Participants will discuss the oral and injectable medications that are used to treat types 1 and 2 diabetes mellitus.
After completing this continuing education course, the participant will be able to meet the following objectives:
Diabetes mellitus is a huge public health problem. Approximately 30.3 million (9.4%) Americans have diabetes mellitus, 7.2 million have the disease but are undiagnosed, and 84.1 million (33.9%) US adults have pre-diabetes.1 In addition, the prevalence of diabetes mellitus has been steadily increasing since the late 1950s2 and despite improvements in the number of people who have attained the recommended A1C level,3 there are still many, many Americans who have not achieved glycemic control.3
In the coming years, nurses will be caring for more patients with diabetes than ever before, and they will need a comprehensive understanding of the medications used for maintaining glycemic control. This module will provide professional nurses with the information they need to administer anti-hyperglycemic medications safely.
The term diabetes mellitus is used to distinguish this disease from diabetes insipidus. For the remainder of the module, the term diabetes will be used to identify diabetes mellitus.
The primary derangement of type 1 and type 2 diabetes is hyperglycemia, elevated blood glucose caused by the absence of insulin production (type 1 diabetes) or decreased insulin production and increased insulin resistance (type 2 diabetes). Chronic hyperglycemia is the defining characteristic of the disease, it is the primary cause of the microvascular complications of diabetes, i.e., retinopathy, nephropathy, and neuropathy,4-6 and it is a contributing factor in the pathogenesis of cardiovascular disease in patients who have diabetes.
There is a direct relationship of the level and duration of hyperglycemia and the incidence of microvascular and macrovascular complications, and in addition, the level and duration of hyperglycemia have a negative effect on the progression of diabetes.
Patients who have type 1 diabetes must use insulin and for patients who have type 2 diabetes, initiation of pharmacologic therapy with an oral hypoglycemic at the time of diagnosis is usually recommended.7 There is strong evidence that remission of type 2 diabetes by way of lifestyle changes like weight loss, exercise, and (possibly) smoking cessation can be attained.8,9 These interventions can help with glycemic control 9,10, 12-15 and they have value for diabetic patients aside from their role in glycemic control. However, for the reasons listed below, glycemic control in type 2 diabetes will, in effect, require the use of medications, often multiple medications, and many patients who have type 2 diabetes will eventually need insulin.16-18
Given the number of people who have diabetes, the widespread use of anti-hyperglycemics, and the complex pharmacological regimens used to treat the disease, it is imperative that nurses understand the mechanisms by which the anti-hyperglycemics control HbA1c and blood glucose, the risks and benefits of the anti-hyperglycemics, and how and for whom these drugs should be used.
The first section of the module will discuss the mechanism (s) of action, the dosages, indicated use, adverse effects, and contraindications of each of the anti-hyperglycemic medications. The information in this section was obtained from package inserts and from Lexicomp®, a widely used and frequently updated drug database. Pharmacokinetic information for each drug was supplied when it was available. The adverse effects discussed here are the ones that are mentioned most prominently in Lexicomp®, in the package inserts, and the medical literature. Combination products of the oral anti-hyperglycemics are available, but these will not be discussed. Generic names are used first, and brand names are in parentheses. The second section of the module will provide detailed information on the risks and benefits of each drug and outline how, when and for whom they are used.
Insulin binds with insulin receptors on cell membranes. Insulin-insulin receptor binding moves the GLUT4 and GLUT2 insulin transporter molecules to the cell membranes, allowing diffusion of glucose into the cells.
Insulin is used for the treatment of type 1 and type 2 diabetes.
The insulins are classified by their onset of action:
There are also combination products. Regular and NPH are human insulins; the others listed are insulin analogs; the difference between the two will be explained later. Insulins are typically 100 units per mL, aka U-100, but U-500 concentrations are available.
Insulins are rapid-acting, short-acting, intermediate-acting, long-acting, and combination preparations. Brand names are in parentheses; not all the brand names are listed.
Many of the insulins in use today are analogues. Analogue insulin is insulin that has been genetically engineered to change its absorption, distribution, metabolism, and excretion, and these changes can provide advantages in of glycemic control.
Biochemical and physical barriers and manufacturing challenges have, to this point, prevented the development of an oral insulin preparation.
Insulin dosages are prescribed to meet the goals of therapy, e.g., the pre-prandial glucose level, the fasting glucose level, and the HbA1c level that are specific for each patient.
Pramlintide is a synthetic analog of the hormone amylin. Amylin is secreted by pancreatic β cells along with insulin at a ratio of 1:100. Pramlintide lowers post-prandial glucose by:
Pramlintide is used as an adjunctive treatment for patients who have type 1 or type 2 diabetes who have not attained optimal glycemic control using insulin.
When pramlintide is being started, reduce the pre-prandial insulin dose by 50%.
The GLP-1 receptor agonists are analogs of human glucagon-like peptide-1 (GLP-1), an incretin hormone. The incretin hormones decrease blood glucose by increasing the secretion and release of insulin in response to food and decreasing glucagon secretion. Dulaglutide, exenatide, liraglutide, lixisenatide, and semaglutide are GLP-1 receptor agonists. They bind to and activate GLP-1 receptors on the pancreatic β cells, and as with human incretin, this increases insulin secretion and release. The GLP-1 receptor agonists also slow gastric emptying, regulate post-prandial glucagon secretion, and enhance satiety.
