check and Ascencia Contour) are not sensitive to oxygen levels.
- Temperature: All monitors have an acceptable temperature range for accuracy. Most monitors will show an error message if the temperature is out of range, while others will provide a result with a message stating that the reading may be incorrect.
- Interfering Substances: There are several physiologic and pharmacologic factors that may interfere with SMBG accuracy. Some examples include: uric acid, galactose, xylose, acetaminophen, L-dopa, and ascorbic acid (for glucose oxidase meters).
PRINCIPLES OF DRUG INTERACTIONS
There are many factors to consider when selecting pharmacotherapy for a patient, including how the patient’s other medications and/or lifestyle may or may not complement a new diabetes medication. As this course progresses, you will be given specific information about drugs that may interact with each other; but it is also important to understand drug interactions, in general, so that you may identify potential interactions that are not specifically listed here. A complete review would reach beyond the scope of this activity.
Drug interactions may be classified as either pharmacodynamic or pharmacokinetic. Pharmacodynamic drug interactions occur when two separate drugs cause the same or opposing physiologic effects. For instance, if two hypoglycemic agents are given together, they will put the patient at an increased risk of experiencing clinical hypoglycemia. Conversely, if an individual receiving treatment with an oral hypoglycemic agent were to receive long-duration therapy with a corticosteroid, the corticosteroid could reduce the efficacy of the hypoglycemic agent because long-term corticosteroid use will contribute to worsening hyperglycemia.
Pharmacokinetic drug interactions occur when the presence of one drug results in increased or decreased levels of a co-administered drug. This happens when one drug affects the absorption, metabolism, distribution, or excretion of another. A common source of pharmacokinetic drug interactions is through inhibition or induction of enzymes in a drug’s metabolic pathway. For instance, sulfonylureas are metabolized through an enzyme called cytochrome P-450 (CYP) 2C9.11 Drug interactions may occur if another medication is given to a patient that inhibits or induces CYP 2C9. If CYP 2C9 is inhibited, then the sulfonylurea will be metabolized more slowly, leading to elevated levels of the sulfonylurea in the patient’s blood. This interaction may happen quickly. Conversely, if CYP 2C9 is induced, then the sulfonylurea will be metabolized more rapidly, leading to reduced levels of the sulfonylurea in the patient’s blood. This interaction usually takes a couple of weeks of simultaneous administration to occur. As you proceed through this course, pay close attention to the metabolic pathways of each drug so that you may better predict which other medications may cause adverse drug interactions when co-administered.
MEDICATIONS THAT CAN AFFECT GLUCOSE LEVELS
As mentioned above, there are a number of medications that can impact glucose control – by contributing to hyperglycemia, hypoglycemia, or dysglycemia. The following sections discuss some of the more commonly used and/or noteworthy medications and medication classes that can result in glycemic fluctuations.
Medications alter more than just how we measure glycemic control. Certain drugs have been shown to dramatically affect glycemic control itself. A large population of patients with diabetes experience depression or other forms of mental illness.12 Overall, people with T2D have a 2-fold higher incidence of depression than the general population, with 1 study finding occurrences in 24% of women and 13% of men.13,14 In addition, studies of individuals with serious mental illness, particularly schizophrenia, have found increased rates of T2D.15 The increased risk of T2D in this population, at least in part, is attributable to the use of second-generation antipsychotic medications.12
The second-generation antipsychotic medications are notorious for negatively affecting blood glucose and this class of agents has even been implicated as a cause of new-onset diabetes for some patients. These drugs initially were touted as being better tolerated by patients because they are associated with fewer extrapyramidal adverse events when compared to first-generation agents.16 Despite the lower risk of extrapyramidal symptoms with second-generation agents, these medications are associated with accelerated weight gain, insulin resistance, diabetes, dyslipidemia, and increased cardiovascular risk. These adverse effects can develop in as few as 6 months after the initiation of pharmacotherapy for those without preexisting diabetes.17 Second-generation antipsychotic medications may cause abnormal glucose metabolism that can lead to insulin resistance and T2D; therefore, it is important that patients with severe mental illness who are placed on antipsychotic medications be screened for diabetes.18 Pharmacists can assist with identifying individuals who may be appropriate for screening, thereby helping with an early diagnosis. A consensus statement has been developed by the ADA, in conjunction with other professional organizations, which provides recommendations for monitoring fasting BG levels for 12 weeks after starting therapy and annually, thereafter, for patients without preexisting diabetes. The monitoring schedule recommended in the ADA consensus statement is summarized in Table 1.19 If blood glucose values move out of acceptable ranges, it may be prudent to switch a patient to another antipsychotic with lower risk, such as aripiprazole (Abilify) or ziprasidone (Geodon).
