Risk Of Metformin-associated Lactic Acidosis Research Articles

Determination of metformin from micro-liter plasma and blood glucose test strip using eco-friendly micro-extraction procedures for point-of-care diagnostics

Metformin is commonly used in the treatment of type 2 diabetes and polycystic ovary syndrome. Beyond these common applications, it also holds promise in treating chronic pain, and as an antiaging and anticancer agent. In addition, it has cardiovascular protective and neuroprotective effects. However, elevated concentrations of metformin in the plasma, such as in patients with renal impairment or with conditions that can disrupt lactate clearance, could cause metformin-associated lactic acidosis. Moreover, metformin can cause a deficiency of vitamin-B12 and folic acid and impact one-carbon metabolism negatively. This study employs micro-extraction procedures to extract metformin from the human plasma and blood glucose test strips followed by detection using matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS). Under the optimized micro-extraction procedures and by using an eco-friendly base and solvent, the proposed method required only 10 µL of the human plasma and a small piece of the blood glucose test strip for metformin analysis. The method exhibits a linear range of 0.05–5 μg mL−1 with a coefficient of determination (r2) of 0.999 and a limit of detection of 0.01 μg mL−1. The relative standard deviation (RSD) and relative error (RE) were both below 6.7 %. The test strip is a disposable product; its reuse before disposal could increase its additional applicability. Furthermore, major blood proteins and their modifications could be identified using this tiny volume of blood by mass spectrometry after protein digestion. The proposed technique could be invaluable in point-of-care diagnostics, enabling rapid monitoring of metformin plasma concentration and major plasma proteins to help patients mitigate the risk of metformin-associated lactic acidosis. To reduce organic waste in clinical applications, micro-extraction is a simple and efficient protocol for sample preparation using minute volumes of blood samples.

Treatment of severe metformin-associated lactic acidosis with renal replacement therapy and tris-hydroxymethyl aminomethane: a case report

BackgroundType B lactic acidosis is a rare but serious side effect of metformin use. The risk of metformin-associated lactic acidosis is elevated in renal or liver impairment, heart failure and in metformin overdose. Metformin-associated lactic acidosis is treated with renal replacement therapy although this can be limited by metformin’s large volume of distribution and a patient’s hemodynamic instability. Tris-hydroxymethyl aminomethane is a buffer that rapidly equilibrates in liver cells and increases the intracellular pH of hepatocytes. Intracellular alkalosis increases lactate uptake by the liver and can promote gluconeogenesis which results in increased lactate metabolism and decreased lactate production. Unlike intravenous bicarbonate which can worsen acidosis due to carbon dioxide retention and hypocalcemia, tris-hydroxymethyl aminomethane does not generate large amounts of carbon dioxide and can improve cardiac contractility in experimental models.Case presentationWe present a case of a 43-year-old African American male who intentionally ingested 480,000 g of metformin. He developed severe metformin-associated lactic acidosis that was refractory to 21 hours of high flux hemodialysis. This was followed by an additional 12 hours of high flux hemodialysis augmented by continuous intravenous infusion of tris-hydroxymethyl aminomethane. After initiating tris-hydroxymethyl aminomethane, the patient had rapid reversal of lactic acidosis and was weaned off vasopressors and mechanical ventilation.ConclusionsWhile metformin-associated lactic acidosis can be treated with renal replacement therapy, severe cases of lactic acidosis may not be amenable to renal replacement therapy alone. Through its unique buffer mechanisms, tris-hydroxymethyl aminomethane can be used in conjunction with dialysis to rapidly improve acidosis associated with metformin.

Safety of metformin continuation in diabetic patients undergoing invasive coronary angiography: the NO-STOP single arm trial

