Author: Elaine Ogden, PharmD, BCPS, BC-ADM
MSHP Secretary/Kansas City VA Medical Center
Going GLP-1Authors: James Rhodes, PharmD Candidate 2019,
UMKC School of Pharmacy
Amanda Stahnke, PharmD, BCACP:
UMKC School of Pharmacy/Kansas City
VA Medical Center
Since the first-in-class approval in 2005, there have been more glucagon-like peptide-1 (GLP-1) receptor agonists approved for type 2 diabetes mellitus (T2DM) than any other noninsulin monotherapy agent.1 These agents provide clinicians more options in the diabetes armamentarium to individualize their patients’ regimens to meet individualized short-term and long-term goals. According the American Diabetes Association, a GLP-1 may be added if noninsulin monotherapy failed to help patients reach their A1c target.2 Alternatively, practitioners may also need an additional agent for glycemic control after basal insulin has been maximized. Should a clinician decide to use a GLP-1, it is important to know how either short-acting (SA-GLP-1) or long-acting (LA-GLP-1) agonist subgroups can help a patient reach their goals, with an understanding of each agent’s pharmacokinetic profiles and clinical trial data.
An Incretin Introduction3GLP-1 is a physiologic regulator of appetite and caloric intake. These gut-derived agents also manage glucose control by influencing hyperglycemic insulin secretion, euglycemic glucagon inhibition, anoretic effects, and slowing gastric emptying. Mechanistic discovery of GLP-1s began after gastrointestinal secretion was identified to induce pancreatic insulin release after eating carbohydrates and fats. Also known as the incretin effect, dietary caloric intake has been identified to secrete GLP-1 from intestinal cells, thus contributing to glucose-dependent pancreatic insulin release. This process becomes impaired in individuals with T2DM,4 further disrupting glucose homeostasis which leads to uncontrolled hyperglycemia. Endogenous GLP-1 plays a significant role in augmenting these insulin secretions, which has led to the development of exogenous GLP-1 agents resistant to degradation by dipeptidyl peptidase 4 (DPP4).
Short-Acting GLP-1sUse of SA-GLP1s have been shown to reduce hyperglycemia and glucose excursions in the postprandial state.3 There are two SA-GLP-1s currently approved for glycemic control in adults with T2DM: exenatide (Byetta™) and lixisenatide (Adlyxin™). These exogenous GLP-1 agents have N-terminal modifications to provide half-lives between 2-6 hours.5,6 These agents slow intestinal absorption of nutrients and reduce postprandial hyperglycemia by reducing the rate of gastric emptying into the duodenum; providing a suitable alternative to bolus insulin in combination with basal insulin to reduce postprandial glycemic excursions and incidences of hypoglycemia. However, this notable short-acting therapeutic property requires special considerations for additional medications for patients. For oral medications which the efficacy is concentration-dependent (i.e. antibiotics or oral contraceptives), it is recommended to take these at least 1 hour prior to SA-GLP-1 administration. If such medications are advised to be taken with food, these medications should be administered at a different meal than the SA-GLP-1.5,6
Long-Acting GLP-1sSubgroup LA-GLP-1s notably reduce basal hyperglycemia for greater than 24 hours due to the prolonged pharmacokinetics. There are five LA-GLP-1’s currently authorized for clinical use as an adjunct to diet and exercise in adults with T2DM: exenatide XR (Bydureon™), liraglutide (Victoza™ & Saxenda™), dulaglutide (Trulicity™), and newly approved semaglutide (Ozempic™). Each active agent possesses unique chemical modifications to sustain half-lives longer than 12 hours,7-11 which would allow for once daily or weekly administrations. These modifications include albumin-binding (liraglutide3, semaglutide11), immunoglobulin-binding (dulaglutide3), or encapsulation of slow-release polymicrosperes (exenatide XR3). Consistent therapeutic drug levels induce hyperglycemic insulin release from the pancreas. However, such concentrations also lead to prolonged activation and tachyphylaxis of the GI tract receptors,3 consequently having a less pronounced effect on gastric motility compared to SA-GLP-1s. Nevertheless, the clinical outcomes of LA-GLP-1s have been superior regarding the control of basal hyperglycemia3 over SA-GLP-1 counterparts.
Cardiovascular Outcomes of LA-GLP-1sThere have been two LA-GLP-1 agents identified to reduce long-term cardiovascular (CV) risk as evidenced by the LEADER12 (liraglutide) and SUSTAIN-613 (semaglutide) trials (Appendix A). These trials were designed as time-to-event analyses of a primary composite endpoint of CV death, nonfatal myocardial infarction, or nonfatal stroke in participants with T2DM and established CV disease. Liraglutide and semaglutide both significantly decreased the incidence of the primary composite endpoint versus placebo. A subgroup analysis of the LEADER trial revealed significant interactions favoring patients with reduced renal function (CrCl < 60 mL/min/1.73 m2; p = 0.01) and established CVD (≥ 50 years of age and established CVD; p = 0.04), but no significant interactions were identified for the SUSTAIN-6 trial. Neither agent showed benefit regarding secondary heart failure outcomes.12,13
An Added Benefit by Subtracting WeightWeight reduction is also a common outcome attributed to delayed gastric emptying and suppressing appetite centers in the brain. Although weight loss has been observed as a significant secondary measure for most GLP-1 clinical studies, the SCALE14trial was statistically powered to determine liraglutide’s effect on weight loss (Appendix A). Obese T2DM participants received either liraglutide 3mg, 1.8mg, or placebo comparator over 56 weeks to measure three coprimary endpoints: relative change in body weight, reduction in 5% or more from baseline body weight, and reduction in more than 10% of body weight from baseline. Weight loss was significantly greater with liraglutide (3.0mg) and liraglutide (1.8mg) than the matching placebos for all three co-primary endpoints.14
Considering a Place in TherapyIn the absence of precautions5-11 (e.g. gallbladder disease, acute pancreatitis) and contraindications7-11 (e.g. personal or familial history of thyroid cancer), injectable GLP-1s are useful agents in glucose-lowering strategies as second line option after metformin, if weight gain is a concern or as a third line agent, particularly in combination with metformin and basal insulin. GLP-1s are also offered in fixed-combinations with basal insulin to reduce daily injections. The adverse effects7-11 are primarily gastrointestinal such as nausea, vomiting, and diarrhea but hypoglycemia is still possible when used in combination with other agents. When deciding between GLP-1s, either SA or LA-GLP-1 are acceptable; dosing convenience may give preference for the latter subclass. An additional consideration may also be room temperature stability of GLP-1s as times vary significantly (Appendix A) and proper refrigeration may not always be widely accessible. While these antidiabetic agents may be considered effective for individuals with T2DM, they do so at the expense of higher rates of gastrointestinal side effects and cost. Therefore, it is important to discuss these potential barriers with patients prior to starting GLP-1 treatment.
1. U.S. Department of Health and Human Services. Food & Drug Administration (FDA). (2017). FDA-Approved Diabetes Medicines. Retrieved from https://www.fda.gov/forpatients/illness/diabetes/ucm408682.htm2. American Diabetes Association (ADA). 8. Pharmacologic Approaches to Glycemic Treatment. Diabetes Care. 2018; 41(Suppl. 1): S73-S85.
3. Meier JJ. GLP-1 receptor agonists for individualized treatment for type 2 diabetes mellitus. Nat. Rev. Endocrinol. 2012; 8: 728-742.
4. Madsbad S. The role of glucagon-like peptide-1 impairment in obesity and potential therapeutic implications. Diabetes, Obesity, and Metabolism. 2014; 16: 9-21.
5. Byetta (exenatide) injection [package insert]. AstraZeneca Pharmaceuticals LP. Wilmington, DE; 2015.
6. Adlyxin (lixisenatide) injection [package insert]. Sanofi-Aventis US LLC. Bridgewater, NJ; 2016.
7. Bydureon (exenatide extended-release) injectable suspension [package insert]. AstraZeneca Pharmaceuticals LP. Wilmington, DE; 2017.
8. Victoza (liraglutide) injection [package insert]. Novo Nordisk A/S. Bagsvaerd, Denmark; 2017.
9. Saxenda (liraglutide [rDNA origin] injection) [package insert]. Novo Nordisk A/S. Bagsvaerd, Denmark; 2017.
10. Trulicity (dulaglutide) injection [package insert]. Eli Lilly and Company. Indianapolis, IN; 2017.
11. Ozempic (semaglutide) injection [package insert]. Novo Nordisk A/S. Bagsvaerd, Denmark; 2017.
12. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. New England Journal of Medicine. 2016, 375(4): 311-322.
13. Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. New England Journal of Medicine. 2016; 375: 1834-1844.
14. Davies MJ, Bergenstal R, Bode B, et al. Efficacy of liraglutide for weight loss among patients with type 2 diabetes. Journals of American Medical Association. 2015; 314(7): 687-699.