|Table 1. Recommended Monitoring Protocol for Patients on Second-Generation Antipsychotics.
||Every 5 Years
|Fasting plasma glucose
|Fasting lipid profile
|*More frequent assessments may be warranted based on clinical status.
For those patients who have already been diagnosed with diabetes and who are being prescribed antipsychotic medications for the first time, it is important to discuss possible changes in diabetes control. It is known that some antipsychotic agents cause weight gain, which, of course, affects insulin resistance.16 The increase in weight caused by antipsychotic medications is often unpredictable. Clozapine (Clozaril) and olanzapine (Zyprexa) cause the greatest rise in weight, while aripiprazole (Abilify) and other newer agents may lead to less weight gain.17 There seem to be other mechanisms, besides weight gain, that are involved in the development of diabetes in patients using some antipsychotic medications, but these have not yet been fully elucidated. Table 2 shows the extent to which antipsychotic medications (inclusive of first-generation agents) can contribute to weight gain and associated metabolic risk:19-23
|Table 2. General risk of weight gain with antipsychotic medications.
- High Risk: clozapine, olanzapine
- Intermediate Risk: quetiapine, risperidone, paliperidone, iloperidone, sertindole, zotepine
- Low Risk: aripiprazole, amisulpride, ziprasidone, asenapine, lurasidone, and most high- to mid-potency first-generation antipsychotics
Although the risk of developing diabetes is increased in individuals on antipsychotic medications, there is likely insufficient screening for metabolic abnormalities in patients taking these agents. In late 2003, the U.S. Food and Drug Administration (FDA) announced that it was requiring class warnings to be added to the labeling of second-generation antipsychotic drugs, describing increased risks of hyperglycemia and diabetes. In some cases, the hyperglycemia was profound and subsequently associated with ketoacidosis, hyperosmolar coma, or death.24 The results of a time-series analysis of over 100,000 Medicaid patients who are taking second-generation antipsychotic medications showed that, despite the warning announced by the FDA, most individuals do not typically receive baseline serum glucose and lipid testing.25 Better screening practices are needed, and providing education to both HCPs and patients is an important step in making this change. Keep in mind that these drugs have helped thousands of people to overcome severe mental illness, so careful attention to the benefit-versus-risk profile is a must for patients on these medications.
Statins, which are the most commonly prescribed medication for high cholesterol, have also been implicated in altering glucose metabolism. In 2012, the FDA mandated updates to safety labeling for statin medications to include language about the potential for these agents to increase A1C and fasting serum glucose levels.26 Following an initial report suggesting that statins may increase diabetes risk,27 several meta-analyses have confirmed the initial findings and suggest an increased incidence of approximately 10-12% in those receiving statins versus placebo.28-30 That said, not all studies have confirmed this finding. The exact mechanisms of how statins may increase diabetes risk have not yet been fully elucidated, but some have proposed that statins downregulate glucose transporters. While statins have been associated with this risk, statins remain central in managing dyslipidemia to decrease cardiovascular risk. Likewise, the ADA continues to strongly recommend statin use in people with diabetes.
