Safety and Efficacy of GLP-1 Receptor Agonists and SGLT2 Inhibitors Among Veterans With Type 2 Diabetes.

Background: Choosing the best medication regimen for a patient with type 2 diabetes mellitus (T2DM) depends on glycemic control, adherence, adverse effect profile, and comorbid conditions. Two new medication classes, glucagon-like peptide 1 receptor agonists (GLP-1 RA) and sodium-glucose cotransporter 2 inhibitors (SGLT2i), have demonstrated cardiovascular and renal protective properties, creating a new way to care for patients with T2DM. Methods: This study evaluated the safety and efficacy of the combined use of GLP-1 RA and SGLT2i medications in a veteran population with T2DM. We conducted a pre-post, retrospective chart review of patients at the Veterans Affairs Ann Arbor Healthcare System in Michigan who were prescribed both a GLP-1 RA and SGLT2i medications. The primary objective was to determine the effect on hemoglobin A1c levels (HbA1c) at 12 weeks when using a GLP-1 RA and SGLT2i in combination. Results: HbA1c levels decreased by 1% after 12 weeks of combination therapy from baseline (P < .001), and this reduction was sustained through the duration of the study period. At 26 and 56 weeks of combination therapy, body weight decreased by about 5 kg (5%) from baseline (P < .001). Systolic blood pressure (BP) reduction from baseline reached statistical significance after 26 and 52 weeks of combination therapy (P < .01 and P < .05, respectively). There was no significant change in diastolic BP, serum creatinine, or estimated glomerular filtration rate during the study period. Conclusions: The combined use of GLP-1 RA and SGLT2i resulted in statistically significant improvement in HbA1c levels, weight, and systolic BP compared with separate use.

The Clinical Pharmacy Specialists' Role in Antihypertensive Management Surrounding Bariatric Surgery in a Veterans Affairs Population.

BACKGROUND: No guidelines exist for de-escalating antihypertensive medications surrounding bariatric surgery. This study analyzed clinical pharmacy specialist (CPS) management of antihypertensive medications in patients undergoing bariatric surgery at a Veterans Affairs medical center. OBJECTIVES: The primary objective was to describe the CPS role in antihypertensive management surrounding bariatric surgery through evaluation of number of CPS encounters, number and type of antihypertensive medications and medication interventions by CPSs and all other providers, over 5 time periods between a pre-operative assessment and up to 6 months post-operatively. METHODS: Electronic medical records of patients taking antihypertensive medication who underwent bariatric surgery between 1/1/2014 and 2/27/2018, had primary care through our facility, and at least 1 encounter with a CPS were reviewed. RESULTS: Forty patients were included out of 221 screened. There were 109 total medication interventions in 37 patients. CPSs provided 60 medication interventions (55% of total interventions) in 26 patients. Mean antihypertensive agents per patient was 2.18 at baseline versus 0.95 at 6-months post-operative. Dihydropyridine calcium channel blockers had the highest discontinuation rate. Thiazide diuretics were most commonly discontinued prior to surgery and angiotensin converting enzyme inhibitors were discontinued more steadily over the study duration. Nineteen patients (48.7%) had blood pressure <140/90 mmHg and were off all antihypertensive medications at the final CPS encounter. CONCLUSION: The results of this small study support the role of CPSs in antihypertensive medication management surrounding bariatric surgery.

Understanding the impact of commonly utilized, non-insulin, glucose-lowering drugs on body weight in patients with type 2 diabetes.

INTRODUCTION: The majority of patients with type 2 diabetes also have obesity. Obesity increases the risk of developing diabetes and is associated with worsened glycemic control and increased morbidity and mortality in individuals with diabetes. Sustained weight loss is associated with improved glycemic control, potential for diabetes remission, and decreased medical expenditures. AREAS COVERED: Herein, the impact of commonly utilized, non-insulin, glucose-lowering drugs on body weight in patients with type 2 diabetes is discussed. The weight change magnitudes, mechanisms, and any within-class differences are also explored. EXPERT OPINION: The weight impact of diabetes medications should be considered when designing treatment regimens, especially in patients who are overweight or have obesity. Lifestyle modification is paramount for optimal diabetes management. Therapeutic regimens should ideally be designed to maximize weight loss and at least minimize or avoid weight gain. Future glucose-lowering medications should continue to offer improvement in cardiovascular risk factors, including weight, in order to be accepted into the armamentarium of diabetes therapy. Therapeutic regimens should be designed to help patients with diabetes and obesity achieve both glycemic and weight goals. Management of these disease states is expected to become increasingly integrated.

Pharmacokinetic drug evaluation of extended release lorcaserin for the treatment of obesity.

INTRODUCTION: Lorcaserin is a serotonin 2C receptor antagonist that was FDA approved in 2012. Lorcaserin is recently available as an extended-release (ER) formulation for the treatment of obesity as an adjunct to lifestyle modification. Areas covered: The pharmacokinetics, pharmacodynamics, efficacy, and safety of lorcaserin ER will be reviewed. Expert opinion: Lorcaserin ER 20mg daily provides drug exposure bioequivalent to lorcaserin immediate release (IR) 10mg twice daily. Lorcaserin IR is associated with 3.3 and 3.0% placebo-subtracted weight loss in patients without and with diabetes, respectively. A1C was reduced by 0.9% in patients with diabetes. Common side effects include headache, dry mouth, constipation, dizziness, fatigue, and nausea. Lorcaserin provides potential advantages over other antiobesity medications in regards to tolerability and simplicity of medication initiation, but may not be as effective as other options. Lorcaserin ER offers improved ease of administration and anticipated adherence compared to the IR formulation. The place in therapy for lorcaserin ER and other antiobesity medications will be further clarified by results of pending clinical trials addressing cardiovascular outcomes as well as the role pharmacogenomics and comorbid disease states may play in choosing patient-specific therapy.

Pharmacodynamic and pharmacokinetic evaluation of insulin glargine U300 for the treatment of type 1 diabetes.

INTRODUCTION: Glargine 300 units/ml (Gla-300) is a novel basal insulin formulation approved in 2015 for the treatment of diabetes. This more concentrated form of glargine causes delayed redissolution from the subcutaneous depot after injection and thus altered action profile. Areas covered: The pharmacokinetics, pharmacodynamics, efficacy, and safety of Gla-300 in patients with type 1 diabetes mellitus (T1DM) will be reviewed. Expert opinion: Gla-300 has a flatter and more prolonged pharmacokinetic profile compared to glargine 100 units/ml (Gla-100), but is less potent on a unit per unit basis. The prolonged duration of Gla-300 should provide 24h coverage with a single daily dose in all patients. Two phase III trials comparing Gla-300 and Gla-100 were conducted in patients with T1DM. A1C reduction and other measures of glycemic control were similar between groups. Hypoglycemia rates were similar among groups in one trial, but favored Gla-300 in the other. Evidence for improvement in hypoglycemia with Gla-300 is more convincing in the type 2 diabetes population. Gla-300 is available in an insulin pen to mitigate potential dosing errors with different glargine concentrations; the maximum dose per injection is 80 units. Future research should include direct comparison with degludec and use in insulin-resistant populations.

Evaluation of lorcaserin for the treatment of obesity.

INTRODUCTION: Obesity is an epidemic associated with significant morbidity. Lorcaserin , a novel serotonin 2C receptor antagonist, was recently approved as an adjunct to lifestyle modification for long-term weight loss and maintenance. Clinical studies in patients without diabetes demonstrated 5.8% mean weight loss from baseline with lorcaserin compared to 2.5% with placebo and over twice as many patients achieved ≥ 5% weight loss. Patients with diabetes achieved mean weight loss of 4.5% with lorcaserin compared to 1.5% with placebo as well as modest improvements in glycemic outcomes. AREAS COVERED: The authors review the pharmacology and clinical efficacy as well as the safety and tolerability of lorcaserin. This was achieved through a PubMed search (1960 - present) on lorcaserin to generate the key literature in the area. The lorcaserin package insert and Food and Drug Administration briefing documents were also used to identify relevant information. To assess long-term clinical efficacy and safety, the authors used studies with a minimum duration of one year. EXPERT OPINION: Lorcaserin induces moderate but significant weight loss compared to placebo as an adjunct to lifestyle modification. Although head-to-head comparison trials are not available, lorcaserin is likely less effective but better tolerated than its recently approved competitor, phentermine/topiramate. Cardiovascular outcome data will be invaluable in determining lorcaserin's eventual utilization and place in therapy.

Effect of sulfonylurea dose escalation on hemoglobin A1c in Veterans Affairs patients with type 2 diabetes.

Sulfonylureas are often titrated to maximum doses despite evidence that their efficacy plateaus above half-maximum doses. The aim of this study was to determine the impact of doubling the dose of glyburide and glipizide to high doses on hemoglobin A1c (HbA1c) in Veterans Affairs patients with type 2 diabetes. A retrospective review of 131 patient cases with prescriptions for high-dose glyburide or glipizide from July 1 through December 18, 2008, was conducted. Three dosage groups were examined: glyburide 5 mg twice daily increased to 10 mg twice daily (GLYB), glipizide 5 mg twice daily increased to 10 mg twice daily (GLIPA), and glipizide 10 mg twice daily increased to 20 mg twice daily (GLIPB). Each patient served as his or her own control; HbA1c after at least 75 days on each dose was compared. There was a statistically significant decrease in HbA1c in GLIPA only (mean ± SD 8.0 ± 1.0 vs. 7.6 ± 1.0%, P = 0.03). No significant change in HbA1c was detected in GLYB (8.1 ± 1.1 vs. 8.1 ± 1.3%, P = 0.80) and the evaluation of GLIPB (8.6 ± 1.7 vs. 8.2 ± 1.1%, P = 0.41) was not adequately powered due to the small sample size. In this small retrospective study, increasing glipizide, but not glyburide, from 5 mg to 10 mg twice daily significantly decreased HbA1c in patients with diabetes.

Glucagon-like peptide-1 receptor agonists as add-on therapy to basal insulin in patients with type 2 diabetes: a systematic review.

The prevalence of obesity and diabetes continues to rise in the US. Glucagon-like peptide-1 receptor agonist (GLP-1RA) is an effective treatment option for type 2 diabetes mellitus (T2DM) that promotes weight loss. Common and effective treatment options added to metformin therapy (basal insulin, sulfonylureas, and pioglitazone) contribute to weight gain, which makes the addition of GLP-1RAs advantageous. Exenatide was the first agent in this class and has recently been approved for use in combination with insulin glargine by the US Food and Drug Administration and the European Medicines Agency. Until recently, there was a lack of data examining basal insulin combined with these agents. The main purpose of this article is to review the prospective interventional data on the safety and efficacy of GLP-1RAs (exenatide, liraglutide, albiglutide, lixisenatide) combined with basal insulin therapy in nonpregnant adults with T2DM. Databases searched were PubMed, Cochrane Central Register of Controlled Trials and the Database of Systematic Reviews (inception to January 2012). Abstracts presented at relevant diabetes and endocrine meetings from 2009 to 2011 were also reviewed, as were reference lists of identified publications. A total of five studies met the criteria and were included in the review. Data from these studies demonstrated that this combination therapy offers advantages for the treatment of diabetes, such as additional lowering of A1c without major risk for hypoglycemia, lower basal insulin requirements, decreased postprandial glucose levels (with or without fasting plasma glucose decreases), and weight loss, or at the very least, less weight gain. However, the gastrointestinal side effects and high cost of these agents may limit their use. This review demonstrates that adding a GLP-1RA to an existing basal insulin regimen is a reasonable treatment strategy in nonpregnant adult patients with T2DM.

Drug-drug interactions with glucagon-like peptide-1 receptor agonists.

OBJECTIVE: To review drug interaction studies of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and concurrent oral medications. DATA SOURCES: PubMed was searched (to December 5, 2011) using the terms exenatide, liraglutide, albiglutide, and lixisenatide. The search was limited to studies published in English and conducted in adults. Abstracts from the American Diabetes Association Scientific Sessions from 2004 through 2011 were also searched. STUDY SELECTION AND DATA EXTRACTION: All abstracts were screened for eligibility, which consisted of studies reporting the effects of GLP-1RA administration on the pharmacokinetics and pharmacodynamics of concurrent oral medications. Data extracted from eligible trials included study and population characteristics; pharmacokinetic parameters including maximum concentration (C(max)), time to maximum concentration (t(max)), and area under the concentration-time curve (AUC); and pharmacodynamic properties. DATA SYNTHESIS: Our search identified 254 potentially relevant articles; of those, 11 articles evaluating 15 drug interactions were reviewed. Only 1 study was conducted in patients with type 2 diabetes. Equivalence in AUC was demonstrated in the majority of drug interactions studied (11 of 15). The AUCs of acetaminophen and lovastatin were decreased after exenatide administration and those of lisinopril and digoxin were decreased after liraglutide administration. In 10 studies, GLP-1RAs decreased the C(max) and, in 14 studies, prolonged the t(max) of study drug. Pharmacokinetic properties of drugs and differences in study design can explain differences in interaction potential. CONCLUSIONS: GLP-1RAs may produce clinically significant interactions with drugs that require achievement of target peak concentrations or a rapid onset of action. Studies in patients with type 2 diabetes are needed to further assess and allow comparison of several GLP-1RA agents' impact on steady-state pharmacokinetics and pharmacodynamics of concomitant oral medications.

Lorcaserin: an investigational serotonin 2C agonist for weight loss.

PURPOSE: The pharmacology, pharmacokinetics, and adverse effects of the selective serotonin (5-HT) agonist lorcaserin are reviewed, with an emphasis on efficacy and safety data from Phase III clinical trials. SUMMARY: Lorcaserin is highly selective for a subtype of 5-HT receptors important in appetite regulation, with low affinity for other 5-HT-receptor subtypes whose activation is thought to underlie serious cardiovascular adverse effects; such effects have been seen with nonselective serotonergic agents for weight loss (e.g., fenfluramine). In two Phase III trials of lorcaserin, the cumulative proportion of patients who achieved weight loss of ≥5% over 12 months was about 47% with lorcaserin use versus 20-25% among placebo users (p < 0.0001 for both trials). Lorcaserin was generally well tolerated in the clinical trials to date; nausea and vomiting, headache, and dizziness were the most commonly reported adverse effects. In two of the three Phase III trials to date, lorcaserin use was not found to increase the risk of cardiac valvulopathy; however, in the other Phase III trial, which focused on patients with diabetes, lorcaserin use was associated with an increased rate of new valvulopathy. In a carcinogenicity evaluation involving laboratory rats, lorcaserin was linked to the development of various malignancies, a finding with uncertain implications for its potential future use in humans. CONCLUSION: Lorcaserin, a 5-HT(2C) agonist, has demonstrated efficacy in patients who are obese or are overweight with associated comorbidities. Phase III trials have found that more than 35% of patients lost greater than 5% of their baseline weight. The maker of lorcaserin has indicated it will continue to seek U.S. marketing approval of the drug for the indications of long-term weight loss and weight-loss maintenance in specific patient populations.

Efficacy and safety of long-acting glucagon-like peptide-1 receptor agonists compared with exenatide twice daily and sitagliptin in type 2 diabetes mellitus: a systematic review and meta-analysis.

BACKGROUND: Long-acting glucagon-like peptide-1 receptor agonists (LA-GLP-1RAs) may deliver additional therapeutic benefits over other available incretin-based therapies. OBJECTIVE: To pool results of randomized controlled trials comparing the efficacy and safety of maximum dose LA-GLP-1RAs (liraglutide, exenatide once weekly) with exenatide twice daily and dipeptidyl-peptidase-IV inhibitors in patients with type 2 diabetes. METHODS: We searched PubMed, Cochrane Central Register of Controlled Trials and Database of Systematic Reviews, EMBASE (all from inception-December 2010), and abstracts presented at the American Diabetes Association Scientific Sessions in 2009 and 2010 to identify English-language reports of studies of at least 24 weeks' duration. The primary endpoint was mean change in hemoglobin A(1c) (A1C) from baseline to study endpoint. Weighted mean differences or odds ratios and their 95% confidence intervals for each outcome relative to control were calculated as appropriate. RESULTS: A1C was reduced favoring LA-GLP-1RAs compared with exenatide twice daily and sitagliptin (weighted mean difference [WMD] -0.47% [95% CI -0.69 to -0.25] and WMD -0.60% [95% CI -0.75 to -0.45], respectively). Odds ratios greater than 1 favored LA-GLP-1RAs for reaching the A1C target goal of less than 7%. Fasting plasma glucose (FPG) was reduced and favored the LA-GLP-1RA-based regimens. Exenatide demonstrated significantly greater reductions in postprandial glucose (PPG) after the morning and evening meals, compared with LA-GLP-1RAs. Body weight was reduced similarly between LA-GLP-1RAs and exenatide, but favored LA-GLP-1RAs in the sitagliptin comparator trials. LA-GLP-1RA therapy was not associated with severe hypoglycemia or acute pancreatitis. Compared with exenatide twice daily, vomiting was reduced significantly with LA-GLP-1RAs (OR 0.55; 95% CI 0.34 to 0.89); there was a trend toward decreased nausea (OR 0.58; 95% CI 0.32 to 1.06) and no difference in the incidence of diarrhea (OR 1.03; 95% CI 0.67 to 1.58). CONCLUSIONS: Compared with other incretin-based therapies, LA-GLP-1RAs produce greater improvement in A1C and FPG. They provide lesser effect on PPG, similar reduction in body weight, and result in a potentially favorable adverse event profile compared with exenatide twice daily.

Antidiabetic prescribing trends and predictors of thiazolidinedione discontinuation following the 2007 rosiglitazone safety alert.

This study aimed to examine the change in antidiabetic medication prescribing trends and predictors of thiazolidinedione (TZD) discontinuation six months after the 2007 rosiglitazone safety alert. We performed a retrospective cohort analysis. Patients with two prescriptions for a TZD between 1 January and 21 May 2007, including one covering 21 May 2007, and continuous enrolment during 2006-2007 were identified from the MarketScan database. Multivariate logistic regression analysis was used to compare characteristics between patients who continued and discontinued each TZD. We identified 40,836 and 37,183 individuals with a current prescription for rosiglitazone and pioglitazone, respectively. Significantly more rosiglitazone (53.5%) compared to pioglitazone users (21.4%) discontinued initial therapy six months after the alert (p<0.001). Approximately 23% of patients who discontinued rosiglitazone were switched to pioglitazone, while <1% was switched from pioglitazone to rosiglitazone. Notably, 19.4% of patients who discontinued rosiglitazone and 36.1% of those who discontinued pioglitazone did not have evidence of any antidiabetic drug at follow-up. There was a significant decrease in metformin and an increase in sitagliptin prescribing in patients who discontinued TZDs. Age, sex, region, cardiovascular comorbidities and physician specialty predicted TZD discontinuation. These findings suggest that FDA advisories may be associated with substantial changes in medication use.

Naltrexone/bupropion: an investigational combination for weight loss and maintenance.

Naltrexone/bupropion is an investigational combination for weight loss and maintenance in patients who are obese or have a BMI ≥ 27 kg/m(2) with comorbid diabetes, hypertension or hyperlipidemia. Pooled results from four phase 3 trials reveal placebo-subtracted mean weight loss of 4.7% (range 3.2-5.2%) with naltrexone/bupropion after 1 year (p < 0.001 vs. placebo in each trial). The placebo-subtracted proportion of patients achieving ≥5% weight loss with naltrexone/bupropion ranged from 26 to 33% (p < 0.001 vs. placebo in each trial). In the majority of phase 3 trials, naltrexone/bupropion significantly improved proportion of patients achieving ≥10% weight loss, waist circumference, triglycerides, high-density lipoprotein, fasting insulin, insulin resistance, and obesity-specific quality of life compared to placebo. In patients with diabetes, naltrexone/bupropion therapy decreased hemoglobin A1c (HbA1c) approximately 0.5% more than placebo (p < 0.001). Common side effects associated with naltrexone/bupropion include nausea, constipation, vomiting, dizziness, and dry mouth. Greater improvement in systolic blood pressure and pulse were seen with placebo compared to naltrexone/bupropion (p < 0.001). Further studies are necessary to determine the effect of naltrexone/bupropion on cardiovascular outcomes. The safety and efficacy of naltrexone/bupropion in weight management is reviewed in this article.

Probable interaction between warfarin and bee pollen.

PURPOSE: A probable interaction between warfarin and honeybee-collected pollen is reported. SUMMARY: A 71-year-old Caucasian man arrived at an anticoagulation clinic for routine warfarin monitoring with an International Normalized Ratio (INR) value of 7.1 (therapeutic range, 2.0-3.0). His medical history included atrial flutter, hypertension, hyperlipidemia, diabetes mellitus, erectile dysfunction, obesity, and hypothyroidism. His medication regimen included warfarin, hydrochlorothiazide, lisinopril, levothyroxine, simvastatin, glyburide, metformin, vardenafil, aspirin, a multivitamin, and the herbal products Cataplex E2, Cataplex B, and Cyruta. The dosages of all medications and herbal products had been stable for the previous nine months, including warfarin (INR, 1.9-3.3). The patient began taking bee pollen granules (one teaspoon orally twice daily) for a perceived general health benefit one month before this clinic visit. He denied use of alcohol and tobacco, changes in dietary phytonadione intake, missed or extra doses of warfarin, any other medication changes, and acute illness and diarrhea. Warfarin was withheld, and the patient was seen at the anticoagulation clinic three days later with an INR of 3.7. Warfarin was held for a fourth day and then restarted with the weekly dose decreased by 11%. The patient continued to take bee pollen, and all INR values during the next seven months were within or near the therapeutic range. Use of the Drug Interaction Probability Scale indicated that there was a probable interaction between bee pollen and warfarin. CONCLUSION: Consumption of bee pollen led to increased INR values in a patient taking warfarin.