#95324: Diabetes Pharmacology

Diabetes, known clinically as diabetes mellitus, is a progressive disease process affecting the fuel metabolism functioning within the body [3]. According to the Centers for Disease Control and Prevention (CDC), the prevalence of diagnosed diabetes has increased from less than 1% of the U.S. population in 1958 to 7.4% in 2015 [4]. As of 2019, 11.3% of the U.S. population, or 37.3 million Americans, have diabetes. Unfortunately, 8.5 million of these individuals are unaware of their diabetes diagnosis [5,6]. Diabetes has been considered epidemic since the 1970s, and the percentage of Americans expected to have diabetes or impaired glucose tolerance (IGT) is estimated to reach 15% to 20% by the year 2025 [7].

The scope of the problem is vast and diverse. From 1994 through 2015, the prevalence of diagnosed diabetes increased across all states. In 1994, only one state had a prevalence greater than 6.0%. In 2018, all states had prevalences greater than 6.0%, and 35 exceeded 9.0% [8]. According to data from the Behavioral Risk Factor Surveillance System, West Virginia has the highest rate of adults with diabetes (13.4%). Eight of the 10 states with the highest rates (12% to 12.9%) are in the South. Colorado ranked last at 6.6% [8]. Genetics, race, age, and lifestyle influence the onset and progression of the disease process significantly [9]. According to the 2022 National Diabetes Statistics Report, the percentage of adults with diagnosed diabetes was highest among American Indians/Alaska Natives (14.5%), non-Hispanic Black Americans (12.1%), and people of Hispanic origin (11.8%), followed by non-Hispanic Asians (9.5%) and non-Hispanic White Americans (7.4%) [10]. Native Americans/Alaskan Natives present the greatest risk for the development of type 2 diabetes; their risk is more than two times greater than that of White Americans. Among Native American subgroups, the rate of diabetes among Alaska Natives is 6.0%, while Native Americans in Southern Arizona have rates of 22% [6].

The most rapid increase in prevalence in the last decade has been among adolescents. Historically, children and adolescents with hyperglycemia have been diagnosed with type 1 diabetes, a result of the body being unable to produce adequate amounts of insulin. However, the rate of new cases of diabetes in those younger than 20 years of age increased in the United States between 2002 and 2015, with a 4.8% increase per year for type 2 diabetes and a 1.9% increase per year for type 1 diabetes [11]. The incidence of type 1 diabetes increased in all age, sex, and race/ethnicity groups, except for those younger than 5 years of age and American Indians primarily from one southwestern tribe. The steeper increases in incidence of type 1 diabetes were seen among non-Hispanic Black Americans (2.7% per year), Hispanics (4.0% per year), and Asians/Pacific Islanders (4.4% per year) while the increase among non-Hispanic White Americans was much lower (0.7% per year). For type 2 diabetes, incidence during the period increased in all age, sex, and race/ethnicity groups, with the exception of non-Hispanic White Americans. The steepest increase was seen among Asians/Pacific Islanders (7.7% per year) followed by Hispanics (6.5% per year), non-Hispanic Blacks (6.0% per year), and American Indians primarily from one southwestern tribe (3.7% per year) [11].It has been predicted that children born in this millennium will have a one in three chance of developing diabetes in their lifetime; among high-risk ethnic groups, the estimate is as high as one in two [12].

In order to fully comprehend the action of exogenous insulin, healthcare providers require a solid understanding of insulin physiology. Glucose regulation is maintained by a sophisticated mechanism of regulatory and counter-regulatory reactions. When an individual consumes food, specifically carbohydrates, sugars are released into the blood circulatory system [16]. The chemical reactions to this sugar introduction help maintain homeostasis in the body.

The National Institute of Health's sponsored study, the Diabetes Prevention Program (DPP), was sanctioned to determine if diabetes could be prevented or delayed through the use of various interventions. The study was conducted in 27 centers throughout the United States, and the study participants were randomized into one of four treatment groups [21]. Treatment groups included lifestyle and behavior change or therapy with metformin, troglitazone, or placebo [21].

All 3,234 study participants were 25 years of age or older, overweight, and had IGT and elevated fasting plasma glucose, which are risk factors for the development of type 2 diabetes. In addition, 45% of the participants were from minority groups—African American, Alaskan Native, Native American, Asian American, Hispanic/Latino, or Pacific Islander—and 20% were 65 years of age or older. The study lasted more than three years but was halted earlier than expected due to 25 of the 27 centers demonstrating remarkable findings proving the hypothesis [21].

The first group, referred to as the lifestyle intervention group, received intensive education and counseling pertaining to diet, physical activity, and behavior modification. For individuals in this group, the overall goal was to maintain a loss of 7% of total body weight by consuming a decreased amount of fat and fewer calories and engaging in 150 minutes of exercise per week. The metformin treatment group was prescribed 850 mg of metformin twice per day, while the placebo group received placebo pills twice per day. Both the metformin and placebo groups also received education regarding lifestyle interventions (e.g., diet, exercise) but not intensive counseling. The troglitazone group was prescribed 400 mg of the drug daily, but this arm of the study was discontinued due to concerns that troglitazone was associated with liver toxicity. Participants in the troglitazone group continued to be followed but were not included as one of the intervention groups [21]. Troglitazone was removed from the U.S. market in 2000 [22].

The researchers found that participants who lost a modest amount of weight through dietary changes and increased physical activity sharply reduced their chances of developing diabetes [21]. The metformin treatment group also displayed a reduced risk for the development of diabetes, but the decrease was less dramatic.

The DPP Outcomes Study (DPPOS) has continued to follow most DPP participants since 2002. To date, the DPPOS has shown that participants who took part in the DPP Lifestyle Change Program or who are taking metformin continue to prevent or delay type 2 diabetes for at least 15 years [21]. The DPPOS also has shown that the lifestyle change program is cost effective and that metformin is cost-saving after 10 years. DPPOS researchers also are following other health problems in participants (e.g., cancer, CVD, and kidney and eye disease) [21].

Research has also proven that tight glycemic control can prevent the development of chronic microvascular complications in diabetic patients. Initial research in the Diabetes Complication and Control Trial (DCCT) focused on the benefits of conventional versus intensive therapy for the prevention of complications related to type 1 diabetes [14,23]. The study involved 1441 individuals and demonstrated enough statistical power to unequivocally demonstrate the importance of glycemic control with utilization of multiple daily insulin injections [23,24].

This randomized controlled trial found that the risk of microvascular complications was reduced by intensive glycemic control in patients with type 1 diabetes. Participants in the intensively treated group (goal glycosylated hemoglobin [HbA1c]: <6.05%; mean achieved HbA1c: approximately 7%) demonstrated an approximately 60% reduction in development or progression of diabetic retinopathy, nephropathy, and neuropathy compared to the standard group (mean achieved HbA1c: approximately 9%) over an average of 6.5 years. The relationship between glucose control and risk of complications was linear and extended down to the normal HbA1c range (<6%) with no threshold noted [25].

When the DCCT ended in 1993, researchers began a follow-up study called the Epidemiology of Diabetes Interventions and Complications (EDIC). The EDIC continues to follow more than 90% of DCCT participants, assessing the incidence and predictors of cardiovascular disease events (e.g., heart attack, stroke, needed heart surgery) and diabetic complications related to the eye, kidney, and nerves. For example, the EDIC has shown that an individualized eye exam schedule results in fewer eye exams, lower costs, and faster diagnosis and treatment of advanced diabetic eye disease [23]. The EDIC also is examining the impact of intensive versus standard control on participants' quality of life [23].

Research from the DCCT trial was further substantiated in the United Kingdom Prospective Diabetes Study (UKPDS), a clinical trial of patients with newly diagnosed type 2 diabetes conducted between 1977 and 1997. Once more, the groups were separated into a conventional therapy study arm or an intensive therapy arm to determine the efficacy and outcomes of the differing treatments [14]. Intensive blood glucose control was achieved utilizing sulfonylurea medications or insulin in normal-weight people and metformin in participants who were overweight. The UKPDS aimed to treat patients using only a single medication even if blood glucose became quite high because, at the time, there were some concerns that utilizing multiple medications had the potential of being harmful. In the conventional therapy cohort, lifestyle alone was used to control blood glucose. This was the first study to establish the now well-known association between level of glucose control and the reduction of microvascular complications (i.e., retinopathy, nephropathy, neuropathy) in individuals with type 2 diabetes [26].

When researchers revisited the participants of the UKPDS after 10 years, it was found that those who had been in the tight glycemic control arm during the trial had a lower risk of myocardial infarction and death than those who participated in the conventional glycemic control arm [27]. This finding was somewhat surprising because within one year of UKPDS ending, differences in HbA1c levels between the intensive and conventional treatment groups had disappeared. However, 10 years later, the follow-up study reported that myocardial infarction risk was reduced 15% in the sulfonylurea/insulin group and 33% in the metformin group, while overall risk of death was reduced 13% and 27%, respectively [27]. With this knowledge, the goal for diabetes treatment is striving for euglycemia by utilizing behavior change, meal planning, and lifestyle change followed by medication management [7].

The Treat-to-Target Trial was designed to determine if the addition of basal insulin at bedtime to an existing oral therapy regimen could improve achievement of the recommended 7% HbA1c target. Its secondary goal was to assess the efficacy and safety of glargine compared to neutral protamine Hagedorn (NPH) insulin as the basal insulin of choice in this treatment approach [28].

Researchers found that the addition of bolus insulin at bedtime (either glargine or NPH) reduced the average HbA1c level from 8.6% to 7%, with almost 60% of patients reaching 7% or less [28]. This high success rate may be attributed to the fact that the average baseline HbA1c was lower than in most other studies, the majority of study participants had advanced diabetes (suggested by poor glucose control on two oral agents), and more than 90% of participants adhered to the treatment, indicating it was an easy regimen to follow. Researchers also systematically titrated the insulin dosage to target [28].

Although fasting glucose and HbA1c levels were similar with both types of insulin, glargine was associated with fewer symptoms of hypoglycemia and less variability in fasting glucose levels [28]. Rates of severe hypoglycemia were low for both insulins, but nocturnal hypoglycemia was significantly more likely with NPH insulin. Nocturnal hypoglycemia was reduced from 42% to 48% in the glargine group, indicating that this insulin's lower peak of action would make it a better choice for this treatment approach [28].