Niacin is another antihyperlipidemic agent that has been associated with contributing to elevation in blood glucose. One 16-week study that involved 148 patients with diabetes evaluated glucose control as one of the endpoints. The higher doses of niacin – 1000 to 1500 mg daily – resulted in an average A1C increase of 0.3%. A meta-analysis of niacin users that looked at cardiac risk and diabetes risk endpoints showed niacin therapy to be associated with a moderately increased risk of developing diabetes regardless of background statin use.31
That said, niacin use is no longer recommended by the ADA, and its use is much less frequent due to recent clinical trial findings. In 2016, the FDA withdrew approval of the indications related to the coadministration of niacin extended-release (ER) tablets with a statin.32 This decision was based on results from two large clinical event trials, Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes (AIM-HIGH) and Heart Protection Study 2–Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE), which concluded that niacin added to statin therapy did not provide clinical event beneﬁt over statin alone.33 The ADA states that “Combination therapy with a statin and niacin is not recommended given the lack of efficacy on major atherosclerotic cardiovascular disease outcomes and increased side effects.”34
Perhaps the most notorious offending drug class of medications for altering glucose metabolism in patients with diabetes and prediabetes are corticosteroids. Oral and intravenous corticosteroids in some circumstances are unavoidable; they are excellent medications for treating inflammatory or autoimmune conditions, such as chronic obstructive pulmonary disease exacerbations, asthma, vasculitis, and other inflammatory conditions.16
The mechanisms for the influence of corticosteroids on glucose regulation are complex and multifactorial. Corticosteroids promote gluconeogenesis in the liver and decrease glucose uptake and utilization by antagonizing the insulin response in skeletal muscle and fat tissue.16 Corticosteroids also regulate glycogen metabolism in the liver by increasing glycogen storage. In skeletal muscle, glucocorticoids permit the breakdown of glycogen, thereby resulting in higher circulating levels of glucose. Even more importantly, corticosteroids directly modulate the function of pancreatic alpha and beta cells that normally regulate the secretion of glucagon and insulin.35 During a normal stress response, the body requires excess glucose, but when this pathway is artificially stimulated, it can lead to dramatic hyperglycemia commonly making glucose levels uncontrollable in a patient with diabetes within hours of starting on an oral corticosteroid. Table 3 provides a list of select mechanisms thought to contribute to corticosteroid-induced diabetes.36 It is incumbent on the pharmacist to advise patients with diabetes that their blood sugar control will probably change, so a plan should be in place to modify insulin dosing or medication, if necessary, after collaborating with their primary care practitioner.
- Reduced peripheral insulin sensitivity and/or promotion of weight gain
- Increase in glucose production through promotion of hepatic gluconeogenesis
- Pancreatic beta-cell injury
- Beta-cell dysfunction
- Impaired insulin release
There have been a myriad of studies illustrating the correlation between hyperglycemia and corticosteroid use. In one study of patients with rheumatoid arthritis, nearly 9% developed diabetes within two years of starting glucocorticoid therapy, which was significantly higher than the control group not receiving corticosteroid therapy.37 In a case-controlled study, the odds ratio of starting an oral hypoglycemic agent or insulin was 1.77 for those receiving a hydrocortisone-equivalent dose of 1 to 39 mg/day, 3.02 for 40 to 79 mg/day, 5.82 for 80 to 119 mg/day, and 10.34 for 120 mg/day or more.38,39 For people who will require chronic immune suppression with corticosteroids after transplantation, there are published guidelines on managing glucocorticoid-related diabetes. Guidelines suggest checking the fasting plasma glucose level once a week for the first four weeks after transplantation, then at three months, then at six months, and then once a year thereafter.40 Diabetes is the leading cause of end-stage renal disease (ESRD) in the U.S., accounting for more than 44% of all patients with ESRD. Transplantation is recommended, if possible, over dialysis because of improved morbidity and mortality.41
It is also important to note that posttransplantation diabetes mellitus (PTDM), sometimes also referred to as new-onset diabetes after transplantation (NODAT), is a serious complication of immunosuppressant use. Once again it is evident that certain medications have the ability to either potentially worsen diabetes control or actually cause new-onset diabetes in patients. It appears that immunosuppressant therapy in addition to oral corticosteroids may act as triggers in developing diabetes in certain at-risk individuals, where risk factors such as age, family history, and certain antibody titers are measured.42 Different drugs were studied and compared for their ability to potentially contribute to PTDM in patients who have had a transplant. Though all antirejection agents can have an effect on BG metabolism, some may affect BG more than others. For example, agents such as cyclosporine, tacrolimus, and sirolimus have been associated with PTDM.43,44 Transplant patients are on complex drug regimens and must be monitored frequently for disease progression and signs of rejection. The ADA provides the following recommendations for screening and management of PTDM:45
- Patients should be screened after organ transplantation for hyperglycemia, with a formal diagnosis of PTDM being best made once a patient is stable on an immunosuppressive regimen and in the absence of an acute infection.
