Diabetic Medications (FL INITIAL Autonomous Practice - Pharmacology)

Onset and duration of action, parenteral insulins (Masharani, 2023):

1. Rapid-acting: Onset of 0.25 to 0.5 hours and duration, 3 to 5 hours.
2. Short-acting: Onset of 0.25 to 5 hours and duration, 4 to 12 hours (Longer for certain preparations).
3. Intermediate-acting: Onset of 1 to 2 hours and duration, 14 to 24 hours.
4. Long-acting: Onset of 1 to 6 hours and duration, 6 to > 24 hours.
5. Combination products: Insulin combination products are a mixture of basal insulin and short-acting prandial insulin. Basal insulin is the level of endogenous insulin that is consistently in the blood to maintain blood sugar at normal levels during the day and sleep. Prandial insulin is the level of endogenous insulin that is secreted after a meal. The combination insulins provide an exogenous basal and prandial insulin in a single preparation. Some basal and prandial insulins can be mixed in the same syringe. Combination products are convenient for people who cannot do this (Masharani, 2023).

Afrezza® is a rapid-acting insulin, and it is used for post-prandial glucose control. Onset of action is ~ 12 minutes and the duration of action is 90 to 270 minutes, depending on the dose (Afrezza®, 2018).

Inhaled insulin appears to be less commonly used than parenteral insulin. Clinical studies have shown that it is safe. In fact, its adverse effect profile, compared to parenteral insulin, is good, and it provides good glucose control, fewer hypoglycemic shifts, and a more rapid onset and quicker return to baseline that rapid-acing insulin analogs (Heinemann & Parkin, 2018; Khan et al., 2022; Levin et al., 2021; McGill et al., 2020).

Insulin can be given subcutaneously (Sub-Q), intravenously (IV), or it can be inhaled (Afrezza®, 2018; Frid et al., 2016; Elsayed et al., 2023):

• Sub-Q is the recommended route of administration.
• Regular insulin and insulin aspart can be given IV.
• Inhaled insulin can be used for patients who have T1DM or T2DM and who do not have a chronic pulmonary disease like asthma or COPD or lung cancer.
• Insulin should not be given intramuscularly (IM).
• The rate of insulin absorption through a muscle is unpredictable (usually faster), and this causes poor and unpredictable glycemic control, and it increases the risk of hypoglycemia.
• Insulin cannot be given orally because it is broken down by proteolytic enzymes in the GI tract, and this significantly reduces its bioavailability.

Animal-derived insulins are no longer produced in the United States and synthetic insulins, either recombinant human insulin or insulin analogs, are used exclusively.

Recombinant human insulin is produced by recombinant DNA technology, and it is identical to exogenous insulin (Sugumar et al., 2022). The first recombinant insulin was manufactured in 1983, Humulin®, i.e., human insulin (Sugumar et al., 2022).

Analog insulins are also manufactured using recombinant DNA technology, but they are not identical to endogenous insulin. Analog insulins are modified by adding free fatty acid chains to the parent molecule or by changing the sequence of amino acids of the insulin (Misra & Mathieu, 2018). These alterations result in a different pharmacokinetic profile of the drug, mostly by changing the Sub-Q tissue absorption of insulin (Misra & Mathieu, 2018). Because the absorption is changed, the onset and duration of action are changed, the baseline and post-prandial insulin levels more closely resemble normal insulin secretion patterns, and this has several advantages (Misra & Mathieu, 2018; Grunberger, 2014; Robard & Robard, 2020). Example: The rapid-acting analog insulin, lispro, is faster than human insulin to reach the capillary bed (Misra & Mathieu, 2018). Because of this, the onset of action is quicker so the lispro can be taken closer to a meal (Misra & Mathieu, 2018).

Analog insulins are the recommended choice for treating DM (Kim et al., 2023; Robard & Robard, 2020). Human insulins have variable onsets of action and variable peak actions (Sugumar et al., 2022).

It is important to notice that the rapid-acting and the long-acting insulins are divided into categories. These categories refer to specific changes in the composition of the insulins, changes that differentiate them from human insulin and influence their pharmacokinetic profile. Example: Insulin is made of two polypeptide chains that are comprised of amino acid residues, and the aspart insulin Novolog is made by changing the normal sequence of aspartic acid (an amino acid that is involved in protein synthesis) at a specific position in one of those chains and replacing it with proline (Masharani, 2023; Sugumar et al., 2022).

Insulin is cleared by the liver (Najjar & Perdomo, 2019). Hepatic impairment can reduce insulin clearance and cause insulin resistance (Puri & Kotwal, 2023). This puts patients at risk for hypoglycemia, and patients who have hepatic impairment may need their insulin dose adjusted (Puri & Kotwal, 2023).

Many diabetic medications prevent blood glucose from becoming too high, but insulin, along with sulfonylureas and meglitinides, directly lowers blood glucose, and it can cause hypoglycemia.

Hypoglycemia is a relatively common adverse effect of an insulin therapy technique called intensive glycemic control (IGC) that was designed to maintain HgA1C within tight limits to prevent diabetic microvascular complications (ElSayed et al., 2023b; Fullerton et al., 2014). IGC does reduce the risk of these complications developing (ElSayed et al., 2023c).

Hypoglycemic episodes can be more than an inconvenience. The short-term and long-term consequences of hypoglycemia can be quite serious (Elsayed et al., 2023c). Hypoglycemic events are associated with an increased risk of cardiovascular events and cognitive dysfunction, especially if a patient has frequent events, and severe hypoglycemia can cause coma, seizures, and death (ElSayed et al., 2023c; O’ Connell et al., 2021). The use of real-time continuous glucose monitors that have hypoglycemia alarms has helped to reduce the risk of hypoglycemia and maintain blood glucose within narrow levels (O’Connell et al., 2021).

Insulin affects the Na+/K+ ATPase enzyme that maintains the normal intracellular concentration of potassium. This increases the intracellular potassium level and can cause hypokalemia. Hypokalemia usually happens when insulin is given intravenously (Rietjens et al., 2023).

Renal impairment and chronic kidney disease (CKD) can significantly change glucose and insulin metabolism (de Boer et al, 2022; Galindo et al., 2020). These pathologies also interfere with the accuracy of HgA1C measurement, and they increase the risk of hypoglycemia (de Boer et al., 2022; Galindo et al., 2020). Unfortunately, the prescribing information for insulins and professional associations/authoritative associations do not have specific dosing adjustment guidelines for patients who have CKD or renal impairment. Examples:

• The American Diabetes Association (ADA) and Kidney Disease: Improving Global Outcomes (KDIGO) recommends that if a patient’s eGFR is < 45 mL/min/1.73 m², dosing adjustments may be necessary. For patients who have renal impairment, initiate and titrate insulin conservatively in order to avoid hypoglycemia (de Boer et al., 2022).
• Regular Insulin: No specific dosage adjustments recommended in the manufacturer's labeling.
• Inhaled Insulin: Renal impairment effects on Afrezza® has not been studied. It may be necessary to employ frequent glucose monitoring for those with renal impairment. Dose adjustment should be done as frequently as needed as well (Afrezza®, 2018).
• Lantus: Kidney impairment effects on Lantus have not been studied. It may be necessary to employ frequent glucose monitoring for those with renal impairment. Dose adjustment should be done as frequently as needed as well (Lantus®, 2022).

Lipodystrophy is a fat tissue disorder and is a common adverse effect of insulin injections (Lombardo et al., 2022; Frid et al., 2016). There are two types of lipodystrophies caused by chronic insulin injections: lipohypertrophy and lipoatrophy (Frid et al., 2016; Lombardo et al., 2022).

Lipohypertrophy is an accumulation of fat tissue at injection sites, and lipoatrophy is characterized by a depression/indentation and shrinking of the tissue at injection sites (Frid et al., 2016; Lombardo et al., 2022).

Lipohypertrophy is much more common than lipoatrophy (Wang et al., 2021). A meta-analysis by Wang et al. (2021) found that in patients who were chronic insulin users the prevalence of lipohypertrophy was 41.8% and the longer the duration of use, the greater the risk. A study done by Lombardo et al. (2022) followed 212 T1DM patients for three months, and the prevalence of lipohypertrophy and lipoatrophy were 44.3% and 0.9%, respectively.