The Treating to Target Type 2 Diabetes, or 4-T, Trial was established to determine the effects of adding biphasic, prandial, or basal insulin to oral therapy for type 2 diabetes [29]. Participants in the trial had suboptimally controlled diabetes (mean HbA1c: 8.5%) despite treatment with sulfonylurea plus metformin. Subjects were randomized into three treatment groups: biphasic insulin aspart (twice daily), prandial insulin aspart (three times daily), or basal insulin detemir (once or twice daily, as required). All patients continued their established oral therapy, and dose titration, glucose monitoring, and follow-up visits were provided for all. After one year, the mean HbA1c level had decreased in all treatment groups, to 7.3% with biphasic insulin, 7.2% with prandial insulin, and 7.6% with basal insulin. However, no group met the goal of 6.5% or less; only 17%, 23.9%, and 8.1% of participants, respectively, met the goal. Although biphasic and prandial insulin more effectively lowered mean HbA1c levels, they were associated with greater risks of hypoglycemia and weight gain [29]. The authors concluded, based on a comparison of the risks and benefits of each approach, that the treatment of choice would be adding once-daily basal insulin to an established oral medication regimen for type 2 diabetes patients [29,30]. Three years after the study concluded, the majority of patients in each group were receiving a second type of insulin (67.7% of the biphasic group, 81.6% of the prandial group, and 73.6% of the basal group) [29].

The Outcome Reduction with Initial Glargine Intervention (ORIGIN) Trial was a large study attempting to identify the advantages of insulin glargine therapy and omega-3 fatty acids (fish oil) in managing type 2 diabetes and associated cardiovascular risks. The trial was completed in 2013 [31]. Because the majority of individuals who experience a myocardial infarction have impaired fasting glucose and/or IGT, investigators believed that achieving lower blood glucose levels (using insulin) might reduce the risk of cardiovascular events. The ORIGIN Trial randomized participants into groups receiving standard insulin glargine or variable-dose glargine, and further into subgroups receiving 865 mg of omega-3 fatty acid or placebo. The trial followed 12,500 individuals to determine the effect on the incidence of cardiovascular events [31]. Results indicated no difference in the incidence of cardiovascular events between the insulin glargine and standard care groups. Additionally, there was no difference in the incidence of cardiovascular death between the omega-3 fatty acid supplement and placebo groups. Insulin glargine provided better glucose control and lower risk of new diabetes. Side effects included a small increase in risk of hypoglycemia and weight gain of approximately 1.6 kg over a period of more than six years [32].

The Cardiovascular Outcome Study of Linagliptin versus glimepiride (CAROLINA) trial was a randomized, noninferiority clinical trial that compared the effect of linagliptin with glimepiride on major cardiovascular events in more than 6,000 participants with type 2 diabetes and elevated cardiovascular risk [33]. Participants were randomized to receive 5 mg of linagliptin once daily or 1–4 mg of glimepiride once daily in addition to usual care. The primary outcomes were time to first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. The median duration of follow-up was 6.3 years. A cardiovascular event occurred in 356 (11.8%) participants in the linagliptin group and 362 (12%) participants in the glimepiride group. Results indicated that the use of linagliptin compared with glimepiride resulted in a noninferior risk of composite cardiovascular outcome [33].

As discussed, the most common types of diabetes are type 1 and type 2. However, gestational diabetes is also relatively common and is a source of significant morbidity and mortality. Gestational diabetes complicates approximately 10% of all pregnancies [34,35]. For many years, gestational diabetes has been defined as any degree of glucose intolerance first recognized during pregnancy, but this definition has limitations. Many cases of gestational diabetes represent pre-existing hyperglycemia that is first detected by routine screening in pregnancy (as routine screening is not widely performed in nonpregnant women of reproductive age) [35]. Ideally, women with risk factors who are planning pregnancy should be tested for undiagnosed diabetes prior to conception [35]. If not screened preconception, universal early screening before 15 weeks' gestation for undiagnosed diabetes may be considered, particularly in populations with a high prevalence of risk factors, including women of non-Hispanic Black, Hispanic/Latino, and Native American ethnicity, women who are obese, women with a personal history of gestational diabetes, and those with a family history of diabetes [35,36]. Otherwise, testing should be done at between 24 and 28 weeks' gestation, usually with a glucose tolerance test [35]. Patients with gestational diabetes present special challenges, and the need for tight glycemic control often necessitates the use of insulin therapy. After conception and early in the first trimester, the risk of hypoglycemia is amplified as a result of increases in the peripheral utilization and storage of glucose. Late in the third trimester, overnight hypoglycemia can occur if a bedtime snack is insufficient to meet the intensified fetal demands for glucose. Lastly, during the postpartum period, the risk of hypoglycemia results from the loss of placental hormones [37].

Adequate glucose control should be maintained in order to prevent adverse effects to fetal health. Potential adverse effects include hyperbilirubinemia (jaundice), respiratory distress syndrome, hypocalcemia, polycythemia, macrosomia, and neonatal hypoglycemia [37,38].

Macrosomia occurs when a high level of glucose in the maternal blood results in the elevated glucose to the fetus. Sensing this elevation, the fetal pancreas begins producing insulin to normalize the glucose levels. The result of this is increased adipose tissue in the organs, chest, and abdomen, leading to disproportionate size of the trunk and shoulders in relationship to the head. These infants are often large for gestational age, increasing likelihood of cesarean delivery, vaginal tearing, and other birth traumas, such as shoulder dystocia, brachial plexus injury, Erb palsy, and asphyxia [38].

If the fetal pancreas has been overproducing insulin in response to elevated maternal blood glucose levels, hypoglycemia will occur when the umbilical cord is clamped and glucose-rich maternal blood is no longer circulating in the neonate. Neonatal hypoglycemia occurs in the first 12 hours of life and resolves with infusions or oral administration of glucose until euglycemia is restored. The risks associated with neonatal hypoglycemia include seizure, cerebral damage, and death [38].

The first-line treatment for gestational diabetes is conventional therapy of diet, exercise, and other lifestyle changes [34]. The goals for blood glucose levels during this period of pregnancy are very strict [34]:

When these goals are not being met, insulin therapy should be initiated, if needed, to achieve glycemic targets [35]. Insulin is the preferred medication, as it does not cross the placenta to a measurable extent. Metformin and glyburide should not be used as first-line agents, as they do cross the placenta. All oral agents lack long-term safety data [35].

Other less common types of diabetes do occur, and it is important to have a basic understanding of these forms as well. Less common types of diabetes include [7,14]:

The U.S. Preventive Services Task Force recommends screening for abnormal blood glucose as part of cardiovascular risk assessment in adults 35 to 70 years of age who are overweight or obese.

(https://jamanetwork.com/journals/jama/fullarticle/2783414 Last Accessed: October 28, 2022)

Strength of Recommendation: B (There is high certainty that the net benefit is moderate or there is moderate certainty that the net benefit is moderate to substantial.)

Criteria for screening for diabetes or prediabetes in asymptomatic adults include [35]:

The diagnostic criteria for type 2 diabetes are fairly straightforward and are based on fasting plasma glucose and plasma glucose levels (Table 1). After a diagnosis of type 2 diabetes has been definitively made, education on self-care management is necessary in order to obtain euglycemia and prevent complications related to the detrimental effects of hyperglycemia [3]. The healthcare team involved in providing care should include, at a minimum, the primary care physician, certified diabetes educator, dietitian, and support person/system. Education should focus on healthy eating habits, blood glucose monitoring, exercise planning, medication management, risk reduction, and healthy coping techniques [39]. As previously stated, it is estimated that as many as 90% of patients with type 2 diabetes will require oral medications to achieve adequate glucose control within five years of diagnosis [15]. When glucose levels cannot be adequately controlled with oral medications, the use of injectable medications is necessary. If elevated blood glucose levels are untreated and continue to rise, the result can be hyperosmolar hyperglycemia syndrome (HHS) and ultimately death [2].

The original sulfonylurea agents are now known as the first-generation sulfonylureas. Although effective in controlling hyperglycemia, first-generation sulfonylureas were hindered by the frequency of hypoglycemia related to therapy and high dosage requirements. The second-generation sulfonylureas have improved on the effectiveness of the earlier agents by requiring smaller doses and demonstrating a lower incidence of side effects [3,40]. Although no first-generation sulfonylurea agents are currently used in the United States, it is important to have an understanding of all medications within this category in the rare case a patient presents with a history of having taken one of these agents.

The second generation of sulfonylureas was developed to include a shorter duration of action and shorter half-lives, which decrease the frequency and severity of side effects related to medication therapy [3]. These agents are most commonly used in the treatment of type 2 diabetes today.

As with any drug therapy, a hypersensitivity reaction can potentially occur with sulfonylurea therapy. However, hypersensitivity to one agent does not necessarily indicate a cross-sensitivity with other sulfonamide agents. Care should be taken when treating geriatric, malnourished, or debilitated patients, as these groups are at particular risk for hypoglycemia. Furthermore, any person with adrenal, pituitary, or hepatic insufficiency who is particularly susceptible to the hypoglycemic effects of glucose-lowering agents should be closely monitored while on a sulfonylurea therapy regimen [3]. Alteration in hepatic enzyme activity may also alter the clearance of sulfonylurea agents.

A secondary side effect of sulfonylurea therapy is weight gain as a result of a greater amount of circulating insulin [42]. This increase results in a greater amount of circulating glucose being stored as adipose tissue. Less commonly seen sulfonylurea side effects include [42]:

It is important to mention that there is ongoing research regarding a possible correlation between sulfonylurea therapy and suspected deaths in patients with a past myocardial infarction [50,51]. Although a causal relationship has not been established, it is important to understand this concept and to counsel patients to discuss any concerns with their primary care physician [52].

Sulfonylurea agents may also interact with a variety of other medications. These interactions have the potential to affect the action of the sulfonylurea agent, the other medication, or both. Drug-drug interactions are more commonly seen with the first-generation sulfonylurea agents [53]. One of the primary causes for drug interactions is a competition for protein binding sites, which results in a greater amount of circulating sulfonylurea agent in the bloodstream and can increase the hypoglycemic effect, seen more often with the longer acting agents (e.g., chlorpropamide, glibenclamide [i.e., glyburide]) [54]. Medications that may interact with sulfonylureas include beta blockers, corticosteroids, thiazide diuretics, cyclic antidepressants, and antifungals [42,54].

Patient M is a white woman, 32 years of age, presenting to her primary care physician with complaints of polyuria for the past four weeks. Further assessment reveals an upcoming appointment with her optometrist for new onset blurred vision. The patient is 5 feet 5 inches tall and weighs 142 pounds; her calculated BMI is 23.6 kg/m². She confirms a family history of diabetes on her father's side and admits to a generally sedentary occupation and lifestyle. A random finger stick reveals a blood glucose level of 257 mg/dL.