BackgroundDespite paucity of data, it is common practice to discontinue metformin before invasive coronary angiography due to an alleged risk of Metformin-Associated Lactic Acidosis (M-ALA). We aimed at assessing the safety of metformin continuation in diabetic patients undergoing coronary angiography in terms of significant increase in lactate levels.MethodsIn this open-label, prospective, multicentre, single-arm trial, all diabetic patients undergoing coronary angiography with or without percutaneous coronary intervention at 3 European centers were screened for enrolment. The primary endpoint was the increase in lactate levels from preprocedural levels at 72-h after the procedure. Secondary endpoints included contrast associated-acute kidney injury (CA-AKI), M-ALA, and all-cause mortality.Results142 diabetic patients on metformin therapy were included. Median preprocedural lactate level was 1.8 mmol/l [interquartile range (IQR) 1.3–2.3]. Lactate levels at 72 h after coronary angiography were 1.7 mmol/l (IQR 1.3–2.3), with no significant differences as compared to preprocedural levels (p = 0.91; median difference = 0; IQR − 0.5 to 0.4 mmol/l). One patient had 72-h levels ≥ 5 mmol/l (5.3 mmol/l), but no cases of M-ALA were reported. CA-AKI occurred in 9 patients (6.1%) and median serum creatinine and estimated glomerular filtration rate remained similar throughout the periprocedural period. At a median follow-up of 90 days (43–150), no patients required hemodialysis and 2 patients died due to non-cardiac causes.ConclusionsIn diabetic patients undergoing invasive coronary angiography, metformin continuation throughout the periprocedural period does not increase lactate levels and was not associated with any decline in renal function.Trial registration: The study was registered at Clinicaltrials.gov (NCT04766008).Graphical

LBODP034 Metformin Associated Lactic Acidosis, Rare But Real

Abstract Background Metformin has been widely used as a first-line agent to treat type 2 diabetes mellitus. Although metformin has become a drug of choice for the treatment of type 2 diabetes mellitus, some patients may not receive it owing to the risk of lactic acidosis. Metformin increases plasma lactate levels in a plasma concentration-dependent manner by inhibiting mitochondrial respiration predominantly in the liver. Elevated plasma metformin concentrations (as occur in individuals with renal impairment) and a secondary event or condition that further disrupts lactate production or clearance (e. g., cirrhosis, sepsis, or hypoperfusion), are typically necessary to cause metformin-associated lactic acidosis (MALA). Case description We present a case of a severe metformin-induced lactic acidosis in a patient with type 2 DM admitted to the emergency department with a history of dehydration due to diarrhea and complicated by acute renal failure Our patient is a 57-year-old female with a medical history of DM on metformin 1000 mg twice daily, hypertension, hyperlipidemia, and hypothyroidism who presented to the hospital with a concern of altered mental status. Upon presentation, the patient could not provide much history, but her daughter confirmed that she was in her normal state of health until 2 weeks ago when she started complaining of knee pain and stated that she was taking ibuprofen 600 mg every 8 hours for pain with good response. Later, 2 days prior to her presentation she started having severe nausea, vomiting, weakness and was noted to be confused so she was brought to the emergency department. Upon arrival the patient's blood pressure was noted to be 104/50, GCS 15, rest of the vitals were within normal. Potassium was 5.5(3.4 - 5.3 mmol/L), bicarbonate 5(22 - 33 mmol/L), creatinine 10.2(0.4 - 1.1 mg/dL) compared to normal creatinine 6 months ago, GFR<5(>59 ml/min/1.73 sq meters, anion gap 41(4-16), PH 6.7(7.33 - 7.43), After resuscitation, her severe acidemia persisted despite aggressive intervention with volume resuscitation and vasopressors, leading to the initiation of renal replacement therapy. After multiple dialysis treatments, her severe acidemia resolved and creatinine improved back to baseline after which she was discharged home in stable condition. Conclusion The reported incidence of lactic acidosis in clinical practice has proved to be very low (<10 cases per 100,000 patient-years). This literature-based review provides an update on the impact of renal function and other conditions (cirrhosis, sepsis, or hypoperfusion) on metformin plasma levels and the risk of MALA in patients with type 2 diabetes. As these secondary events may be unpredictable and the mortality rate for MALA approaches 50%, metformin has been contraindicated in moderate and severe renal impairment to minimize the potential for toxic metformin levels and MALA. Presentation: No date and time listed

114-LB: Metformin-Associated Lactic Acidosis Risk Assessment in Veterans on Continuous Oxygen Therapy

Metformin is the most prescribed oral medication for type 2 diabetes in the US due to its low cost, efficacy in reducing insulin resistance, and overall safety profile. However, literature shows that metformin can cause a rare but serious side effect of lactic acidosis (LA) with an incidence of 0.03-0.06 per 1000 patients. Persons requiring continuous oxygen therapy (COT) may be at risk for LA associated with hypoxia and decreased tissue perfusion, but the risk of metformin associated lactic acidosis (MALA) in persons requiring COT is unclear. Due to lack of evidence, some clinicians may empirically discontinue metformin in patients on COT, compromising glycemic stability. The objective of this drug utilization evaluation was to determine the frequency of metformin use and incidence of MALA in patients receiving COT. A retrospective review was conducted at a large regional Veterans Affairs Medical Center for patients with active prescriptions of metformin and supplemental oxygen therapy from 4/2017-4/2020. Of 578 unique patients identified, manual medical-record review was conducted for 6 patients who had serum lactate levels >4 mmol/L while using concomitant metformin and COT. All were white males with mean: age of 71, pH of 7.35, and eGFR of 56. No cases of LA or DKA were identified. In all cases, elevated lactate levels were attributed to advanced medical conditions including: COPD, sepsis, CHF, CKD, and liver disease. None had serum metformin levels drawn. In conclusion, the association of elevated serum lactate among persons using concomitant metformin and COT was low and occurred in persons with advanced medical conditions. It could not be determined if metformin use was a contributing factor without metformin levels. These findings confirm the importance of clinical judgement when prescribing and continuing metformin for persons with advanced underlying medical conditions. Further study with serum metformin levels may help to better characterize the risk of MALA for persons on COT. Disclosure S. J. Lutz-mccain: None. B. E. Desanzo: None. B. Herk: None. M. Mclinden: None. M. M. Dinardo: None. R. Codario: None.

1013-P: Long-Term Metformin Use and Risk of Death and CV-Renal Outcomes in Type 2 Diabetes with Chronic Kidney Disease (Stage 1-4)

Introduction: The overall evidence for the long-term exposure of metformin on cardiovascular-renal (CV) outcomes in patients with type 2 diabetes (T2D) at different stages of chronic kidney disease (CKD) remains controversial. Methods: We conducted a prospective analysis of 14,766 Chinese patients with T2D enrolled between 2000 and 2016 observed until 31 December 2019. We compared all-cause mortality and incidence of major adverse CV events (MACE) and end-stage kidney disease (ESKD) in prevalent and new metformin users versus other glucose lowering drugs (GLDs) users stratified by CKD stage. Results: During a mean follow-up of 9.6 years (141,310 person-years), we identified 1,798 deaths in metformin users (n=13,967) and 352 deaths in other-GLDs users (n=799). The mean daily dosage of metformin was 1,450 mg and duration of exposure was 7.8 years in CKD stage 1-2 (n=12,375). The respective figures were 1000 mg and 5.7 years in CKD stage 3-4 (n=1,592). Compared with other-GLDs, metformin exposure was associated with reduced risk of all-cause mortality (All: HR=0.48, 95% CI: 0.43-0.54; CKD stage 1-2: HR=0.38, 0.33-0.44; stage 3A: HR=0.53, 0.41-0.69); MACE (All: HR=0.85, 0.72-0.99; stage 1-2: HR=0.80, 0.65-0.99; stage 3-4: HR=0.97, 0.74-1.27) and ESKD (All: HR=0.65, 0.54-0.80; stage 1-2: HR=0.53, 0.33-0.85; stage 3-4: HR=0.80, 0.63-1.02). New users of metformin (n=4,013) had reduced risk of all-cause mortality across all CKD stages; MACE in stage 1-2 and ESKD in stage 1, 2 and 3 compared with users of other oral-GLDs (n=536). Increasing duration and dosage of metformin (up to 1500 mg/day) was associated with reduced or neutral risk of MACE, ESKD and all-cause mortality. The rate of metformin-associated lactic acidosis (MALA) was 5.39 per 100,000 patient-years in CKD stage 3-4. Conclusion: Long-term metformin use was associated with reduced or neutral risk of all-cause mortality, MACE and ESKD among Chinese patients with T2D at CKD stage 1-3 with low risk of MALA. Disclosure A. Yang: None. E. S. H. Lau: None. H. Wu: None. R. C. Ma: Other Relationship; Self; AstraZeneca, Medtronic, Research Support; Self; AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Novo Nordisk, Pfizer Inc., Sanofi-Aventis, Tricida, Inc. A. P. Kong: Advisory Panel; Self; Lilly Diabetes, Speaker’s Bureau; Self; Abbott, AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Lilly Diabetes, Sanofi, Stock/Shareholder; Self; Aptorum. A. Luk: None. A. W. Fu: Research Support; Self; Merck KGaA. J. C. Chan: Consultant; Self; Bayer AG, Boehringer Ingelheim International GmbH, MSD Corporation, Sanofi, Other Relationship; Self; Asia Diabetes Foundation, GemVCare, Research Support; Self; Applied Therapeutics, AstraZeneca, Hua Medicine, Lilly Diabetes, Merck KGaA. E. Chow: Research Support; Self; Medtronic, Speaker’s Bureau; Self; Novartis Pharmaceuticals Corporation, Sanofi-Aventis. Funding Asia Diabetes Foundation; Merck Pharmaceutical (HK) Limited; Chinese University of Hong Kong (to A.Y.)

METFORMIN CONTINUATION VERSUS INTERRUPTION FOLLOWING CORONARY ANGIOGRAPHY: CONTEMPORARY RISK OF LACTIC ACIDOSIS. A PILOT SINGLE-CENTER RANDOMIZED CONTROL TRIAL

Metformin-associated lactic acidosis occurs very infrequently; however, with the significantly greater comorbidity burden and acuity of patients with diabetes undergoing coronary angiography/angioplasty (CA), the inherent risk of metformin-associated lactic acidosis may be significantly increased. Additionally, significant variations in contemporary practice pattern around peri-CA metformin use still continue to exist.

Metformin: time to review its role and safety in chronic kidney disease

■Metformin is recommended as first-line therapy for type 2 diabetes because of its safety, low cost and potential cardiovascular benefits. ■The use of metformin was previously restricted in people with chronic kidney disease (CKD) - a condition that commonly coexists with diabetes - due to concerns over drug accumulation and metformin-associated lactic acidosis. ■There are limited data from observational studies and small randomised controlled trials to suggest that metformin, independent of its antihyperglycaemic effects, may be associated with lower risk of myocardial infarction, stroke and all-cause mortality in people with type 2 diabetes and CKD. ■Research into the risk of metformin-associated lactic acidosis in CKD has previously been limited and conflicting, resulting in significant variation across international guidelines on the safe prescribing and dosing of metformin at different stages of renal impairment. ■Present-day large scale cohort studies now provide supporting evidence for the safe use of metformin in mild to moderate renal impairment (estimated glomerular filtration rate [eGFR] 30-60mL/min/1.73m2 ). However, prescribing metformin in people with severe renal impairment (eGFR<30mL/min/1.73m2 ) remains a controversial issue. Due to observed increased risk of lactic acidosis and all-cause mortality in people with type 2 diabetes and severe renal impairment, it is generally recommended that metformin is discontinued if renal function falls below this level or during acute renal deterioration.

Risk of Metformin-Associated Lactic Acidosis (MALA) in Patients After Gastric Bypass Surgery.

Pharmacokinetic data suggest that the risk of metformin-associated lactic acidosis (MALA) may be increased after Roux-en-Y gastric bypass (RYGB) surgery. The aim of this study was to examine the impact of metformin on plasma lactate levels before and after RYGB surgery. Retrospective study of plasma lactate levels before and 3months after RYGB surgery in patients with type 2 diabetes mellitus (T2DM) not using metformin (MET-0, N=58), on a stable dose (MET-S, N=138), or on a decreasing dose (MET-D, N=85) of metformin. Preoperatively, lactate levels were similar in patients on metformin (1.8±0.05mmol/L) and those not on metformin (1.7±0.08mmol/L), P=0.21. Three months postoperatively, lactate levels had decreased in all groups (P<0.001) to 1.3±0.07 (SE), 1.4±0.05, and 1.2±0.05mmol/l in MET-0, MET-S, and MET-D, respectively. Lactate levels differed between the groups (P=0.03), with the lowest level in MET-D. The number of patients with hyperlactatemia (lactate >2mmol/l) decreased from 31 to 14%, from 22 to 8.6%, and from 26 to 4.7% in MET-S, MET-0, and MET-D, respectively. Mild hyperlactatemia (lactate >2mmol/l) is common in morbidly obese patients with T2DM. It is probably related to increase lactate production by adipocytes. Lactate levels decreased after RYGB-induced weight loss, irrespective of the use of metformin. We therefore conclude that there is no need for routinely lowering of the metformin dose after uncomplicated RYGB surgery, as long as normal renal function is preserved.

Pharmacodynamics Drug Interactions of Metformin with Aspirin and Nifedipine

Metformin is now being recognized as the standard therapy in T2D patients who are overweight. Metformin has many drug-disease interactions that can increase the risk of metformin-associated lactic acidosis. Therefore this study was conducted to evaluate any possible pharmacodynamic interactions between metformin and drugs used to treat chronic diseases e.g. Hypertension. The rats were fasted overnight before inducing diabetes with streptozotocin. The rats were given an intraperitoneal injection of streptozotocin (50 mg kg−1) freshly prepared in 0.1M sodium citrate buffer. The diabetic state was confirmed 72 h after streptozotocin injection. Diabetic rats were grouped into seven groups each group of five rats and distributed among the normal control group diabetic control group and the treatment groups. The treatment continued for 10 days. Blood samples were taken before treatment and after 10 days and analyzed for serum glucose, cholesterol, HDL, LDL, and triglycerides. In the diabetic control group which was given STZ alone the blood glucose level decreased significantly (p &amp;lt; 0.05) after 10 days but still above the hyperglycemic level (200mg/dl). The same was observed in the group treated with metformin. The group treated with nifedipine and aspirin showed significant reduction (p &amp;lt; 0.01) in the glucose level below the hyperglycemic level (200mg/dl). While the groups treated with (Metformin + Nifedipine) and (Metformin +Aspirin) showed highly significant reduction (P&amp;lt;0.001) in blood glucose level. These results conclude that the combination of (metformin +Nifedipine) and the combination of (Metformin + Aspirin) have highly significant hypoglycemic effect. It also showed that Nifedipine has promising role in reducing blood glucose level, lipid profile especially LDL-cholesterol, and body weight.

Unleash Metformin

To evaluate the expanded use of metformin in renal impairment. The MEDLINE database via PubMed, Web of Science, and Cumulative Index to Nursing and Allied Health were searched in August 2013 and included studies from 1950 onward. The search included comparative trials, observational cohort studies, and meta-analyses using the terms diabetes mellitus, metformin, renal insufficiency, and acidosis, lactic. One randomized controlled trial, 1 meta-analysis, 1 case-control, and 3 prospective-cohort studies, representing about 150 000 patients, revealed that metformin is safe in patients with stable mild-moderate renal impairment. The incidence of lactic acidosis is low and similar to sulfonylureas. In addition, reduced risks of cardiovascular disease, all-cause mortality, or any acidosis/serious infection were seen with metformin use in mild-to-moderate renal impairment. Data over the past decade refute the historical contraindication in patients with renal impairment and suggest that the risk of metformin-associated lactic acidosis is low in stable mild-to-moderate renal impairment and similar to the risk with other type 2 diabetes mellitus (DM2) medications with no renal impairment restrictions. Because of its unique impact on microvascular and macrovascular complications, it is advantageous to utilize metformin as the cornerstone in DM2 treatment for as long as possible, including in those patients with mild to moderate stages of renal impairment with no additional contraindications. A dosage reduction is recommended if estimated glomerular filtration rate (eGFR) is between 30 and 45 mL/min/1.73 m(2) and discontinuation if eGFR is <30 mL/min/1.73 m(2).

Metformin Use in Decompensated Heart Failure

Metformin is associated with decreased mortality and morbidity in stable heart failure patients with diabetes mellitus type II. Diabetic heart failure patients with elevated systolic blood pressure are at increased risk for developing acute decompensated heart failure, which is often associated with decreased kidney function. Metformin-associated lactic acidosis is a rare but fatal side effect that may occur when kidney function is decreased. During acute decompensated heart failure, timely treatment may prevent the decrease in kidney function to the threshold associated with an increased risk of metformin-associated lactic acidosis. Metformin should not be withheld in diabetic patients with stable heart failure who do not have other risk factors for acute decompensated heart failure or lactic acidosis.

Metformin-associated lactic acidosis treated with continuous renal replacement therapy

Introduction: Lactic acidosis is an infrequent complicationof metformin therapy for diabetes mellitus. The presence of clinical conditions, such as renal failure, increases the risk of metformin-associated lactic acidosis (MALA). We present a case of lactic acidosis in a patient with diabetes treated with metformin, complicated by acute renal failure in preexisting chronic nephropathy. Case summary: A 70-year-old white male, weighing 77 kg, with diabetes mellitus, coronary heart disease, congestive heart failure (New York Heart Association class III), moderate essential hypertension (stage 2), and renal dysfunction (serum urea, 90 mg/dL; serum creatinine, 1.5 mg/dL; creatinine clearance, 49.8 mL/min/1.73 m2) presented to the emergency department of the General Hospital of Rhodes (Rhodes, Greece), complaining of malaise, respiratory distress, myalgias, disorientation, abdominal discomfort, and increasing somnolence of insidious onset. The patient's regimen included isosorbide mononitrate 60 mg QD, furosemide 40 mg QD, quinapril 20 mg QD, and metformin 850 mg TID. Before this hospitalization, he had received a 2-week course of oral diclofenac sodium 25 mg TID for low back pain. Preliminary laboratory evaluation found leukocytosis (27,300/mm 3), severe renal failure (serum urea, 215 mg/dL; serum creatinine, 7.4 mg/dL; calculated creatinine clearance, 10.1 mL/min/1.73 m2), and a high anion gap metabolic acidosis (pH, 6.95; anion gap, 33 mEq/L) in arterial blood gas analysis. His medical and drug history, the clinical and laboratory findings, and the determination of lactate in samples of plasma (7.8 mEq/L), aroused the suspicion of MALA. The Naranjo algorithm scores for metformin and diclofenac sodium were 6 and 7, respectively. The patient received a single session of bicarbonate-buffered continuous venovenous hemodiafiltration (CWHDF) that lasted 16 hours. Ultimately, he was stabilized, and progressive restoration of acid-base balance and renal function was observed. Discussion: We suspect that lactic acidosis mayhave been related to the use of metformin, the presence of heart and renal failure (contributing to metformin toxicity), and previous use of diclofenac sodium. CVVHDF has an advantage over conventional intermittent hemodialysis in that it corrects acidosis and removes lactate and metformin without risk of hypernatremia or fluid overload. Conclusions: MALA should be strongly suspected in diabetic patients presenting with high anion gap metabolic acidosis and increased serum lactate level. In the case described, prompt recognition of lactic acidosis and early application of bicarbonate-buffered CVVHDF produced successful results.

Treatment of non-insulin-dependent diabetes mellitus with metformin.

Metformin alleviates hyperglycemia of non-insulin-dependent diabetes mellitus (NIDDM) by inhibiting hepatic glucose production and improving peripheral insulin sensitivity. In contrast to sulfonylureas, metformin does not stimulate insulin-secretion, promote weight gain, exacerbate hyperinsulinemia, or cause hypoglycemia. It also favorably affects serum lipids. A comprehensive review of the medical literature from 1968 to the present was conducted using the key words "metformin" and "non-insulin-dependent diabetes mellitus." Metformin monotherapy was superior to placebo and comparable to sulfonylureas in reducing fasting plasma glucose and glycosylated hemoglobin levels in patients with NIDDM uncontrolled by diet. Metformin and sulfonylureas, however, had diverse effects on body weight and fasting plasma insulin levels; both weight and insulin levels remained unchanged or decreased with metformin and increased with sulfonylureas. In patients with secondary sulfonylurea failure, the combination of metformin and a sulfonylurea synergistically improved glycemic control better than either drug alone and was comparable to insulin plus sulfonylurea. When hyperglycemia is uncontrolled by insulin after secondary sulfonylurea failure, limited data suggest the efficacy of metformin plus insulin. The mild, transient, self-limited gastrointestinal side effects that sometimes occur can be minimized by gradually increasing the doses and by taking metformin with food. Risk of metformin-associated lactic acidosis is low if prescribing guidelines are adhered to. Potential adverse drug interactions include hypoglycemia during concurrent sulfonylurea therapy and elevated metformin plasma concentrations when metformin is taken concomitantly with cimetidine. Metformin can be used safely and effectively as first-line monotherapy in NIDDM or in combination with a sulfonylurea when monotherapy with either agent fails. It can be particularly suitable when weight gain, hyperlipidemia, and hypoglycemia are clinically important issues.