Lipohypertrophy can negatively affect the pharmacokinetics of insulin (Bochanen et al., 2022; Famulla et al., 2016; Lombardo et al., 2022; Peng et al., 2022). Lombardo et al. (2022) indicated that the patients who had lipohypertrophy demonstrated a decent difference in glycemic parameters when compared to individuals without lipohypertrophy. Famulla et al. (2016) found that insulin injected into lipohypertrophic tissue reduced insulin absorption and resulted in a postprandial blood glucose level that was ≥ 26% higher than when insulin was injected into normal adipose.

Pramlintide, trade name Symlin®, is the only amylinomimetic that is available in the United States.

Symlin is given by Sub-Q injection. It is given immediately before a major meal.

The manufacturer’s prescribing information states that there are no recommended dosing adjustments of Symlin® for patients who have hepatic impairment and that this clinical issue has not been studied (Symlin®, 2020).

The manufacturer’s prescribing information states that there are no recommended dosing adjustments of Symlin® for patients who have renal impairment, mild to severe, Clcr 15-29 mL/min (Symlin,® 2020). The use of Symlin® for patients who have end-stage renal disease has not been studied (Symlin,® 2020).

Pramlintide is an injectable antidiabetic medication that is categorized as an amylinomimetic, and it is a synthetic analog of amylin. Amylin, also known as isle amyloid polypeptide, is a peptide hormone that is produced in the beta-cells of the pancreas, and it is co-secreted with insulin in response to glucose (Boyle et al., 2022; Katzung et al., 2019; Timmons et al., 2022).

Amylin decreases post-prandial glucose by (Timmons et al., 2022):

1. Suppressing the release of glucagon
2. Reducing hepatic glucose production
3. Delaying gastric emptying
4. Increasing post-prandial satiety

Pramlintide reduces post-prandial blood sugar levels in three ways:

1. Prolongation of gastric emptying
2. Reducing post-prandial glucagon secretion
3. Reducing food intake by way of appetite suppression

Amylin secretion is reduced in patients who have T1DM and T2DM (Boyle et al, 2022; Timmons et al., 2022). Pramlintide has a labeled use as an adjunctive treatment for patients who have T1DM or T2DM who use meal-time insulin but who do not have good glycemic control (Symlin®, 2020).

Pramlintide is contraindicated if a patient has hypoglycemia unawareness, and/or gastroparesis (Symlin®, 2020).

Pramlintide and insulin are typically given together, immediately before a major meal, and current use of Symlin and insulin can cause severe hypoglycemia (Kleppinger & Vivian, 2003; Ryan et al., 2005; Symlin®, 2020). This typically happens two to three hours after Symlin is injected (Symlin®, 2020). This adverse effect can occur in patients who have T1DM or T2DM, but it is more likely to occur in type 1 diabetics (Symlin®, 2020; Kleppinger & Vivian, 2003; Ryan et al., 2005).

Pramlintide itself does not cause hypoglycemia, but because Symlin® and insulin taken together can cause severe hypoglycemia and pramlintide inhibits glucagon release, Symlin should not be prescribed for patients who have hypoglycemia unawareness (Symlin®, 2020).

The prescribing information for Symlin® recommends:

1. Frequent monitoring of blood glucose
2. Decreasing the mealtime insulin dose by 50% during the initial stages of treatment 

Note: Glucagon is a hormone that is produced in the pancreas. Glucagon increases blood sugar by stimulating/increasing hepatic glycogenolysis (breakdown of glycogen to glucose) and gluconeogenesis (formation of glucose from non-carbohydrates) (Katzung et al., 2019; Powers et al.,2022c). This process requires a sufficient store of hepatic glycogen in order to occur.

One concern is the issue of hypoglycemia, which has already been discussed.

Gastroparesis is a disease characterized by signs and symptoms of a gastric obstruction like abdominal distention, bloating, nausea, vomiting, and abnormal gastric emptying in the absence of mechanical obstruction (Jalleh et al., 2022; Papdakis & McPhee, 2023).

Diabetes itself can cause gastroparesis, and many diabetic patients have disordered gastric emptying (Jalleh et al., 2022; Papadakis & McPhee, 2023). Pramlintide slows gastric emptying, so it should not be prescribed for patients who have gastroparesis (Symlin®, 2020).

Pramlintide and insulin should not be mixed in the same syringe as this can change the pharmacokinetics of both drugs (Symlin®, 2020).

Pramlintide slows gastric emptying and if the effectiveness of an oral medication depends on the rapid onset of action, these drugs should be taken one hour before or two hours after a pramlintide injection (Symlin,®, 2020).

Adverse effects: ≥ 5% of patients experience anorexia, headache, nausea, and vomiting (Symlin®, 2020).

Glucagon-like peptide-1 (GLP-1) receptor agonists are primarily injectables. There is one oral preparation. The GLP-1 receptor agonists that are currently available in the United States are listed below in Table 2.

The parenteral GLP-1 receptor agonists should be injected subcutaneously, not IM or IV. They should not be mixed in the same syringe with insulin or other medications. Some of the GLP-1-receptor agonists are taken once a week, and some are immediate-release formulations and are taken every day.

Some but not all the GLP-1 receptor agonists have a recommendation in their prescribing information to either use the drug cautiously or do not use it if a patient has renal impairment and an eGFR below a specific level. Check the prescribing information for each drug before giving it. Use these medications cautiously in patients who have renal impairment and in patients who have risk factors for renal damage.

Glucagon-like peptide-1 (GLP-1) is an incretin hormone that is secreted by the α cells of the pancreas, the colon, and the distal ileum (Chen et al., 2022). The incretin hormones GLP-1 and glucose-dependent insulinotropic polypeptide (GIP, which will be discussed later) stimulate insulin release in response to blood glucose after a meal. They also reduce the release of glucagon. The GLP-1 receptor agonists are analogs of the GLP-1 hormone, and they regulate blood sugar by (Chen et al., 2022; Katzung et al, 2019):

1. Delaying gastric emptying
2. Increasing satiety and reducing appetite
3. Reducing the release of glucagon
4. Promoting glucose-stimulated insulin release

People who have T2DM have a diminished level of incretin hormone activity, and the GLP-1 receptor agonists have a labeled use as a treatment for children ≥ 10 years old and adults who have T2DM as an adjunct to lifestyle changes to improve glycemic control (Karagiannis et al., 2022). The GLP-1 receptor agonists are typically used as a second-line drug, after metformin (Zhao et al., 2021).

In addition, the GLP-1 receptor agonists are recommended for diabetic patients who have cardiovascular disease (CVD) or who have risk factors for CVD (ElSayed, 2023b). The GLP-1 receptor agonists have been shown to reduce the risk for/incidence of serious CVD events like myocardial infarction, and they may help reduce the risk of renal diabetic complications (ElSayed et al., 2023b; Li et al, 2021; Viljoen & Bain, 2023).

The 2023 American Diabetes Association (ADA) Standards of Care noted that a sodium–glucose cotransporter 2 inhibitor and/or glucagon-like peptide 1 receptor agonist with established cardiovascular disease benefit is recommended as part of the glucose-lowering regimen and comprehensive cardiovascular risk reduction for T2DM patients who have either of the following (ElSayed et al., 2023b):

• Established atherosclerotic cardiovascular disease (CVD)
• Indicators of high cardiovascular risk
• Established kidney disease
• Established heart failure (HF)

Use of a GLP-1 receptor agonist is contraindicated if a patient has a family history or a personal history of medullary thyroid cancer or if a patient has multiple endocrine neoplasia syndrome type 2. (See the US Boxed Warning and Warning/precautions sections for additional information).

The use of Byetta® (Exenatide) is contraindicated in patients who have a history of drug-induced immune-mediated thrombocytopenia caused by an exenatide product (Byetta, 2022). Serious, sometimes fatal, bleeding, from drug-induced immune-mediated thrombocytopenia, has occurred with exenatide use (Byetta®, 2022). This is not a contraindication mentioned in the prescribing information of the other GLP-1 receptor agonists.

The prescribing information for the GLP-1 receptor agonists states that the use of GLP-receptor agonists caused thyroid C-cell tumors in animals. The relevance of these studies, vis a vis the use of these drugs in humans, has not been determined, and it is not known if these drugs cause thyroid cancer in humans, but GLP-receptor agonists are contraindicated if a patient has a family history or a personal history of medullary thyroid cancer or if a patient has a history of multiple endocrine neoplasia syndrome type 2.