Latent Autoimmune Diabetes of Adults
Authors: Dorothy Holzum, PharmD Candidate 2018,
St. Louis College of Pharmacy
Weston Thompson, PharmD, LCDR, BCPS, NCPS
Latent autoimmune diabetes of adults (LADA) is an intricate subset of diabetes that is complex and difficult to diagnosis. The American Diabetes Association (ADA) does not specify LADA as a separate diagnostic entity with confirmed treatments. As a result, the exact prevalence of LADA is unknown. However, 10% of patients in the United Kingdom Prospective Diabetes Study (UKPDS) trial most likely met criteria for LADA, totaling around 500 patients.1
Patients with LADA present with symptoms of type 2 diabetes, including BMI > 30 kg/m2, adult onset, and comorbidities including hypertension and hyperlipidemia. However, they also test positive for a glutamic acid decarboxylase (GAD) antibody, which resembles type 1 diabetes.1-5
While it can be difficult to clinically diagnose LADA based on patient symptoms and history on presentation, there are three set diagnostic criteria that a patient must have in order to be diagnosed with LADA. Patients first must have a GAD antibody. The GAD acts as an autoantigen, which provokes the generation of antibodies. The patient’s T cells mistakenly identify beta cells in the pancreas as foreign and thus produce antibodies to destroy the beta cells. This is consistent with type 1 diabetes. In addition, patients present with diabetes at an older age, specifically over the age of 18 years. Finally, patients must have retention of their beta cell function, meaning they will not require insulin for at least six months. The last two characteristics are consistent with type 2 diabetes.1,2
There are two subsets of LADA, based on bimodal distribution of GAD titers. Patients that have high GAD titers will resemble type 1 diabetics, as they are younger and leaner.6 These patients generally have higher A1c levels and lower C-peptide levels. On the other hand, patients with low GAD titers will resemble type 2 diabetics, as they are older and have a high BMI.6,7
The pathophysiology of LADA is a combination of the autoimmune destruction of pancreatic beta cells, which leads to insulin deficiency, as well as insulin resistance. Insulin resistance is the result of several risk factors including age > 45 years, BMI > 25 kg/m2, and habitual physical inactivity. Due to these risk factors, the body’s normal response to a given amount of insulin is reduced. As a result, higher levels of insulin are needed in order for insulin to have its proper effects.6,8
Patients can present with polydipsia, or increased thirst, polyuria, or increased urination, polyphagia or increased hunger, or they can be asymptomatic. Laboratory tests will show a positive GAD antibody and elevated blood glucose levels. Patients can progress into diabetic ketoacidosis or hyperglycemic hyperosmolar syndrome and develop microvascular complications including retinopathy, peripheral neuropathy, and nephropathy, as well as macrovascular complications including peripheral artery disease and cerebrovascular disease.1
Currently there is not an established therapeutic regimen for the treatment of LADA. Ultimately, treatment is tailored to preserve beta cell function as long as possible. Clinical trials are difficult to design because there is not a gold standard method to measure beta cell mass.1 A few studies have shown sulfonylureas are harmful in LADA patients, causing them to require insulin at an accelerated rate.9 Sulfonylureas stimulate the pancreas to secrete insulin. This stimulation causes an increased autoantigen expression, which further augments the autoimmune process in LADA patients.1 Thus, sulfonylureas should not be used in LADA patients. If the patient is still secreting some insulin, metformin is the first line medication, as it is the only medication shown by the UKPDS trial to decrease the development of macrovascular complications.9 Metformin should be titrated to a maximum of 2,000 mg per day and then all other oral antidiabetic therapies should be maximized.6 Once all oral therapies are at the maximum dose and the patient is still not at their A1c goal, insulin must be initiated.5
The goals of therapy for LADA include reducing the risk of any acute complications and preventing micro and macrovascular complications. Blood sugars should be treated to an A1c of < 7%, FPG 80-130 mg/dl and PPG < 180 mg/dl per the ADA guidelines. There are some circumstances where a patient’s goal A1c is only < 8%, particularly in elderly patients with a decreased life expectancy or if the patient has several episodes of hypoglycemia when trying to treat their A1c to < 7%. On the other hand, there are some patients whose A1c goal will be < 6.5%, specifically if the patient is young and the goal can be obtained without significant hypoglycemia. Furthermore, for non-pharmacological treatment, patients should be educated about the disease state, the importance of keeping their blood sugars controlled, and signs of hypo and hyperglycemia. Medical nutrition therapy, a nutrition assessment to evaluate a patient’s nutrition intake and metabolic status should also be recommended. Furthermore, patients should get 150 minutes of exercise per week and check their blood sugars regularly, which is different for every patient.10
In conclusion, LADA is a subset of diabetes where patients present with symptoms of type 2 diabetes, however they also have a positive GAD antibody. These patients will require insulin sooner than traditional type 2 diabetes patients.1 Pharmacists must address barriers to insulin therapy early in LADA patients. In addition, robust clinical trials are needed to determine the appropriate treatment that will lengthen the beta cell function in these patients.
References: 1. Cernea S, Buzzetti R, Pozzilli P. Beta-cell protection and therapy for latent autoimmune diabetes in adults. Diabetes Care. 2009;32(2):246-252.
2. Laugesen E, Ostergaard JA, Leslie RD. Latent autoimmune diabetes of the adult: current knowledge and uncertainty. DIABETICMedicine. 2015;32(7):843-852.
3. Hernadez M, Lopez C, Real J, et al. Preclinical carotid atherosclerosis in patients with latent autoimmune diabetes in adults (LADA), type 2 diabetes and classical type 1 diabetes. Cardiovasc Diabetol. 2017;16:94:1-9.
4. Grant SA, Hakonarson H, Schwartz S. Can the genetics of type 1 and type 2 diabetes shed light on the genetics of latent autoimmune diabetes in adults? Endocrine Reviews. 2010;31(2):183-193.
5. Stenstrum G, Gottsatter A, Bakhtaedze E, et al. Latent autoimmune diabetes in adults: definition, prevalence, beta-cell function, and treatment. Diabetes. 2005;54(2):68-72.
6. Yang Z, Zhou Z, Li X, et al. Rosiglitazone preserves islet beta-cell function of adult-onset latent autoimmune diabetes in 3 years follow-up study. 2009;83:54-60.
7. Lu J, Hou X, Pang C, et al. Pancreatic volume is reduced in patients with latent autoimmune diabetes in adults. Diabetes Metab Res Rev. 2016;32:858-866.
8. Grant SA, Hakonarson H, Schwartz S. Can the genetics of type 1 and type 2 diabetes shed light on the genetics of latent autoimmune diabetes in adults? Endocrine Reviews. 2010;31(2):183-193.
9. Brophy S, Brunt H, Davies H, et al. Interventions for latent autoimmune diabetes (LADA) in adults (review). Cochrane Database of systematic Reviews. 2007;3:1-3.
10. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes—2018. Diabetes Care. 2017;41(Supplement 1). doi:10.2337/dc18-s002.
Management of Diabetic Ketoacidosis in Critically Ill Patients
Authors: Anahit R. Simonyan, PharmD Candidate 2018, St. Louis College of Pharmacy
Gabrielle A. Gibson, PharmD, BCPS, BCCCP: Barnes-Jewish Hospital
Introduction/Epidemiology:It is estimated that patients with diabetes are more likely to be hospitalized and experience longer hospital stays than those without diabetes.1 Additionally, severe hyperglycemia can lead to either diabetic ketoacidosis (DKA) and/or hyperosmolar hyperglycemic state (HHS), which are two of the most serious acute complications of diabetes associated with significant morbidity and mortality. Diabetic ketoacidosis is an acute complication of diabetes, responsible for over 500,000 hospital stays per year.2 The remainder of this paper will be focused on the management of DKA.
Pathophysiology:The pathophysiology of DKA can be explained by an absolute insulin deficiency leading to ketosis. The decrease in effective insulin concentration causes an increase in production of counterregulatory hormones. These hormones cause a decrease in glucose utilization, increase in gluconeogenesis, and increase in glycogenolysis. The characteristic finding of ketoacidosis is due to upregulation of lipolysis and availability of free fatty acids. The liver converts the free fatty acids to ketone bodies, resulting in ketonemia and acidosis. Diabetic ketoacidosis can be precipitated by several factors, including infection, non-adherence to therapy, concomitant illnesses, and medications such as corticosteroids and sympathomimetic agents. Although DKA may present with symptoms ranging from abdominal pain to severe polyuria, polydipsia, or polyphagia, diagnosis of DKA is based on abnormal pH and serum bicarbonate values, an elevated anion gap with additional fluid and electrolyte abnormalities, and positive urine and serum ketones.1,2
Goals of DKA treatment include improvement of organ perfusion through increasing circulatory volume, gradual reduction of osmolality and serum glucose, clearance of both serum and urine ketones, and normalization of electrolytes. The three main treatments for DKA are fluid therapy, reversal of hyperglycemia, and correction of electrolyte abnormalities while concomitantly identifying and treating the underlying cause.
Management: Intravenous (IV) fluids1,2Administration of IV fluids is utilized in the treatment of DKA in order to correct hypovolemia. In the absence of cardiac compromise, all patients should receive normal saline (0.9% NaCl) for intravascular volume repletion. The initial isotonic saline should be infused at a rate of 15-20 mL/kg/hr or 1-1.5 L during the first hour. Subsequent choices of fluid are determined by the patient’s volume and hemodynamic status, corrected sodium, and the patient’s urine output in addition to cardiac and renal function. Fluids may then be changed to include dextrose once the patient’s serum glucose reaches an acceptable level of 200 mg/dL. As patients become volume resuscitated, monitoring for improved renal function, blood pressure, lab values, and clinical exam should occur within the first 24 hours.
Insulin1-4The cornerstone of DKA treatment lies with administration of insulin. The optimal initial treatment regimen for DKA patients is IV regular insulin. A randomized, prospective study performed by Fisher and colleagues evaluated 45 patients with DKA to determine the most efficacious route of insulin administration. The group receiving IV regular insulin had a statistically significant faster decrease in plasma glucose (two hours vs four hours, P<0.01) and ketone bodies (4 hours versus 6 hours, P<0.05) compared to subcutaneous or intramuscular insulin. About 90% of participants receiving IV insulin had a decrease in plasma glucose by at least 10% in the first hour, compared to only 30-40% of the participants in the subcutaneous and intramuscular insulin groups. Thus, the administration of continuous IV regular insulin infusions are preferred because of the short half-life and ability to easily titrate.
Guideline recommendations suggest a bolus of 0.1 units/kg of regular insulin with subsequent continuous infusion of regular insulin at 0.1 units/kg/hour. The patient can be transitioned to subcutaneous short-acting insulin once the hyperglycemic crisis has resolved and certain criteria have been met. A patient must have a blood glucose <200 mg/dL in addition to two of the following: serum bicarbonate >15 mEq/L, pH >7.3, or calculated anion gap <12 mEq/L. In order to prevent hyperglycemia, the short-acting subcutaneous injection should be overlapped with the infusion by 1-2 hours. In the case that patients are to remain NPO, a regular insulin infusion should be continued with appropriate IV fluids. Hypoglycemia is one of the most common complications from treatment of DKA, thus it is imperative that these patients have frequent blood glucose monitoring at least every 1-2 hours to prevent and manage hypoglycemia.
Patients with DKA may experience elevations in potassium as a result of insulin deficiency and metabolic acidosis. Potassium is stored in the intracellular compartment, and in the presence of acidosis the potassium shifts from the intracellular to the extracellular space. This causes an increase in serum potassium, despite the fact that most patients have a total body deficit of potassium. With insulin and fluid therapy, and subsequent correction of acidosis and volume status, a decrease in serum potassium may occur. Supplementation may be initiated once the serum potassium < 5.2 mEq/L. It is rare to have a patient present with hypokalemia, but if this does occur, insulin therapy should be held until the serum potassium is restored to >3.3 mEq/L, to avoid arrhythmias and respiratory muscle weakness.
Phosphate2At presentation of DKA, levels of phosphate may be elevated. However, patients receiving insulin therapy for treatment of DKA will have decreased phosphate levels. In order to avoid cardiac dysfunction, muscle weakness, and respiratory distress secondary to hypophosphatemia, vigilant monitoring and replacement of phosphate must be employed. In those with a serum phosphate <1.0 mg/dL, supplementation with 20-30 mEq of potassium phosphate should be administered in addition to IV fluids. Correction of phosphate should not exceed 4.5 mmol/hour in order to prevent severe hypocalcemia and further complications.
Bicarbonate5The American Diabetes Association (ADA) does not recommend the routine use of bicarbonate therapy unless the patient has extreme acidosis (pH <6.9) with severe systemic complications, such as impaired myocardial contractility. Duhon and colleagues performed a retrospective analysis to determine whether the use of IV bicarbonate therapy led to improved outcomes in DKA patients. The primary outcome was the time it took to resolve acidosis, with secondary outcomes of hospital length of stay, and additional therapy requirements within the first 24 hours of admission. The study showed no statistically significant difference in the time it took to resolve acidosis between the two groups. The only statistically significant difference found was an increase in insulin and fluid requirements in those receiving bicarbonate therapy than those not receiving it. However, this study is limited by its retrospective nature and its small sample size with 40 patients included in each group.
