Diabetic Medications (FL INITIAL Autonomous Practice - Pharmacology)

• Regular insulin
• Rapid-acting

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 significantly reduce the risk of developing diabetic nephropathy, neuropathy, retinopathy, and cardiovascular complications of diabetes (ADA, 2019). The basic goals/objectives and methods of intensive insulin therapy are (ADA, 2019):

• An HbA1c of < 7%
• A glucose level of 70-180 mg/dL
• Twice a day injection of an intermediate- or long-acting insulin to provide a basal level of insulin or an infusion pump delivering a continuous basal level of rapid-acting insulin
• Prandial insulin before each meal with a rapid-acting or short-acting insulin
• The use of insulin analogues is recommended

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, comorbidities, the duration of their disease, and other factors.

Animal-derived insulins are no longer used in the United States, and synthetic insulins, either recombinant human insulin or insulin analogs, are used exclusively, and the insulin analogs are the preparation of choice (ADA, 2019). The insulin analogues are preferred because:

1. The purpose of insulin therapy is to attain glycemic control without hypoglycemia and mimic the endogenous basal and postprandial insulin secretion (Misra & Mathieu, 2018).
2. The insulin analogs better replicate endogenous insulin secretion patterns than recombinant human insulin (Misra & Mathieu, 2018).
3. Insulin analogs have been genetically engineered to change absorption, distribution, metabolism, and excretion, and these changes can provide advantages in attaining glycemic control.
4. Two examples of the advantages of the pharmacokinetic profiles of the insulin analogues:
   1. Lispro insulin has a quicker onset of action and a longer duration of action than regular insulin, and these effects make it more useful than regular insulin for postprandial glucose control (Misra & Mathieu, 2018).
   2. The long-acting insulin analogs, in contrast, have a slower rate of absorption and a longer duration of action, and these pharmacokinetic properties have been shown to reduce the incidence of nocturnal hypoglycemia (Kristensen et al., 2017).

Continuous subcutaneous insulin infusion (CSII) uses an insulin pump to deliver a continuous basal insulin level of rapid-acting insulin, usually an insulin analog, and CSII can be used with self-injections of pre-prandial insulin (Weinstock, 2019). Continuous subcutaneous insulin infusion can be more effective than multiple insulin injections for attaining the optimal HbA1c and preventing hypoglycemia, but the level of glycemic control depends in part on the type of device that is used; the level of effectiveness can be modest but with pumps that have continuous glucose monitoring the level of glycemic control can be significant (Roze et al., 2019).

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 (Weinstock, 2019).

Most patients prefer insulin pens compared to syringes 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. The risk of hypoglycemia is less (Klonoff & Kerr, 2018). In 2017, the Food and Drug Administration (FDA) approved the first insulin pen 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, and for most patients checking HbA1c every three months or so is enough. 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 (ADA, 2019). 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 using 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. These advantages are especially strong for patients with frequent episodes of hypoglycemia or hypoglycemic unawareness (ADA, 2019). However, using a CGM does not mean that patients never need to check blood glucose (ADA, 2019).

The amount of insulin absorbed can vary significantly from patient to patient and from dose to dose, and there can be intra-patient variation in absorption. 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.

1. Intramuscular injection: Intramuscular injection of insulin causes rapid and irregular absorption (Powers & D'Alessio, 2018).
2. Needle size: Studies have shown that using needle sizes of 4 mm, 5 mm, 6 mm, or 8 mm did not significantly affect insulin absorption, and regardless of the patient's body mass index (BMI), there is no need to use a needle > 8 mm in length (Spollett et al., 2016).
3. Size of the dose: Increasing the amount of the dose slows absorption (Powers & D'Alessio, 2018).
4. Skin temperature and local blood flow: Higher skin temperature or increased local blood flow caused by exercise, massage, and high ambient skin temperature can increase insulin absorption (Powers & D'Alessio, 2018). Smoking decreases peripheral blood flow and can decrease insulin absorption (Powers & D'Alessio, 2018).
5. Injection site: Insulin can be injected in the abdominal wall, buttocks, upper arms, and upper legs, and the speed of insulin absorption differ between these sites: it is fastest in the abdominal wall, the slowest in the buttocks and legs, and in between those two areas for the upper arms (Mccullock, 2018). All of these areas can be used, but a planned rotation can help reduce day-to-day changes in blood glucose, it can reduce HbA1c and reduce the total daily insulin dose, and prevent lipoatrophy, lipohypertrophy, and subcutaneous scarring (Powers & D'Alessio, 2018). Lipohypertrophy occurs in approximately 50% of diabetic patients, and injecting insulin into a lipohypertrophic area can significantly reduce insulin absorption and cause erratic insulin absorption (Powers & D'Alessio, 2018).
6. Injection angle and technique: The injection angle should be 90° (Mccullock, 2018). Using or not using a lifted skin fold technique will depend on the length of the needle, and if the needle is at least 4 mm, lifting a fold of skin is not needed (Becton-Dickinson, 2019). When using an insulin pen, the needle should be left in place for 5-10 seconds to ensure the dose is delivered and to avoid insulin leaking from the injection site (Cryer & Davis, 2019).

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, and as many as one in five of these episodes is severe, severe, defined as the patient requiring assistance for administration of carbohydrates or glucagon. (Cryer & Davis, 2019).

Persistent episodes of hypoglycemia cause very serious consequences:

• Hypoglycemia increases the risk for morbidities like cardiovascular events and dementia (Lucidi et al., 2018).
• 6%-10% of patients with type 1 diabetes die from hypoglycemia (Cryer & Davis, 2019).
• Hypoglycemia itself, by initiating a process called hypoglycemia-associated autonomic failure (explained below), will increase the frequency and severity of hypoglycemic episodes (Cryer & Davis, 2019).

Hypoglycemia in type 1 diabetics is caused by intensive insulin therapy, but an absolute or relative excess of insulin is not the only cause of hypoglycemia in this patient population (Cryer & Davis, 2019). 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 (Cryer 2018b) 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, creating a vicious cycle of more frequent and more severe hypoglycemia. The latter phenomenon, called hypoglycemia unawareness, occurs in approximately 17%-50% of patients who have type 1 diabetes (Little et al., 2018).

Sub-optimal adherence to and compliance with a prescribed insulin regimen is common. 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 (Farsaei et al., 2014).

Pramlintide is the only drug other than insulin that has an FDA-approved use to treat 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 (Warnes, 2018). 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 (Warnes, 2018). However, 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.

Metformin is the drug of choice for starting treatment in patients who have type 2 diabetes, and there are many reasons why it is recommended as the first medication for newly diagnosed type 2 diabetics (McCulloch, 2018b):

• Considerable clinical experience with its use
• Metformin is very effective
• Inexpensive
• No risk of hypoglycemia when used as monotherapy
• No weight gain, possible weight loss, or at least weight stabilization
• Adverse effects are typically mild and diminish after several weeks of therapy
• Possible protective effect against CV events in certain patient populations
• Adverse effects from metformin that may cause serious harm - lactic acidosis and B12 deficiency causing anemia or neuropathy are rare

Metformin causes B12 deficiency and significantly lowers serum B12 concentrations (McCulloch, 2018b). The risk for these complications increases with dose and duration of metformin use, 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 (McCulloch, 2018b) Nonetheless, the ADA recommends that periodic measurement of B12 should be considered, particularly if the patient develops anemia or peripheral neuropathy.

Lactic acidosis is a rare complication of metformin use with an estimated incidence of 5 cases per 100,000 patient-years. However, it is clinically quite important because the fatality rate of metformin-induced lactic acidosis can be as high as 45% (McCulloch, 2018b). Metformin is metabolized by the liver, and the kidneys excrete it. Typically, patients who develop metformin-induced lactic acidosis have renal impairment, comorbidity that decreases renal perfusion or causes hypoperfusion and hypoxemia, or comorbidity that prevents lactate metabolism or increases the production of lactate (McCulloch, 2018b) These comorbidities include the 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 comorbidities as risk factors for metformin-induced lactic acidosis are still not clear (Trinkley et al., 2018).

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:

• Adverse profile of the medication, e.g., potential for hypoglycemia or weight gain
• Availability
• Benefits, e.g., the potential for the drug to reduce the risk for CV events or to promote weight loss
• Contraindications for use
• Cost
• Drug-drug interactions
• Patient preference
• The patient's comorbidities

Metformin is contraindicated if the patient has an eGFR of < 30 mL/minute; active or progressive liver disease; active abuse of alcohol; there is comorbidity like unstable CHF or an acute condition like sepsis that may cause hypoxemia or hypoperfusion; the patient had tried metformin before and developed lactic acidosis, or; the patient has acute or chronic metabolic acidosis, with or without coma, including diabetic ketoacidosis (McCulloch, 2018b).

If glycemic control is not attained after three months of treatment with metformin and lifestyle interventions, another drug should be added to the regimen (ADA, 2019).

There is little head-to-head research comparing the efficacy and long-term safety of the second-line and third-line diabetic medications. There is little research about the advantages/disadvantages of any specific combination of oral hypoglycemics (Garber et al., 2019). 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 (ADA, 2019).

Example: Despite 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 (ADA, 2019). The guidelines are described in the following paragraphs, but they can be viewed online by linking to the journal site: American Diabetes Association. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes-2019. Diabetes Care. 2019;42(Suppl 1): S90-S102.

1. The HbA1c is not at the desired level/no ASCVD or CKD: If metformin and lifestyle intervention do not lower the HbA1c and the patient does not have established ASCVD or chronic kidney disease (CKD), a second drug should be added to the regimen (ADA, 2019).
   1. In this situation, the ADA recommends using a GLP-1 agonist, a thiazolidinedione, an SGLT2 inhibitor, or a DPP-IV inhibitor; no preference for one over another is given (ADA, 2019). If adding one of these does not lower the HbA1c, add the other regimen, a GLPI-1 does not work, try an SGLT2 inhibitor or one of the other drugs, and if that is not successful, a sulfonylurea or basal insulin would be the next step (ADA, 2019).
2. The HbA1c is not at the desired level/the patient has ASCVD or CKD, or CHF: For patients who have ASCVD, prescribe an SGLT2 inhibitor that has been shown by a cardiovascular outcome trial to have a positive effect for reducing the risk for CV events or a GLP-1 receptor agonist that has a labeled use and a proven benefit for reducing the risk for CV events: liraglutide, semaglutide, or extended-release exenatide, or canagliflozin or empagliflozin (ADA, 2019). If this approach is not successful, or the patient cannot tolerate the GLP-1 agonist or the SGLT2 inhibitor, use the drug that was not prescribed, a DPP-IV inhibitor if the patient is not taking a GLP-1 agonist, a sulfonylurea, basal insulin, or a thiazolidinedione (ADA, 2019).
   1. For patients who have CKD or CHF, prescribe an SGLT2 inhibitor that has been shown through a cardiovascular outcome trial to reduce CHF or CKD if the eGFR is adequate; canagliflozin or empagliflozin (ADA, 2019). If the eGFR is not adequate, prescribe a GLP-1 agonist with a labeled use and a proven benefit for reducing risk CV events: liraglutide, semaglutide, or extended-release exenatide (ADA, 2019).
   2. If these approaches are not successful, do not use a thiazolidinedione if the patient has CHF. Use a GLP-1 agonist or an SGLT2 receptor inhibitor that has been shown through a cardiovascular outcome trial to reduce the risk for CV events: liraglutide, semaglutide, or exenatide, or canagliflozin or empagliflozin (ADA, 2019). Basal insulin or sulfonylurea can be used (ADA, 2019).
3. The HbA1c is not at the desired level, and the patient must lose weight: Prescribe an SGLT2 receptor inhibitor or a GLP-1 agonist that has been proven to promote weight loss; in descending order, the preference would be semaglutide, liraglutide, dulaglutide, exenatide, or lixisenatide (ADA, 2019).
   1. If this approach fails, try the other medication, i.e., if the patient was taking a GLP-1 agonist, use an SGLT2 receptor inhibitor, and if that is unsuccessful, metformin, an SGLT2 receptor inhibitor a GLP-1 agonist can be used together. If the HbA1c is still not lowered using a DPP-IV inhibitor (if the patient is not taking a GLP-1 agonist), and finally, try basal insulin, a sulfonylurea, or a thiazolidinedione (ADA, 2019).

Bromocriptine, α-glucosidase inhibitors, colesevelam, and pramlintide are not mentioned in the ADA Standards of Care - Pharmacologic Approaches to Glycemic Treatment, and these drugs are not typically recommended for treatment of type 2 diabetes because they have limited efficacy and side effects that can be difficult to tolerate (Garber et al., 2018).

If the patient has signs of catabolism, the HbA1c is > 10%, or the blood glucose is > 300 mg/dL, consider starting therapy with insulin (ADA, 2019). Metformin can be started along with insulin, and the patient has ketonuria but no weight loss. A GLP-1 agonist or insulin can be used (Wexler, 2018). Starting therapy with a sulfonylurea can be done, as well, if insulin therapy will be difficult for the patient (Wexler, 2018).

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. It can produce long-lasting hypoglycemic control and drug-free remission of the disease (Nunez et al., 2019). There are considerable research and clinical experience that support this approach's effectiveness, but the difficulty in identifying patients that will benefit and the time and effort involved are barriers to its use, and it has not been widely used (Wexler, 2019).

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 (Wexler, 2019). Insulin can prevent microvascular complications, and it can help the patient attain glycemic control, but as with any diabetic therapy, there are benefits and risks (Mishriky et al., 2018). 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. It may cause weight gain hypoglycemia, increase the risk of developing metabolic syndrome, and worsen the level of insulin resistance (Mishriky et al., 2018).

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:

• Fear of failure: Many people with diabetes see insulin as representing failure. A patient's inability to adhere to lifestyle changes indeed contributes to the progression of diabetes, but patients should be reminded that diabetes, in many cases for reasons that cannot be controlled, is a progressive disease.
• People with diabetes need insulin: All diabetics, to some degree, have a lack of insulin. Injecting is simply a way of providing the body with what it needs.
• Insulin has many benefits: Patients with type 2 diabetes who need insulin should be told that insulin provides benefits not available from oral antihyperglycemics. The primary benefit is a more effective way of controlling blood sugar, and this, in turn, reduces the risk of diabetic complications and can slow the progression of diabetic complications. Insulin is also more effective than oral anti-hyperglycemics at lowering HbA1c.
• Insulin therapy is not always permanent: Some patients may need insulin for only brief periods.
• Fear of pain: The needles used to inject insulin are very fine, and an injection into subcutaneous tissue is relatively less painful than intramuscular injections or other procedures that involve needles. Pain is subjective, but it is reasonable to say that an insulin injection's pain is brief and minor.
• Insulin therapy is not complicated: Insulin therapy can be complex, but most patients quickly learn that using insulin and monitoring blood sugar is simple with proper teaching. In addition, insulin therapy, in one sense, frees patients from concerns about future complications and provides more control of the disease.

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 or insulin or for elderly diabetic patients (Freeman, 2019). 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 (Cryer 2019b).

α-glucosidase inhibitors: Acarbose may reduce the risk of CV events, but the evidence for this effect is limited, conflicting, and inconclusive (Holman, 2018).

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 an eGFR of 30 ml/minute. Metformin can be used in patients with 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 (Nesto, 2019). There is evidence that for patients who have type 2 diabetes, metformin may reduce the risk of developing CHF, reduce mortality from CHF, and improve the progression of the disease, but these conclusions have not been confirmed by large-scale research (Dziubak et al., 2018).

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, 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 (McCulloch, 2018b)

Colesevelam: Colesevelam can help reduce the risk of developing CAD.

Dipeptidyl peptidase IV (DPP- IV) inhibitors: The SAVOR-TIMI study clearly showed that the use of saxagliptin for patients with type 2 diabetes significantly increased the risk for hospitalization heart failure (Cryer 2019b). However, the prescribing information for the other DPP-IV inhibitors 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 (Dugan et al., 2019). 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 (ADA, 2019b). (Note: Alogliptin is no longer manufactured)

The DDP-IV inhibitors have not been shown to harm the development of ASCVD (Dugan et al., 2019).

GLP-1 receptor agonists: The GLP-1 receptor agonists are recommended by the ADA for type 2 diabetes and CVD (ADA, 2019). Moreover, for patients whose HbA1c is not controlled by metformin or who cannot take metformin (ADA, 2019).

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, but this protective effect appears to vary between the GLP-receptor agonists (ADA, 2019b). Semaglutide may reduce this risk, but extended-release exenatide and lixisenatide do not appear to have this benefit (ADA, 2019b). 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 (ADA, 2019).

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 (ADA, 2019b).

SGLT2 receptor inhibitors: The SGLT2 receptor inhibitors are recommended by the ADA for patients who have type 2 diabetes and CVD, 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 (ADA, 2019). 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 (ADA, 2019b). 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, and again, there is strong evidence that these SLGLT2 receptors reduce the risk of hospitalization from CHF and they may prevent the development of CHF, as well (ADA, 2019b). 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).

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 (Powell et al., 2018). Compared to metformin DPP-IV inhibitors, GLP-1 receptor agonists, and thiazolidinediones, their risk for this is higher. However, data on sulfonylureas and CV risk have 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 (Powell et al., 2018).

There is little information about the sulfonylureas and the risk for heart failure, and the available data cannot be used to determine their safety vis a vis heart failure (Powell et al., 2018). It is interesting to note that the ADA recommends that for patients 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.

Thiazolidinediones: Pioglitazone does not increase the risk of CV events or CVD disease-related death, and it may slow the progression of CVD (DeFronzo et al., 2019). Research on rosiglitazone and its increased risk for CV events have been inconclusive (Asleh et al., 2018). 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.

Insulin: Insulin has not been associated with an increased risk for CV events or CHF (cheng, 2019).

Amylinometic: Pramlintide has not been associated with an increased risk for major CV events (Herrman et al., 2016).

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 (Chao et al., 2018).

Miglitol is not recommended if the CrCl is <25 ml/minute/1.73 m2 because the drug is primarily renal excreted, and 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, and the prescribing information for alogliptin, saxagliptin, and sitagliptin advise that they are used with caution in this patient population (Lo et al., 2018).

There is no need to adjust the linagliptin dose in patients with 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 (ADA, 2019).

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, but there is no recent (past 10 years) information about this issue (Dugan et al., 2019).

Meglitinide analogs: Metabolism of nateglinide produces pharmacologically active metabolites. These metabolites are renally excreted. They can accumulate if the patient has renal impairment, which may cause hypoglycemia.

Nateglinide should be used cautiously and at a reduced dose for patients with severe renal impairment and during therapy with the drug or when the dose is changed. 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 a 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; glyburide is not recommended in patients with CKD (Berns & Glickman, 2018). The dose of sulfonylureas should be decreased if the patient has ESRD (Mcculloch, 2018c).

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 (Woo et al., 2019). These benefits (Noted during the CANVAS program study) were consistent in patients who had an eGFR of 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 (Mcculloch, 2018c). In addition, several recent (2019) reviews concluded that the risk reduction for renal damage provided by the SGLT inhibitors might benefit patients with and without CKD (Woo et al., 2019).

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, and this warning is the likely source for the cautions mentioned above and the conflicting information about real impairment/diminished eGFR and the use of these drugs (DeSantis, 2019). However, research done after that warning concluded that the SGLT2 inhibitors did not cause acute renal failure. Alicic et al. (2019) wrote that current recommendations to limit the use of SGLT2 inhibitors by eGFR criteria might change once results of CREDENCE and other ongoing clinical trials with primary CKD outcomes are reported.

Nevertheless, the current prescribing information for the SGLT2 inhibitors recommends:

• Renal function should be measured before starting therapy and during therapy with canagliflozin, dapagliflozin, or empagliflozin.
• The dose of these drugs should be reduced, or they should not be used if the patient has a specific level of renal impairment as measured by eGFR.
• The presence of medical conditions or drugs that increase the risk of renal damage should be determined before initiation of therapy.
• If the patient has a medical condition or is taking a drug that increases the risk of renal damage, kidney function should be closely monitored.
• Therapy with the drug should be stopped if acute renal damage occurs.

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; glyburide is not recommended in patients with CKD (Berns & Glickman, 2018). The dose of sulfonylureas should be decreased if the patient has ESRD (Mcculloch, 2018c).

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, 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 (Berns & Glickman, 2018). However, edema and fluid retention can affect 3%-5% of patients taking a thiazolidinedione (Satirapoi et al., 2018). (somewhat higher in patients taking insulin), Moreover, 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 (Rajput et al., 2017). Prescribing information for insulins does not provide specific dosing recommendations, but it does state that the dose may need to be decreased in a patient with impaired renal function because of these pharmacokinetic issues.

Pramlintide: The kidneys primarily metabolize Pramlintide, and the urine excretes it. 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; the other diabetic drugs may cause weight loss or not affect body weight (Garber et al., 2019).

For patients who have not attained glycemic control with metformin and 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.