- Immunosuppressive regimens shown to provide the best outcomes for patient and graft survival should be used, irrespective of PTDM risk.
As highlighted in the recommendations above, a diagnosis of PTDM is best made after the stress of surgery and potential short-term hyperglycemia has resolved. Unfortunately, no studies to date have established which glucose-lowering agents are safest and most efficacious in PTDM.45
Thiazide diuretics, which are widely used and recommended for the treatment of hypertension in the setting of diabetes,34 have been implicated in both contributing to hyperglycemia in patients with diabetes and also contributing to new-onset diabetes in some individuals.16 The exact mechanism of how thiazide diuretics cause alterations in BG metabolism is poorly understood. Some theories that have been postulated include worsening of insulin resistance, decreasing insulin release, lowering serum potassium, and activating the renin angiotensin-aldosterone system.46 Hydrochlorothiazide has been implicated as a cause of new-onset diabetes in as few as 9 to 18 weeks after initiation of therapy. Keeping patients on a lower dose of hydrochlorothiazide (12.5 to 25 mg) may help ameliorate the chances of hyperglycemia in patients with or without preexisting diabetes. While thiazide diuretics may contribute to worsening glucose control when initiated in patients with diabetes, they are still widely used and recommended. It is prudent to monitor for changes in glycemic control when initiating thiazide therapy and adjust the antihypertensive or glucose-lowering regimen as deemed clinically appropriate if hyperglycemia develops.
Beta-blockers are another class of antihypertensive agents that, like thiazide diuretics, have been found to contribute to glycemic fluctuations.16 The ADA states that beta-blockers may be used for treatment of prior myocardial infarction (MI), active angina, or heart failure but have not been shown to reduce mortality as blood pressure-lowering agents in the absence of these conditions.34 As pharmacists, we have always been taught that beta-blockers can mask the signs of hypoglycemia by slowing the heart rate and blunting sympathetic response to low blood sugar. The main mechanism for increasing insulin resistance is thought to be due to vasoconstriction of small blood vessels in muscle tissue, which impairs glucose transport across the vascular membrane.47 New-onset diabetes may also be increased in those on beta-blockers for yet-to-be-clarified reasons. While beta-blockers have a profoundly positive effect on reducing cardiac morbidity and mortality, it is important to consider potential effects on glycemic control if these agents are added for cardiovascular indications.48
Protease inhibitors (PIs) and nucleoside reverse transcriptase inhibitors (NRTIs) are a mainstay of HIV therapy, and these classes of medications has been shown to increase the risk of diabetes.12 New-onset diabetes is estimated to occur in more than 5% of patients infected with HIV who are receiving PIs, with more than 15% potentially having prediabetes.49 The ADA recommends the following for people with HIV:12
- Patients with HIV should be screened for diabetes and prediabetes with a fasting glucose test before starting antiretroviral therapy, at the time of switching antiretroviral therapy, and 3-6 months after starting or switching antiretroviral therapy. If initial screening results are normal, checking fasting glucose every year is advised.
If patients do develop antiretroviral-associated hyperglycemia, the ADA goes on to say that it may be appropriate to consider discontinuing the problematic agent if safe and effective alternatives are available.12
Those with diabetes are more prone to infections than those without. Persistent hyperglycemia creates an environment ripe for bacteria to grow and a suppressed immune system in these patients significantly heightens the risk of serious infection.50 Therefore, antibiotics are often needed in people with diabetes when infections occur. Thus, it is crucial to realize that certain antibiotics may contribute to BG fluctuations in this group of patients.