Rationale and comments : Patient M's evaluation has resulted in adequate findings to diagnose diabetes. Any random blood glucose greater than 200 mg/dL with additional symptoms (in this case, polyuria and blurred vision) is considered diagnostic for diabetes.

Patient M is referred for fasting blood work, which reveals the following results:

Patient M is referred to an ADA-recognized diabetes education program for further education in diabetes self-management, self-monitoring of blood glucose (SMBG), and exercise and meal planning education [55].

Patient M returns to her primary care physician after three months. Her follow-up HbA1c demonstrates minimal change, with a result of 8.2% (estimated average glucose: 189 mg/dL) and a fasting blood glucose level of 156 mg/dL. SMBG records reveal blood glucose levels consistently between 135 mg/dL and 160 mg/dL fasting and between 230 mg/dL and 300 mg/dL postprandial. Patient M states that she is following her meal and exercise planning goals with little success.

The patient's physician evaluates all of her blood work and patient history information and determines that the best course of treatment would be to initiate sulfonylurea therapy. Patient M is started on glipizide 5 mg each morning, and continuation with her meal and exercise plans is emphasized.

Rationale and comments : This is an appropriate treatment plan for Patient M because, although she has a sedentary occupation, she is not considered obese. She has been adherent to her meal and exercise plan without success. Her fasting blood glucose levels are elevated, but it is the postprandial levels that have instigated the elevated HbA1c levels. The sulfonylurea secretagogue glipizide should improve the high postprandial levels resulting from loss of first-phase insulin release.

Nateglinide is a very rapid acting amino-acid derivative known as D-phenylalanine. Nateglinide interacts with the adenosine triphosphate (ATP)-sensitive potassium channel on pancreatic beta cells to produce calcium influx and insulin secretion. As with repaglinide, the extent of insulin release is glucose dependent and diminishes at low glucose levels [42,58]. Nateglinide is rapidly absorbed, and the onset of action is approximately within 20 minutes of ingestion. This medication is taken just prior to a meal due to this mechanism of action [7,42]. Due to the short half-life (1.5 hours), nateglinide stops acting on the pancreatic beta cells shortly after the meal, decreasing the possibility of hypoglycemia. This medication is excreted in the feces after it is metabolized in the intestinal tract [7]. Nateglinide can be used as monotherapy or in combination with metformin, TZD, or both. It is important to note that if adequate control is not achieved using a sulfonylurea agent, it is unlikely that nateglinide will be effective [42].

As with all medications, there are precautions when considering glinide therapy. These medications should not be used during pregnancy, in women who are breastfeeding, or in children [35]. Repaglinide should be used cautiously in persons with hepatic dysfunction, and routine, close monitoring of liver function is necessary. Individuals who are elderly, malnourished, debilitated, or have adrenal or pituitary dysfunction are particularly susceptible to hypoglycemia, the most common side effect related to this class of medication (<10%). The key measure for preventing hypoglycemia in patients taking glinides is patient education stressing the need to omit the medication if a meal is not going to be consumed [42].

Aside from hypoglycemia, there are less common side effects associated with glinides, including [3]:

As with any pharmaceutical preparation, healthcare professionals should be aware of potential interactions between medications that an individual is prescribed. In the case of both sulfonylureas and nonsulfonylurea secretagogues, potential effects of drug-to-drug interactions include [56]:

Herbs that may increase the effects of secretagogues include burdock, dandelion, eucalyptus, and marshmallow. As noted, it is imperative to understand these interactions and the impact they have on blood glucose levels. Rapid identification of hypoglycemic or hyperglycemic emergencies utilizing blood glucose monitoring and assessment skills is also critical [56].

Patient L is an African American man, 52 years of age, presenting to his primary care physician with complaints of frequent urination and excessive thirst, particularly in the late afternoon and early evening. He is a truck driver and works 12 hours each day. Patient L is 6 feet 1 inch tall and weighs 215 pounds, with a calculated BMI of 28.4 kg/m². He confirms a family history of diabetes on both his father's and mother's sides. A random finger stick results in a blood glucose level of 243 mg/dL.

Rationale and comments : The information gained from Patient L's initial examination indicates diabetes. Again, any random blood glucose greater than 200 mg/dL, accompanied by symptoms (polyuria and excessive thirst for this patient), is considered diagnostic for diabetes.

Patient L is referred for fasting blood work, which reveals the following:

Patient L is diagnosed with type 2 diabetes and is referred to an ADA-recognized diabetes education program. A follow-up appointment in three months is scheduled.

Upon the follow-up primary care appointment, Patient L's HbA1c shows minimal change, with a result of 8.8% (estimated average glucose: 206 mg/dL) and a fasting blood glucose level of 148 mg/dL. The patient's SMBG records reveal fasting blood glucose levels consistently between 150 mg/dL and 165 mg/dL and postprandial levels steadily between 230 mg/dL and 290 mg/dL. Patient L states that he has difficulty eating meals at consistent times due to his profession and exercises when he is able. There has been little change in his weight since his last visit.

Patient L's physician determines that the best course of therapy would be to initiate nonsulfonylurea secretagogue therapy. The patient is started on repaglinide 2 mg 15 minutes prior to his first three main meals. He is advised not to take the medication if he does not eat the meal. He is strongly encouraged to continue with his meal and exercise plans.

Rationale and comments : This is an appropriate choice of medication for Patient L due to his inconsistent eating habits and continued postprandial hyperglycemia, his sedentary occupation, and his weight (not considered obese). His postprandial levels are the problematic factor, and repaglinide will allow Patient L the freedom to adjust his medication therapy to his eating schedule.

Acarbose is prescribed in doses of 25–100 mg, with a maximum daily dose of 300 mg [7,42]. Acarbose should be taken in equal doses three times a day for maximum efficacy [7]. The onset of action of acarbose is immediate, with peak effect seen in one hour. Acarbose has a half-life of two hours and a duration of action of approximately six hours [42,56]. Acarbose is excreted via the renal and fecal routes without being metabolized [7].

Miglitol has a dose range of 25–100 mg taken at the beginning of each meal, up to a maximum of 300 mg/day. Miglitol has a rapid onset of action, and peak effect is reached in about two to three hours. The half-life is roughly two hours, and the duration of action is believed to be less than four hours [42,56]. No metabolites have been detected in plasma, urine, or feces, indicating a lack of either systemic or presystemic metabolism [42,61]. The drug is excreted via the renal route [7,42].

Due to the location and mechanism of action, alpha-glucosidase inhibitors are not well absorbed in the intestinal tract. Elevated plasma levels of acarbose have been found in persons with a creatinine clearance of less than 25 mL per minute, suggesting accumulation. With this in mind, caution should be used in these patients. In addition, use of alpha-glucosidase inhibitors is contraindicated in patients with [42]:

Furthermore, women who are pregnant or breastfeeding and children should not use these agents [42].

Side effects for alpha-glucosidase inhibitors are typically confined to the gastrointestinal system and usually occur during initiation of therapy or when adjustments to the dose are made [42]. Potential side effects of alpha-glucosidase inhibitors include [42]:

These side effects are generally self-limiting and transient and can be minimized by starting with a lower dosage and titrating up to desired effect or maximum therapeutic dose [42,56]. When caring for a patient being treated with alpha-glucosidase inhibitors, two-hour postprandial blood glucose levels should be monitored to identify effectiveness of the therapy [3,42]. Studies have demonstrated elevations in serum transaminases (aspartate aminotransferase [AST] or alanine aminotransferase [ALT]), so liver function should also be monitored periodically.

Lastly, alpha-glucosidase inhibitors' effects have the potential to be altered by charcoal products and may diminish the bioavailability of ranitidine, propranolol, and digoxin [42,62].

Potential drug-drug interactions with the use of acarbose include decreased drug levels and/or efficacy when taken in combination with calcium channel blockers, corticosteroids, estrogens, fosphenytoin, hormonal contraceptives, isoniazid, nicotinic acid, phenothiazine, phenytoin, sympathomimetics, thiazides and other diuretics, and thyroid products [42]. Digestive enzyme preparations containing carbohydrate-splitting enzymes (e.g., amylase, pancreatin) and intestinal absorbents (e.g., activated charcoal) may reduce the effects of acarbose [42]. As mentioned, digoxin levels may be reduced when taken in combination with acarbose.

Although in the same category as acarbose, miglitol has different drug interactions including [42,56,62]:

Patient V is a Hispanic man, 61 years of age, presenting to the primary care physician with complaints of polydipsia, polyphagia, and fatigue for the past month. Upon further assessment, he states that he has recently had his eyeglass prescription adjusted due to blurred vision. He is 5 feet 10 inches tall and weighs 245 pounds; his calculated BMI is 35.2 kg/m². The patient reveals a family history of diabetes on both sides. He works a physical job in a warehouse lifting 50-pound boxes. A random finger stick reveals a blood glucose level of 220 mg/dL. As previously discussed, this is sufficient information to diagnose diabetes.

Patient V's fasting blood work reveals the following:

Patient V is referred to an ADA-recognized diabetes education program and is instructed to return for follow-up in three months.

When the patient returns to his primary care physician, his follow-up HbA1c demonstrates minimal change with the result of 8.2% (estimated average glucose: 189 mg/dL) and a fasting blood glucose level of 156 mg/dL. SMBG records reveal fasting blood glucose levels consistently between 135 mg/dL and 160 mg/dL and postprandial levels steadily between 220 mg/dL and 248 mg/dL. His lipid levels remain greater than goal as well. Patient V indicates that he has been following his meal and exercise planning goals but has experienced minimal success.

After evaluation of the patient's blood work, history, and progress to date, the physician decides to utilize the alpha-glucosidase inhibitor, acarbose. Patient V is started on acarbose 25 mg with each meal, and adherence to his culturally specific meal and exercise plans is stressed.

Rationale and comments : Although not commonly utilized, acarbose is appropriate for Patient V due to his elevated lipid levels and postprandial hyperglycemia. His fasting blood glucose levels are above normal, and the physician has determined that his postprandial levels are the cause of the elevated HbA1c levels. Acarbose should improve the patient's postprandial glucose levels and his lipid levels.