The GLP-1 receptor agonists (GLP-1 RAs) may or may not increase the risk of developing thyroid malignancy (Bezin et al., 2023; Frias et al., 2019). Thompson and Stürmer (2023) discovered that diabetes itself increases the risk (20% to 30%) for thyroid cancer, and GLP-1 RAs may cause a small increase in thyroid cancer risk.

Multiple endocrine neoplasia type 2 is a very rare inherited cancer. The GLP-1 receptor agonists’ prescribing information state that these drugs are contraindicated if a patient has this malignancy, but no more information is provided. No published information on the GLP-1 receptor agonists and this malignancy was located.

Acute gallbladder disease: The prescribing information for GLP-1 receptor agonists warns that these drugs have been associated with acute gallbladder disease, e.g., cholelithiasis and cholecystitis. A systematic review and meta-analysis of randomized controlled trials and an examination of cases from the US Food & Drug Administration’s (FDA) adverse effect reporting system confirms this risk (He et al., 2022; Woronow et al., 2022). Specifically, He et al. (2022) found that using GLP-1 RAs increased risk of gallbladder or biliary diseases, especially when used:

• At higher doses
• For longer durations
• For weight loss

Acute kidney injury: The GLP-1 receptor agonists have been associated with acute kidney injury (AKI) and exacerbation of chronic renal failure (Dong & Sun, 2022; Seo, 2021). Most, but not all cases occurred in patients who had a risk factor for AKI like dehydration, diarrhea, nausea, and vomiting, the latter two being common adverse effects of these drugs (Dong & Sun, 2022; Yeo, 2021). Renal function should be monitored, especially if patients have a risk for factors for AKI or diabetic nephropathy (Dong & Sun, 2022; Yeo, 2021).

Diabetic retinopathy: The prescribing information for dulaglutide and semaglutide warns that these drugs have been associated with a risk of increasing diabetic retinopathy (DR) complications (Albert et al., 2023; Ozempic®, 2022; Trulicity.® (2022). The GLP-1 receptor agonists may have a direct effect on the retina, and a rapid improvement in glycemic control may cause a worsening of DR (Ozempic, 2022; Yoshida et al., 2022). Several recently published studies concluded that the cardio-protective GLP-1 receptor agonists, dulaglutide and semaglutide, are associated with a risk of exacerbation/worsening of DR (Albert et al., 2023; Yoshida et al., 2022). An ophthalmologist should be consulted before treatment with a GLP-1 receptor agonist is started (Albert et al., 2023).

Hypoglycemia: The GLP-1 receptor agonists do not, by themselves, cause hypoglycemia because these drugs stimulate insulin release in response to the blood glucose level (Powers et al, 2022c). However, the prescribing information of the GLP-1 receptor agonists warns that concurrent use of insulin or a sulfonylurea and a GLP-1 receptor agonist can cause hypoglycemia, and decreasing the dose of the insulin or the sulfonylurea should be considered (Li et al., 2021; Gallwitz, 2022). George et al. (2022) and Meyer et al. (2023) found that adding a GLP-1 receptor agonist to a patient’s medication regimen reduced the patient’s insulin requirements.

Pancreatitis: The prescribing information of the GLP-receptor agonists warns that during clinical trials, some patients developed pancreatitis. There is some evidence (albeit inconsistent) that incretin analogs cause a low-grade pancreatic inflammation (Suryadevara et al., 2022). Suryadevara et al. (2022) discussed that although there was some evidence, the RCTs did not distinguish pancreatic adverse events between the control patients and those receiving incretin. During therapy with a GLP-1 receptor agonist, it is prudent, and recommended, to monitor patients for signs and symptoms of pancreatitis.

Severe Gastrointestinal Disease: The GLP-1 receptor agonists can cause delayed gastric emptying. In addition, these drugs should not be used in patients who have gastroparesis or severe gastrointestinal disease (Preda et al., 2023).

Diarrhea, nausea, and vomiting are the most common adverse effects of the GLP-1 receptor agonists (Katzung et al., 2019; Viljoen & Bain, 2023). Nausea occurs in one in five patients, and diarrhea and vomiting in one in 10 patients (Viljoen & Bain, 2023).

There is one GIP/GLP-1 receptor agonist available, tirzepatide, trade name Mounjaro™.

Tirzepatide is given as an Sub-Q injection, a single injection every four weeks.

There are no dosing adjustments of Mounjaro™ required for a patient who has hepatic or renal impairment (Mounjaro™, 2022).

Tirzepatide is a GIP/GLP-1 receptor agonist. Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone, and it has metabolic and glucose-lowering effects that are like GLP-1. The mechanisms of action of tirzepatide are listed below (Bradley et al, 2022;  Naseralallah & Aboujabal, 2023):

1. Insulin secretion and release in response to blood glucose after a meal.
2. GLP-1 decreases glucagon secretion and GIP increases glucagon secretion.
3. Delayed gastric emptying.
4. Stimulation of GIP and GLP-1 receptors has an additive effect in terms of decreasing appetite, which often, in turn, decreases food intake.

Tirzepatide is used as a second-line antidiabetic drug for patients who have T2DM, as an adjunct to diet and exercise to improve glycemic control (Mounjaro™, 2022; Naseralallah & Aboujabal, 2023).

Tirzepatide causes thyroid C-cell tumors in rats. It is unknown whether Mounjaro™ causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as the human relevance of tirzepatide-induced rodent thyroid C-cell tumors has not been determined.

Mounjaro™ is contraindicated in patients with a personal or family history of MTC or patients with multiple endocrine neoplasia syndrome type 2 (MEN 2) (Mounjaro™, 2022). Counsel patients regarding the potential risk of MTC and symptoms of thyroid tumors.

Tirzepatide is contraindicated if a patient has a family history of a personal history of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia syndrome type 2 (Mounjaro™, 2022).

The Mounjaro™ package insert states that tirzepatide has caused thyroid C-cell tumors in animals. The relevance of these studies, vis a vis the use of these drugs in humans, has not been determined, and it is not known if these drugs cause thyroid cancer in humans (Mounjaro™, 2022).

Multiple endocrine neoplasia type 2 is a very rare inherited cancer. The Mounjaro™ package insert states that tirzepatide is contraindicated if a patient has this malignancy, but no more information is provided. No published information on tirzepatide and this malignancy was located.

Acute kidney injury: Diarrhea, nausea, and vomiting are very common adverse effects of tirzepatide (Mishra et al., 2023; Naseralallah & Aboujabal, 2023). Cases of acute kidney injury and worsening of chronic renal failure have been reported. Most of these occurred in patients who had developed diarrhea, nausea, vomiting, and dehydration (Mounjaro™, 2022).

Diabetic retinopathy: Cases of diabetic retinopathy did occur during clinical trials of tirzepatide, but there were very few (< 0.2 of the patients) (Naseralallah & Aboujabal, 2023). The Mounjaro™ prescribing information notes that rapid improvement in glycemic control has been associated with a temporary worsening of diabetic retinopathy. This adverse effect was noted in the Diabetes and Complications Control Trial (DCCT) study (Ting et al., 2016). However, this study did not include tirzepatide.

Gallbladder disease: Gallbladder disease occurred during clinical trials of tirzepatide, but the number of cases of cholecystitis, cholelithiasis, and hepatic steatosis was < 1.0% and the number of cases was often no more than what occurred in patients treated with a placebo (Mishra et al., 2023; Naseralallah & Aboujabal, 2023; Mounjaro™, 2022).

Heart rate: The GI receptors have a direct effect on the cardiovascular system, and during the SURPASS 1 to SURPASS 5 clinical trials of tirzepatide, 4.6% to 10% of the patients had sinus tachycardia (heart rate of ≥ 15 beats above baseline) compared to 4.3% of the patients who were given a placebo (Gallwitz, 2022; Mori et al., 2020). The clinical significance of this is not known (Mounjaro™, 2022).

Hypoglycemia: Tirzepatide by itself does not cause hypoglycemia. However, concurrent use of tirzepatide and insulin or an insulin secretagogue like a sulfonylurea may increase the risk of hypoglycemia and severe hypoglycemia, and the insulin/secretagogue dose may need to be reduced (Bradley et al., 2022; Mounjaro™, 2022). Hypoglycemia was noted as an adverse effect during the clinical trials of tirzepatide, but it was an uncommon adverse effect, it was seldom clinically significant, and there were only a few cases of severe hypoglycemia that required treatment (Karagiannis et al., 2022; Mishra et al., 2023).