ConclusionIt is imperative to treat the manifestations of DKA in order to prevent complications and reduce mortality in critically ill patients. Appropriate IV fluid, insulin, and correction of electrolyte abnormalities is necessary for the safe and effective treatment of DKA. Patients should be educated on how to prevent DKA, including the medications and conditions that may precipitate its occurrence. Pharmacists can play a vital role in the education and prevention process, and should promote awareness to diabetic patients regarding this condition.
References:1. Moghissi ES, Korytkowski MT, DiNardo M, et al.; American Association of Clinical Endocrinologists; American Diabetes Association. American Association of Clinical Endocrinologists and American Diabetes Association consensus statement on inpatient glycemic control. Diabetes Care. 2009;32:1119–1131.
2. Kitabchi AE, Guillermo UE, Miles JM, Fisher JN. Hyperglycemia Crises in Adult Patients with Diabetes. Diabetes Care. 2009;32:1335-1343.
3. Fisher JN, Shahshahani MN, Kitabchi AE, et al. Diabetic ketoacidosis: low-dose insulin therapy by various routes. N Engl J Med. 1977;297(5):238-241.
4. Finfer S, Blair D, Bellomo R, et al. Intensive versus Conventional Glucose Control in Critically Ill Patients (NICE-SUGAR). N Engl J Med. 2009;360(13):1283-1297.
5. Duhon B, Attride RL, Franco-Martinez AC, Maxwell PR, Hughes DW. Intravenous sodium bicarbonate therapy in severely acidotic diabetic ketoacidosis. Ann Pharmacother. 2013;47(8):970-975.
Subcutaneous Administration of Testosterone as an Alternative to Intramuscular Injection
Authors: Jackson Warner, PharmD Candidate 2018, UMKC School of Pharmacy
Andrew Bzowyckyj, PharmD, BCPS, CDE: UMKC School of Pharmacy/Truman Medical Center
IntroductionSubcutaneous (SC) testosterone is a novel delivery method that may alleviate concerns associated with intramuscular injections, improving adherence and patient attitude towards therapy. Intramuscular (IM) testosterone injections are often reported to cause pain, bruising, and a need to schedule injections with a healthcare provider if unable to self-administer.1 IM injections often result in supraphysiologic levels of testosterone, followed by subtherapeutic troughs. This fluctuation in hormone levels can lead to an undesirable variability in mood, energy, and libido. Topical formulations can have adverse events such as local reactions, risk of skin-to-skin transmission, unpleasant odors, and unreliable absorption.2 These formulations are not often covered by insurance and may be cost-prohibitive. A form of SC testosterone is currently available as implantable pellets. However, this formulation requires placement by a physician and carries the risk of infection and fibrosis, or extrusion of the pellets.2 Ease of administration, less pain compared to IM injections, and decreased fluctuation of hormone levels are all attractive qualities that may sway patients and providers alike to prefer SC injections of current testosterone formulations.
Pharmacokinetic Profile of SC TestosteroneSeveral studies have observed the effects of SC administration of testosterone cypionate (TC) and enanthate (TE) on serum levels, alleviation of the hypogonadal symptoms, and masculinization of transgender patients to determine its viability as an alternative to IM injections. Spratt et al.1 measured the testosterone levels in 96 female-to-male (FTM) transgender patients using weekly SC injections. The initial dose was 50mg (TC or TE, based on availability) SC once weekly. Doses were increased sequentially until normal serum total testosterone levels were attained (348-1197ng/dL). All patients (n=63) achieved normal serum total testosterone levels, regardless of BMI, suggesting that obesity is not a limitation of SC testosterone. Average levels were significantly different between the normal weight and obese patients (754 vs. 606 ng/dL, p-0.04), but not overweight patients (765ng/dL). Though not clinically significant, all subjects who received at least six months of optimized therapy experienced satisfactory masculinization. Kaminetsky et al.2 compared TE 50mg SC (n=15) and 100mg SC (n=14) once weekly to TE 200mg IM every two weeks in males with hypogonadism. The 50mg dose provided an increase in total testosterone levels, which fell back to baseline between doses. However, the 100mg dose demonstrated a rise in total testosterone levels for the first three weeks. At week four and beyond, this group demonstrated steady-state exposure. The apparent half-life was 239.63 hours (100 mg SC) and 172.57 hours (200 mg IM). The kinetic profile of SC testosterone appears to be dose-proportional, with AUC and Cmax values for the 100mg SC dose being approximately twice those of the 50mg SC dose. 100mg SC testosterone demonstrated a similar overall AUC compared to 200mg IM testosterone at week five and six, suggesting that bioavailability is similar. McFarland et al.3 observed the total testosterone levels of 11 FTM transgender patients who were already on weekly doses of TC SC with documented therapeutic levels. Levels were taken prior to injection and at serial intervals post-injection (mean dose: 75mg weekly). Serum concentrations significantly increased between pre-injection and six hours post-injection (497 vs. 656 ng/dL; p=0.02), but did not significantly decrease between the sample drawn prior to injection and the sample seven days afterwards (497 vs. 477 ng/dL, p=0.58). The regression analysis of the relationship between SC testosterone dose and serum total testosterone concentration yielded a significant positive correlation (r2=0.59, p=0.006), further demonstrating dose-dependent kinetics. A separate regression model included BMI as a covariate (mean BMI 28.5 ± 7.4, range of 20.3–39.3 kg/m2). In this model, only the dose of testosterone was found to be a significant predictor of the total testosterone level, (standardized β coefficient, 0.77, p=0.005) showing that BMI is likely not a predictor of serum testosterone levels and should not be regarded as a limitation to using SC testosterone. Olson et al.4 measured the total testosterone levels in 35 FTM transgender patients naïve to hormone replacement therapy. TC doses were started at 25mg SC every two weeks and gradually increased to 50mg weekly as tolerated (mean dose: 46.4mg). Thirty-two of the 35 patients achieved testosterone levels within the normal male range at six months. The six-month total testosterone levels significantly increased from baseline levels (521.4 vs 35.2 ng/dL, p<0.001).
Lastly, a pilot study5 investigated the effect of subcutaneous TE in 22 hypogonadal men. The starting doses ranged from 25–50mg SC weekly. One week after initial injection, a trough and peak total testosterone level were taken with doses adjusted based on these levels and patient-reported symptoms (mean dose: 55 mg weekly). The mean trough was 418 ng/dL (normal range 288–1110) and the mean peak was 624 ng/dL. All 22 patients had both peaks and troughs within the normal range.
Safety and TolerabilitySC testosterone is well tolerated and generally safe with injection site reactions being the most commonly reported concern. One case of cellulitis was observed, but resolved without intervention.1 Insomnia (n=2), acne (n=1), and minor pain at the injection site have also been reported.2 Some patients have reported erythema, swelling, and pain at the injection site that subsided after switching from a sesame oil formulation to one with cottonseed oil. In one trial, the six-month mean systolic blood pressure increased (114.5 vs. 119.5mmHg, p=0.041) but this increase was not found to have clinical significance. Depression and suicidality have been reported with testosterone use, but it was not reported in any of the studies above. Surveys given to patients switching from IM to SC showed that the vast majority of subjects preferred SC.4
On the HorizonThe 2015 Subcutaneous Testosterone Enanthate Safety in Adult Men Diagnosed with Hypogonadism (STEADY™) trial was presented at the Endocrine Society Annual Meeting in April 2017 and American Urology Association Annual Meeting in May 2017. Antares Pharma claims the results of this trial (which are not yet published) demonstrated Xyosted®, formerly called QuickShot Testosterone, achieved steady state testosterone levels.7 However, the FDA has declined to approve Antares Pharma’s new drug application for Xyosted® based on two safety concerns: risk of increased blood pressure and occurrence of depression and suicidality.8 The FDA’s response letter did not cite any manufacturing, device, or efficacy issues. The company plans to meet with the FDA to discuss a path to the approval of Xyosted®.
ConclusionWhen injected at weekly intervals, SC testosterone appears to be a safe and effective alternative to IM injection. Overall, weekly SC testosterone offers stable total testosterone levels with infrequent supraphysiologic peaks or subtherapeutic troughs. In transgender men, SC testosterone results in appropriate masculinization. In cisgender men, it alleviates symptoms of hypogonadism. BMI does not appear to affect the ability of SC testosterone to achieve appropriate serum levels. Weekly SC testosterone appears to have dose-proportional kinetics with an increase in dose resulting in a proportional increase in serum testosterone levels. Mild, transient injection site reactions appear to be the most frequently reported adverse reaction to SC testosterone. With the evidence supporting the use of SC testosterone and at least one pharmaceutical company already seeking approval for it, a testosterone suspension product approved for subcutaneous administration is likely to become available soon.
References:1. Spratt DI, Stewart II, Savage C, et al. Subcutaneous injection of testosterone is an effective and preferred alternative to intramuscular injection: demonstration in female-to-male transgender patients. J Clin Endocrinol Metab. 2017;102(7):2349–55.
2. Kaminetsky J, Jaffe JS, Swerdloff RS. Pharmacokinetic profile of subcutaneous testosterone enanthate delivered via a novel, prefilled single-use autoinjector: a phase II study”. Sex Med. 2015;3:269–279.
3. McFarland J, Craig W, Clarke NJ, Spratt DI. Serum testosterone concentrations remain stable between injections in patients receiving subcutaneous testosterone. J Endo Soc. 2017;1(8):1095-1103.
4. Olson J, Schrager SM, Clark LF, Dunlap SL, Belzer M. Subcutaneous testosterone: an effective delivery mechanism for masculinizing young transgender men. LGBT Health. 2014;1(3)165–7.
5. Al-Futaisi AM, Al-Zakwani IS, Almahrezi AM, Morris D. Subcutaneous administration of testosterone: a pilot study report. Saudi Med J. 2006;27(12):1843–6.
6. McMahon CG, Shusterman N, Cohen B. Pharmacokinetics, clinical efficacy, safety profile, and patient-reported outcomes in patients receiving subcutaneous testosterone pellets 900mg for treatment of symptoms associated with androgen deficiency. J Sex Med. 2017;14:883–90.
7. “Antares Pharma Announces Poster Presentation of Quickshot Testosterone Data at the Endocrine Society Annual Meeting”. https://globenewswire.com/news-release/2017/04/03/953464/0/en/Antares-Pharma-Announces-Poster-Presentation-of-Quickshot-Testosterone-Data-at-the-Endocrine-Society-Annual-Meeting.html. 03 Apr. 2017. Accessed November 8, 2017.
8. “Antares Pharma Receives Complete Response Letter from the FDA for XYOSTED™”. https://seekingalpha.com/article/4115409-update-antares-pharma-post-complete-response-letter. 20 Oct. 2017. Accessed November 8, 2017.