Although metformin is beneficial for many people, it should be used with caution in some populations. Women who are pregnant or breastfeeding should not utilize metformin therapy. There have been no formal studies to show benefit or risk analysis when metformin is used during pregnancy. Metformin use should also be temporarily halted in patients who are acutely ill or who are predisposed to acute renal failure or tissue hypoperfusion. Lastly, metformin should be withheld for a minimum of two days or until renal function has returned following any radiologic test utilizing iodinated contrast media [42]. Examples of such tests include urograms, angiography, intravenous cholangiography, and any scans using intravascular contrast media.

Metformin therapy is contraindicated in patients for whom the adverse effects may be life-threatening. This includes patients with elevated serum creatinine levels greater than 1.5 mg/dL for men or greater than 1.4 mg/dL for women, abnormal creatinine clearance from any cause, and patients with an eGFR <30 mL/minute/1.73 m² [7,42,67]. Because metformin is excreted through the kidneys, accumulation of the medication can occur in the presence of renal dysfunction. In 2016, the FDA issued a drug safety communication, new recommendations, and a label change requirement for metformin and metformin-containing medications for use in certain patients with mild-to-moderate renal impairment. The new FDA recommendations include [67]:

Individuals with hepatic dysfunction who are receiving biguanide therapy can be predisposed to lactic acidosis [42]. Due to the potential damaging effects of alcohol on the liver, any individual with a history of alcohol abuse or binge drinking would not be a good candidate for metformin therapy. Finally, individuals with a history of chronic obstructive pulmonary disease or cardiac function impairment should not be prescribed metformin due to the potential of lactate accumulation in these hypoxic conditions [7,42].

Side effects of metformin are relatively mild and self-limiting, with the exception of lactic acidosis. Typically, the side effects are gastrointestinal in nature and resolve within the first few weeks of therapy. Potential side effects include [42]:

Biguanide therapy rarely causes serious side effects, but lactic acidosis has occurred in some cases and is an important consideration for patients taking metformin [42]. Lactic acidosis, although rare, is a potentially fatal metabolic complication. Persons at risk include those with renal insufficiency and those with acute or unstable heart failure who are at risk for hypoperfusion and hypoxemia. Characteristics of lactic acidosis include:

The onset of lactic acidosis symptoms are generally vague and subtle at presentation [3]. The person's symptoms may include malaise, myalgia, nonspecific abdominal pain, increased somnolence, and/or respiratory distress. Serum lactate levels should be monitored periodically or when a patient is at risk for lactate accumulation [62]. If a patient develops symptoms of lactic acidosis while taking metformin, the agent should be discontinued immediately [42,62].

Metformin can interact with other medications and herbs. Knowledge of these interactions is necessary to ensure appropriate patient care. If taken with metformin, beta blockers may potentiate hypoglycemia. There are many medications that may potentiate hyperglycemia, including [56]:

Several medications compete for the same renal tubular transport systems as metformin, which can increase the serum levels of both drugs. Medications with this effect include amiloride, cimetidine, digoxin, morphine, nifedipine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, and vancomycin [42]. In addition to these interactions, consumption of guar gum may decrease hypoglycemic effect of metformin.

Patient K is a white woman, 71 years of age, presenting to her primary care physician with complaints of fatigue, polyuria, polyphagia, and polydipsia for the past few months. She is 5 feet 4 inches tall and weighs 205 pounds, with a calculated BMI of 35.3 kg/m². She confirms a family history of diabetes on her mother's side, a personal history of having given birth to a child weighing more than 9 pounds, and arthritis of her bilateral knees. A finger stick reveals a blood glucose level of 198 mg/dL.

Rationale and comments : Based on the information gathered during the initial examination, Patient K cannot be definitively diagnosed with diabetes. Although symptoms of diabetes are present, a blood glucose level of 198 mg/dL is not diagnostic unless further laboratory testing is completed.

In order to gain additional information, Patient K is referred for a complete blood work-up. The results of this work-up reveal:

Based on this additional information, Patient K is diagnosed with type 2 diabetes and is referred to an ADA-recognized diabetes education program. At her three-month follow-up appointment, the patient's HbA1c level has increased to 8.6% (estimated average glucose: 200 mg/dL) and her fasting blood glucose level is 205 mg/dL. Sporadic SMBG records reveal fasting levels consistently between 180 mg/dL and 210 mg/dL and postprandial levels between 150 mg/dL and 170 mg/dL. Patient K states she did not attend the education class as recommended but has attempted to limit her sugar intake. She denies starting an exercise program because of the pain she experiences in her knees when she tries to walk.

It is determined, taking into account Patient K's blood glucose level and failure to make lifestyle changes, that the best course of treatment is medication therapy utilizing metformin. The patient is prescribed metformin 500 mg each evening and water aerobics for exercise. Her physician again stresses the importance of SMBG and participation in diabetes self-management education.

Rationale and comments : The therapy prescribed is appropriate for Patient K for many reasons. Her fasting blood glucose levels are higher than normal, her postprandial levels are slightly elevated, and she is suspected to have insulin resistance. She is obese and has been non-adherent to her meal and exercise plans. Her SMBG has been erratic. Metformin will positively impact the patient's fasting blood glucose levels by decreasing the liver's production of endogenous glucose, decreasing insulin resistance, and decreasing the reabsorption of carbohydrates in the gut.

Pioglitazone is initially prescribed at a dose of 15–30 mg once daily, which may be increased to the desired response up to a maximum of 45 mg/day [42]. The exact onset of action of pioglitazone is unknown, but peak effect is reached in approximately two hours, a time that may be delayed with food. The half-life of pioglitazone is 16 to 24 hours [42,56]. Pioglitazone is extensively metabolized by hydroxylation and oxidation; the metabolites also partly convert to glucuronide or sulfate conjugates. Following oral administration, approximately 15% to 30% of the dose is excreted in the urine. Renal elimination of pioglitazone is negligible, and the drug is excreted primarily as metabolites and their conjugates. It is presumed that most of the oral dose is excreted into the bile either unchanged or as metabolites and eliminated in the feces [68].

Rosiglitazone should be started at an initial daily dose of 4 mg, regardless of whether it is being used as monotherapy or as part of combination therapy [42]. After several weeks, the dose may be titrated up, if necessary, to a maximum of 8 mg/day. Rosiglitazone may be taken in two divided doses [42,48]. The onset of action for rosiglitazone is unknown; maximum effects may not be present for up to 12 weeks. The drug has a peak action time of about one hour with a half-life of three to four hours [42,56]. Rosiglitazone is extensively metabolized, and the major routes of metabolism are N-demethylation and hydroxylation, followed by conjugation with sulfate and glucuronic acid. All the circulating metabolites are considerably less potent than the parent drug and, therefore, are not expected to contribute to the insulin-sensitizing activity of rosiglitazone. The majority of rosiglitazone metabolites are eliminated in the urine (64%) and the feces (23%) [42,70].

Weight gain is the most recognized side effect with TZD therapy and is thought to be a result of plasma volume expansion leading to edema [42]. As a result of this plasma volume expansion, there is also a small reduction in hemoglobin, hematocrit, and neutrophil counts [7]. Other notable side effects include [3,42]:

In addition, rosiglitazone is associated with specific adverse effect risks, such as [3,42]:

TZD therapy has several known drug-drug interactions, including [56,62]:

The concurrent administration of certain herbs, such as burdock, dandelion, eucalyptus, and marshmallow, can result in potentiation of TZDs' hypoglycemic effects.

Patient H is an African American woman, 38 years of age, presenting to her primary care physician for a routine physical with complaints of fatigue and constant hunger. She is 5 feet 7 inches tall and weighs 235 pounds, with a calculated BMI of 36.9 kg/m². She has a strong history of diabetes and coronary artery disease on both sides of her family, a personal history of gestational diabetes with her last two children, and is employed as a legal secretary. A finger stick reveals a blood glucose level of 213 mg/dL. A diagnosis of diabetes is made, and the patient is referred for fasting blood work, which reveals:

The physician refers Patient H to an ADA-recognized diabetes education program so she may receive information regarding blood glucose monitoring and exercise and meal planning. At her follow-up appointment, the patient's HbA1c has not significantly changed, with a result of 7.7% (estimated average glucose: 174 mg/dL) and a fasting blood glucose level of 172 mg/dL. SMBG records reveal fasting blood glucose levels consistently between 155 mg/dL and 190 mg/dL and postprandial levels steadily between 190 mg/dL and 213 mg/dL. Patient H claims to be adherent to her meal and exercise planning goals but is struggling with weight loss and hunger. As a result, her physician initiates her on TZD therapy. The patient is prescribed pioglitazone 15 mg each morning, and she is advised to continue with her meal and exercise plans. Patient H is also given instructions to report any signs of sudden weight gain, shortness of breath, or chest pains, as these could be signs of excessive fluid retention related to TZD therapy.

Rationale and comments : Patient H has been adherent to her meal and exercise plan with little success and growing frustration. Her morning and postprandial blood glucose levels are above normal, and both contribute to the elevated HbA1c levels. TZD therapy is indicated for Patient H because of her family history of coronary heart disease, obesity, and suspected insulin resistance.

Sitagliptin is generally dosed at 100 mg/day, with decreased doses necessary for patients with renal impairment [42]. It is given once daily and may be used alone or with other medications to obtain the best results. The drug is rapidly absorbed, with time to peak action within one to four hours after ingestion. Sitagliptin has a half-life of 12 hours, with a duration of action equaling 24 hours. Metabolism is a minor pathway of elimination [42]. Six metabolites have been detected at trace levels and are not expected to contribute to the plasma DPP-4 inhibitory activity of sitagliptin. Following administration of sitagliptin, approximately all of the active drug was eliminated in feces (13%) or urine (87%) within one week of dosing, and renal clearance is approximately 350 mL/minute [57]. An estimated 79% of sitagliptin that is excreted in the urine is unchanged drug [42].

Sitagliptin is indicated for patients with type 2 diabetes who are not achieving adequate blood glucose control with medical nutrition therapy and exercise alone. It can be utilized as a monotherapy or in combination with metformin, a secretagogue, or a TZD [7,42]. Sitagliptin may be used for a person with mild renal insufficiency at the full dosage. For patients with moderate renal insufficiency (creatinine clearance of 30–50 mL/minute), the dose should be 50 mg, and for those with a creatinine clearance of less than 30 mL/minute or end-stage renal disease and hemodialysis, the dosage should be 25 mg [42,48].