Pancreatitis: Cases of pancreatitis and elevated lipase levels have been associated with the use of tirzepatide (Mishara et al., 2023; Mounjaro™, 2022; Naseralallah & Aboujabal, 2023). Patients should be monitored for signs and symptoms of pancreatitis.

Severe Gastrointestinal Disease: Tirzepatide can cause GI adverse effects, and it delays gastric emptying. The prescribing information for Mounjaro™ recommends that it should not be used in patients who have severe GI disease, including gastroparesis.

Acarbose is the alpha-glucosidase inhibitor (α-glucosidase inhibitor) that is available. It is available in generic form, 25 mg and 50 mg tablets. Brand name formulations of acarbose were discontinued.

Acarbose is given three times a day, the maximum daily dose is 300 mg.

The α-glucosidase inhibitors help control blood glucose by delaying glucose absorption in the gut and decreasing post-prandial hyperglycemia (Chiasson et al., 2002).

Adult patients who have T2DM, as an adjunctive treatment, along with diet and exercise, to improve glycemic control.

The α-glucosidase inhibitors are not included in the ADA’s 2023 Standards of Care list of glucose-lowering medications used for patients who have T2DM (ElSayed et al., 2023b). In the 2023 Standards, section 3 “Prevention or Delay of Type 2 Diabetes and Associated Comorbidities”, it is mentioned that there is evidence that α-glucosidase inhibitors can lower the incidence of diabetes within specific populations (Chiasson et al., 2002; Gerstein et al., 2020; Holman et al., 2017; Moelands et al., 2018; Elsayed et al., 2023d).

Acarbose is contraindicated if a patient has any of the following conditions (Chiasson et al, 2002; Gerstein et al., 2020):

• Cirrhosis (see the Warnings & Precautions section)
• A chronic GI disease associated with disorders of absorption or digestion
• Colonic ulceration
• Diabetic ketoacidosis
• Inflammatory bowel disease
• Partial intestinal obstruction
• A predisposition to intestinal obstruction
• A condition that would deteriorate if the patient had increased gas formation

Elevated serum transaminases: If a patient has hepatic impairment, use acarbose cautiously and if the patient’s serum transaminases become elevated, reduce the dose, or stop the use of the drug. Acarbose can cause transaminase elevations > 3 times the upper limit of normal, but this adverse effect is dose-related, it typically resolves without treatment, no liver injury occurs, and patients are not symptomatic (Liver Tox, 2021). However, cases of fulminant, acute, hepatitis-like liver injury have been associated with acarbose, and fatalities have been reported. This is a rare occurrence (LiverTox, 2021).

Hypoglycemia: Concurrent use of acarbose and insulin, metformin, or sulfonylurea may cause hypoglycemia (Gerstein et al., 2020). Consider reducing the dose of the other drugs.

Renal impairment: Acarbose is not recommended for patients who have significant renal impairment (serum creatinine > 2 mg/dl or CrCl < 25 mL/minute/1.73m²).

The 2023 ADA Standards of Care/Chronic Kidney Disease and Risk Management does not mention the α-glucosidase inhibitors (ElSayed et al., 2023d).

Hahr et al. (2022) indicated that when glomerular filtration rate (GFR) is reduced, the serum level of acarbose and its metabolites are significantly elevated, and the authors recommend that acarbose not be given to patients who have a GFR < 26/mL/minute/1.73m².

Dietary issues: A diet that is high in sucrose can cause GI side effects like bloating, diarrhea, flatulence, and loose stools. These GI problems are common side effects of acarbose, and sucrose may worsen them.

Abdominal pain, diarrhea, and flatulence are common adverse effects of acarbose, and GI complaints could exacerbate the conditions listed above.

Metformin is the only biguanide that is available in the United States.

Metformin is available as immediate-release (IR) oral tablets and extended-release (XR) tablets. It is also available as an oral solution and suspension.

Combination products are also available:

1. Metformin and a sulfonylurea (glipizide)
2. Metformin and a thiazolidinedione (pioglitazone)
3. Metformin and an SGLT2 inhibitor (dapagliflozin)

Metformin XR is slowly absorbed, it produces a therapeutic level of the drug over a 12 to 24-hour period, and this means that metformin XR needs only to be taken once per day (Akram, 2021).

Lactate is metabolized in the liver, hepatic impairment can cause an accumulation of lactate, and metformin itself, in some situations, can increase serum lactate (Chidiac et al., 2022). It is recommended to decrease the metformin dose for patients who have documented hepatic impairment, if hepatic impairment occurs, or if the patient develops metformin-induced liver damage. Metformin-induced liver damage has been reported, but, fortunately, it is a rare occurrence (LiverTox, 2020).

Metformin is excreted in the urine, renal impairment is a risk factor for serious complications (See the sections, US Boxed Warning and Warnings & Precautions), and metformin should not be used if a patient’s eGFR is < 30 mL/minute/1.73 m².

Metformin maintains glycemic control and lowers basal and post-prandial glucose by (Akram, 2021; Katzung et al., 2019):

• Improving insulin sensitivity
• Decreasing intestinal absorption of glucose
• Decreasing hepatic glucose production

Metformin does not cause hypoglycemia (Katzung, 2019). Hypoglycemia associated with metformin has occurred, but these cases involved an overdose of the drug, drug-drug interactions, fasting, the presence of lactic acidosis, sustained physical exercise, and other specific, contributing causes (Akram, 2021; Al-Abri et al., 2013; Aldobeaban et al., 2018; DiMauro et al., 2022; Juneja et al., 2022).

Metformin is used to treat patients who have T2DM and who cannot control their blood sugar with diet and exercise alone. Metformin is typically the first medication used to treat T2DM (Di Mauro et al., 2022; ElSayed et al, 2023b). The 2023 ADA Standards, Pharmacologic Approaches to Glycemic Treatment states that metformin is safe and effective as well as inexpensive (ElSayed et al, 2023b). In addition, it may reduce risk of cardiovascular events and death (ElSayed et al, 2023b). Compared with sulfonylureas, metformin, when used as first-line therapy, has had beneficial effects on a patient’s HgA1C, weight, and cardiovascular mortality (ElSayed et al, 2023b).

Contraindications for metformin include severe renal dysfunction (eGFR < 30 mL/minute/1.73 m²), acute or chronic metabolic acidosis with/without coma, and diabetic ketoacidosis.

Metformin is cleared by renal filtration and excreted in the urine, approximately 90% of the drug is eliminated by the kidneys, and the use of metformin in patients who have severe kidney disease can cause metformin-associated lactic acidosis, aka MALA (ElSayed et al, 2023b; Hai et al., 2022; Katzung et al., 2019; Rahman & Tuba, 2022; Thammavaranucupt et al., 2022; DiMauro et al., 2022). The risk of developing MALA is the rationale for these contraindications.

Metformin can cause lactic acidosis with blood lactate levels > 5 mmol/L, and MALA can cause resistant bradyarrhythmias, hypotension, hypothermia, and death. The onset of MALA is subtle, and the signs and symptoms are non-specific. Factors that increase the risk of developing MALA include (ElSayed et al, 2023b; Hai et al., 2022; Katzung et al., 2019; Rahman & Tuba, 2022; Thammavaranucupt et al., 2022; DiMauro et al., 2022):

• Age ≥ 65 years
• Alcohol abuse
• An acute hypoxic state like CHF
• Concurrent use of certain drugs
• Hepatic impairment
• Renal impairment
• Surgery
• Undergoing a radiological study that uses contrast media

Metformin-associated lactic acidosis is a rare complication of metformin but is a potentially deadly pathology with a mortality rate of up to 50% (Thammavaranucupt et al., 2022; DiMauro et al., 2022; ElSayed et al., 2023b).