The Role of Non-Insulin Therapies in the Treatment of Type 1 Diabetes
Authors: Sara Lingow, PharmD, PGY2 Ambulatory Care Pharmacy Resident
St. Louis College of Pharmacy/Saint Louis County
Department of Public Health
Justinne Guyton, PharmD, BCACP,
Assistant Professor, Pharmacy Practice
St. Louis College of Pharmacy
Program Number: 2017-12-09
Approval Dates: 2/7/2018 to 5/6/2018
Approved Contact Hours: One (1) CE(s) per LIVE session.
Submit Answers to CE Questions to Jim Andrews at: firstname.lastname@example.org
I. Describe the proposed role of GLP-1 receptor agonists and SGLT inhibitors in type 1 diabetes.
II. Identify adverse effects that may limit the use of GLP-1 receptor agonists or SGLT inhibitors.
III. Evaluate primary literature to determine the risks and benefits of both GLP-1 receptor agonist and SGLT inhibitor therapy in patients with type 1 diabetes.
IV. Select the best non-insulin therapy for a patient with type 1 diabetes who is not achieving glycemic control with insulin therapy alone.
IntroductionType 1 Diabetes Mellitus (T1DM) is characterized by autoimmune pancreatic β-cell destruction, leading to an insulin deficiency. Pancreatic α-cell dysfunction is also present, resulting in excess glucagon in both the fasting and postprandial state. Onset is most common during adolescence, but adults have also been diagnosed with T1DM. Patients with T1DM will have autoimmune markers present, and little to no residual C-peptide (a marker of insulin production).1,2
The Center for Disease Control and Prevention (CDC) estimates that 5 to 10% of patients with diabetes have type 1.3 Insulin is the mainstay of therapy for T1DM, as the characteristic β-cell destruction in T1DM results in minimal to no endogenous insulin production. While exogenous insulin is necessary, it does not account for the excess glucagon production or the altered gastric emptying rate in T1DM. Additionally, the two most common adverse effects of insulin are hypoglycemia and weight gain, which is of concern in patients with T1DM.2 A study published in 2015 found that patients in the United States with T1DM have an average A1C of 8.2%, with only 30% of patients achieving an A1c goal of less than 7%. Furthermore, 68% of patients are overweight or obese, diabetic ketoacidosis (DKA) occurs at a rate of 10% per year in some age groups, and severe hypoglycemia occurs at a rate of 9 – 20%.4 These data alone illustrates the need for alternative therapies to treat T1DM without risking further weight gain and hypoglycemia with insulin monotherapy.
In 2016 Schwartz and colleagues introduced the β-cell-centric classification schema of diabetes in which abnormal β-cell function is the common denominator for all types of diabetes. This model also identified ten other pathways of hyperglycemia, highlighting the idea that different treatment pathways can reduce hyperglycemia through different mechanisms in order to achieve glycemic goals.5 The ideal treatment regimen for a patient with T1DM would not only target the β-cell dysfunction, but also decrease blood glucose by targeting hyperglycemic pathways independent of β-cell function.
Pramlintide was FDA-approved for the treatment of T1DM in 2005.6 Pramlintide is an amylin analogue that delays gastric emptying, blunts pancreatic secretion of glucagon, and enhances satiety.7 Clinical trials showed that when pramlintide 30 or 60 mcg was administered subcutaneously three to four times daily, in addition to insulin therapy, the agent provided several positive benefits. The combination modestly lowered A1c, lowered the total daily dose (TDD) of insulin, and resulted in a decrease in body weight in patients with T1DM.8-10 Despite these benefits, pramlintide is rarely used in T1DM due to the multiple daily injections, significant nausea and vomiting, and overall cost of the medication. Metformin, dipeptidyl-peptidase-4 (DPP-4) inhibitors, and thiazolidinediones (TZD) have also been studied in T1DM, but have not shown clinically significant beneficial outcomes and therefore are not FDA-approved for treatment.2 The role of two other non-insulin classes of medications, sodium-glucose co-transporter (SGLT) inhibitors and glucagon-like-peptide 1 receptor agonists (GLP-1 RA), have been recently studied in T1DM. The remainder of this article will focus on a literature review of these agents with regard to lowering A1c, reducing insulin dose, and reducing body weight in patients with T1DM.
Sodium-Glucose Co-Transporter-InhibitorsThe SGLT-2 receptor is located in the proximal tubule of the kidney and is responsible for 90% of renal glucose reabsorption. Inhibition of this transporter reduces reabsorption of filtered glucose, thereby increasing glucosuria and reducing plasma glucose concentrations.7 The SGLT-1 receptor is located both in the proximal renal tubule and in the proximal small intestine. In the proximal renal tubule, it is responsible for the remaining 10% of renal glucose reabsorption. In the small intestine, it is the primary transporter in glucose and galactose absorption. Inhibition of this receptor therefore prevents glucose absorption in the small intestine, and a small amount of reabsorption in the kidneys. 11,12 Because the mechanism of SLGT inhibitors are independent of beta-cell function, this drug class may offer A1c lowering benefit to patients with T1DM, both by increasing glucose excretion in the kidney through SGLT-1 and-2 inhibition, and preventing glucose absorption in the small intestine through SGLT-1 inhibition.2 Currently, only SGLT-2 inhibitors are available in the United States. Known adverse effects of SGLT inhibitors include lipid abnormalities, genital infections, hypotension, and euglycemic diabetic ketoacidosis.7 A list of all available agents and their respective average wholesale prices can be found in Appendix I, Table 1. The first studies of SGLT inhibitors in patients with T1DM were limited by small sample size and a short duration. However, a few key findings warrant the necessity of future trials. Reduction in A1c, varying from -0.24% to -0.7%, a significant decrease in body weight, and a decrease in TDD were all seen in preliminary literature. While these benefits were apparent, patients receiving SGLT inhibitors also experienced more episodes of ketoacidosis and genital infections. 11,13-16
Two new, larger scale, landmark clinical trials were recently published in September 2017 evaluating the role of SLGT inhibitors in T1DM. The DEPICT-1 trial evaluated the role of dapagliflozin, an SGLT-2 inhibitor added to insulin therapy in 833 patients with T1DM. The primary outcome, change in A1c at 24-weeks, favored treatment with both dapagliflozin 5 mg (-0.42%) and dapagliflozin 10 mg (-0.45%) compared to placebo (p<0.0001). Severe hypoglycemia occurred in 21 (8%), 19 (6%) and 19 (7%) of the patients in the dapagliflozin 5 mg, dapagliflozin 10 mg, and placebo groups respectively. Adjudicated definite diabetic ketoacidosis occurred in four (1%), five (2%), and three (1%) patients in the dapagliflozin 5 mg, dapagliflozin 10 mg, and placebo groups respectively. This trial was still relatively short in duration, and excluded patients at a higher risk for hypoglycemia and DKA, however, it still offers promising benefit of an SGLT-2 inhibitor in addition to insulin for patients with T1DM who are not achieving glycemic goals.17
The inTandem 3 trial was also published in September 2017. This trial evaluated the role of sotagliflozin, an SLGT-1 and SLGT-2 inhibitor, in 1402 patients with T1DM. The primary outcome targeted both efficacy and safety endpoints, assessing the number of patients to achieve an A1c < 7.0% without hypoglycemia or DKA. Two hundred of the patients in the sotagliflozin group (28.6%) achieved this primary outcome, while only 107 (15.2%) patients in the placebo group achieved the outcome (p<0.001). This resulted in a number needed to treat of eight patients. Conversely, there were also more patients in the sotagliflozin group who did not meet the A1c goal and had at least one episode of DKA compared to placebo (16 patients (2.3%) vs. 13 patients (1.8%) respectively, p <0.003). This resulted in a number needed to harm of 50 patients. This trial was also relatively short in duration at only 24 weeks, excluded patients with a recent history of DKA or hypoglycemia, and demonstrated an increased risk of DKA in the treatment group.12
The data from these two recent landmark trials confirm the benefits of A1c reduction, weight loss, and reduction in total daily insulin doses with SGLT inhibitors seen in preliminary literature. Furthermore, the literature does not show an increased risk of hypoglycemia with these agents, though both trials excluded patients at baseline with a recent history of severe hypoglycemia. However, these benefits do not come without the risk of ketoacidosis, and should therefore not be used in patients with a history of, or at an increased risk for DKA. Additionally, the cost of these newer, brand-name agents may introduce an additional barrier (Appendix I, Table 1). Future trials that are longer in duration and specifically evaluate the safety of these medications in patients with T1DM are essential. Additionally, future studies should be designed so that the primary outcome is patient-related, evaluating the benefit of this class in prevention or delay of microvascular and/or macrovascular diabetic complications.
Glucagon-Like-Peptide-1 Receptor Agonists (GLP-1 RA)Human GLP-1 is a peptide that, in conjunction with glucose-dependent insulinoptropic polypeptide (GIP), is responsible for over 90% of the increased insulin secretion seen from an oral glucose load. GLP-1 is secreted from L-cells, located in the intestine and colon, in response to meals. Human GLP-1 levels rise shortly after food ingestion, enhancing insulin secretion, suppressing glucagon secretion, slowing gastric emptying and reducing food intake by increasing satiety.18 GLP-1 receptor agonists are analogs of human GLP-1 which increase glucose-dependent insulin secretion, delay inappropriate glucagon secretion, increase β-cell growth and replication, delay gastric emptying, and decrease food intake. The proposed benefit of GLP-1 receptor agonists in T1DM is mostly related to the mechanistic avenues independent of β-cell function. However, the potential to improve residual β-cell function and increase glucose-dependent insulin secretion may be beneficial early on in the diagnosis of T1DM. The most common adverse effects of GLP-1 receptor agonists include gastrointestinal disturbances, such as nausea and vomiting, increased heart rate, and headache. This class should not be used in patients with a personal or family history of thyroid cancer or multiple endocrine neoplasia syndrome (MENS).7,19 A list of available GLP-1 receptor agonists and their respective costs are available in (Appendix I, Table 2).