As an adjunctive treatment, along with diet and exercise, for attaining hyperglycemic control in patients who have type 2 diabetes. Liraglutide is also indicated for reducing the risk of major cardiovascular events in patients who have type 2 diabetes and cardiovascular disease.
Exenatide, time to peak plasma level, immediate release formulation, 2.1 h. In most people, exenatide concentrations are measurable for ~ 10-hours post-injection.
These drugs are injected subcutaneously (SC).
Insulin binds with insulin receptors on cell membranes. Insulin-insulin receptor binding moves the GLUT4 and GLUT 2 insulin transporter molecules to the cell membranes, allowing diffusion of glucose into the cells.
Hyperglycemic control for patients who have type 1 or type 2 diabetes. The efficacy of inhaled insulin and injected insulin appear to be similar, but a lack of patient acceptance and patient discontinuation of its use have limited the popularity of inhaled insulins.
The onset is 12 minutes, the peak effect is ~ 33-53 minutes, and the duration of action is ~ 190-270 minutes, proportional to the dose.
The oral anti-hyperglycemics are discussed based on their mechanisms of action.
The α-glucosidase inhibitors lower blood glucose by inhibiting the action of α-glucosidase, an enzyme in the gut that breaks down ingested carbohydrates and disaccharides into glucose. Glucose absorption is delayed, post-prandial glucose is lowered, and the metabolism of sucrose to glucose and fructose is inhibited.
An adjunctive treatment, along with diet and exercise, to attain glycemic control in patients who have type 2 diabetes.
The α-glucosidase inhibitors are not mentioned in the American Diabetes Association’s (ADA) 2019 Standards of Care or in recent (2019) authoritative reviews as a first-, second- or, third-line treatment for type 2 diabetes20,21 and the adverse effects of diarrhea and flatulence can limit patient acceptance.19,20 The efficacy of acarbose and miglitol appear to be similar.21
Metformin is the only available biguanide.
Hyperglycemic control for patients who have type 2 diabetes when diet and exercise are not enough to attain glycemic control.
The mechanism by which colesevelam lowers blood glucose has not been identified. A review of clinical studies found that when colesevelam was used as an adjunctive treatment for type 2 diabetes the average decrease in HbA1c was ~ 0.5%.23 Because of cost, limited effectiveness, and side effects, colesevelam is not often used to treat type 2 diabetes.20
Glycemic control for patients who have type 2 diabetes, as an adjunct to diet and exercise.
Dipeptidyl peptidase IV is an enzyme that is involved in the breakdown of the endogenous incretin hormones GLP-1 and GIP. The incretin hormones decrease glucagon secretion and increase insulin synthesis and release. Inhibition of DPP-IV thus increases the activity of GLP-1 and GIP and lowers blood glucose by increasing insulin secretion and release and by decreasing glucagon secretion.
Glycemic control for patients who have type 2 diabetes. The DPP-IV inhibitors can be used as monotherapy along with diet and exercise or in combination with other medications.
The DPP-IV inhibitors are rapidly absorbed, and the peak effect occurs within several hours.
The mechanism of action of bromocriptine that lowers blood glucose has not been identified.20,23
As an adjunct, along with diet and exercise, to attain glycemic control for patients who have type 2 diabetes. Cycloset is the only form of bromocriptine approved for the treatment of diabetes. Wexler (January 2019) and Lamos et al. write that bromocriptine has only a modest ability to lower glucose and it has frequent gastrointestinal side effects.20,23
The meglitinide analogs increase calcium movement through calcium ion channels in the pancreatic β cells, and the increased intracellular calcium stimulates the release of insulin.
As an adjunct, along with diet and exercise, to attain glycemic control for patients who have type 2 diabetes.
Dosing adjustments are determined by the blood glucose response, usually fasting blood glucose. Double the pre-prandial dose up to 4 mg until a satisfactory blood glucose response is achieved. There should be at least 1 week between dosage adjustments.
Dosage range: 0.5-4 mg, with meals. The maximum recommended a daily dose of 16 mg.
Sodium-glucose co-transporter type 2 (SGLT2) is a glucose transporter that is found in the renal tubules. SGLT2 reabsorbs a significant amount of filtered glucose from the proximal tubules, and inhibition of SGLT2 increases the renal excretion of glucose and lowers plasma glucose.
The onset of action of canagliflozin is within 24 hours, and the duration of action is ~ 24 hours.
Chlorpropamide, tolbutamide, and tolazamide are first-generation sulfonylureas and are rarely prescribed because the second-generation sulfonylureas are safer, better tolerated, and equally effective at controlling blood glucose as the first-generation drugs.
The sulfonylureas bind to SUR1 receptors on the β cells of the pancreas, and this binding stimulates the release of insulin. The sulfonylureas also decrease glycogenolysis and increase insulin sensitivity.
As an adjunct, along with diet and exercise, to attain glycemic control in patients who have type 2 diabetes.