Saxagliptin is dosed at 2.5–5mg/day, with a lower dose used in patients with moderate or severe renal impairment or when the agent is prescribed in conjunction with a strong cytochrome P450 3A4 inhibitor [42,77]. This agent is approved for use with other drugs or as monotherapy for the treatment of type 2 diabetes in adults. The time to peak action for saxagliptin is approximately two hours, and the drug is metabolized hepatically to 5-hydroxy saxagliptin, an active metabolite [77]. The majority of the drug and the metabolite are excreted in the urine (75%) and the feces (22%) [42].

Saxagliptin may be initiated as a single therapy or in conjunction with metformin, under the brand name Kombiglyze XR [42]. It may also be added on to an ongoing metformin, sulfonylurea, or TZD regimen. No adjustment of dosage is necessary for BMI, gender, or age. For patients with a creatinine clearance of 50 mL/minute or less, the recommended dosage is 2.5 mg once daily; for those with end-stage renal disease, a dose of 2.5 mg should be given once daily after dialysis [42].

Linagliptin was approved by the FDA in 2011 for the treatment of patients with type 2 diabetes that is uncontrolled by diet modification and exercise [77]. In addition to monotherapy, it has also been studied as add-on therapy with metformin, pioglitazone, and a sulfonylurea. When used with a secretagogue, the dose of the secretagogue should be lowered in order to reduce the risk of hypoglycemia [62,80]. Linagliptin is absorbed rapidly, with an onset of action of about 1.5 hours [42]. It is primarily excreted as unchanged drug in the feces (80%) and urine (5%) [42].

No dosage adjustment is necessary for patients with renal or hepatic impairment. Concurrent use of linagliptin with either insulin or a secretagogue is associated with an increased risk for hypoglycemia [42]. The medication may be taken with or without food, and the only significant contraindication is allergy or hypersensitivity to linagliptin [42,77].

Approved by the FDA in 2013, alogliptin is now available in the United States. It is usually dosed at 12.5–25 mg/day and is available in fixed-dose formulations with metformin (brand name Kazano) and with pioglitazone (brand name Oseni) [42,73]. Alogliptin is approved for use with diet and exercise to improve blood sugar control in adult patients with type 2 diabetes.

Alogliptin or its combination formulations may be added to an ongoing regimen. It has been shown to be safe and effective in reducing HbA1c in 14 clinical trials involving more than 8,500 patients [73]. The most common side effects are nasal congestion, headache, and upper respiratory tract infection [42]. In 2013, the FDA requested that the manufacturer complete postmarking studies related to the safety of the drug, including a cardiovascular outcomes trial, a study monitoring for liver abnormalities, and three pediatric studies [73]. A safety review published by the agency in 2016 found that alogliptin may increase the risk of heart failure, particularly in patients with heart or kidney disease [79]. As a result, the agency has added new warnings to drug labels.

Patient B is a Pacific Islander woman, 64 years of age, presenting to the primary care physician with complaints of a urinary tract infection (UTI) and fatigue. She attributes the fatigue to waking frequently at night due to the UTI. The patient denies any recent history of febrile states or pain with urination. She is 5 feet 1 inch tall and weighs 170 pounds, with a calculated BMI of 32.2 kg/m². She confirms a family history of diabetes on her mother's side and admits to a sedentary lifestyle.

Patient B's urine sample is negative for infection. A random finger stick reveals a blood glucose level of 207 mg/dL. She is diagnosed with type 2 diabetes based on her blood glucose level and the characteristic symptoms (polyuria and fatigue).

In order to gain additional information, Patient B is referred for fasting blood work. The results of this blood work indicate:

Patient B is referred to an ADA-recognized diabetes education program and is initiated on treatment for dyslipidemia based on her very high LDL level and borderline high triglycerides.

When Patient B returns for her three-month follow-up appointment, she acknowledges compliance to her meal and exercise planning goals with very little success. Her repeat HbA1c demonstrates minimal change with a result of 7.6% (estimated average glucose: 171 mg/dL) and a fasting blood glucose level of 165 mg/dL. Her fasting levels during SMBG are generally between 145 mg/dL and 170 mg/dL; her postprandial levels are between 170 mg/dL and 190 mg/dL.

DPP-4 therapy is determined to be the best treatment choice to control Patient B's diabetes. She is started on sitagliptin 100 mg each morning and continues her meal plan and exercise program.

Rationale and comments : Patient B's higher than normal fasting and postprandial blood glucose levels are contributing to the elevated HbA1c levels, and she has been adherent to her meal plan and exercise program with minimal success. This treatment is appropriate for Patient B because DPP-4 therapy assists in weight loss while impacting blood glucose levels.

The most common side effects associated with SGLT2 inhibitors are vulvovaginal candidiasis and urinary tract infection [82]. Other possible adverse effects include increased serum potassium, renal insufficiency, and hypoglycemia [42]. In 2013, the FDA requested that the manufacturer of canagliflozin complete postmarking studies, including a cardiovascular outcomes trial; an enhanced pharmacovigilance program to monitor for malignancies, liver abnormalities, pancreatitis, hypersensitivity reactions, photosensitivity reactions, and adverse pregnancy outcomes; a bone safety trial; and two pediatric studies [82].

In 2015, the FDA issued a warning that canagliflozin, dapagliflozin, and empagliflozin may lead to ketoacidosis. The warning was based on the identification of 20 cases of diabetic ketoacidosis requiring hospitalization in patients treated with SGLT2 inhibitors between March 2013 and June 2014. Later in the year, the FDA revised the labels of SGLT2 inhibitors, warning about the risks of ketoacidosis as well as serious urinary tract infections. Additionally, the FDA is requiring manufacturers of the drugs to conduct enhanced pharmacovigilance studies to evaluate spontaneous reports of ketoacidosis in patients treated with SGLT2 inhibitors. The enhanced studies include a five-year period of specialized follow-up to collect additional information [85,86,87].

In 2022, the FDA approved changes to the prescribing information for SGLT2 inhibitors. To lessen the risk of ketoacidosis following surgery, the agency recommends that healthcare professionals consider stopping canagliflozin, dapagliflozin, and empagliflozin at least three days prior to surgery and ertugliflozin at least four days prior to surgery [88]. Patients are advised to stop taking their SGLT2 inhibitor and to seek medical attention immediately if they have any symptoms of ketoacidosis (e.g., nausea, vomiting, abdominal pain, fatigue, trouble breathing) or signs or symptoms of a urinary tract infection [88].

In 2016, the FDA alerted the public about interim safety results from an ongoing clinical trial that found an increase in leg and foot amputations, mostly affecting the toes, in patients treated with canagliflozin. Also in 2016, the FDA strengthened the existing warning about the risk of acute kidney injury with canagliflozin and dapagliflozin. The warning was based on reports of 101 confirmable cases of acute kidney injury, some requiring hospitalization and dialysis, with canagliflozin or dapagliflozin use [89].

In 2017, based on data from two large clinical trials, the FDA confirmed the increased risk of leg and foot amputations with canagliflozin and issued requirements for a new boxed warning [90]. In 2020, the FDA removed the boxed warning about amputation risk with canagliflozin after review of new data from three clinical trials [91]. In 2018, the FDA issued a warning about rare but serious necrotizing fasciitis of the perineum associated with SGLT2 inhibitor therapy [92].

Let us revisit Patient K, who has been taking metformin to control her type 2 diabetes. One year ago, Patient K was started on metformin 500 mg each evening with recommendations to attend diabetes self-management education. Since then, her dosage has been titrated up, and she currently takes metformin 1,000 mg twice per day. At her scheduled appointment, Patient K has an HbA1c level of 8.8% (estimated average glucose: 206 mg/dL) and claims to be adherent with her meal and exercise plan the majority of the time. Occasional SMBG indicates fasting levels between 145 mg/dL and 170 mg/dL and postprandial levels between 180 mg/dL and 230 mg/dL. Although the metformin achieved a small decrease in Patient K's blood glucose levels, she has not obtained satisfactory results. More intensive therapy, with a second antihyperglycemic agent, is necessary, and the physician prescribes glyburide 2.5 mg daily. Upon hearing this, the patient becomes teary-eyed and expresses concerns about the cost of the new medication. She states she is on a fixed income and can barely make ends meet. The physician offers to prescribe a combination medication that is less expensive than the two agents separately. Patient K agrees and is prescribed Glucovance 2.5 mg/500 mg in the morning and continues with metformin 1,000 mg in the evening.

Patient K returns for a three-month follow-up. Her HbA1c demonstrates a decrease, with the result of 8.1% (estimated average glucose: 186 mg/dL) and a fasting blood glucose level of 110 mg/dL. SMBG records show fasting blood glucose levels consistently between 98 mg/dL and 120 mg/dL and postprandial levels between 160 mg/dL and 200 mg/dL. The patient has also made great improvements in adhering to meal plans, exercise goals, and SMBG. However, the physician stresses the need for Patient K's HbA1c level to be less than 7.0%, and they agree to change therapy to Glucovance 2.5 mg/500 mg twice per day. The patient agrees to wake at 3 a.m. at least twice in the first week to test her morning blood glucose level to assess for nocturnal hypoglycemia.

Rationale and comments : Patient K's morning blood glucose levels are close to optimal, but her postprandial levels remain elevated and her HbA1c level remains suboptimal. She has demonstrated greater adherence to her meal, exercise, and SMBG plans. Metformin will continue to impact her fasting and mid-day blood glucose levels by decreasing the liver's production of endogenous glucose, decreasing insulin resistance, and decreasing the reabsorption of carbohydrates in the gut. In addition, glyburide will assist the pancreas in the production of insulin. Patient K will require education regarding the importance of determining the presence of nocturnal hypoglycemia, signs and symptoms of hypoglycemia, and conditions that require communication with her primary care physician.

One available insulin analog that may be administered in bolus therapy is insulin aspart (recombinant DNA [rDNA] origin). This type of insulin is rapid-acting and is nearly homologous with regular human insulin. It is produced using Pichia pastoris or Saccharomyces cerevisiae, also known as baker's yeast [101]. A slight change in the insulin chain makes insulin aspart more rapidly absorbed than regular insulin. Insulin aspart is available in a concentration of 100 units/mL (U100). Its onset of action is 5 to 15 minutes, and the peak of action is one to three hours. The effective duration of action for insulin aspart is less than five hours [42,48]. Unlike oral antihypoglycemic agents, insulin aspart does not have a maximum dosage, but is specific to the individual [102].