Preliminary literature evaluating the role of GLP-1 RAs in T1DM are largely inconclusive. Most trials had a small sample size and duration ranged from four to 26 weeks, with the exception of one 56-week trial. The results of the trials were variable regarding A1c reduction (-0.3 to -2.3%), weight loss (-0.5 kg to 6 kg), and reduction in TDD of insulin up to 20%. While the results of these earlier studies suggest potential benefit of this class, many were retrospective, open-label, or observational, limiting their usefulness.20-26. The ADJUNCT-ONE trial, published in 2016, evaluated the role of liraglutide added to treat-to-target insulin with regard to effects on A1c, insulin requirement, and body weight in patients with T1DM. The trial was a double-blind, randomized controlled trial including 1,398 adults with a duration of 52 weeks. Subjects were randomized in a 3:1 fashion to receive either liraglutide 0.6 mg, 1.2 mg, 1.8 mg or placebo added to insulin. At 52 weeks, liraglutide at both the 1.8 mg and 1.2 mg doses significantly reduced A1c compared to placebo (-0.54% and -0.49% vs. -0.34% respectively). Reduction in total daily insulin dose also significantly favored liraglutide at the 1.8 mg and 1.2 mg doses when compared to placebo (-5% and -2% vs. +4% respectively). Reduction in weight was significant for all three treatment groups compared to placebo. While benefits were seen at the higher doses of liraglutide, they were accompanied by an increased rate of symptomatic hypoglycemic events. The rate of symptomatic hypoglycemia events observed was 16.5/patient-year of exposure (PYE) and 16.1/PYE in the liraglutide 1.8 mg and 1.2 mg groups, respectively compared with a rate of only 12.3/PYE in the placebo group (p<0.05). Additionally, liraglutide 1.8 mg was associated with a higher rate of hyperglycemic episodes with ketosis. Gastrointestinal adverse effects were notable in all liraglutide groups. In the subgroup analysis, ADJUNCT-ONE authors identified that patients with residual C-peptide levels (n=17%) at baseline had a greater decrease in A1c with liraglutide 1.8 mg and 1.2 mg compared to those without residual C-peptide at baseline at the same dose. Additionally, patients with residual C-peptide experienced fewer episodes of hypoglycemia or hyperglycemia with ketosis.27
The ADJUNCT-TWO trial, published shortly after ADJUNCT-ONE in 2016, evaluated the efficacy and safety of liraglutide added to a capped insulin dose in patients with T1DM. This was a 26-week randomized, double-blind trial enrolling 835 patients randomized in a 3:1 fashion to receive liraglutide 0.6 mg, 1.2 mg, 1.8 mg or placebo added to capped insulin. At 26-weeks, there was a statistically significant reduction in A1c with all three doses of liraglutide compared to placebo (-0.35%, -0.23%, -0.24% and +0.01% for liraglutide 1.8 mg, 1.2 mg, 0.6 mg and placebo respectively). Reduction in total daily dose of insulin and body weight also significantly favored all three liraglutide doses. The highest rate of symptomatic hypoglycemia was unexpectedly seen in the liraglutide 1.2 mg arm. Like the ADJUNCT-ONE trial, hyperglycemia with ketosis was seen most often in the liraglutide 1.8 mg arm. The subgroup analysis of ADJUNCT-TWO revealed that, similar to the ADJUNCT-ONE findings, patients with residual C-peptide (15%) at baseline also showed a greater reduction in A1c with liraglutide 1.8 mg compared to those without residual C-peptide.28
ADJUNCT-ONE and ADJUNCT-TWO are the largest trials available to date to evaluate liraglutide in T1DM. While the results of both trials are favorable with regard to A1c reduction, weight loss, and reduction in insulin doses, the treatment arms did show an increased risk of dose-dependent hypoglycemia and hyperglycemia with ketosis as well as gastrointestinal adverse events. Similar to the SGLT inhibitors, all available GLP-1 RAs are brand-name with a high price tag, often limiting their use (Appendix I, Table 2). Future studies focused on patient-oriented evidence that matters, such as prevention of microvascular or macrovascular outcomes, would be beneficial to truly determine their clinical utility.
When to Choose an SLGT Inhibitor or GLP-1 RA in T1DM?A patient with T1DM may be a good candidate for an SLGT inhibitor if overweight or obese and interested in an oral agent in addition to an insulin regimen. Duration of diabetes does not appear to be a factor affecting efficacy of SGLT inhibitors in T1DM. This class may be considered in patients who are at risk for hypoglycemia, as the recent clinical trials did not show an increase rate of hypoglycemia in the treatment groups. This class should be avoided in patients with a recent history of, or who are at high risk for, a DKA episode. On the other hand, a GLP-1 RA may be the best option to add on in a patient with newer-onset T1DM, residual β-cell function, or residual C-peptide levels, as the preliminary literature and subgroup analyses show the most benefit in this population. Obese and overweight patients with T1DM may benefit from the weight loss properties, and the class should be used with caution in patients at a higher risk of DKA or hypoglycemic events, as the recent evidence showed a higher incidence of these adverse effects. Overall, the benefits of both classes in addition to insulin therapy in T1DM appear to be promising. However, due to the potential for adverse effects, in addition to cost, lack of FDA-approval, and lack of insurance coverage, the practicality of using either class is relatively low at this time.
Paradigm ShiftOver the past few years there has been a shift in framework for managing diabetes. Landmark trials such as the Diabetes Control and Complications Trial (DCCT) and the Epidemiology of Diabetes Interventions and Complications (EDIC) demonstrated that the longer amount of time patients with T1DM spend meeting glycemic goals, the lower risk of long-term microvascular and macrovascular complications.29,30 Newer trials, such as LEADER and EMPA-REG, have shown cardiovascular benefit (and even renal benefits) with specific drug classes in patients with type 2 diabetes within 3 to 5 years.21,32 Perhaps, there is more to prevention of complications in patients with diabetes than merely meeting glycemic goals. Future trials evaluating the prevention of microvascular and macrovascular complications with SLGT inhibitors and GLP-1 RAs in the treatment of T1DM have the potential to transform the current treatment algorithms.
References:1. American Diabetes Association. Classification and diagnosis of diabetes. Sec 2. In Standards of Medical Care in Diabetes 2017. Diab Care 2017;40(Suppl. 1):S11-S24
2. Fransden CS, Dejgaard TF, Madsbad S. Non-insulin drugs to treat hyperglycaemia in type 1 diabetes mellitus. Lancet Diabetes Endocrinol. 2016;4:766-80.
3. Centers for Disease Control and Prevention. National Diabetes Statistics Report, 2017. 1-20. https://www.cdc.gov/diabetes/pdfs/data/statistics/national-diabetes-statistics-report.pdf. Accessed October 05, 2017.
4. Miller KM, Foster NC, Beck RW. Current state of type 1 diabetes treatment in the U.S.: updated data from the T1D exchange clinic registry. Diab Care. 2015;38:971-978
5. Schwartz SS, Epstein S, Corkey BE et al. The time is right for a new classification system for diabetes: rationale and implications of the β-cell-centric classification schema. Diab Care. 2016;39:179-186.
6. Symlin (pramlintide) [package insert]. AstraZeneca Pharmaceuticals LP, Wilmington, DE; June 2014.
7. Lexicomp Online®. Lexi-Drugs®. Hudson, Ohio: Lexi-Comp, Inc.; Updated September, 2017. Accessed October, 2017
8. Whitehouse F, Kruger DF, Fineman M, et al., A randomized study and open-label extension evaluating the long-term efficacy of pramlintide as adjunct to insulin therapy in type 1 diabetes. Diab Care. 2002;25: 724-30
9. Ratner RE, Dickey R, Fineman M, et al., Amylin replacement with pramlintide as adjunct to insulin therapy improves long-term glycaemic and weight control in type 1 diabetes mellitus: a 1-year randomized controlled trial. Diabet Med. 2004;21:1204-12
10. Edelman S, Garg S, Frias J, et al., A double-blind, placebo-controlled, trial assessing pramlintide treatment in the setting if intensive insulin therapy in type 1 diabetes. Diab Care. 2006;29:2189-95.
11. Sands AT, Zambrowicz BP, Rosenstock J, et al. Sotagliflozin, a dual SGLT1 and SGLT2 Inhibitor, as Adjunct Therapy to Insulin in Type 1 Diabetes. Diab Care. 2015;38(7):1181-8.
12. Garg SK, Henry RR, Banks P, et al. Effects of Sotagliflozin Added to Insulin in Patients with Type 1 Diabetes. N Engl J Med. 2017;[online first]:1-11
13. Perkins BA, Cherney DZ, Partridge H, et al. Sodium-glucose cotransporter 2 inhibition and glycemic control in type 1 diabetes: results of an 8-week open-label proof-of-concept trial. Diab Care. 2014;37(5):1480-3.
14. Pieber TR, Famulla S, Eilbracht J, et al. Empagliflozin as adjunct to insulin in patients with type 1 diabetes: a 4-week, randomized, placebo-controlled trial (EASE-1). Diabetes Obes Metab. 2015;17(10):928-35.
15. Henry RR, Thakkar P, Tong C, Polidori D, Alba M. Efficacy and safety of canagliflozin, a sodium-glucose cotransporter 2 inhibitor, as add-on to insulin in patients with type 1 diabetes. Diab Care. 2015;38(12):2258-65.
16. Kuhadiya ND, Ghanim H, Mehta A, et al. Dapagliflozin as additional treatment to liraglutide and insulin in patients with type 1 diabetes. J Clin Endocrinol Metab. 2016;101(9):3506-15.
17. Dandona P, Mathieu C, Phillip M, et al. Efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes (DEPICT-1): 24 week results from a multicentre, double-blind, phase 3, randomised controlled trial. Lancet Diabetes Endocrinol. 2017;[online first]:1-13.
18. Triplitt CL, Repas T, Alvarez C. Diabetes Mellitus. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 10e New York, NY: McGraw-Hill; Accessed October 05, 2017.
19. American Diabetes Association. Classification and diagnosis of diabetes. Sec 8. In Standards of Medical Care in Diabetes 2017. Diab Care 2017;40(Suppl. 1):S64-S74
20. Kielgast U, Krarup T, Holst JJ, Madsbad S. Four weeks of treatment with liraglutide reduces insulin dose without loss of glycemic control in type 1 diabetic patients with and without residual beta-cell function. Diab Care. 2011;34(7):1463-8.
21. Kuhadiya ND, Malik R, Bellini NJ, et al. Liraglutide as additional treatment to insulin in obese patients with type 1 diabetes mellitus. Endocr Pract. 2013;19(6):963-7.
22. Hari kumar KV, Shaikh A, Prusty P. Addition of exenatide or sitagliptin to insulin in new onset type 1 diabetes: a randomized, open label study. Diabetes Res Clin Pract. 2013;100(2):e55-8.
23. Traina AN, Lull ME, Hui AC, Zahorian TM, Lyons-Patterson J. Once-weekly exenatide as adjunct treatment of type 1 diabetes mellitus in patients receiving continuous subcutaneous insulin infusion therapy. Can J Diabetes. 2014;38(4):269-72.
24. Frandsen CS, Dejgaard TF, Holst JJ, Andersen HU, Thorsteinsson B, Madsbad S. Twelve-Week Treatment With Liraglutide as Add-on to Insulin in Normal-Weight Patients With Poorly Controlled Type 1 Diabetes: A Randomized, Placebo-Controlled, Double-Blind Parallel Study. Diab Care. 2015;38(12):2250-7.
25. Dejgaard TF, Fransden CS, Hansen TS, et al. Efficacy and safety of liraglutide for overweight adult patients with type 1 diabetes and insufficient glycaemic control (Lira-1: a randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 2016;4:221-32
26. Kuhadiya ND, Dhindsa S, Ghanim H, et al. Addition of Liraglutide to Insulin in Patients With Type 1 Diabetes: A Randomized Placebo-Controlled Clinical Trial of 12 Weeks. Diab Care. 2016;39(6):1027-35.