The micronized tablets (Glynase® PresTabs®) are started at 1.5-3 mg a day and taken in the morning. Lower starting dosages can be used if the patient is sensitive to anti-hyperglycemic drugs. The dosage can be increased by increments of 1.5 mg a day, every week. The maximum daily dosage is 12 mg.
The thiazolidinediones lower blood glucose by a number of complex mechanisms that increase insulin utilization and decrease insulin resistance.
As an adjunct, along with diet and exercise, to attain glycemic control for patients who have type 2 diabetes.
The dose of insulin or a sulfonylurea should be decreased if the patient is taking pioglitazone.
Patients who have type 1 should start insulin therapy at the time of diagnosis, and insulin therapy will need to be continued for the life of the patient. Research has shown that as many as 74% of people who have had type 1 diabetes for five years or longer still secrete tiny amounts of insulin,24 and some patients who have type 1 diabetes secrete an amount of insulin that is clinically important,24 but insulin therapy is still necessary for type 1 diabetics to survive.
The insulin therapy that is currently recommended is often called intensive insulin therapy, and it is intended to mimic as closely as possible the normal physiological profile of insulin secretion and release. This approach has been shown to produce better glycemic control and to significantly reduce the risk of developing diabetic nephropathy, neuropathy, and retinopathy and the cardiovascular complications of diabetes.25-27 The basic goals/objectives and methods of intensive insulin therapy are:25-28
Glycemic control is the goal of treatment for diabetes, but not all patients can reach the standard HbA1c goal and a lower or higher HbA1c may be acceptable, depending on the patient’s age, co-morbidities, the duration of their disease, and other factors.28
Animal-derived insulins are no longer used in the United States, and synthetic insulins, either recombinant human insulin or insulin analogues, are used exclusively, and the insulin analogues are the preparation of choice.25 The insulin analogues are preferred because:
Continuous subcutaneous insulin infusion (CSII) uses an insulin pump to deliver a continuous basal insulin level of rapid-acting insulin, usually an insulin analogue, and CSII can be used with self-injections of pre-prandial insulin.32 Continuous subcutaneous insulin infusion can be more effective than multiple insulin injections for attaining the optimal HbA1c and preventing hypoglycemia,25,33 but the level of glycemic control depends in part on the type of device that is used; the level of effectiveness can be modest25,33 but with pumps that have continuous glucose monitoring the level of glycemic control can be significant.34
There are no consensus guidelines for choosing between CSII and multiple daily injections and the decision as to which to use depends on cost, patient preference, and which of the two works best for the patient in terms of maintaining the optimal HbA1c level and avoiding hypoglycemia.32
Insulin pens are preferred by most patients and compared to syringe and vials, insulin pens are more convenient, the delivered dose is more accurate, glycemic control is better (the dose is consistently more accurate, and the shorter needle length avoids intra-muscular injection), patient adherence to the medication regimen is improved, and the risk of hypoglycemia is less.35,36 In 2017, the Food and Drug Administration (FDA) approved the first insulin pen that can be combined with a smartphone application. This device, the InPen®, automatically tracks many aspects of insulin therapy and helps patients calculate doses and manage their insulin therapy.
Measuring HbA1c is the primary method of assessing long-term glycemic control,28 and for most patients checking HbA1c every three months or so is enough.28 However, the HbA1c cannot measure glucose level variability or detect hypoglycemia so checking blood glucose is necessary, and self-monitoring of blood glucose should be done before meals, at bedtime, if there are signs and symptoms of hypoglycemia, before exercising, and in other situations.33 This may require checking blood glucose by fingerstick six to 10 times a day, and the need for such frequent blood glucose checks can be reduced by use of a continuous glucose monitoring device (CGM). Continuous glucose monitoring devices can provide better glycemic control (decreased HbA1c) than self-monitoring, their use can reduce the incidence of hypoglycemic events, and these advantages are especially strong for patients who have frequent episodes of hypoglycemia and/or hypoglycemic unawareness.33,37-39 The use of a CGM, however, does not mean that patients never need to check blood glucose.33
The amount of insulin that is absorbed can vary significantly from patient to patient and from dose to dose, and there can be intra-patient variation in absorption, as well. The pharmacokinetics of insulin and thus its actions and effectiveness can be influenced by many factors related to the injection process, and optimal insulin injection technique can improve glycemic control.
Self-injection of insulin is not complicated, but newly diagnosed type 1 diabetics will need to be taught the proper techniques, i.e., needle size, angle of injection, etc., as they apply to the patient. Physicians, nurses, and pharmacists can perform the necessary patient teaching, and Certified Diabetes Educators can be especially effective in this role.