Metformin-associated lactic acidosis, or MALA, is defined as (Chidiac et al., 2022; Rahman & Tuba, 2022):

• Arterial pH < 7.35
• Serum lactate level > 5 mmol/L
• Exposure to metformin  

The signs and symptoms of MALA are non-specific and include (but are not limited to) (Chidiac et al., 2022; DiMauro et al., 2022):

• Agitation
• Coma
• Confusion
• Hypotension
• Lethargy
• Metabolic acidosis
• Seizures
• Tachycardia

Factors that increase the risk of developing MALA include the following (Chidiac et al., 2022; DiMauro et al., 2022; Katzung et al., 2019, Kuno et al., 2023; Lewis et al., 2015; Rahman & Tuba, 2022; Thammavaranucupt et al., 2022; Hai et al., 2022; Juneja et al., 2022; Katzung et al., 2019; Rai et al., 2020).

• A high blood level of metformin: A high blood metformin level increases the cellular production of lactate. This can occur after an acute overdose or when there is a condition that decreases the excretion of metformin.
• Hepatic impairment/renal impairment: Hepatic impairment decreases the metabolism of lactate, potentially causing an accumulation of lactate and increasing the risk of developing MALA. Alcohol abuse and hepatic impairment are risk factors for MALA.
• Renal impairment: Renal impairment decreases the excretion of metformin, and it is an important risk factor for MALA. It is important to remember that MALA can develop in patients who have acute renal impairment caused by dehydration, diarrhea, and/or vomiting.
• Tissue hypoxia: Any condition that causes tissue hypoxia and can cause anaerobic glycolysis can increase the serum lactate level and increase the risk of developing MALA, including (but not limited to) acute myocardial infarction, a chronic lung disease with hypoxia, CHF, dehydration, diabetic ketoacidosis, heart disease, sepsis, shock, and recent surgery.

Bariatric surgery: The absorption of XR metformin tablets may be decreased in patients who have had gastric bypass surgery or sleeve gastrectomy, and in these situations, it has been advised to use IR tablets. Also, decreased absorption could be problematic if a patient has impaired renal function. The most current information on this topic is from 2018. Deden et al. (2018) measured plasma lactate levels in patients taking or not taking metformin who had Roux-en-Y gastric bypass surgery (Deden et al., 2018). The levels were done before and after the surgery, and the authors concluded that if a normal renal function was preserved, there was no need to decrease the metformin dose after an uncomplicated Roux-en-Y procedure (Deden et al., 2018).

The ADA Standards of Care 2023 advises that metformin should not be given on the day of a surgical procedure (ElSayed et al., 2023e).

Iodinated contrast: Iodinated contrast can cause acute kidney injury (AKI). The metformin package inserts states that it should be withheld for patients undergoing any radiological study in which intravenous iodinated contrast media is being utilized because of the risk of resulting acute kidney injury that would lead to a buildup of metformin, and ultimately a clinical result of lactic acid accumulation (ACR, 2023).

The American College of Radiology Committee on Drugs and Contrast Media 2023 Manual of Contrast Media includes guidelines for the management of patients taking metformin (ElSayed et al., 2023e):

1. Those taking metformin are not at higher risk for post-contrast acute kidney injury (AKI) when compared to other patients not taking metformin.
2. A potential concern for furthering renal damage in patients with AKI, stage 4 severe chronic kidney disease (CKD), or stage 5 severe CKD.
3. In patients who have been properly selected to receive metformin administration, there have been no reports of lactic acidosis following intravenous iodinated contrast medium administration.
4. The ACR Committee recommends that patients taking metformin are classified into one of two categories based on the patient’s renal function (as measured by eGFR):
   1. Category I: In those with no evidence of AKI and with eGFR ≥ 30 mL/min/1.73m², it is not necessary to discontinue metformin either before or following the intravenous administration of iodinated contrast media. It is also not necessary to reassess the patient’s renal function following the test or procedure.
   2. Category II: In those taking metformin who are known to have acute kidney injury or severe CKD (stage 4 or 5; i.e., eGFR< 30), or are undergoing arterial catheter studies that might result in emboli (atheromatous or other) to the renal arteries, metformin should be held temporarily at the time of or before the procedure and continued to be withheld for 48 hours after the procedure. It is recommended that it is reinstituted only after renal function has been re-evaluated and found to be normal.
5. Metformin and Gadolinium: It has been deemed unnecessary to stop metformin before a contrast medium administration in the event that the amount of gadolinium-based contrast material administered is in the usual dose range. The usual dose range is 0.1 to 0.3 mmol per kilogram of body weight.
6. Hepatic and renal impairment: Metformin should be used cautiously in patients who have renal impairment, and the dose of metformin should be adjusted (decreased) in patients who have renal impairment. These issues were discussed in the available forms and dosing section and the US Boxed Warning section.

Occurring in approximately 30% of patients, common adverse effects of metformin include (ElSayed et al., 2023b; Katzung et al., 2019; Rahman & Tuba, 2022):

• Abdominal discomfort
• Bloating
• Diarrhea
• Nausea
• Vomiting 

The use of metformin has been associated with vitamin B12 deficiency, especially long-term use of the drug and (possibly) with higher doses (ElSayed et al., 2023d; Khattab et al., 2022). This adverse effect has been associated with an increased risk of developing diabetic foot ulcers and causing or worsening distal symmetrical, autonomic, and cardiac neuropathy (Bell, 2022; Karakousis et al., 2022).

The ADA’s 2023 Standards of Care recommends considering the periodic measurement of B12, especially in patients who have anemia. We know that anemia may increase the loss of B12 from the liver (Bell, 2022; ElSayed et al., 2023e). It is reasonable to presume that patients who have peripheral neuropathy require B12 level monitoring because many diabetics have peripheral neuropathy, and it would be important know if a low B12 level is contributing to a patient’s signs and symptoms (Bell, 2022; ElSayed et al., 2023e).

Regarding the “when” and “how often” to monitor B12 levels, the ADA 2023 Standards of Care indicates that even though there are not formal recommendations for periodicity of monitoring, it is important to note that the lowering effect of metformin on vitamin B12 has been shown to increase with time (ElSayed, 2023d).

Colesevelam is available as a generic and as a brand name formulation, as Welchol® tablets, and as an oral suspension.

The mechanism by which colesevelam lowers blood glucose has not been identified (Welchol,® 2022).

Glycemic control for patients who have type 2 diabetes, as an adjunct to diet and exercise (Welchol®, 2022). The ADA 2023 Standards of Care do not mention colesevelam.

There are three contraindications for the use of colesevelam (Welchol®, 2022; Esan et al., 2022; Grundy et al., 2019):

1. Serum triglyceride level > 500 mg/dL: Colesevelam can increase serum triglyceride levels, and hypertriglyceridemia can cause pancreatitis.
2. A history of pancreatitis that was hypertriglyceridemia-induced.
3. A history of bowel obstruction or gastroparesis: Colesevelam can cause bowel obstruction, and constipation is a relatively common adverse effect of the drug, occurring in > 11% of patients.

Colesevelam can increase serum triglycerides, and a high serum triglyceride level can cause pancreatitis (Welchol®, 2022). Patients who have signs and symptoms of pancreatitis should discontinue the use of the drug.

Colesevelam can cause bowel obstruction, and its use is not recommended for patients who have gastroparesis, patients who may be at risk for a bowel obstruction, or patients who have had major gastrointestinal surgery (Welchol®, 2022).

Colesevelam lowers bile acid concentration, and bile acids are required for the absorption of the fat-soluble vitamins A, D, E, and K require bile acids (Esan et al., 2022). During the licensing studies of colesevelam, the levels of vitamins A, D, and E were not affected, and the level of vitamin K (assessed indirectly by measuring PT and PTT) was not affected (Esan et al., 2022). However, the prescribing information recommends states that colesevelam may (italics added) decrease the absorption of fat-soluble vitamins, and patients who are at risk for vitamin K deficiency (malabsorption syndrome, patients taking warfarin) or who have/are at risk of a vitamin A, D, or E deficiency may be at risk for this adverse effect (Welchol®, 2022). Oral vitamin supplements should be taken at least four hours before taking colesevelam and vitamin supplementation should be considered for patients who will be taking the drug for a long time (Esan et al., 2022; Welchol®, 2022).

Common effects of colesevelam include constipation, dyspepsia, and nausea (Welchol®, 2022).

There are four DPP-4 inhibitors available in the United States: 

1. Alogliptin (Nesina®)
2. Linagliptin (Tradjenta®)
3. Saxagliptin (Onglyza®)
4. Sitagliptin (Januvia®)

All four of these medications are available in tablet form. They are to be taken once a day.