27. Mathieu C, Zinman B, Hemmingsson JU, et al. Efficacy and Safety of Liraglutide Added to Insulin Treatment in Type 1 Diabetes: The ADJUNCT ONE Treat-To-Target Randomized Trial. Diab Care. 2016;39(10):1702-10.
28. Ahrén B, Hirsch IB, Pieber TR, et al. Efficacy and Safety of Liraglutide Added to Capped Insulin Treatment in Subjects With Type 1 Diabetes: the ADJUNCT TWO Randomized Trial. Diab Care. 2016;39:1693-1701
29. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329(14):977-86.
30. Nathan DM, Cleary PA, Backlund JY, et al. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med. 2005;353(25):2643-53.
31. Marso SP, Daniels GH, Brown-Frandsen K et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375(4):311-322.
32. Zinman B, Wanner C, Lachin JM. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015l373(22):2117-28
33. Micromedex Solutions. Ann Arbor (MI): Truven Health Analytics; publication year [5 October 2017]. Available from: www.micromedexsolutions.com.
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Initial Combination versus Monotherapy for the Treatment of Type 2 DiabetesAuthors: Kacie Kuehn, PharmD: PGY-2 Ambulatory Care Resident
St. Louis College of Pharmacy/St. Louis County Department of Public Health – St. Louis, MO
Justinne Guyton, PharmD, BCACP: Assistant Professor, Pharmacy Practice
St. Louis College of Pharmacy
Program Number: 2017-12-11
Approval Dates: 2/7/2018 to 5/6/2018
Approved Contact Hours: One (1) CE(s) per LIVE session.
Submit Answers to CE Questions to Jim Andrews at: email@example.com
Objectives1) Describe the safety and efficacy outcomes of recent literature pertaining to initial combination therapy treatment of type 2 diabetes.
2) Create a patient-specific treatment plan for the management of type 2 diabetes.
IntroductionThe primary goals in the management of patients with type 2 diabetes are to reduce mortality and prevent microvascular and macrovascular complications. Although glycemic targets may be individualized, a targeted glycated hemoglobin (A1c) less than 7% set by the American Diabetes Association (ADA) is a glycemic goal of therapy to reduce the incidence of diabetes-related complications.1 However, only half of patients with diabetes are meeting this treatment goal, illustrating a need for improving diabetes management.2
In most patients, treatment begins with lifestyle modifications and the addition of one antihyperglycemic agent. If glycemic control is not met after titration, patients are managed with sequential add-on agents at subsequent visits. However, there are instances in which dual therapy is recommended initially. The ADA recommends considering initial combination therapy in patients with an A1c at or above 9%.1 In contrast, the American Association of Clinical Endocrinologists (AACE) indicates that combination therapy be initiated when patients present with an initial A1c above 7.5%.3 This contrast leaves practitioners with an important clinical question: why might initial combination therapy be beneficial and when should it be utilized? To help answer this question, this article will focus on four characteristics that may influence the decision: efficacy, hypoglycemia, side effects, and cost.
EfficacyThe concept of metabolic memory in type 2 diabetes has been discussed since the publication of the UKPDS 10-year follow-up in 2008. This trial established that a sustained period of early A1c control can have a long-term impact on subsequent risk of microvascular and macrovascular complications. In the UKPDS trial, a cohort of 3,867 patients newly diagnosed with type 2 diabetes was followed for 10 years. Patients were randomized to a standard A1c goal or an intensive A1c goal and then treated with a sulfonylurea alone or in combination with insulin. At 10 years, those in the standard A1c arm achieved a median A1c of 7.9% while the intensive A1c arm achieved a median A1c of 7.0% (P<0.001). Those treated with a sulfonylurea had a hypoglycemia rate of 17.7%, compared to 36.5% for those treated with insulin. Patients with diabetes managed with diet changes alone had a 1.2% rate of hypoglycemia. The patients in the intensive arm had a 25% risk reduction in microvascular complications (P<0.05), with no significant impact on cardiovascular outcomes.4 Interestingly, during post-trial monitoring, the A1c converged between arms within 1 year. At the end of the 10-year post-trial follow-up, both groups had a similar A1c at approximately 7.8% (P=0.71). Despite having a similar A1c upon completion of the follow-up period, those initially randomized to intensive A1c control still experienced long-term benefits. This intensive A1c arm had a 24% relative risk reduction in microvascular complications (P<0.05), a 15% relative risk reduction in myocardial infarctions (P<0.05), and a 13% relative risk reduction in all-cause mortality (P<0.01), compared to those with standard control at 10 years.5 These data support the concept of metabolic memory and begin to establish that a more aggressive early approach to glycemic control is essential to the treatment of type 2 diabetes.
Literature and guidelines have established metformin as first-line therapy for the treatment of type 2 diabetes, in the absence of contraindications, due to evidence of safety, efficacy, and a reduction in cardiovascular events.2,6 As new literature is published establishing the pleotropic benefits of other anti-hyperglycemic medications, thought must be given to when it is appropriate to initiate a second anti-hyperglycemic medication. In particular, focused research has been done to establish microvascular and macrovascular outcomes related to glucagon-like peptide-1 receptor agonists (GLP1-RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2-Is).7
The LEADER trial randomized patients with type 2 diabetes to receive liraglutide or placebo. At the end of the almost 4-year trial period, the 3-point major adverse cardiac events (MACE) primary outcome occurred in 13% of patients in the liraglutide group, compared to 14.9% in placebo (P=0.01).8 Another randomized controlled trial of patients with type 2 diabetes and risk of cardiovascular disease found that treatment with liraglutide compared to placebo reduced new-onset, persistent A3 albuminuria; at 15% and 19%, respectively (P=0.003)9. Similarly, empagliflozin was compared to placebo in the EMPA-REG OUTCOME trial, which included patients with type 2 diabetes. Treatment with empagliflozin significantly reduced the incidence of the 3-point MACE; 10.5% vs. 12.1% (P<0.01).10 The EMPA-REG ESRD trial found that empagliflozin reduced progression to A3 albuminuria when compared to placebo; 11.2% vs. 16.2%, respectively (P<0.001).11 This evidence supports the use of these medication classes, or certain medications within these classes, to prevent complications, particularly renal and cardiovascular complications. Delaying add-on treatment with one of these medications because a patient’s A1c is not above 9% at initial presentation (as the ADA guidelines recommend) may not be best practice because of the additional benefits of complication prevention.
Clinical inertia, the resistance to treatment initiation or intensification, despite a patient not reaching glycemic goals, also factors into the delay of add-on treatment.12 One study identified the prevalence of clinical inertia, with less than 50% of patients with type 2 diabetes and an A1c greater than 8% receiving treatment intensification.13 In 2014, Rajpathak and colleagues retrospectively analyzed the impact of timing of treatment intensification with oral add-on therapy on glycemic goal attainment among patients with type 2 diabetes failing metformin monotherapy. Almost 6,000 patients were evaluated and analyzed based on time to treatment intensification: no treatment intensification, early intensification at 3 months, intermediate intensification at 4 to 9 months, or late intensification within 10-15 months of first A1c above 7.5%. The majority of patients, 51%, stayed on metformin monotherapy during the study: 23% in the early group, 15% in the intermediate, and 11% in the late group. The baseline A1c was on average 8.01-8.5%. However, most patients never received therapy escalation, but if they did it was within 3 months. Patients with a baseline A1c of more than 8% and received early add-on of second agent, were more than 1.5 times more likely to reach their A1c goal of less than or equal to 7% at 2 years than those in the late add-on group.14 Use of dual initial therapy in patients with an A1c above 8% may help prevent clinical inertia and increase the chance of reaching an A1c goal of less than 7%, based on these results.
In addition to reaching an A1c goal, maintaining A1c at goal is another long-term target. The EDICT trial, published in 2015, aimed to determine the efficacy and durability of initiating a combination of agents to treat new-onset diabetes, compared to the sequential addition of agents. This randomized controlled trial included only drug-naïve patients with type 2 diabetes diagnosed within two years. Patients were randomized to receive conventional, sequential addition of therapy or initial combination therapy. Conventional therapy consisted of metformin combined with glipizide and then insulin glargine at one, two and three months. Initial combination therapy consisted of metformin, pioglitazone, and exenatide titrated at one and three months, if glycemic goals were not being met. On average, patients included in the trial were within six months of diagnosis and had a baseline A1c of 8.6%. At 24 months, patients who received conventional therapy reached an A1c of 6.5% and those with initial combination therapy reached an A1c of 5.95% (P<0.05). These results, although statistically significant, have less clinical significance because both groups reached the A1c goal. However, less than 75% of patients in the conventional group maintained an A1c less than 7%, compared to those in the initial combination group, in which over 90% maintained A1c at goal. In the conventional group, 46% of patient experienced mild hypoglycemic events compared to 14% in the initial combination group.15 This is an expected result considering the variability of insulin use between arms. Data from this study provides evidence that an effective and durable A1c reduction can be achieved using agents with a lower hypoglycemia risk. The EDICT trial utilized triple therapy in the combination group, which may not be practical for most clinical situations where the close monitoring of a randomized controlled trial cannot be duplicated. However, translating combination therapy to clinical practice may be achieved through dual therapy.
HypoglycemiaLimiting the risk of hypoglycemia is a major clinical consideration when choosing antihyperglycemic therapy. The EDICT trial illustrated that it is possible to achieve glycemic control without increasing the risk of hypoglycemia.15 The crux of this outcome is the choice of antihyperglycemic agents. Many agents confer a risk of hypoglycemia that increases with additional agents (Table 1). Excluding insulin, the highest rates of hypoglycemia occur with sulfonylureas, both as monotherapy and combination therapy. Therefore, if initiating dual initial combination therapy and hypoglycemia is a concern due to patient characteristics, it would be prudent to avoid sulfonylureas when possible. In addition, sulfonylureas have not demonstrated the same pleotropic benefits seen with SGLT2-Is or GLP1-RAs, further limiting their use in combination therapy.7
Hypoglycemia is often cited as a reason for not initiating more aggressive initial therapy. A 2016 systematic review found that physicians cited fear of hypoglycemia and other side effects as an influence on diabetes treatment.16 Conversely, in a 2014 systematic review, patients indicated they would prefer glucose control over avoiding minor hypoglycemic events.17 While hypoglycemia should remain at the forefront of clinical decision-making, this research may highlight the value of having patient-centered conversations of the risk versus benefits. Thus, the potential roadblock of hypoglycemia may be less of a concern in the decision to use monotherapy or combination therapy for initial treatment.
Side EffectsBesides hypoglycemia, other side effects influence clinical decisions for use in combination therapy as well. Interestingly, more research has begun to identify possible combinations of medication classes that would strategically reduce risk of side effects through their mechanisms of action. For example, when SGLT2-Is were added to pioglitazone, there was a reduction in hypervolemia typically seen secondary to thiazolidinediones18. Dipeptidyl peptidase 4 inhibitors (DPP4-Is), when added to SGLT2-Is, reduced the incidence of genital infections, although the mechanism of action of this benefit has not been established19.