Hypoglycemia is a significant complication of type 1 diabetes. Patients who have type 1 diabetes typically have one-two episodes of hypoglycemia per week,47 and as many as one in five of these episodes are severe, severe defined as the patient requires assistance for administration of carbohydrates and/or glucagon.48
Persistent episodes of hypoglycemia cause very serious consequences:
Hypoglycemia in type 1 diabetics is caused by intensive insulin therapy,47,51 but an absolute or relative excess of insulin is not the only cause of hypoglycemia in this patient population; as previously mentioned, hypoglycemic episodes cause hypoglycemia. Patients who have continued and persistent episodes of hypoglycemia develop an abnormal response to low blood sugar that is characterized by decreased glucagon and epinephrine excretion and decreased suppression of insulin secretion, a phenomenon that is called hypoglycemia-associated autonomic failure.52 This change in the normal compensatory responses to hypoglycemia causes hypoglycemia and decreases awareness of hypoglycemia which, in turn, prevents self-treatment and predisposes the patient to more episodes of hypoglycemia,49 creating a vicious cycle of more frequent and more severe hypoglycemia. The latter phenomenon, which is called hypoglycemia unawareness, and it occurs in approximately 17%-50% of patients who have type 1 diabetes.48,49
The patient requires the assistance of another person to administer carbohydrate, glucagon, or another resuscitative action.
Neurologic recovery that results from restoring plasma glucose to normal is considered enough evidence that the event was caused by hypoglycemia
Typical signs and symptoms of hypoglycemia and a documented glucose of ≤70 mg/dL
Blood glucose of ≤ 70 mg/dL but no signs or symptoms of hypoglycemia
Typical hypoglycemia signs and symptoms of hypoglycemia, but blood glucose was not measured
An event during which the diabetic person has the typical symptoms of hypoglycemia with measured plasma glucose > 70 mg/dL
Sub-optimal adherence to and compliance with a prescribed insulin regimen is a common problem.54 Farsaei et al. (2014) found that 14.3% of type 1 diabetics had low adherence and 63.4% had medium adherence to their insulin regimens. Non-adherence can be due to factors such as the number of daily injections, embarrassment, feeling worse after an insulin injection, forgetfulness, injection site pain, perceived time-consuming nature of the regimen, and weight gain.54
Pramlintide is the only drug other than insulin that has an FDA-approved use for the treatment of type 1 diabetes. Pramlintide has been shown to decrease HbA1c, lower body weight and reduce postprandial hyperglycemia, and it may help reduce the total daily insulin dose.25,55,56 The need for additional injections would be a disincentive to add pramlintide to an insulin regimen.
Metformin, DPP-IV inhibitor, GLP receptor inhibitors, and SGLT2 inhibitors have been used to treat type 1 diabetes, and there is evidence that they can be beneficial,55,56 but the American Diabetes Association (ADA) does not recommend their use, stating: “The risks and benefits of adjunctive agents beyond pramlintide in type 1 diabetes continue to be evaluated through the regulatory process; however, at this time, these adjunctive agents are not approved in the context of type 1 diabetes."18
Metformin is the drug of choice for starting treatment in patients who have type 2 diabetes,25 and there are many reasons why it is recommended as the first medication for newly diagnosed type 2 diabetics:25,57,58
Metformin clearly causes B12 deficiency and significantly lowers serum B12 concentrations.57,59 The risk for these complications increases with dose and duration of metformin use,57,59 but although there have been reports of anemia and peripheral neuropathy caused by metformin a recent (January 2019) meta-analysis concluded that there is no significant (italics added) association between metformin use and developing anemia or neuropathy.59 Nonetheless, the ADA recommends that periodic measurement of B12 should be considered, particularly if the patient develops anemia or peripheral neuropathy.25
Lactic acidosis is a rare complication of metformin use25,57 with an estimated incidence of 5 cases per 100,000 patient-years, but it is clinically quite important because the fatality rate of metformin-induced lactic acidosis can be as high as 45%.60 Metformin is metabolized by the liver, and it is excreted by the kidneys. Typically, patients who develop metformin-induced lactic acidosis have renal impairment, a co-morbidity that decreases renal perfusion and/or causes hypoperfusion and hypoxemia,57 or comorbidity that prevents lactate metabolism or increases the production of lactate.57,61 These co-morbidities include age of 80+ years, alcohol abuse, chronic obstructive pulmonary disease, hepatic dysfunction, heart failure, hypoglycemia, a history of lactic acidosis, or renal insufficiency. These conditions are usually considered to be contraindications to the use of metformin or at least, cautions for its use; for example, the use of metformin is contraindicated in patients who have an eGFR < 30 mL/min, and therapy with metformin should not be started if the eGFR is between 30 and 45 mL/min. The strength and importance of these co-morbidities as risk factors for metformin-induced lactic acidosis is still not clear.61
If the use of metformin is contraindicated or metformin is not tolerated, an oral hypoglycemic should be prescribed, and the drug should be chosen based on these factors:
Metformin is contraindicated if the patient has an eGFR of < 30 mL/minute; active or progressive liver disease; active abuse of alcohol; there is a comorbidity like unstable CHF or an acute condition like sepsis that may cause hypoxemia or hypoperfusion; the patient has tried metformin before and developed lactic acidosis, or; the patient has acute or chronic metabolic acidosis, with or without coma, including diabetic ketoacidosis.57
If glycemic control is not attained after three months of treatment with metformin and lifestyle interventions25 another drug should be added to the regimen.7,25
There is little head-to-head research comparing the efficacy and long-term safety of the second-line and third-line line diabetic medications,7 and there is little research about the advantages/disadvantage of any specific combination of oral hypoglycemics.62 Given those limitations, deciding which drug to add to the regimen will depend on the basic principles of drug prescribing that were previously mentioned, e.g., cost, adverse effect profile, risks and benefits, and comorbidities.25
Example: Despite the use of metformin and lifestyle interventions, the HbA1c is not at the desired level. The patient has atherosclerotic cardiovascular disease (ASCVD) and normal renal function, an eGFR of 75 mL/minute. The GLP- 1 receptor agonists and the SGLT2 receptor inhibitors have been shown to reduce the risk for major CV events, and as the renal function is normal, an SGLT2 receptor inhibitor can be used, and either one of these drugs is appropriate for this situation.