The DPP-4 inhibitors are also combined with metformin, an SGLT-2 inhibitor, metformin and an SGLT-2 inhibitor, and with a thiazolidinedione.

Hepatic impairment: The prescribing information for Tradjenta® states that dosing adjustments of the drug do not need to be made for patients who have hepatic impairment (Tradjenta®, 2022).

The prescribing information for Januvia® and Onglyza® does not mention the issue.

The prescribing information for Nesina® states that dosing adjustments of the drug do not need to be made for patients who have mild to moderate liver impairment, the drug has not been studied in patients who have severe hepatic impairment, and Nesina® should be used cautiously in patients who have liver disease.

Renal impairment: The prescribing information for Onglyza®, Januvia®, and Nesina® recommends decreasing the dose in patients who have renal impairment.

Linagliptin is primarily eliminated by the enterohepatic system, and the prescribing information for Tradjenta® does not recommend decreasing the dose for patients who have renal impairment (Florentin et al., 2022).

The DPP-4 inhibitors inhibit dipeptidyl peptidase-4 (DPP-4), and DPP-4 is an enzyme that degrades GLP-1 and other incretins like GIP (Florentin et al., 2022; Katzung et al., 2019).

Glucagon-like peptide-1 is an incretin hormone that is secreted by the α cells of the pancreas, the colon, and the distal ileum (Chen et al., 2022). Glucagon-like peptide-1 stimulates insulin release in response to blood glucose after a meal. It also reduces the release of glucagon. Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone, and it has metabolic and glucose-lowering effects that are like GLP-1. Inhibition of DPP-4 increases/maintains the levels of these incretin hormones. This is the mechanism by which the DPP-4 inhibitors control blood glucose levels.

The DPP-4 inhibitors are used for patients who have T2DM, along with diet and exercise, to maintain glycemic control (ElSayed et al., 2023b). The DPP-4 inhibitors are typically used as a second-line/third-line medication, in addition to metformin (ElSayed et al., 2023b; Florentin et al., 2022).

There are no specific contraindications for the use of the DPP-4 inhibitors.

Arthralgia: In 2015 the US Food & Drug Administration (FDA) issued a warning about the DPP-IV inhibitors and the risk of severe arthralgia (Wang et al., 2019). Subsequent research has found that patients taking a DPP-4 inhibitor – any of the four – had a higher risk of developing arthralgia, but the risk decreased in long-time users (Wang et al., 2019). The prescribing information notes that when the use of the drug is stopped, the symptoms are resolved (Januvia®, 2022; Ni et al., 2022; Onglyza®, 2019).

Bullous pemphigoid: The prescribing information for all four DPP-4 inhibitors states in the post-marketing period, cases of bullous pemphigoid that required hospitalization developed in patients taking a DPP-4 inhibitor. Bullous pemphigoid is an auto-immune disease that usually occurs in the elderly (Roy, et al., 2021; Yancey et al., 2022). It is characterized by blistering skin lesions that usually develop on the lower abdomen, the groin, the flexor surfaces of the extremities and occasionally on the oral mucosa, and the patient may have severe pruritus (Roy, et al., 2021; Yancey et al., 2022). The use of DPP-4 inhibitors significantly increases the risk of developing bullous pemphigoid (Roy et al., 2021; Yang et al., 2021). The onset can be delayed by many months (Kridin & Bergman, 2018). Most patients do well when the use of the drug is stopped, but serious complications can happen (Kridin & Bergman, 2018). If a patient has signs and symptoms of bullous pemphigoid, the use of the DPP-4 inhibitor should be stopped immediately.

Heart failure: The prescribing information for all four DPP-IV inhibitors states that cases of heart failure have been associated with the use of these drugs, and the DPP-4 inhibitors should be used cautiously for patients who have a history of heart failure or who have a risk of developing heart failure. This warning is based on clinical trials that involved patients who had poor glycemic control and had atherosclerotic vascular disease (ASCVD) or had risk factors for ASCVD (Florentin et al., 2022). Recent reviews of the literature concluded that saxagliptin was associated with an increased risk of hospitalization for heart failure, and linagliptin was not (Florentin et al., 2022; Mannucci et al., 2021). Mannucci et al. (2021) did conclude that, as a class, DPP-4s are not associated with any increase nor reduction of major adverse cardiac events (MACE), mortality, and heart failure (HF) (Mannucci et al., 2021).

Hypoglycemia: Concurrent use of a DPP-4 inhibitor and insulin or a sulfonylurea increases the incidence of hypoglycemia (Januvia®, 2022; Ni et al., 2022; Onglyza®, 2019). Consider decreasing the dose of the insulin or the sulfonylurea as needed to prevent this.

Pancreatitis: The prescribing information for all four DPP-4 inhibitors states that during clinical trials and in post-marketing experience, cases of acute and fatal pancreatitis were reported. The prescribing information also states that it is not known if patients who have a history of pancreatitis are at risk for developing this adverse effect. If a patient taking a DPP-4 inhibitor develops signs and symptoms of pancreatic damage, use of the drug should be discontinued (Januvia®, 2022).

A recent (2020) review of the literature stated that the available data do not currently support an association of DPP-4 treatment with pancreatitis nor pancreatic cancer (Dicembrini et al., 2020). Yang et al. wrote that there is no consensus on DPP-4s pancreatic safety (Yang et al., 2022).

Common adverse effects of the DPP-4 inhibitors are:

• Cough: Linagliptin.
• Diarrhea: Linagliptin.
• Headache: Alogliptin, saxagliptin.
• Nasopharyngitis: Linagliptin, sitagliptin.
• Urinary tract infection: Alogliptin, saxagliptin.
• Upper respiratory tract infection: Alogliptin, saxagliptin.

Nateglinide and repaglinide come in oral tablets. The brand name formulations of these drugs were discontinued.

Nateglinide and repaglinide are taken orally, three times a day, before meals (National Library of Medicine, 2022a; National Library of Medicine, 2022b).

Nateglinide and repaglinide are used to treat patients who have T2DM and who do not have adequate glycemic control using diet and exercise (National Library of Medicine, 2022a; National Library of Medicine, 2022b). The meglitinide analogs are second and third-line drugs (DeMarsilis et al., 2022). The ADA 2023 Standards of Care does not mention nateglinide or repaglinide in the section Pharmacologic Approaches to Glycemic Treatment (ElSayed et al., 2023e).

There are no specific contraindications to the use of nateglinide.

Concurrent use of repaglinide and a strong CYP2C8 inhibitor like gemfibrozil (Lopid®) can significantly increase the serum concentration of repaglinide and cause hypoglycemia. The combination of these drugs is contraindicated.

Bariatric surgery: A meglitinide should not be given during the immediate postoperative period to a patient who has had bariatric surgery (Mechanick et al., 2019).

Hypoglycemia: The meglitinide analogs, like insulin and sulfonylureas, directly lower blood glucose by stimulating endogenous insulin secretion, and hypoglycemia is a common adverse effect of these drugs, occurring more often with the use of repaglinide (National Library of Medicine, 2022a; National Library of Medicine, 2022b; DeMarsilis et al., 2022; Powers et al., 2023).

Renal impairment: Both nateglinide and repaglinide can be used for patients who have renal impairment, but dosing adjustments need to be made, based on a patient's eGFR (LeRoith et al., 2019).

Weight gain: Both nateglinide and repaglinide can cause weight gain (National Library of Medicine, 2022a; National Library of Medicine, 2022b).

The most common adverse effects of nateglinide and repaglinide (aside from hypoglycemia) are headache (repaglinide) and upper respiratory tract infection (National Library of Medicine, 2022a; National Library of Medicine, 2022b).

The Sodium-glucose cotransporter type 2 (SGLT2) inhibitors are available in tablet form. There are currently four SGLT2 available:

• Canagliflozin (Invokana®)
• Dapagliflozin (Farxiga®)
• Empagliflozin (Jardiance®)
• Ertugliflozin (Steglatro®). 

The SGLT2 inhibitors are also available as a combination product with metformin or a DPP-IV inhibitor.

The SGLT2 inhibitors are oral preparations, and they are taken once a day.

Dosing adjustment may be needed if the patient has hepatic impairment.