Insulin aspart is available in 10 mL vials containing U100 insulin aspart and in prefilled and cartridge pens containing 3 mL of U100 insulin. These preparations can be stored unopened until the expiration date; however, once opened or punctured, insulin aspart will expire in 28 days regardless of storage location [42,56]. If stored in a refrigerator, it is important to allow the insulin aspart to warm to room temperature before administration for greater absorption rates and comfort [101]. It is important to note that although refrigeration is permissible, cartridges should not be refrigerated after they are punctured [56,101]. Although cartridge pens have been available for several years, in 2010 and 2011 the manufacturer began to discontinue these pens in favor of the prefilled types.

Afrezza (insulin human) inhalation powder is indicated to improve glycemic control in adult patients with type 1 and type 2 diabetes [42,103]. Inhaled insulin can be useful for patients who have an aversion to injection [35]. Afrezza inhalation powder is available in three strengths: 4-U, 8-U, and 12-U single-use cartridges that are color-coded for patient ease of use. The inhaler is individually packaged. It must be discarded after 15 days of use and replaced with a new inhaler [103]. The initial dose in insulin-naïve patients is 4 U at each meal. A conversion scale is available to guide replacement of prandial or premixed insulin with inhaled insulin [42,103]. Dosage adjustments may be needed based on the patient's metabolic needs, blood glucose monitoring results, glycemic control goal, changes in physical activity, or changes in meal patterns [103]. Afrezza is contraindicated during episodes of hypoglycemia and in patients with chronic lung disease (e.g., asthma, COPD). The agent contains a boxed warning of risk of acute bronchospasm in patients with chronic lung disease [103]. Hypoglycemia is the most common adverse reaction [42,103].

Insulin lispro (rDNA origin) is also a rapid-acting human insulin analog. This type of insulin is created from a non-pathogenic strain of Escherichia coli that has been genetically altered by the addition of the gene for insulin lispro [104]. Like insulin aspart, insulin lispro is available in a U100 concentration and has no labeled maximum dose [102]. Its onset of action is 15 to 30 minutes, and peak effect is experienced in 30 minutes to 2.5 hours. Insulin lispro has an effective duration of action of less than five hours [42,48].

Insulin lispro is available in 10 mL vials for subcutaneous injection, intravenous injection, or infusion via insulin pump. It can be stored at room temperature or refrigerated unopened until the expiration date [42,56]. After the vial has been opened, it must be used within 28 days. If the vial is stored in the refrigerator, it should be allowed to warm to room temperature prior to use [104].

Insulin glulisine (rDNA origin) is another rapid-acting insulin analog. As with insulin lispro, insulin glulisine is synthesized from non-pathogenic E. coli. It is available in U100 concentration in 10 mL vials or 3 mL cartridges [42,48,56]. The onset of action for insulin glulisine is 15 to 30 minutes, with peak action reached within approximately 1.5 to 2.5 and a duration of action of three to four hours [42].

Insulin glulisine may be administered via subcutaneous injection, intravenous injection, or insulin pump. Like other insulin analogs, opened vials of insulin glulisine must be used within 28 days and may be stored at room temperature or refrigerated. Refrigerated vials should be brought to room temperature before use [42]. Preparations mixed for intravenous use are stable at room temperature for 48 hours [42].

There are two preparations of regular human insulin on the market: Humulin R and Novolin R. Both preparations are similar in action but differ in chemical make-up. Both have an onset of action of 15 to 30 minutes, and peak action is noted at 2.5 to 5 hours. The effective duration of action is between 2 to 12 hours [42]. Regular insulin can be utilized as a subcutaneous injection, intravenous infusion, insulin pump infusion, or inhaled mist, although insulin analogs are now more widely used [96,105].

Humulin R is created in a non-pathogenic strain of E. coli and consists of zinc-insulin crystals dissolved in a clear fluid. It is a sterile solution and is for subcutaneous, not intramuscular, injection [104]. The concentration of Humulin R is U100 or U500 [42,56].

Novolin R (rDNA origin) is structurally identical to natural human insulin and is produced utilizing S. cerevisiae [106]. Novolin R is only available in the U100 concentration in 10 mL vials [56]. Humulin R and Novolin R may be stored at room temperature until expiration or up to 31 days after the vial is opened [42].

In addition to their use in the everyday management of diabetes, the action and short half-life of these insulins, both regular and analogs, makes them well suited for use in the treatment of hyperglycemic states resulting from metabolic changes in response to system stresses, such as surgery, trauma, and sepsis. Hyperglycemia and insulin resistance are common in critically ill patients, even when glucose homeostasis has previously been normal. This effect is amplified in diabetics because diabetic patients cannot increase insulin production to counteract the effect of the increase in catabolic hormones. In some patients, the insulin requirements may increase more than 10-fold [107]. Many critically ill patients are also receiving high-carbohydrate feedings in the form of hyperalimentation or enteral feeding, which can contribute to increased blood glucose levels. Therefore, providing adequate amounts of insulin to promote euglycemia and enough nutrition to avoid hypoglycemia, proteolysis, and lipolysis is a challenge in critically ill patients [108]. When this balance is not maintained, either due to poor diabetes control or illness/trauma, hyperglycemic crises, such as diabetic ketoacidosis or HHS, may develop.

Diabetic Ketoacidosis

Diabetic ketoacidosis is caused by the body's inability to utilize glucose due to a lack of insulin. Because glucose is unavailable for energy needs, fat is used as a fuel source. The byproducts of this fat metabolism (i.e., ketones) accumulate, and electrolyte disturbances, acidosis, and severe dehydration result [109]. It occurs most often in persons with type 1 diabetes, but it can occur in patients with type 2 diabetes as well [110]. Children younger than 5 years of age and those without ready access to health care are at the greatest risk to develop diabetic ketoacidosis [111]. Factors that can precipitate the development of this disorder include [96,110,112]:

• Severe infection

• Serious illness, such as myocardial infarction

• Inappropriate dosing or skipped or missed doses of insulin

• Continuous subcutaneous insulin infusion failure

• Leaving insulin pump infusion sets intact for longer than the manufacturer recommendation

• Growth spurts in children and adolescents

• Steroid therapy

• Alcohol or illicit drug use

• Stress

The diagnostic criteria for diabetic ketoacidosis includes a plasma glucose level greater than 250 mg/dL and an arterial pH less than 7.3 [110,113]. It is further classified based on arterial pH level and mental status as mild (pH 7.25–7.3, alert), moderate (pH 7–7.24, alert/drowsy), or severe (pH <7, stupor/coma). Conditions associated with diabetic ketoacidosis requiring prompt treatment and correction include [2,110]:

• Chronic hyperglycemia and glucotoxicity

• Acidosis

• Low blood volume

• Hyperosmolality and associated potassium loss

The Institute for Clinical Systems Improvement recommends that for insulin-deficient patients, despite reductions or the absence of caloric intake, basal insulin must be provided to prevent diabetic ketoacidosis.

(https://www.icsi.org/wp-content/uploads/2019/02/Diabetes.pdf Last Accessed: October 28, 2022)

Level of Evidence: Expert Opinion/Consensus Statement

Diabetic ketoacidosis is considered a medical emergency, and if left untreated, it can result in death. Healthcare professionals require the knowledge and critical thinking skills to swiftly recognize the signs and symptoms of diabetic ketoacidosis and provide rapid treatment [110].

In critically ill patients, symptoms of diabetic ketoacidosis can prevent the treatment of the triggering condition. The early signs of ketoacidosis, such as unexplained hyperglycemia, nausea, weakness, fatigue, and confusion, can prevent the individual from partaking in SMBG and insulin administration [96,110].

A successful outcome is based on the recognition and prompt treatment of this medical emergency, initiation of intensive therapy, and careful clinical follow-up. Goals for treatment include rehydration, providing adequate insulin to restore normal glucose metabolism, and correction of electrolyte deficiencies and acidosis [110,112,114].

Fluid Replacement

The partial correction of dehydration within the first few hours of therapy is necessary to significantly reduce hyperglycemia and ketonemia. This is accomplished by fluid replacement [110,113]. Adults with diabetic ketoacidosis may present with a deficit of more than 6 liters of fluid [115]. Initial fluid replacement consists of 50% normal saline or 100% normal saline, depending on serum sodium levels, urine output, and the individual's state of dehydration [112,113,114].

Phosphate concentration decreases with insulin therapy. Although studies have failed to show any beneficial effect of phosphate replacement on the clinical outcome in diabetic ketoacidosis, the ADA states that phosphate replacement may be indicated in patients with cardiac dysfunction, anemia, or respiratory depression, or in patients whose serum phosphate concentration is less than 1.0 mg/dL. The ADA recommends that 20–30 mEq/L potassium phosphate be added to replacement fluids when needed [113].

Insulin Replacement

All individuals with diabetic ketoacidosis require insulin therapy, which should be started soon after initiation of fluid replacement therapy. Insulin therapy is best accomplished by a continuous insulin infusion of rapid- or short-acting insulin [110,114]. Intravenous insulin is the most effective route in this case because it can be adjusted rapidly and is not dependent on tissue perfusion for absorption, as is subcutaneous delivery [110,113]. The initial intravenous bolus of regular insulin or insulin analog is 0.1–0.15 units/kg. This is followed by an infusion of 0.1 units/kg/hour, which is titrated to lower blood glucose 50–75 mg/dL/hour. A decrease in blood glucose greater than 75 mg/dL/hour is associated with the potential complication of cerebral edema [110,114]. Insulin therapy should continue until metabolic control is achieved [110].

Correction of Electrolyte Imbalances

It is necessary to provide aggressive potassium supplementation for all individuals with diabetic ketoacidosis, as depletion of potassium can lead to cardiac dysrhythmias. However, renal function must be replaced prior to the administration of potassium [115]. If the potassium level is 4.5–6 mEq/L, administer 10 mEq/h of potassium chloride. If the level is 3–4.5 mEq/L, administer 20 mEq/h of potassium chloride. Supplementation is not needed if the potassium level is greater than 6 mEq/L. Monitor serum potassium levels hourly and stop if the level is greater than 5 mEq/L [110].

The use of bicarbonate for the treatment of acidosis is no longer routine unless the metabolic acidosis is severe [110,113,114,115]. If bicarbonate therapy is utilized, 1–2 mEq/kg should be administered over two hours followed by an assessment of plasma bicarbonate levels until the venous pH is >7.0 [113]. Total bicarbonate treatment should not exceed 5 mEq/kg in a 12-hour period [116].

Prevention

The prevention of diabetic ketoacidosis can often be accomplished with patient education regarding the condition and recognition of the initial signs and symptoms. Patients with type 1 diabetes or ketosis-prone type 2 diabetes should be educated and assessed for understanding regarding the recognition of the early warning signs. Individuals with infections or who are on injection or infusion insulin therapy may benefit from regularly measuring urine ketones and adjusting insulin doses and diet in accordance with findings [117].