If a second medication is required, clinicians can refer to guidelines published by the ADA.25 The guidelines are described in the following paragraphs, but they can be viewed online by linking to the journal site: American Diabetes Association. 9 Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes-2019. Diabetes Care. 2019;42(Suppl 1): S90-S102.
Bromocriptine, α-glucosidase inhibitors, colesevelam, and pramlintide are not mentioned in the ADA Standards of Care - Pharmacologic Approaches to Glycemic Treatment 25 and these drugs are not typically recommended for treatment of type 2 diabetes20 because they have limited efficacy and they have side effects that can be difficult to tolerate.63,64
If the patient has signs of catabolism, the HbA1c is > 10%, or the blood glucose is > 300 mg/dL, consider starting therapy with insulin.25 Metformin can be started along with insulin,7 and the patient has ketonuria but no weight loss a GLP-1 agonist or insulin can be used.7 Starting therapy with a sulfonylurea can be done, as well, if insulin therapy will be difficult for the patient.7
Short-term intensive insulin therapy initiated soon after diagnosis of type 2 diabetes has been shown to reverse beta-cell dysfunction, decrease insulin resistance, and preserve beta-cell function, and it can produce long-lasting hypoglycemic control and drug-free remission of the disease.65-69 There are considerable research and clinical experience that supports the effectiveness of this approach, but the difficulty in identifying patients that will benefit and the time and effort involved are barriers to its use,67,68,69 and it has not been widely used.17
Most patients who have type 2 diabetes will eventually fail to meet the target HbA1c level and attain glycemic control, and because damage to beta-cells is progressive, insulin therapy will eventually be needed.17 Insulin can prevent microvascular complications, and it can help the patient attain glycemic control,70 but as with any diabetic therapy, there are benefits and risks. Insulin therapy increases the risk for hypoglycemia, and because insulin resistance and associated hyperinsulinemia are part of the pathophysiology of type 2 diabetes, exogenous insulin increases insulin levels and may cause weight gain, hypoglycemia, increase the risk of developing metabolic syndrome, and worsen the level of insulin resistance.70
The barriers that prevent early and effective use of insulin and adherence to insulin therapy in patients who have type 2 diabetes are significant but certainly are not insurmountable. Key points for patient education should include:
Hypoglycemia is less common in patients who have type 2 diabetes than type 1 diabetes, but it is still a significant concern, particularly if the patient is taking a sulfonylurea and/or insulin or for elderly diabetic patients.71 Bromocriptine, α-glucosidase inhibitors, colesevelam, metformin, amylin agonists, DPP-IV inhibitors, GLP-1 agonists, SGLT2 receptor inhibitors, and the thiazolidinediones do not, by themselves cause hypoglycemia.53,62
Cardiovascular disease, nephropathy, and weight gain are common in patients who have diabetes, and these issues must be considered when using diabetic medications.
α-glucosidase inhibitors: Acarbose may reduce the risk of CV events, but the evidence for this effect is limited, conflicting, and inconclusive.72
Biguanides: Metformin can cause lactic acidosis, and because of this, current guidelines recommend that metformin not be used in patients who have unstable CHF, patients who have CHF and are hospitalized, or patients who have CHF and an eGFR of 30 ml/minute.25 Metformin can be used in patients who have stable CHF and an eGFR > 30 mL/minute or a serum creatine < 1.5 mg/dL and for these people, the risk of lactic acidosis is very low.73 There is evidence that for patients who have type 2 diabetes metformin may actually reduce the risk of developing CHF, reduce mortality from CHF, and improve the progression of the disease,74,75 but these conclusions have not been confirmed by large-scale research.74,75
For certain type 2 diabetic patients, e.g., those who are obese, who have established CAD, or who are taking insulin, metformin can decrease the risk for, and incidence of CV events like MI and stroke,57 and it may decrease mortality caused by diabetes, but the evidence for these benefits comes from two randomized, placebo-controlled studies, and several observational cohort studies.76
Colesevelam: Colesevelam can help reduce the risk of developing CAD.77
Dipeptidyl peptidase IV (DPP- IV) inhibitors: The SAVOR-TIMI 53 study clearly showed that for patients who have type 2 diabetes the use of saxagliptin significantly increased the risk for hospitalization because of heart failure,25,78-80 but the prescribing information for the other DPP-IV inhibitors simply states that these drugs should be used cautiously in patients who have heart failure or kidney failure. At this time, no causal mechanism of action linking DPP-IV inhibitors with heart failure has been identified, it is not clear if the risk for heart failure is specific to saxagliptin or it is a class effect shared by all the DPP-IV inhibitors, or the increased risk is likely only in patients who have CVD, heart failure, or kidney disease.78 A recent literature review and the ADA 2019 Standards of Care both concluded that alogliptin, linagliptin, and sitagliptin do not increase the risk for heart failure.80,81 (Note: Alogliptin is no longer manufactured)
The DDP-IV inhibitors have not been shown to have a negative effect on the development of ASCVD.78
GLP-1 receptor agonists: The GLP-1 receptor agonists are recommended by the ADA for patients who have type 2 diabetes and CVD25 and for patients whose HbA1c is not controlled by metformin or who cannot take metformin.25
Liraglutide has an FDA-approved use for reducing the risk of major CV events: death from CV, MI, and stroke.