Fluoroquinolones are one group of antibiotics particularly know for contributing to glucose fluctuations in people with diabetes.16 A study that involved over 78,000 people with diabetes in Taiwan looked at these patients’ use of the following 3 classes of antibiotics: fluoroquinolones, macrolides, and cephalosporins. An endpoint was any emergency-department list or hospitalization for severe blood glucose fluctuations within 1 month (30 days) after starting the antibiotic(s).51 The study’s results showed that those patients on fluoroquinolones were more likely to experience severe blood glucose fluctuations when compared to those who took other classes of antibiotics. Interestingly, moxifloxacin (Avelox, Vigamox) was implicated as causing the highest risk for hypoglycemia.52
To learn how the fluoroquinolone class causes these metabolic derangements, the studies referenced above point toward the important role of the adenosine triphosphate (ATP)-sensitive K+ channels in the pancreatic beta cell and the importance of anti-insulin hormones. In any event, this study shows that caution should be exercised when patients with diabetes are started on any fluoroquinolone.
In addition, metronidazole (Flagyl), fluconazole (Diflucan), and sulfamethoxazole-trimethoprim (Zotrim) have been linked to episodes of hypoglycemia in patients with diabetes who were taking oral antihyperglycemic agents, such as glipizide (Glucotrol, Glucotrol XR) and glyburide (DiaBeta, Micronase).53 In conclusion, more frequent monitoring of blood sugars is recommended if a patient taking a sulfonylurea is also prescribed an antibiotic associated with hypoglycemia.
Diabetes is a complex disease that requires a great deal of thought when evaluating blood glucose patterns. If a patient with diabetes has an illness, his or her blood sugar will likely rise in response to the stress of illness. Once an antibiotic is given, it is possible that blood sugars will normalize because the patient is “getting better.” The above antibiotics may be useful for treating patients with diabetes and are certainly not contraindicated, but caution is advised in making sure blood glucose fluctuations are monitored and addressed to keep patients safe.
The biggest concern with drinking alcohol for people with diabetes is the potential for alcohol-induced hypoglycemia. That said, many alcoholic beverages also contain high amounts of carbohydrate, which can also contribute to weight gain and acute hyperglycemia. In terms of hypoglycemia, it can be delayed in nature and can present many hours after alcohol consumption. For most people, the risk for hypoglycemia happens at night, when the patient is most vulnerable. Alcohol is metabolized in the body in a manner that makes it especially dangerous for a patient with diabetes. Glucagon will not work as effectively after alcohol consumption, thereby leading to an impaired sympathetic response to hypoglycemia. To add to the confusion, alcohol’s neurologic effects may be confused with signs of hypoglycemia.42 The ADA offers the following recommendations related to alcohol consumption in people with diabetes:54
- Adults with diabetes who drink alcohol should do so in moderation (no more than one drink per day for adult women and no more than two drinks per day for adult men).
- Alcohol consumption may place people with diabetes at increased risk for hypoglycemia, especially if taking insulin or insulin secretagogues. Education and awareness regarding the recognition and management of delayed hypoglycemia are warranted.
Patients with diabetes often have other comorbidities that must be treated. This often leads to polypharmacy
With the expanding role of the pharmacist in the new health care landscape, it is incumbent to identify potential adverse drug reactions (ADRs) and to report them when necessary. ADRs constitute a leading cause of hospital admissions, which is significant because many of the ADRs are preventable. With medication therapy management (MTM) at the forefront of pharmacy practice, pharmacists can make a huge impact on the nation’s health. Regular documentation and identifying potential drug therapy issues will surely become the new business model.