This potential benefit of combination therapy comes with the caveat that any medication combination does: with each additional medication the side effect profile grows. If two medications started at the same time share a side effect, it may be difficult to discern which medication is the true cause. For example, GLP1-RAs and metformin can both cause gastrointestinal upset.20,21 If both medications were start concomitantly and the patient experienced nausea, it would be difficult to determine which medication to decrease to a lower dose or discontinue. This must be considered with dual initial therapy and patient education on side effects would be especially vital.
CostDepending on a given patient’s insurance status, cost may play a critical role in the choice of antihyperglycemic agents. As has been established, dual initial therapy provides efficacy and durability benefits in the treatment of type 2 diabetes. These benefits could make a higher initial cost of multiple medications worthwhile. In addition, combination pills are available for a variety of drug classes (Table 2), which may eliminate the increased cost incurred with multiple medications. This depends heavily on the route of administration for a given drug class, as GLP1-RAs clearly cannot be included in a combination with an oral medication and typically have higher co-pays associated with them.20,21 Monotherapy will usually be less expensive and therefore may be the only option for certain patients. Every avenue for assisting patients in this situation should be explored, including combination pills, discounted generic medications at certain pharmacies, and patient-assistance programs through medication manufacturers.
ConclusionThe ADA guidelines and AACE guidelines have established two different thresholds for when initial combination therapy should be considered; at or above 9% and above 7.5%, respectively.2,3 This establishes a “grey area” between an A1c of 7.5% and 9% -- should initial dual therapy be utilized in this range?
The early treatment of type 2 diabetes is integral to long-term prevention of complications. Metabolic memory resulting from early glycemic control establishes pleotropic benefits that are sustained, even if glycemic control is lost.22 ,Certain medication classes or medications within these classes have microvascular and macrovascular beyond the benefit established with glycemic control. This makes early initiation with classes, such as GLP1-RAs and SGLT2-Is, an integral component of patient-centered care. Clinical inertia may be a barrier to attaining these benefits. Therefore, it may not be prudent to rely on escalation of therapy over time to achieve glycemic control or to prevent complications. However, initial combination therapy may help prevent clinical inertia. If hypoglycemia is concern, care should be taken to appropriately titrate medications and the choice of medications is vital. Avoiding combinations with sulfonylureas will help reduce the risk of hypoglycemia. However, as evidenced in the EDICT trial, combination therapy can be utilized effectively to reach glycemic control, increase durability of control, and decrease risk of hypoglycemia.
In the evidence presented in this review, the majority of patients had a baseline A1c between 8-8.5%. Clearly, benefit is seen with initiating combination therapy in this population. Therefore, in treatment-naïve patients with an A1c greater than 8%, an initial dual oral antihyperglycemic regimen is favored.
References:1. Glycemic Targets. Diabetes Care. 2017;40(Suppl 1):S48-S56.
2. Dodd AH, Colby MS, Boye KS, Fahlman C, Kim S, Briefel RR, Treatment approach and HbA1c control among US adults with type 2 diabetes: NHANES 1999-2004. Curr Med Res Opin. 2009; 25:1605-1613.
3. T2D Algorithm, Executive Summary, Endocr Pract. 2017;23(2).
4. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352(9131):837-53.
5. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359(15):1577-89.
6. Lamanna C, Monami M, Marchionni N, et al. Diabetes Obes Metab. 2011;13(3):221-8.
7. Schnell O, Standl E, Catrinoiu D, et al. Report from the 2nd cardiovascular outcome trial (CVOT) summit of the diabetes and cardiovascular disease (D&CVD) EASD study group. Cardiovasc Diabetol. 2017;16(1):35.
8. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375(4):311-22.
9. Mann JF, Orsted DD, Brown-Frandsen K, et al. Liraglutide and renal outcomes in type 2 diabetes. N Engl J Med. 2017;377(9):839-48.
10. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117-28.
11. Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med. 2016:375(4):323-34.
12. Bailey CJ. Under-treatment of type 2 diabetes: Causes and outcomes of clinical inertia. Int J Clin Pract. 2016;70(12):988-995.
13. Shah BR, Hux JE, Laupacis A, Zinman B, Van walraven C. Clinical inertia in response to inadequate glycemic control: do specialists differ from primary care physicians?. Diabetes Care. 2005;28(3):600-6.
14. Rajpathak SN, Rajgopalan S, Engel SS. Impact of time to treatment intensification on glycemic goal attainment among patients with type 2 diabetes failing metformin monotherapy. J Diabetes Complicat. 2014;28(6):831-5.
15. Abdul-ghani MA, Puckett C, Triplitt C, et al. Initial combination therapy with metformin, pioglitazone and exenatide is more effective than sequential add-on therapy in subjects with new-onset diabetes. Results from the Efficacy and Durability of Initial Combination Therapy for Type 2 Diabetes (EDICT): a randomized trial. Diabetes Obes Metab. 2015;17(3):268-75.
16. Rushforth B, Mccrorie C, Glidewell L, Midgley E, Foy R. Barriers to effective management of type 2 diabetes in primary care: qualitative systematic review. Br J Gen Pract. 2016;66(643):e114-27.
17. Von arx LB, Kjeer T. The patient perspective of diabetes care: a systematic review of stated preference research. Patient. 2014;7(3):283-300.
18. Kovacs CS, Seshiah V, Swallow R, et al. Empagliflozin improves glycaemic and weight control as add-on therapy to pioglitazone or pioglitazone plus metformin in patients with type 2 diabetes: a 24-week, randomized, placebo-controlled trial. Diabetes Obes Metab. 2014;16(2):147-58.
19. Scheen AJ. DPP-4 inhibitor plus SGLT-2 inhibitor as combination therapy for type 2 diabetes: from rationale to clinical aspects. Expert Opin Drug Metab Toxicol. 2016;12(12):1407-1417.
20. Trulicity® [package insert]. Eli Lilly & Co. Indianapolis, IN; 2017.
21. Victoza® [package insert]. Novo Nordisk Inc. Princeton, NJ; 2017.
22. Ceriello A. The emerging challenge in diabetes: the "metabolic memory". Vascul Pharmacol. 2012;57(5-6):133-8
23. Januvia® [package insert]. Merck & Co. Kenilworth, NJ; 2017.
24. Onglyza® [package insert]. AstraZeneca Pharmaceuticals LP. Wilmington, DE; 2016.
25. Jardiance® [package insert]. Eli Lilly & Co. Indianapolis, IN; 2016.
26. Invokana® [package insert]. Janssen Pharmaceuticals. Beerse, Belgium; 2017.
27. Lexicomp Online® , Lexi-Drugs® , Hudson, Ohio: Lexi-Comp, Inc., 2017.
28. Missouri Department of Social Services. Pharmacy clinical edits and preferred drug lists. MO.gov. Accessed October 2, 2017.
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Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of morbidity and mortality in patients with diabetes.1,2 In fact, patients with type 2 diabetes are at least two times more likely to die from cardiovascular causes than the general population.3 This disparity underscores the importance of considering therapy impact on cardiovascular morbidity and mortality in patients with type 2 diabetes. In 2008 the Food and Drug Administration (FDA) published a guidance document proposing that all sponsors of antihyperglycemic drugs should conduct cardiovascular outcome trials (CVOTs) to demonstrate that the new drug does not result in an unacceptable increase in cardiovascular risk.4 More recently, the American Diabetes Association (ADA) addressed emerging evidence concerning cardiovascular outcomes by adding a recommendation in their 2018 guideline publication. This recommendation suggests that in patients with established ASCVD, an agent with proven reductions in major adverse cardiovascular events and/or cardiovascular mortality should be incorporated after metformin and lifestyle modifications have failed.5 Of the medications that have come to market since the 2008 FDA guidance document, a class of antidiabetic medications called sodium-glucose co-transporter 2 (SGLT2) inhibitors have demonstrated promising cardiovascular effects.
SGLT2 inhibitors are a class of oral antihyperglycemic medications that include empagliflozin, canagliflozin, and dapagliflozin. When used as add-on therapy to metformin, they provide an intermediate A1c lowering of around 0.5-1.0%.6 Apart from favorable effects on A1c and glucose control, SGLT2 inhibitors produce desirable metabolic effects, such as improved blood pressure and body weight (average reduction of 2 kg).7,8 Additionally, these agents have a low risk of hypoglycemia and may confer renal-protective properties.7,9
The EMPA-REG OUTCOME study was the first CVOT published for the SGLT2 inhibitor class.10 Published in September 2015, this large randomized controlled trial studied the cardiovascular safety of empagliflozin. Nearly two years later in June 2017, the CANVAS Program was published which analyzed cardiovascular safety data pooled from two sister trials comparing canagliflozin to placebo.11 Overall, EMPA-REG and CANVAS were similar in study design. Both trials were multicenter, international, double-blind, non-inferiority to superiority, placebo-controlled, randomized trials. However, only patients with established cardiovascular disease were included in EMPA-REG, while approximately a third of the study subjects in CANVAS did not have a history of cardiovascular disease. The primary outcome studied was the same for both trials and was a composite of death from cardiovascular causes, nonfatal myocardial infarction, and nonfatal stroke. [See Table 1 for comparison of trials]
The results of EMPA-REG and CANVAS were also comparable, with both trials demonstrating a 14% decrease in the primary composite endpoint [empagliflozin: (HR 0.86; 95.02% confidence interval, 0.74 to 0.99; P=0.04 for superiority), canagliflozin: (HR 0.86; 95% confidence interval, 0.75 to 0.97; P=0.02 for superiority)]. However, the individual components of the composite outcome were not necessarily lower. Empagliflozin was found to cause a statistically significant decrease in death from cardiovascular causes (HR 0.62; 95% CI, 0.49 to 0.77), but not in nonfatal myocardial infarction or nonfatal stroke event rates. On the other hand, canagliflozin did not achieve statistical significance for any individual component of the primary composite outcome. Interestingly, subgroup analyses of each of the trials revealed ethnic variations in cardiovascular benefits. These analyses revealed that Asian subjects had more desirable outcomes in the EMPA-REG study, while black patients had more desirable outcomes in the CANVAS Program.12 Although differences in study design prevent the direct comparison of results between these two trials, overall lower rates of adverse cardiovascular events were shown with empagliflozin and canagliflozin compared to placebo. Adding to CVOT data for this class of medications, another trial by the acronym of DECLARE-TIMI 58 evaluating the effects of dapagliflozin on cardiovascular events is anticipated for publication in 2019.13
In addition to the cardiovascular outcomes data garnered from SGLT2 inhibitor CVOT trials, both expected and unexpected adverse events were observed. In line with previously reported adverse events, patients receiving an SGLT2 inhibitor were more likely to experience a genital infection, most often mycotic in nature. Volume depletion was observed at a somewhat increased incidence also in line with previous findings. Euglycemic diabetic ketoacidosis, an extremely rare adverse event for which there is a class warning, was observed at a slightly increased incidence, but at an expected rate of less than 1% of patients taking the interventional drug.14 Furthermore, two unexpected adverse effects were observed in the CANVAS Program that were not observed with SGLT2 inhibitors previously or in the EMPA-REG trial. The first of these was a 23% increased risk of low-trauma fracture (HR 1.23; 95% CI, 0.99 to 1.52). The second unexpected adverse effect was a nearly two-fold increase in lower extremity amputations (6.3 v. 3.4 amputations per 1,000 patient-years; HR 1.97; 95% CI, 1.41 to 2.75) with the majority of the amputations occurring at the toe or metatarsal. Although increased fracture and amputation risk was not observed in the EMPA-REG trial, rates of these complications were not systematically collected.12 Additionally, neither EMPA-REG nor CANVAS were adequately powered to detect a significant difference in fracture and amputation risks. The negative safety data of these agents, combined with the current average monthly cost of about $430, can make SGLT2 inhibitors less ideal for some patients.15
All things considered, the results of the EMPA-REG OUTCOME study and CANVAS Program have changed the overall clinical picture of how SGLT2 inhibitors fit into therapy. As previously mentioned, advantages of SGLT2 inhibitors include weight loss, blood pressure reduction, renal-protective properties and a low hypoglycemia risk profile. Although the increase in low-trauma fracture and lower-extremity amputations observed in the CANVAS Program cannot be confirmed without further research, many practitioners are hesitant to utilize SGLT2 inhibitors because of these risks. Given current knowledge, whether or not the benefits of SGLT2 inhibitors outweigh the risks is not entirely clear. However, the positive cardiovascular outcomes data observed in the EMPA-REG OUTCOME study and CANVAS Program provide a larger picture of how SGLT2 inhibitors may be beneficial in patients with high cardiovascular risk.