Research has confirmed that liraglutide can reduce the risk for significant CV effects,80, 82-84 but this protective effect appears to vary between the GLP-receptor agonists.80,82,85 Semaglutide may reduce this risk 80,82,83 but extended release exenatide and lixisenatide do not appear to have this benefit,80,82,83 and although the ADA recommends using GLP-1 receptor agonists for patients who have type 2 diabetes and CVD, the 2019 Standards of Medical Care Pharmacologic - Approaches to Glycemic Treatment states that for this situation a GLP-1 receptor agonist with proven CVD benefit should be used: “Proven CVD benefit means it has a label indication of reducing CV events. For GLP-1RA evidence strongest for liraglutide > semaglutide > exenatide extended release.”25
There is no evidence that the GLP-1 receptor agonists increase the risk of developing heart failure or increase the risk of being hospitalized because of heart failure.80
SGLT2 receptor inhibitors: The SGLT2 receptor inhibitors are recommended by the ADA for patients who have type 2 diabetes and CVD,25 and canagliflozin and empagliflozin both have an FDA-approved use for reducing the risk of major CV events - death from CVD, MI, and stroke - in patients who have type 2 diabetes. Evidence from placebo-controlled trials of canagliflozin and empagliflozin clearly showed that both drugs significantly reduced death from CVD and reduced the incidence of MI and stroke.80,86,87 The ADA also recommends using canagliflozin or empagliflozin for patients whose HbA1c is not controlled by metformin or who cannot take metformin and who have CHF,25 and again, there is strong evidence that these SLGLT2 receptors reduce the risk of hospitalization from CHF80,81,88 and they may prevent the development of CHF, as well.80,88 The ADA 2019 Standards of Care - Pharmacologic Approaches to Glycemic Treatment states: “Both empagliflozin and canagliflozin have shown a reduction in HF in CVOTs (Cardiovascular outcomes trials).”25
Sulfonylureas: The second-generation sulfonylureas used in the United States, glimepiride, glipizide, and glyburide, do not appear to increase the risk for major CV events.89,90 Compared to metformin DPP-IV inhibitors, GLP-1 receptor agonists, and thiazolidinediones their risk for this is higher, but data on sulfonylureas and CV risk has been limited to small studies that were not specifically designed to study the CV safety of the sulfonylureas and direct, controlled trials of this issue have not been done.89,90
There is little information about the sulfonylureas and the risk for heart failure,91,92 and the data that is available cannot be used to determine their safety vis a vis heart failure. It is interesting to note that the ADA recommends that for patients who are taking metformin, who have not attained glycemic control, and who have CHF, the sulfonylureas are considered a second-line choice to be used if an SGLT2 receptor inhibitor or a GLP-1 agonist is not successful.25
Thiazolidinediones: Pioglitazone does not increase the risk of CV events or CVD disease-related death, and it may slow the progression of CVD.93,94 Research on rosiglitazone and an increased risk for CV events has been inconclusive.95 Both pioglitazone and rosiglitazone can increase the risk of developing heart failure, and the prescribing information for both drugs contains a US Boxed Warning stating that pioglitazone and rosiglitazone can cause or exacerbate CHF and that they should not be used for patients who have symptomatic heart failure or who have NYHA class III or IV heart failure.
Cardiac disease, but no symptoms and no limitations in ordinary physical activity, e.g., no shortness of breath when walking or climbing stairs
Mild symptoms (mild shortness of breath or angina) and slight limitation during ordinary activity
Marked limitation in activity due to symptoms, even during less-than-ordinary activity, e.g., walking short distances (20-100 m). Comfortable only at rest
Severe limitations. Experiences symptoms even while at rest. Mostly bedbound patients
Insulin: Insulin has not been associated with an increased risk for CV events or CHF.66,96
Amylinometic: Pramlintide has not been associated with an increased risk for major CV events.97
α-glucosidase inhibitors: Acarbose is not recommended if the serum creatinine is >2 mg/dL or the CrCl is <25 ml/minute/1.73 m2 because in patients who have significant renal impairment, the AUC can be increased 6-fold. The primary concern is that acarbose has been reported to cause liver injury (This will be discussed later) and impaired renal function might then further increase the risk of hepatic damage; a recent (2018) review did not support this.98
Miglitol is not recommended if the CrCl is <25 ml/minute/1.73 m2 because the drug is primarily renally excreted and because its use in this clinical situation has not been extensively studied.
Biguanides: The issue of impaired renal function and metformin was previously discussed.