The complexity of drug regimens in the patient with diabetes creates an increasing challenge for the pharmacist who is completing a Comprehensive Medication Review and identifying the person’s risks and benefits of medication therapy. Also, because of the increasing older adult population, medications that are appropriate for a given senior patient may be incorrectly dosed for that patient based on their renal and/or hepatic function. In a study conducted at a Veterans Affairs Medical Center in Michigan, many patients with diabetes were found to have experienced potentially dangerous hypoglycemia because their medications were potentially dosed too high.55
As we have seen throughout this module, medications that cause alterations in BG are often implicated in new-onset diabetes, especially in those patients at high risk for developing the disease. It is important to know the symptoms of diabetes, which include polydipsia, polyuria, and polyphagia. Armed with the proper information, we can all make interventions to potentially improve overall care.
Counseling Tips for Common Drugs that Affect Diabetes Control
Potential Counseling Tips
Conditions that can alter A1C and SMBG readings
- The A1C level can be affected by any process that alters the life span of red blood cells (RBC) or makes a higher percentage of young RBCs. These conditions include end-stage kidney disease, having a recent blood transfusion, and hemolytic or other anemias, among other potential conditions.
- A variety of factors can decrease SMBG accuracy including use of counterfeit strips, temperature, and interfering substances (uric acid, L-dopa, etc.)
Medications that impact glycemic control
- Certain drugs have been shown to impact glycemic control.
- Example medications that can alter blood glucose include: second-generation antipsychotic medications, niacin, statins, immunosuppressant medications, certain blood pressure medications (e.g., thiazides and beta-blockers), certain medications for HIV, caffeine and alcohol.
- Teresa Carr: Too many meds? America’s love affair with prescription medication. https://www.consumerreports.org/prescription-drugs/too-many-meds-americas-love-affair-with-prescription-medication/. Accessed April 25, 2019.
- Nolan L, O’Malley K. Prescribing for the elderly. Part 1: Sensitivity of the elderly to adverse drug reactions. J Am Geriatr Soc. 1988;36(2):142-149.
- Bry L, Chen PC, Sacks DB. Effects of hemoglobin variants and chemically modified derivatives on assays for glycohemoglobin. Clin Chem. 2001;47(2):153-163.
- American Diabetes Association. 6. Glycemic targets: Standards of Medical Care in Diabetes – 2019. Diabetes Care. 2019;42(Suppl. 1):S61-S70.
- Tarim O, Küçükerdoğan A, Günay U, et al. Effects of iron deficiency anemia on hemoglobin A1c in type 1 diabetes mellitus. Pediatr Int. 1999;41(4):357-362.
- Arndt PA, Garratty G. The changing spectrum of drug-induced immune hemolytic anemia. Semin Hematol. 2005;42(3):137-144.
- Garratty G, Arndt PA. An update on drug-induced immune hemolytic anemia. 2007;23(3):105-119.
- Garratty G. Immune hemolytic anemia associated with drug therapy. Blood Rev. 2010;24(4-5):143-150.
- Bjarnason I, Hayllar J, MacPherson AJ, Russell AS. Side effects of nonsteroidal anti-inflammatory drugs on the small and large intestine in humans. Gastroenterology. 1993;104(6):1832-1847.
- American Diabetes Association. 7. Diabetes technology: Standards of Medical Care in Diabetes – 2019. Diabetes Care. 2019;42(Suppl. 1):S71-S80.
- Scheen AJ. Drug interactions of clinical importance with antihyperglycemic agents: an update. Drug Saf. 2005;28(7):601-631.
- American Diabetes Association. 4. Comprehensive medical evaluation and assessment of comorbidities: Standards of Medical Care in Diabetes – 2019. Diabetes Care. 2019;42(Suppl. 1):S34-S35.
- Ali S, Stone MA, Peters JL, et al.The prevalence of co-morbid depression in adults with type 2 diabetes: a systematic review and meta-analysis. Diabet Med.2006;23(11):1165-1173.
- Baumeister H, Hutter N, Bengel J. Psychological and pharmacological interventions for depression in patients with diabetes mellitus and depression. Cochrane DatabaseSyst Rev. 2012;12:CD008381.
- Suvisaari J, Perala J, Saarni SI, et al. Type 2 diabetes among persons with schizophrenia and other psychotic disorders in a general population survey. Eur Arch Psychiatry Clin Neurosci. 2008;258:129-136.
- Rehman A, Setter SM, Vue MH. Drug-induced glucose alterations part 2: drug-induced hyperglycemia. Diabetes Spectrum. 2011;24(4):234-238.
- Rojo LE, Gaspar PA, Silva H, et al. Metabolic syndrome and obesity among users of second generation antipsychotics: a global challenge for modern psychopharmacology. Pharmacol Res. 2015;101:74-85.
- Ramaswamy K, Masand PS, Nasrallah HA. Do certain atypical antipsychotics increase the risk of diabetes? A critical review of 17 pharmacoepidemiologic studies. Ann Clin Psychiatry.2006;18(3):183-194.
- American Diabetes Association, American Psychiatric Association, American Association of Clinical Endocrinologists, North American Association for the Stud of Obesity. Consensus development conference on antipsychotic drugs and obesity and diabetes. Diabetes Care. 2004;27(2):596-601.
- Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005;352(12):12091223.
- Newcomer JW, Haupt DW, Fucetola R, et al. Abnormalities in glucose regulation during antipsychotic treatment of schizophrenia. Arch Gen Psychiatry. 2002;59(4):337-345.
- Bak M, Fransen A, Janssen J, et al. Almost all antipsychotics result in weight gain: a meta-analysis. PLoS One. 2014;9(4):e94112.
- Meyer JM, Mao Y, Pikalov A, et al. Weight change during long-term treatment with lurasidone: pooled analysis of studies in patients with schizophrenia. Int Clin Psychopharmacol. 2015;30(6):342-350.
- Bushe CJ, Leonard BE. Blood glucose and schizophrenia: a systematic review of prospective randomized clinical trials. J Clin Psychiatry. 2007;68(11):1682-1690.
- Morrato EH, Druss B, Hartung DM, et al. Metabolic testing rates in 3 state Medicaid programs after FDA warnings and ADA/APA recommendations for second-generation antipsychotic drugs. Arch Gen Psychiatry.2010;67(1):17-24.
- S. Food & Drug Administration. FDA drug safety communication: important safety label changes to cholesterol-lowering statin drugs. https://www.fda.gov/drugs/drugsafety/ucm293101.htm. Accessed April 16, 2019.
- Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359:2195-2207.
- Sattar N, Preiss D, Murray HM, et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomized statin trials. Lancet. 2010;375:735-742.
- Rajpathak SN, Kumbhani DJ, Crandall J, et al. Statin therapy and risk of developing type 2 diabetes: a meta-analysis. Diabetes Care. 2009;32:1924-1929.
- Thakker D, Nair S, Pagada A, et al. Statin use and the risk of developing diabetes: a network meta-analysis. Pharmacoepidemiol Drug Saf. 2016;25:1131-1149.
- Goldie A, Taylor AJ, Nguyen P, et al. Niacin therapy and the risk of new-onset diabetes: a meta-analysis of randomised controlled trials. 2016;102(3):198-203.
- Federal Register. AbbVie Inc. et al; Withdrawal of approval of indications related to the coadministration with statins in applications for niacin extended-release tablets and fenofibric acid delayed-release capsules. https://www.federalregister.gov/documents/2016/04/18/2016-08887/abbvie-inc-et-al-withdrawal-of-approval-of-indications-related-to-the-coadministration-with-statins. Accessed April 16, 2019.
- Superko HR, Zhao XQ, Hodis HN, Guyton JR. Niacin and heart disease prevention: Engraving its tombstone is a mistake. J Clin Lipidol. 2017;11(6):1309-1317.
- American Diabetes Association. 10. Cardiovascular disease and risk management: Standards of Medical Care in Diabetes – 2019. Diabetes Care. 2019;42(Suppl. 1):S103-S123.
- Kuo T, McQueen A, Chen TC, Wang JC. Regulation of glucose homeostasis by glucocorticoids. Adv Exp Med Biol. 2015;872:99-126.
- Suh S, Park MK. Glucocorticoid-induced diabetes mellitus: an important but overlooked problem. Endocrinol Metab (Seoul). 2017;32(2):180-189.
- Panthakalam S, Bhatnagar D, Klimiuk P. The prevalence and management of hyperglycaemia in patients with rheumatoid arthritis on corticosteroid therapy. Scott Med J.2004; 49(4):139-141.
- Uzu T, Harada T, Sakaguchi M, et al. Glucocorticoid-induced diabetes mellitus: prevalence and risk factors in primary renal diseases. Nephron Clin Pract. 2007; 105(2):c54-c57.
- Gurwitz JH, Bohn RL, Glynn RJ, et al. Glucocorticoids and the risk for initiation of hypoglycemic therapy. Arch Intern Med.1994;154(1):97-101.
- Davidson J, Wilkinson A, Dantal J, et al; International Expert Panel. New-onset diabetes after transplantation: 2003 International consensus guidelines. Proceedings of an international expert panel meeting. Barcelona, Spain, 19 February 2003. Transplantation. 2003;75(10 Suppl):SS3-SS24.
- Stewart JH, McCredie MR, Williams SM, et al. Trends in incidence of treated end-stage renal disease, overall and by primary renal disease, in persons aged 20-64 years in Europe, Canada and the Asia-Pacific region, 1998-2002. Nephrology (Carlton).2007;12(5):520-527.
- Chan CM, Chim TM, Leung KC, et al. Simultaneous pancreas and kidney transplantation as the standard surgical treatment for diabetes mellitus patients with end-stage renal disease. Hong Kong Med J.2016;22(1):62-69.
- Mora PF. Post-transplantation diabetes mellitus. Am J Med Sci. 2005;329:86-94.
- Johnston O, Rose CL, Webster AC, Gill JS. Sirolimus is associated with new-onset diabetes in kidney transplant recipients. J Am Soc Nephrol. 2008;19:1411-1418.
- American Diabetes Association. 2. Classification and diagnosis of diabetes: Standards of Medical Care in Diabetes – 2019. Diabetes Care. 2019;42(Suppl. 1):S13-S28.
- Palmer BF. Metabolic complications associated with use of diuretics. Semin Nephrol. 2011;31(6):542-552.
- Fonseca V, Bakris GL, Bell DS, et al. Differential effect of beta-blocker therapy on insulin resistance as a function of insulin sensitizer use: results from GEMINI. Diabet 2007;24(7):759-763.
- Jacob S, Rett K, Henriksen EJ. Antihypertensive therapy and insulin sensitivity: do we have to redefine the role of beta-blocking agents? Am J Hypertens. 1998;11(10):1258-1265.
- Monroe AK, Glesby MJ, Brown TT. Diagnosing and managing diabetes in HIV-infected patients: current concepts. Clin Infect Ds. 2015;60:453-462.
- Casqueiro J, Casqueiro J, Alves C. Infections in patients with diabetes mellitus: a review of pathogenesis. Indian J Endocrinol Metab.2012;16 Suppl 1:S27-S36.
- Aspinall SL, Good CB, Jiang R, et al. Severe dysglycemia with the fluoroquinolones: a class effect? Clin Infect Dis. 2009;49(3):402-408.
- Coblio NA, Mowrey K, McCright P, et al. Use of a data warehouse to examine the effect of fluoroquinolones on glucose metabolism. Am JHealth Syst Pharm. 2004;61(23):2545-2548.
- Parekh TM, Raji M, Lin Y, et al. Hypoglycemia after antimicrobial drug prescription for older patients using sulfonylureas. JAMA Intern Med. 2014;174(10):1605-1612.
- American Diabetes Association. 5. Lifestyle management: Standards of Medical Care in Diabetes – 2019. Diabetes Care. 2019;42(Suppl. 1):S46-S60.
- Sussman JB, Kerr EA, Saini SD, et al. Rates of deintensification of blood pressure and glycemic medication treatment based on levels of control and life expectancy in older patients with diabetes mellitus. JAMA Intern Med. 2015;175(12):1-8.
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