Dosing adjustment may be needed, or the use of the SGLT2 inhibitor may be contraindicated if the patient has end-stage renal disease (Farxiga,® 2023; Invokana®, 2022). Dosing adjustments for patients who have renal impairment are complex and specific to each drug. Check the prescribing information for details.

Sodium-glucose cotransporter type 2 is a glucose transporter found in the renal tubules, and SGLT2 reabsorbs a significant amount of filtered glucose from the proximal tubules. Inhibition of SGLT2 increases the renal excretion of glucose and lowers plasma glucose (Katzung et al., 2019).

There are four indications for the use of the SGLT2 inhibitors (ElSayed et al., 2023b; Farxiga,® 2023; Invokana,® 2022):

1. As an adjunct to diet and exercise, to attain glycemic control for patients who have T2DM.
2. To reduce the risk of major cardiac events in patients who have T2DM and who have cardiac disease.
3. To reduce the risk of hospitalization for heart failure in patients who have T2DM and CKD or T2DM and heart failure.
4. To reduce the risk of increased serum creatinine and the risk of end-stage renal disease (ESRD).

The SGLT2 inhibitors are antidiabetic drugs, but they also have beneficial cardiovascular and renal effects (ElSayed et al., 2023b; Vallon & Verma, 2021). These beneficial effects include their ability to lower the GFR, improve cardiac function, and reduce the risk of heart failure (Vallon & Verma, 2021).

The ADA’s 2023 Standards of Care, Pharmacologic Approaches to Glycemic Treatment section indicates that individuals with T2DM who have established atherosclerotic cardiovascular disease, indicators of high cardiovascular risk, established kidney disease, or heart failure, a SGLT2 and/or GLP-1 receptor agonist with demonstrated cardiovascular disease benefit is recommended as a part of the glucose-lowering regimen (ElSayed et al., 2023b).

The SGLT2 inhibitors are contraindicated for patients on hemodialysis (Farxiga®, 2023; Invokana®, 2022; Jardiance®, 2022; Steglatro®, 2022).

Genital mycotic infections: The use of an SGLT2 inhibitor increases the risk of developing a genital mycotic infection, in females and males, and the incidence has been reported to be > 3% and sometimes > 12% (Farxiga®, 2023; Invokana®, 2022; Jardiance®, 2022; Steglatro®, 2022). A previous history of a genital mycotic infection increases the risk of developing this adverse effect.

Hypoglycemia: Concurrent use of an SGLT2 inhibitor and insulin or a sulfonylurea may cause hypoglycemia (Farxiga®, 2023; Invokana®, 2022; Jardiance®, 2022; Steglatro®, 2022). Hypoglycemia is not an adverse effect of the SGLT2 inhibitors by themselves.

Ketoacidosis: Cases of ketoacidosis have been reported during clinical trials of the SGLT2 inhibitors, and there have been after-market reports of this adverse effect, as well (Farxiga®, 2023; Invokana®, 2022; Jardiance®, 2022; Steglatro®, 2022). Many of these cases were patients who had euglycemic DKA (blood glucose < 250 mg/dL, arterial pH < 7.3, serum bicarbonate < 18 mEq/L, and ketonemia), and recent research has confirmed that the use of the SGLT2 inhibitors significantly increases the risk of developing euglycemic DKA (Wojtas et al., 2023).

Lower limb amputation and fractures: The prescribing information for the SGLT2 inhibitors warns that their use has been associated with a risk of lower limb amputation and fractures. A recent (2022) literature review concluded that those with T2DM and CKD are at elevated risk of amputation and fracture (Arnott et al., 2022). Treatment with SGLT2 inhibitors does not increase the risk of amputation or fracture overall (Arnott et al., 2022). The available data make it unlikely that canagliflozin, or SGLT2 inhibitors more broadly, increase the risk of amputation or fracture either overall or in any specific population subset (Arnott et al., 2022).

Necrotizing fasciitis of the perineum: Necrotizing fasciitis of the perineum, aka Fournier’s gangrene, is an infection of the fascial tissues in the perineum (Jahir et al., 2022; Kasbawala et al. 2020). It is highly progressive, and it can cause sepsis, shock, and multi-organ system failure (Jahir et al., 2022; Kasbawala et al. 2020). Fournier’s gangrene in these cases is likely caused by an increased urinary glucose concentration (Jahir et al., 2022). Necrotizing fasciitis of the perineum is a rare adverse effect of SGLT2 inhibitors: From 2013 to 2020, 491 cases were reported to the FDA, and a mortality rate of 88% was reported (Tran et al., 2022).

Urosepsis: The use of SGLT2 inhibitors increases the risk of urinary tract infections, and pyelonephritis and urosepsis can occur, as well (Farxiga®, 2023; Invokana®, 2022; Jardiance®, 2022; Steglatro®, 2022). This warning is from the prescribing information of these drugs, and the level of risk for these complications and whether the use of SGLT2 inhibitors does increase the risk is a controversial and unresolved issue (Dave et al., 2019; Tada et al., 2022). However, patients who have diabetes are at risk for urinary tract infections and for having complications with a urinary tract infection (Dave et al., 2019). Urosepsis and pyelonephritis are important causes of mortality in this patient population (Dave et al., 2019). Given that, patients who are taking an SGLT2 inhibitor should be monitored for signs and symptoms of urinary tract infections.

Volume depletion: The SGLT2 inhibitors can cause volume depletion, and because of the patient population that takes SGLT2 inhibitors, this adverse effect can cause acute kidney injury (Farxiga®, 2023; Invokana®, 2022; Jardiance®, 2022; Steglatro®, 2022).

Common adverse effects of the SGLT2 inhibitors are an increased incidence of genital infections and urinary tract infections (Katzung et al., 2019).

The sulfonylureas that are currently available include:

1. Glimepiride (Amaryl®)
2. Glipizide (Glucotrol XL®)
3. Glyburide (Glynase®)

All three medications are available as generics. The sulfonylureas are also available as a combination product with metformin.

The sulfonylureas are oral tablets, and they are taken once a day.

The prescribing information for the sulfonylureas does not have dosing recommendations for glimepiride, glipizide, and glyburide for patients who have hepatic impairment.

The prescribing information for the sulfonylureas does not have dosing recommendations for glimepiride, glipizide, and glyburide for patients who have renal impairment.

Hahr and Molitch (2022) stated that as GFR decreases, the clearance of sulfonylureas and their metabolites decrease, and this increases the risk of hypoglycemia. According to the authors, this is not an issue with glipizide, and no dosing adjustments of glipizide are needed for patients that have renal impairment. Dosing adjustments of glimepiride and glyburide should be made if the patient has a low eGFR (Hahr & Molitch, 2022).

The sulfonylureas are used to treat patients who have T2DM and who have not attained optimal glycemic control with diet and exercise (Amaryl®, 2018; Glucotrol®, 2021; Glynase® PresTab®, 2017). Sulfonylureas are a commonly used second-line drug, used in combination with metformin (ElSayed et al., 2023b).

Glyburide is contraindicated for patients who have diabetic ketoacidosis or T1DM.

Concurrent use of glyburide and bosentan is contraindicated (Glynase® PresTab,® 2017). Bosentan is a vasodilator that is used to treat pulmonary arterial hypertension. Concurrent use of these two drugs may decrease the serum concentration of bosentan, increase the serum concentration of glyburide, and even cause liver enzyme elevations.

Concern for cross-reactivity between sulfonamide-containing drugs of different classes, e.g., a sulfonylurea and a sulfonamide antibiotic, and a concern for hypersensitivity reactions has been raised (Wulf & Matuszewski, 2013). The prescribing information for Amaryl® and Glucotrol® states that a known hypersensitivity to a sulfonamide derivative is a contraindication to the use of these drugs. This issue is not mentioned in the Glynase® PresTab® prescribing information.

Hemolytic anemia: Sulfonylureas can cause hemolytic anemia in patients who have glucose 6-phosphate dehydrogenase (G6PD) deficiency (Amaryl®, 2018; Glucotrol®, 2021; Glynase® PresTab,® 2017). There is no current (past five years) published information on this topic, and the published articles on this adverse effect appear to primarily involve first-generation sulfonylureas that are no longer used. The prescribing information also states that there are post-marketing reports of hemolytic anemia in patients who were taking a sulfonylurea and who did not have G6PD deficiency.

Hypoglycemia: All the sulfonylureas can cause hypoglycemia and at times, severe hypoglycemia (Amaryl®, 2018; Douros et al., 2017; Glucotrol®, 2021; Glynase® PresTab®, 2017). There are multiple reasons and risk factors for sulfonylurea-induced hypoglycemia, including (but not limited to) (Amaryl®, 2018; McCall et al., 2023; Glucotrol®, 2021; Glynase® PresTab®, 2017):

• Poor caloric intake
• History of severe hypoglycemia
• Impaired awareness of hypoglycemia
• Advanced age
• Prolonged exercise
• Concurrent use of other diabetic medications
• Hepatic conditions
• Renal conditions

Increased risk of cardiovascular mortality: The sulfonylurea prescribing information warns that the use of oral hypoglycemic drugs has been associated with increased cardiovascular mortality when compared to treatment with diet and exercise (Amaryl®, 2018; Glucotrol®, 2021; Glynase® PresTab®, 2017). However, the prescribing information also states that this warning was based on a study that involved one drug, tolbutamide (a first-generation sulfonylurea that is no longer used), and a recent study (2023) concluded that the sulfonylureas are unlikely to increase the risk for cardiovascular mortality or all-cause mortality (Wang et al., 2023). The authors of this study indicated that there has been controversy over the cardiovascular safety of sulfonylureas (Wang et al., 2023). The sulfonylurea prescribing information acknowledges the limitations of the basis for this warning, but its states that it is prudent to consider that this warning may also apply to other oral hypoglycemic drugs in this class, in view of their close similarities in mode of action and chemical structure to tolbutamide (Amaryl®, 2018; Glynase® PresTab®, 2017). It is recommended that patients be counseled on the potential benefits and risks of sulfonylureas (Amaryl®, 2018; Glucotrol®, 2021; Glynase® PresTab®, 2017).

Common adverse reactions of the sulfonylureas include (Amaryl®, 2018; Glucotrol®, 2021; Glynase® PresTab®, 2017):

• Dizziness
• Headache
• Flatulence
• Flu-like symptoms
• Nausea
• Nervousness
• Tremor

The are two thiazolidinediones currently available (Actos®,2020):

1. Pioglitazone
2. Rosiglitazone

The brand name formulation rosiglitazone, Avandia, was recently discontinued.

Pioglitazone is also available as a combination product with alogliptin, glimepiride, or metformin.

Pioglitazone and rosiglitazone are available as oral tablets, and they are taken once a day.

The prescribing information for pioglitazone and rosiglitazone does not mention dosing adjustments of the drugs for patients who have hepatic or renal impairment.

The thiazolidinediones are used as an adjunct to diet and exercise to treat patients who have T2DM and who do not have good glycemic control (Actos®, 2020). They are considered second or third-line drugs (ElSayed et a., 2023b). They are not used to treat patients who have T1DM or diabetic ketoacidosis.

Thiazolidinediones are contraindicated in patients who have New York Heart Association (NYHA) Class III or Class IV heart failure. This issue will be discussed further in the US Boxed Warning section and the Warnings & Precautions section.

In some patients, thiazolidinediones can cause or exacerbate heart failure. Patients taking thiazolidinedione should be carefully observed for signs and symptoms of heart failure particularly after the dose is increased. If a patient develops signs/symptoms of heart failure including dyspnea, edema, and/or excessive and rapid weight gain, the patient should be managed according to current guidelines.

As mentioned above, it is a boxed warning that thiazolidinediones should not be used for patients who have symptomatic heart failure, and they are contraindicated in patients who have established NYHA Class III or Class IV heart failure (Actos®, 2020).

Bladder cancer: Thiazolidinediones may increase the risk of bladder cancer. They should not be used in patients who have bladder cancer, and they should be used cautiously in patients who have had bladder cancer (Actos®, 2020).

The issue of thiazolidinediones and an increased risk of bladder cancer has been contentious (DeMarsilis et al., 2022). Some research has found that these drugs do increase the risk, but other studies have concluded that both pioglitazone and rosiglitazone are not a cause of an increased risk of bladder cancer (Han et al., 2016; Hsiao et al., 2013; Lewis et al., 2015; Malhotra et al., 2022). The prescribing information itself noted that during the three years of a clinical trial and ten years of follow up that the occurrence of bladder cancer did not differ between patients who received the placebo (Actos®, 2020). However, Lewis et al. (2015) wrote that their analysis of the data they reviewed was that pioglitazone was not associated with an increased risk for bladder cancer, but an increased risk could not be excluded (Lewis et al. 2015). The Actos® prescribing information indicates that there is insufficient data to decide whether pioglitazone promotes tumors for urinary bladder tumors (Actos®, 2020).

Congestive heart failure and edema: Fluid retention may occur and can exacerbate or lead to congestive heart failure. This adverse effect can occur when a thiazolidinedione is used alone or with other diabetic medications, or when the patient has NHYA Class I or Class II heart failure (Actos®, 2020).

Fluid retention has been reported to occur in 5% to 10% of patients who were taking pioglitazone (DeFronzo et al., 2019). This is caused by peripheral vasodilation and sodium retention (DeFronzo et al., 2019). Heart failure is very common in patients who have T2DM, and the thiazolidinediones, in part because they cause fluid retention, they can exacerbate heart failure in patients who have the disease, and they can ultimately lead to heart failure (ElSayed et al., 2023b; Katsiki et al., 2022). This risk is increased with concurrent use of thiazolidinediones and insulin or a sulfonylurea (Actos®, 2020; DeFronzo et al., 2019; Katsiki et al., 2022). Insulin can cause fluid and sodium retention (Katsiki et al., 2022). No current published information on the concurrent use of thiazolidinediones and sulfonylureas and heart failure were located.

Pioglitazone and rosiglitazone are contraindicated in patients who have NYHA Class III or Class IV heart failure, and the 2023 ADA Standards of Care, Pharmacologic Approaches to Glycemic Treatment notes that both edema and heart failure are concerns when using these drugs (ElSayed et al., 2023b). See table 3 below.

Hepatic damage: There have been post-marketing reports of hepatic damage, hepatic failure, and fatal hepatic failure (Actos®, 2020). The prescribing information recommends measuring serum transaminases before beginning treatment with pioglitazone and if the transaminases are abnormal, pioglitazone should be used cautiously (Actos®, 2020). If the liver function test results are > 3 times the upper limit of normal, stop the use of the drug and look for a cause of this abnormality (Actos®, 2020).

Elevations in serum transaminases have been reported with the use of pioglitazone but not with rosiglitazone (LiverTox, 2018). Cases of hepatic failure and death from hepatic failure associated with the use of thiazolidine have occurred, but they are very rare (LiverTox, 2018).

Fractures: The Prospective Pioglitazone Clinical Trial in Macrovascular Events (2004) found that the incidence of fractures in women who took pioglitazone was 5.1% and for women who took a placebo the incidence was 2.5% (Actos, ® 2020). For men, there was no significant difference noted (Actos, ® 2020).

The 2023 ADA Standard of Care, Pharmacologic Approaches to Glycemic Treatment, notes fractures are associated with thiazolidinediones, and the 2023 ADA Standard of Care, Older Adults: Standards of Care In Diabetes, states that the thiazolidinediones should be used very cautiously in older adults on insulin therapy as well as those individuals who are at risk for osteoporosis, falls, or fractures (ElSayed et al, 2023b; ElSayed et al., 2023f).

Macular edema: Macular edema was reported in post-marketing experience with the thiazolidinediones (Actos®, 2020; Ambrosius et al., 2010). The prescribing information recommends that diabetic patients should have a regular ophthalmologic examination and if a diabetic patient has visual disturbances, they should immediately be referred to an ophthalmologist (Actos®, 2020).

Gower et al. (2018) did a longitudinal study of T2DM patients. The authors did not find an association between thiazolidinediones and diabetic macular edema progression or visual acuity outcomes, and they found no consistent evidence of an increased progression of diabetic retinopathy between patients who had been or had never been treated with a thiazolidinedione (Gowers et al., 2018).

The 2023 ADA Standard of Care, Older Adults: Standards of Care In Diabetes, indicated that the thiazolidinediones should be used very cautiously in older adults and for those at risk for macular edema (ElSayed et al., 2023f).

Common adverse effects of thiazolidinediones include:

• Headache
• Myalgia
• Pharyngitis
• Sinusitis
• Upper respiratory tract infection