DPP-IV Inhibitors: Alogliptin, saxagliptin, and sitagliptin are primarily excreted by the kidneys, and the dose should be decreased in patients who have impaired renal function. The clinical effects of the use of these drugs in patients with impaired renal function have not been well studied,99,100 and the prescribing information for alogliptin, saxagliptin and sitagliptin advise that they are used with caution in this patient population.
There is no need to adjust the dose of linagliptin in patients who have renal impairment.
The ADA recommends that for patients who are taking metformin, who have not attained glycemic control, and who have CKD, DPP-IV inhibitors are considered a second-line choice to be used if an SGLT2 receptor inhibitor or a GLP-1 agonist is not successful.25
GLP-1 receptor agonists: The prescribing information for the GLP-1 receptor agonists recommends using these drugs with caution if the patient has impaired renal function, particularly when starting therapy or increasing the dose, not using them if the patient has severe renal disease or ESRD, and notes that there are limited experience and limited information about the use of GLP-1 receptor agonists in the context of renal impairment. Seventy-eight cases of acute renal failure or renal insufficiency associated with the use of exenatide have been reported,82 but there is no recent (past 10 years) information about this issue.
Meglitinide analogs: Metabolism of nateglinide produces pharmacologically active metabolites. These metabolites are renally excreted, they can accumulate if the patient has renal impairment, and this may cause hypoglycemia.101
Nateglinide should be used cautiously and at a reduced dose for patients who have severe renal impairment and during initiation of therapy with the drug or when the dose is changed, and patients taking nateglinide should be closely monitored for hypoglycemia, particularly in those situations.
Repaglinide should be used cautiously and at a reduced dose in patients who have decreased renal function; the use of repaglinide in patients who have severe renal impairment (CrCl < 20 mL/minute) or who require hemodialysis has not been studied. During the initiation of therapy with repaglinide or when the dose is changed, the patient should be closely monitored for hypoglycemia.
Sulfonylureas: The sulfonylureas are not known to cause renal damage. Glimepiride and glipizide have a comparatively short duration of action and pharmacologically inactive metabolites, so these drugs are preferred for treating diabetic patients who have CKD;90,100 glyburide is not recommended in patients who have CKD.100 The dose of sulfonylureas should be decreased if the patient has ESRD.
SGLT2 inhibitors: Canagliflozin, empagliflozin, and dapagliflozin can significantly delay the onset and slow the progression of albuminuria, nephropathy, and ESRD, and reduce the risk of death from kidney disease in patients who have type 2 diabetes.102,103 These benefits (Noted during the CANVAS program study) were consistent in patients who had an eGFR of 30–45, 45–60, 60–90, and ≥90 mL/min/1.73 m2, and the ADA recommends that the SGLT2 inhibitors be used for patients who have not attained glycemic control with metformin and who have CKD and an adequate eGFR.25 In addition, several recent (2019) reviews concluded that the risk reduction for renal damage provided by the SGLT inhibitors may benefit patients with, and without CKD.102,103
However, the ADA’s recommendation seems to imply that these drugs should not be used in patients who do not have an adequate eGFR, and the prescribing information for canagliflozin empagliflozin and dapagliflozin advises that the dose should be reduced if the eGFR is below a certain point (different for each drug) or that use is contraindicated is the eGFR is below a certain point.
Based on data from 101 case reports the FDA did issue a warning noting acute renal failure had been observed in patients taking an SGLT inhibitor,104 and this warning is the likely source for the aforementioned cautions and the conflicting information about real impairment/diminished eGFR and the use of these drugs. But research done subsequent to that warning concluded that the SGLT2 inhibitors did not cause acute renal failure,105 and Alicic et al. (2019) wrote that “.. current recommendations to limit use of SGLT2 inhibitors by eGFR criteria may change once results of CREDENCE and other ongoing clinical trials with primary CKD outcomes are reported.”103
Nevertheless, the current prescribing information for the SGLT2 inhibitors recommends:
Sulfonylureas: The sulfonylureas are not known to cause renal damage. Glimepiride and glipizide have a comparatively short duration of action and pharmacologically inactive metabolites, so these drugs are preferred for treating diabetic patients who have CKD;90,100 glyburide is not recommended in patients who have CKD.100The dose of sulfonylureas should be decreased if the patient has ESRD.
Thiazolidinediones: Less than 1% of a dose of a thiazolidinedione is excreted by the kidneys, the presence of CKD does not increase the level of the drug or metabolites,100,106 and the prescribing information for pioglitazone and rosiglitazone does not recommend using lower doses or decreasing the dose in patients who have impaired renal function.106 However, edema and fluid retention can affect 3%-5% of patients taking a thiazolidinedione106 (somewhat higher in patients taking insulin), and fluid retention in the context of CKD is potentially problematic.
Insulin: Most of a dose of exogenous insulin is metabolized by the kidneys and insulins are excreted in the urine.107 Prescribing information for insulins does not provide specific dosing recommendations, but it does state that because of these pharmacokinetic issues the dose may need to be decreased in a patient who has impaired renal function.
Pramlintide: Pramlintide is primarily metabolized by the kidneys, and it is excreted by the urine. The prescribing information for Symlin notes that patients with moderate to severe renal impairment (CrCl > 20 mL/minute - ≤ 50 mL/minute) did not have an increase in exposure or excretion of the drug, but that Symlin had not been studied in patients who require hemodialysis.