NPH insulin is manufactured by two companies and marketed in the United States as Novolin N or Humulin N [42]. NPH is a zinc insulin suspension that includes the polypeptide protamine. It is produced in a concentration of 100 units/mL and generally appears cloudy or milky [121]. As with some insulin analogs, the insulin in NPH is synthesized using noninfectious E. coli bacteria.

NPH is available only in U100 concentration vials or pre-filled pen preparations [56]. The onset of action is within 1 to 2 hours, with peak effect to be expected within 4 to 12 hours [42]. NPH is considered an intermediate-acting insulin as its effective duration is longer than regular insulin or insulin aspart but not as long as insulin glargine or detemir [42,48]. Due to its wide variation in effective action time, this insulin may be prescribed once or twice per day [2]. As with most insulin preparations, NPH can be stored at room temperature or refrigerated until it expires or for 31 days after it is opened. As with any injectable insulin, it should be room temperature prior to injection [56].

Insulin glargine is a long-acting recombinant human insulin analog. It is available in U100 concentration vials, 3-mL cartridges, or 3-mL disposable devices [56,62]. The onset of action is three to four hours, and glargine is considered to be peakless in terms of action [42]. Insulin glargine was the first insulin to be truly long acting, with an effective duration of action of 20 to 24 hours [48]. The rate of absorption does not differ among various sites of injection, and the pharmacokinetics within various individuals is fairly consistent [2].

In 2021, the first biosimilar insulin (insulin glargine-yfgn) was approved by the FDA [122]. As an agent that is readily interchangeable with insulin glargine, it is hoped that this approval will improve availability and affordability of insulin therapy.

Like insulin glargine, insulin detemir is a long-acting basal insulin analog with up to 24 hours duration of action [62,123]. It was approved in 2005 by the FDA for use in maintaining background insulin in patients with type 1 or type 2 diabetes [124].

Insulin detemir is available in U100 concentration vials, 3-mL cartridges, and 3-mL prefilled syringes [42,56]. The onset of action for insulin detemir ranges from three to eight hours, and it is also considered a peakless insulin. The effective duration of action of insulin detemir is dose-dependent and varies from just under 6 hours to 23 hours [42,48]. The duration is mediated by slow absorption from the injection site and slow distribution to target tissues due to a strong self-association and albumin binding [2].

In 2009, the FDA issued a public health advisory regarding stolen vials of insulin detemir [125]. Stolen vials had reappeared on the market, and because handling and storage of these vials (lots XZF0036, XZF0037, and XZF0038) is unknown, patients should not use them.

Insulin glargine, insulin detemir, and NPH preparations are not appropriate for continuous subcutaneous insulin infusion or intravenous infusions and should only be considered for basal insulin therapy [2]. According to the ADA, subcutaneous basal insulin is a preferred treatment option to correct hyperglycemia in noncritically ill hospitalized patients as part of a basal-bolus or basal-plus-correction insulin regimen [35]. Subcutaneous injection sites for intermediate- or long-acting insulins include the abdomen, buttocks, posterior-lateral area of the arm, and lateral area of the thigh [126].

Insulin degludec is another long-acting insulin with "peakless" action over a 24-hour period. It is preferred in patients with symptomatic hyperglycemia or ketonuria. The initial dose is 10 units once daily or 0.1–0.2 units/kg once daily. A dose of 0.2-0.3 units/kg/day is recommended for insulin resistance [42]. Insulin degludec should not be administered IV or IM or in an insulin infusion pump and should not be used if the solution is viscous or cloudy. The onset of action for degludec is about one hour [17].

As with any other insulin therapy, the greatest side effect risk is hypoglycemia [42]. Hypoglycemia is a result of one of two different issues: hyperinsulinemia (resulting from too much exogenous insulin, an insulin-secreting pancreatic tumor, or excessive diabetes medication) or iatrogenic (alteration in glucose counter-regulation) [127]. In the case of exogenous insulin therapy, hypoglycemia is due to the effects of hyperinsulinemia [100].

The benefits of the intermediate- and long-acting insulins include the benefit of improved blood glucose control with a minimized risk of hypoglycemia [128]. For many patients, the greatest benefit of basal therapy is achieved when used in combination with bolus insulin to more effectively mimic the normal physiology of the pancreas [128].

Patient T is a defense attorney in a busy prestigious law firm. She has dealt with type 1 diabetes since the age of 13 years. She was started on an insulin pump in order to improve her blood glucose control and her overall health. Patient T has been happy with the results achieved with the pump, with the exception of a recent weight gain of 10 pounds and increases in her postprandial blood glucose levels. She confers with her endocrinologist regarding options to decrease the postprandial levels and alleviate any further weight gain.

The endocrinologist suggests treatment with exenatide. However, Patient T is concerned with returning to a twice-daily injection, which is one reason she appreciates insulin pump therapy. The patient and her endocrinologist discuss this option, and although she is hesitant to return to daily injections, the patient chooses to attempt the therapy. The endocrinologist prescribes exenatide 5 mcg twice daily.

After four weeks of therapy with exenatide, Patient T returns for follow-up. She states that although she initially experienced nausea, her weight is starting to trend down and her postprandial levels are improving. Patient T indicates she would like to continue with the exenatide therapy based on seen benefits.

According to the Institute for Clinical Systems Improvement, nonadherence with diabetes medications can limit the success of therapy and help to explain why a patient is not achieving treatment goals. To screen for nonadherence, clinicians can ask patients open-ended, non-threatening questions at each office visit.

(https://www.icsi.org/wp-content/uploads/2019/02/Diabetes.pdf Last Accessed: October 28, 2022)

Level of Evidence: Expert Opinion/Consensus Statement

Patient education is of the utmost importance when it comes to prevention of adverse effects and detrimental outcomes related to diabetes medication therapy. Each class of diabetes medication requires specific instructions and education. Many healthcare providers leave diabetes self-management education to a certified diabetes educator prepared to provide this type of formal education, which is optimal. However, consistent reinforcement is needed and is best done at every patient interaction in the form of teachable moments [14]. It is important to consider each individual's specific comprehension and comfort level. Encompassing a variety of theories and teaching styles is paramount [3].

Fundamental topics for all individuals taking a medication to prevent and correct hyperglycemia include [3,56]:

Any person receiving medication therapy for diabetes should be educated regarding the prevention, signs and symptoms, and treatment of hypoglycemia. Overmedication, meal skipping, alcohol consumption, excessive exercise, drug interactions, illness or infection, and trauma can all precipitate hypoglycemia in patients taking certain medications, particularly insulin secretagogues.

Prevention of hypoglycemia includes not skipping meals and eating prior to exercise. Additionally, patients should be advised regarding what to do in the event of a missed medication dose. Most medication preparations should be taken as soon as the missed dose is realized, with a few exceptions. If the medication is repaglinide or nateglinide, or if it is too close to the time of the next dose, the dose should be skipped altogether [56]. Patients should also know the signs and symptoms of hypoglycemia, which include [142]:

In general, patients can manage instances of hypoglycemia using the 15:15 rule. According to this rule, patients should treat low blood glucose with 15 grams of carbohydrate and recheck their blood glucose level in 15 minutes. Fifteen grams of carbohydrate would consist of three to four glucose tablets, 4 ounces of fruit juice, one-half can of regular soda, or one tube of glucose gel. In cases of severe hypoglycemia, when the individual is unable to swallow or has a potential of choking, the treatment includes dextrose 50% intravenously or, if intravenous access is unavailable, an intramuscular injection of glucagon [2].

Patient selection is critical to the successful use of insulin or noninsulin injectable therapy. The ideal candidate would be motivated, compliant, educable, and without any other medical condition or physical limitations that preclude accurate and reliable SMBG and insulin administration [2]. Caution is required in the elderly population or for any individual who could have difficulty with the identification of signs and symptoms of hypoglycemia. For patients with type 2 diabetes, insulin therapy is most commonly reserved for individuals in whom a sufficient trial of diet, exercise, and oral medication therapy has proven ineffective [2].

Any individual initiating injectable therapy to control diabetes requires specific instructions to safely administer the medications. Necessary education related to injectable therapy includes injection techniques, site rotation, needle disposal, and identification of signs and symptoms of hypoglycemia [143].

Patient W is a Native American woman, 48 years of age, who is admitted to the hospital with complaints of chest pain. She is 5 feet 6 inches tall and weighs 256 pounds; her BMI is 41.4 kg/m². Her vital signs are assessed; her heart rate is 122 beats per minute, regular rate and rhythm, blood pressure is 198/101 mm Hg, and oral temperature is 37.4 degrees Celsius. Her past medical history is positive for gestational diabetes with her fourth child (five years previous), bilateral arthritis of the knees, and tobacco use. Patient W denies use of recreational drugs and homeopathic pharmaceuticals, but she does admit to occasional alcohol usage, generally two beers per day on the weekend. Her family history includes diabetes, heart disease, stroke, lung cancer, and alcohol abuse. Although her electrocardiogram is negative for myocardial infarction, her stress test reveals left coronary artery ischemia. Her cardiac enzymes are negative, but other significant laboratory results include:

Patient W is admitted for a cardiac catheterization and further cardiac work-up. She is started on blood glucose monitoring before meals and at bedtime with weight-based insulin correction with analog (rapid-acting) insulin, a calorie-controlled cardiac diet, antihypertensive medication, a statin for lipid management, an angiotensin-converting enzyme inhibitor, and pain medications as needed for chest pain or discomfort.

On hospital day 2, Patient W has a fasting blood glucose of 210 mg/dL. She receives rapid-acting insulin coverage per weight-based protocol even though she is being prepared for cardiac catheterization in the late morning and has not eaten. At approximately 10 a.m., the patient is taken for a cardiac catheterization, which reveals a 90% blockage of the left coronary artery, and subsequently undergoes percutaneous coronary intervention (PCI). A drug-eluting stent is placed. Postprocedure, Patient W returns to her room mildly sedated with an arterial line in place and a blood glucose level of 201 mg/dL, for which she receives weight-based coverage. At 5 p.m., the patient is alert and hungry. Her arterial line is discontinued, and her blood glucose is 220 mg/dL, for which she again receives weight-based coverage. At 9 p.m., Patient W has been pain free throughout the day and is ready to sleep. Her blood glucose level is 201 mg/dL. She is given insulin and is instructed to notify the nurse of any pain, palpitations, sweating, shakiness, and/or dizziness.

On hospital day 3, Patient W awakens with a blood glucose level of 248 mg/dL. Her physician initiates basal insulin to obtain better glucose control. She is cleared for discharge by her cardiologist, but her primary care physician would prefer to monitor her glucose levels for one more day, including her two-hour postprandial level after her evening meal. Throughout the day, the following blood glucose levels are documented:

The following morning, Patient W is discharged to home with a prescription for glyburide 2.5 mg twice a day for her newly diagnosed type 2 diabetes. She is also referred to an ADA-recognized education program. She receives survival skills education prior to leaving the hospital and is encouraged to contact the outpatient education center within the first week after discharge. Patient W agrees with her discharge plan and states understanding of all instructions given.

Rationale and comments : The treatment approach appears appropriate to manage Patient W's diabetes. Patient education will be extensive for this patient given the many new medications and changes associated with the PCI and her various conditions. Education specific to the glyburide should include instructions to eat meals at a consistent time (not skipping meals) and information regarding the signs, symptoms, and treatment of hypoglycemia.

At her follow-up appointment, Patient W has completed her self-management education and set personal behavior change goals for meal planning and exercise. She is demonstrating competent SMBG assessment; her fasting levels are between 140 mg/dL and 170 mg/dL, and her postprandial levels range from 160 mg/dL to 200 mg/dL. The patient's occasional two-hour postprandial readings range from 190 mg/dL to 230 mg/dL. Her fasting laboratory results are as follows:

In order to improve Patient W's blood glucose control, her physician chooses to increase her glyburide to 5 mg twice a day with instruction to return for follow-up in one month to assess the efficacy of treatment. In one month, Patient W continues to have difficulties achieving optimal control on monotherapy. The decision is made to start combination therapy with pioglitazone, a TZD.

Rationale and comments : Combination therapy with a TZD is the correct choice for Patient W because her BUN and creatinine levels are too high to safely utilize metformin. Furthermore, her casual use of alcohol on the weekends can be an area of concern with the potential for liver dysfunction. Pioglitazone will address the issue of insulin resistance in the presence of the metabolic syndrome and has beneficial effects on coronary artery disease in the presence of type 2 diabetes.

Prior to leaving the physician's office, the nurse reviews the signs and symptoms of hypoglycemia with Patient W. The patient is instructed to alert her primary care physician of frequent episodes of hypoglycemia. She is also counseled regarding the need to eat meals at spaced intervals throughout the day to decrease the chances of developing hypoglycemia.

The heart failure risks associated with TZD use are discussed as well as the need to report any weight increase of 3 to 5 pounds over a two-day period to her primary care physician. Patient W is also advised to contact her primary care physician if she experiences any symptoms related to liver dysfunction/failure, such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or dark urine. Finally, the patient is reminded of the need to monitor her liver function by venipuncture periodically while on pioglitazone.

Patient O is a Hispanic male, 48 years of age, with a seven-year history of type 2 diabetes. He presents to his primary care physician's office for a routine follow-up appointment to assess his diabetes control. His only complaint at the time of his appointment is an occasional burning sensation in his bilateral lower extremities.

Patient O's past medical history is positive for type 2 diabetes diagnosed at 41 years of age, hypertension for the past two years, and new onset of hyperlipidemia within the past six months. He is negative for renal disease, retinopathy, and peripheral vascular disease. The patient's family history is positive for type 2 diabetes, coronary artery disease, cerebral vascular accident, hyperlipidemia, and obesity.

During the physical assessment, Patient O is alert and oriented. His height (5 feet 10 inches), weight (239 pounds), and BMI (34.4 kg/m²) are measured and documented. Blood pressure is 128/68 mm Hg on medications, pulse is 74 beats per minute, and oral temperature is 37 degrees Celsius. Lungs are clear to auscultation, and heart sounds are clear without rubs or murmurs. The patient's abdomen is soft and nontender at all quadrants. Peripheral pulses are present at +2 at all extremities, and feet are free from lesions with a positive Babinski reflex. All extremities are warm to touch and responsive to monofilament test.

Patient O's laboratory results include:

The patient is currently prescribed captopril 25 mg twice a day, simvastatin 40 mg daily at bedtime, metformin 1,000 mg twice per day, and glipizide extended-release 20 mg daily. He has previously met with a registered nurse certified diabetes educator and registered dietitian certified diabetes educator regarding self-care management, blood glucose monitoring, behavior change, meal planning, and goal setting. He tests his blood glucose levels twice a day at various times.

At this visit, Patient O receives the results of his blood work and has expressed concerns regarding his recent SMBG numbers and new onset of burning in his lower extremities. He presents verbalizing frustration and feeling like a failure. It is vital to actively listen to the patient regarding his frustrations and fears related to his diabetes. It is also important to educate him regarding the progressive nature of diabetes, regardless of the attentiveness a person gives to the care of the disease [2].

The nurse reviews Patient O's eating and exercise habits to see if any changes could be made to optimize control. Furthermore, sources of stress are discussed. Patient O is told that worrying about the progression of his diabetes and having anxiety regarding adherence to his meal or exercise plan is normal, but it is possible for this additional stress and anxiety to result in increased blood glucose levels [7]. Patient O states that he was unaware of the impact stress was having on his body.

Due to the continued elevated blood glucose levels, the primary care physician wants to maximize oral medication therapy, most likely by adding a DPP-4 inhibitor, an alpha-glucosidase inhibitor, or a TZD [2]. In order to make a decision regarding the most appropriate agent, each of the classes' benefits and risks should be considered with Patient O in mind. The addition of a DPP-4 inhibitor has been shown to be weight neutral, occasionally demonstrating a reduction in weight. The dose can be decreased for safe use in those individuals who have some renal impairment, such as Patient O [57]. The greatest drawback of DPP-4 inhibitor therapy is the cost.

The addition of an alpha-glucosidase inhibitor is a less expensive option and would benefit Patient O by decreasing the absorption of complex carbohydrates in the intestinal tract. The alpha-glucosidase inhibitors do have objectionable side effects, such as recurrent flatulence, that some patients are unable to tolerate [56]. Patient education needs for those taking alpha-glucosidase inhibitors include timing of medication with meals, gastrointestinal side effects, and the treatment of hypoglycemia [42,56,60].

The addition of a TZD would reduce insulin resistance and reduce cardiovascular risk factors, including markers of vascular inflammation [2]. However, precautions should be taken when this therapy is prescribed. Weight gain and liver damage are possible, and laboratory levels should be regularly monitored. Patient education regarding weight gain and shortness of breath is necessary as these are signs of impending heart failure.

The final option for Patient O would be to continue current therapy and add basal insulin. This would provide long-acting coverage to allow the metformin and extended-release glipizide to have a greater effect. This also has obstacles to acceptance, including fear of injection, fear of acute hypoglycemia, and misconceptions about insulin therapy. All therapy choices would be viable options for Patient O, and as a healthcare provider, understanding of all available agents is needed to support the final decision.

Patient F is a black female resident of a local long-term care facility. She is 87 years of age and has had type 2 diabetes for the past 25 years. In addition to diabetes, Patient F has a past medical history of hypertension, cardiovascular disease, peripheral neuropathy, and mild Alzheimer disease. Her son and daughter-in-law came to visit and found the patient confused, wet with foul urine, and begging for water. She had a temperature of 38.5 degrees Celsius. The family requested her transfer to the emergency department for evaluation and treatment.

Upon admission to the emergency department, Patient F is increasingly confused and combative, with a body temperature of 38.8 degrees Celsius. She is started on oxygen at 2 liters for an oxygen saturation of 88%. Laboratory samples are obtained, and an infusion of 0.9% sodium chloride is initiated at 75 mL/hour for observed signs of dehydration. The laboratory results indicate:

Based on this information, a diagnosis of HHS is made. Because HHS is characterized by profound dehydration, management is initially focused on rehydration. The physician orders an increase in the current 0.9% sodium chloride infusion to 100 mL/hour. Because there are no dysrhythmias noted on the telemetry monitor, the physician continues to monitor the potassium level with subsequent laboratory assessments. Patient F is also started on empirical antibiotic therapy for a suspected UTI until the results of urine and blood culture are known. An additional intravenous access is initiated in order to administer insulin. A regular insulin bolus of 0.1 units/kg followed by an infusion of regular insulin is ordered to run at a rate of 0.1 units/kg/hour.

Patient F's blood glucose levels slowly drop to 275 mg/dL, but her osmolality is 365 mOsm/kg and she remains confused. Because the patient's osmolality remains greater than 350 mOsm/kg and her confusion is unresolved, her blood glucose levels should be maintained between 250 mg/dL and 300 mg/dL. Her potassium level stabilizes without intravenous therapy and is currently 4.2 mEq/L. Her telemetry readings remain in sinus rhythm.

After 36 hours of therapy, Patient F has an osmolality of less than 315 mOsm/kg, and she is back to her baseline mentation. Her blood glucose level is 225 mg/dL, and she is getting prepared to transfer off of the insulin infusion.

Rationale and comments : Several considerations should be made in order to continue to achieve optimal glycemic control. The patient's HbA1c is 11.9%, which is considered uncontrolled. If a long-acting insulin is not started, the glucose levels will rebound. Also, it is vital that hydration status is maintained. Basal insulin should be given at least one hour prior to the discontinuation of the insulin infusion in order to prevent rebound hyperglycemia, which is a risk due to Patient F's continuing UTI and high HbA1c.

Patient F is maintained on 0.9% sodium chloride 75 mL/hour until adequate oral intake is established. She also starts insulin detemir 0.2 units/kg (total dose: 15 units) to be given once per day at night, which should provide weight-based coverage for correction of glucose elevations.

After three days, Patient F's HHS has been resolved, and the team is preparing the patient for discharge. However, she continues to have blood glucose levels between 280 mg/dL and 400 mg/dL.

Rationale and comments : There are several available options for Patient F. Insulin detemir may be continuously increased to desired effect and/or split to a twice daily schedule. If glycemic control is not achieved on the long-acting insulin preparation, addition of bolus insulin therapy may be necessary. Because the patient is a resident of a long-term care facility and has a history of cognitive impairment, the better option for her may be combination therapy.

To combat the consistently high blood glucose levels, Patient F's insulin detemir dose is increased to 15 units twice a day. The next day, the patient has the following glucose results: 146 mg/dL, 175 mg/dL, 188 mg/dL, and 136 mg/dL. Her primary care provider is satisfied with these readings and plans to discharge her the following day.