1. Gregg EW, Li, Y, Wang J, et al. Changes in diabetes-related complications in the United States, 1990–2010. N Engl J Med. 2014; 370:1514-1523.
2. American Diabetes Association. 9. Cardiovascular disease and risk management: Standards of Medical Care in Diabetes—2018. Diabetes Care 2018;41(Suppl. 1):S86–S104.
3. Sarwar N, et al. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet. 2010;375:2215-22.
4. FDA. Guidance for industry: diabetes mellitus--evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. Washington, DC: US Department of Health and Human Resources; 2008.
5. American Diabetes Association. 8. Pharmacologic approaches to glycemic treatment: Standards of Medical Care in Diabetes--2018. Diabetes Care 2018;41(Suppl. 1): S73-S85.
6. Triplitt CL, Repas T, Alvarez C. Diabetes mellitus. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 10e New York, NY: McGraw-Hill; http://accesspharmacy.mhmedical.com/content.aspx?bookid=1861§ionid=146065891. Accessed December 18, 2017.
7. Vasilakou D, Karagiannis T, Athanasiadou E, et al. Sodium-glucose co-transporter 2 inhibitors for type 2 diabetes: a systematic review and meta-analysis. Ann Intern Med. 2013;159:262-74.
8. Cai X, Ji L, Chen Y, et al. Comparisons of weight changes between sodium-glucose cotransporter 2 inhibitors treatment and glucagon-like peptide-1 analogs treatment in type 2 diabetes patients: A meta-analysis. J Diabetes Investig. 2017; 8: 510–517.
9. Cherney DZ, Perkins BA, Soleymanlow N, et al. Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation. 2014;129:587-97.
10. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117–2128.
11. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017 Aug 17;377(7):644-657.
12. Rastogi A, Bhansali A. SGLT2 inhibitors through the windows of EMPA-REG and CANVAS trials: a review. Diabetes Ther. 2017;8:1245-51.
13. AstraZeneca. Bristol-Myers Squibb. The TIMI Study Group. Hadassah Medical Organization. ClinicalTrials.gov [Internet] Bethesda, MD: National Library of Medicine (US); 2000. [Accessed December 15, 2017]. Multicenter trial to evaluate the effect of dapagliflozin on the incidence of cardiovascular events (DECLARE-TIMI58). Available from: https://clinicaltrials.gov/ct2/show/NCT01730534
14. U.S Food and Drug Administration. SGLT2 inhibitors: drug safety communication – labels to include warnings about too much acid in the blood and serious urinary tract infections [Internet], 2015. Available from http://www.fda.gov/safety/medwatch/safetyinformation/safetyalertsforhumanmedicalproducts/ucm475553.htm. Accessed 19 December 2017.
15. Micromedex Healthcare Series. RED BOOK® Online. Greenwood Village, CO: Truven Health Analytics. http://truvenhealth.com/. Accessed 14 December 2017.
Teamwork Makes the Dream Work: Developing Collaborative Experiential Rotation Activities
Authors: Lisa Cillessen, PharmD, BCACP; Elizabeth F. Englin, PharmD, BCPS; April Porter, PharmD, BCACP;
Heather Taylor, PharmD, BCPS
UMKC School of Pharmacy at MSU
Collaborative learning activities involving multiple preceptors and students, within and between institutions, provide benefits to all involved. Due to increased precepting and clinical service demands, preceptors have difficulty incorporating learning activities into introductory/advanced pharmacy practice experiences (IPPE/APPEs). A unique way to overcome these demands, while enhancing student learning, is to develop collaborative learning activities with fellow pharmacy preceptors. The number of student pharmacists completing IPPE/APPEs has grown, due to development of new pharmacy degree programs and the addition of branch sites to established programs. This increase poses challenges for preceptors to meet the experiential education needs while balancing their clinical service and other work responsibilities. Developing collaborative learning activities within and between healthcare institutions can help mitigate precepting burdens. Multiple preceptors practicing within an institution facilitates one mode of collaboration. However, preceptors may practice within settings where they are the sole pharmacy preceptor. In these instances, they can collaborate with colleagues at other institutions. In addition to the preceptor benefits, collaborative learning activities enhance the students’ learning opportunities by increasing exposure to clinical insights and receiving additional feedback through involvement of multiple preceptors and peer learning.
Institutions regularly have multiple students completing IPPE and/or APPE rotations at one time, often from different colleges of pharmacy. While balancing multiple students can be challenging, it also serves as an opportunity to develop collaborative learning activities to meet both student and preceptor needs. One such collaborative activity is site and computer orientation which can provide facility tours, badge access, introduction to electronic medical record, and location of resources. Group orientation can be led by a resident or preceptor, with the responsibility shifting based upon scheduling. Collaborative orientation ensures students are given a standardized overview, allowing preceptors to focus on rotation specific needs. Another collaborative learning activity within institutions is the coordination of topic discussions, journal clubs, and informal and formal presentations. Scheduling these activities to maximize student and preceptor participation allows students exposure to a variety of disease states and experiences. Another collaborative learning activity within institutions is student shadowing of other clinical pharmacists or healthcare professionals. This broadens the students’ exposure to areas of clinical pharmacy and may enhance inter-professional education. Students also get a comprehensive view of patient care services which allows for a greater understanding for cohesive care.
At some institutions, there may be one or a few pharmacy preceptors, making it challenging to provide collaborative learning experiences within the institution. Preceptors can create opportunities to provide collaborative learning activities by identifying nearby pharmacists in similar practice settings to partner with. Collaborative activities can include, but are not limited to, orientation to the type of pharmacy, topic discussions, journal clubs, and informal and formal presentations. Collaborating between institutions allows students to gain different perspectives from other preceptors and students and compare procedures from different institutions to enhance learning.
Benefits and Challenges of Collaborative Learning Activities
Collaborative learning activities can truly be endless when time for patient care is increased and learning experiences are enhanced. By providing you examples of current collaborations and activities, we hope to have sparked your creativity and inspiration for precepting students and working as a team within and outside of your current institution. The need for pharmacy preceptors will continue to increase as our demand for pharmacy-led services continues to expand. Will you help us make a meaningful impact on the training of student pharmacists?
Authors: Anna Parker, PharmD Candidate 2010: UMKC School of Pharmacy
SSHP President – Elect for Kansas City
Jordyn Williams, PharmD Candidate 2010: UMKC School of Pharmacy
SSHP President – Elect for Columbia
At the beginning of the fall semester, SSHP held a membership drive from August to October 2nd. We recruited members through a poster at orientation for the first-year pharmacy students and at an event called "lunch on the lawn" for all pharmacy students. Also, on August 28th we had our first meeting where our guest speaker, Dr. Jeremy Hampton, discussed reasons to join SSHP, MSHP, and ASHP. The Columbia campus also held a joint membership drive for MMSHP and SSHP through a Trivia Night on September 7th. MMSHP and SSHP leadership provided information about joining the organizations. At the end of our membership drive we had a total of 96 members join from Kansas City, Columbia, and Springfield campuses.
Throughout the fall semester, we had monthly general meetings where guest speakers talked about their current employment and their journey to where they are now. Students were able to listen to these three speakers over the lunch hour to learn more about clinical pharmacy career options. We had the pleasure to have Dr. Austin Campbell, a clinical pharmacist specialist at University of Missouri Hospital's psychology department, Dr. Chuck Trebilcock, the Director of Pharmacy at Burrell Behavioral Health, and Dr. Amber Lucas, a chair in the ASHP House of Delegates.
Across all three campuses, we hosted three events this semester. On October 2nd, we held the Clinical Skills Competition where students competed in a team-based analysis of a clinical scenario. This gave students the chance to practice skills in collaboration with other team members. The first round was a case work-up and the second round had the top teams present their cases to the judges. The winning team was then given the chance to compete nationally during the ASHP Mid-Year Clinical Meeting. On October 7th, we held a Residency Roundtable with Dr. Tony Huke as our keynote speaker. Forty-five students and 14 residency programs participated. Participants had the opportunity to network and students learned how to become a strong residency candidate. On November 4th, we held a new event called Residency Prep Day. The goal of the members-only event was to help boost students' confidence when applying for programs. Faculty members gave presentations regarding Midyear, PhORCAS, and interview tips and tricks. As this was a new event this year, we think it will gain popularity in the years to come. This event was very helpful to those that were able to attend.
Our chapter is unique in that it is spread across three campuses, which enables our chapter to reach out to multiple local communities very easily. This past semester, our Columbia campus was able to serve their community through the Vial-of-Life Project at the Harry S. Truman Memorial Veterans’ Hospital. Students helped patients in completing an up-to-date home medication list and provided a sticker to put in their window. If emergency personnel or others see this sticker, they know that the patient has a complete medical history in the house. This project allows our organization to help others and improve patient safety, especially in emergencies. The Columbia campus handed out 76 Vial-of-Life kits and reached patients residing in over 25 different Missouri counties.
For the spring semester, we are looking forward to our monthly general meetings and our next service project. Our Columbia members are teaming up with MMSHP and the Ronald McDonald House in February. Volunteers will prepare meals for patients and families receiving care at the Women and Children's Hospital in Columbia. We are excited to serve our community through this event and hope to make it a tradition.