Insulin, sulfonylureas, and thiazolidinediones can increase body weight;62,63 the other diabetic drugs may cause weight loss or have no effect on body weight.62,63
For patients who have not attained glycemic control with metformin and who do not have established ASCVD or CKD and for whom there is a compelling need to lose weight, the ADA recommends using a GLP-1 receptor agonist or an SGLT2 inhibitor.25
α-glucosidase inhibitors: The prescribing information for Precose states that elevated serum transaminases two to three times the upper normal limit have occurred in up to 14% of all patients taking the drug and that Precose is contraindicated in patients who have cirrhosis. Subsequent clinical experience has shown that the elevations of serum transaminases are less common (2%-3%), they are dose-related, and in almost every case the patients were asymptomatic, and within a short period of time, the transaminases elevations reversed and returned to normal.108 Serious liver injury like fulminant hepatitis has occurred during therapy with acarbose, but this is a rare adverse effect.108 Serum transaminase elevations caused by miglitol are no more common than in patients taking a placebo, and no cases of acute or chronic liver injury caused by/associated with miglitol have been reported.109
DPP-IV inhibitors: The DPP-IV inhibitors have been associated with arthralgia, bullous pemphigoid, and pancreatitis.78
SGLT2 inhibitors: The SGLT2 inhibitors have been associated with amputations, bone fractures, diabetic ketoacidosis, Fournier’s gangrene and genitourinary tract infections, and hypotension.104
A 47-year-old male with no significant PMH visits his primary care physician because he has been experiencing fatigue, dizziness, and lack of energy. These symptoms started approximately four months ago, initially intermittent and mild in nature but worsening in intensity and frequency the week prior to his visit. He cannot attribute their occurrence to any activity or time of day. He does report that his father had diabetes. The patient’s blood pressure is 162/88, and his weight is 118 kg, classifying him for his height as obese, and he smokes. His serum cholesterol is 280 mg/dL, he has elevated triglycerides, his fasting serum glucose is 225 mg/dL, and his HbA1C is 9.9%. There is no evidence on exam or by laboratory testing of retinopathy, nephropathy, or neuropathy. The physician tells the patient he has type 2 diabetes, advises lifestyle alterations (low-fat diet, exercise, smoking cessation, and weight loss) and prescribes metformin, 500mg PO, twice a day, and lisinopril, 20 mg, PO, once a day. The metformin dose is gradually increased to 850 mg PO, twice a day. The patient has some nausea and what he describes as “stomach upset” but after three weeks of taking metformin the gastrointestinal distress subsides. However, after three months of treatment, his fasting serum blood sugar is 189 mg/dL, and his HbA1C is 8.3%. Glipizide, 5mg PO, once a day is started. The patient rededicates himself to losing weight and exercising and three months later he has lost 12 kg. His fasting serum glucose is 140 mg/dL, and his HbA1C is 7.4%. The physician advises the patient that he has made good progress but that he needs to continue with the treatment regimen as there is a risk diabetes will worsen and that the onset of diabetic complications may have already begun.
A 58-year-old female with a PMH of type 2 diabetes and HTN is currently taking metformin, 1000 mg PO, twice a day, repaglinide 1 mg before each meal, and amlodipine. She visits her primary care physician to see the APRN for a checkup, and it is noted that her fasting serum glucose is 276 mg/dL, her HbA1C is 8.9%, her serum creatinine is 2.3 mg/dL, and her blood pressure is 172/88. Six months ago, her HbA1c had been 8.4%, and her fasting glucose was 234 mg/dL; six months prior to that her HbA1c had been 8.0%, and her fasting glucose had been 222 mg/dL. There is no evidence on physical exam or by laboratory studies that the patient has retinopathy or neuropathy. The patient has not lost weight, and she admits that she is not 100% compliant with her medication regimen. The APRN is concerned that after a year of therapy the patient has not reached her glycemic goals. He would like to prescribe insulin because he feels that the patient needs more aggressive lowering of blood glucose and HbA1c, but he is worried that her compliance with self-injecting insulin will be very poor. The APRN advises the patient that she has evidence of kidney damage and that she is at risk for other complications. He arranges a consultation with a Certified Diabetes Educator and adjusts the ant-hypertensive regimen. The Educator sets up several intensive information/education sessions with the patient. The patient quickly learns the techniques of self-injection, but she is very reluctant to use insulin as she feels “it is just too complicated for her.” The Educator arranges for frequent follow-up sessions that focus more on emotional support and encouragement than on technique. After three months of using basal and pre-prandial insulin, the patient’s HbA1c is 7.4%, and her fasting glucose is 151 mg/dL.
Glycemic control, prevention of diabetic complications, and slowing the progression of the disease requires the use of insulin for type 1 diabetics and a combination of oral anti-hyperglycemics and eventually, insulin for most patients who have type 2 diabetes. Patients who have diabetes almost without exception must take diabetic medications, and there is evidence that nurses’ knowledge of oral and injectable diabetic medications is often incomplete and insufficient.126,127 Key learning points for the safe use of the anti-hyperglycemics are: