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N Engl J Med ; 385(6): 503-515, 2021 08 05.
Article in English | MEDLINE | ID: covidwho-2160403


BACKGROUND: Tirzepatide is a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 (GLP-1) receptor agonist that is under development for the treatment of type 2 diabetes. The efficacy and safety of once-weekly tirzepatide as compared with semaglutide, a selective GLP-1 receptor agonist, are unknown. METHODS: In an open-label, 40-week, phase 3 trial, we randomly assigned 1879 patients, in a 1:1:1:1 ratio, to receive tirzepatide at a dose of 5 mg, 10 mg, or 15 mg or semaglutide at a dose of 1 mg. At baseline, the mean glycated hemoglobin level was 8.28%, the mean age 56.6 years, and the mean weight 93.7 kg. The primary end point was the change in the glycated hemoglobin level from baseline to 40 weeks. RESULTS: The estimated mean change from baseline in the glycated hemoglobin level was -2.01 percentage points, -2.24 percentage points, and -2.30 percentage points with 5 mg, 10 mg, and 15 mg of tirzepatide, respectively, and -1.86 percentage points with semaglutide; the estimated differences between the 5-mg, 10-mg, and 15-mg tirzepatide groups and the semaglutide group were -0.15 percentage points (95% confidence interval [CI], -0.28 to -0.03; P = 0.02), -0.39 percentage points (95% CI, -0.51 to -0.26; P<0.001), and -0.45 percentage points (95% CI, -0.57 to -0.32; P<0.001), respectively. Tirzepatide at all doses was noninferior and superior to semaglutide. Reductions in body weight were greater with tirzepatide than with semaglutide (least-squares mean estimated treatment difference, -1.9 kg, -3.6 kg, and -5.5 kg, respectively; P<0.001 for all comparisons). The most common adverse events were gastrointestinal and were primarily mild to moderate in severity in the tirzepatide and semaglutide groups (nausea, 17 to 22% and 18%; diarrhea, 13 to 16% and 12%; and vomiting, 6 to 10% and 8%, respectively). Of the patients who received tirzepatide, hypoglycemia (blood glucose level, <54 mg per deciliter) was reported in 0.6% (5-mg group), 0.2% (10-mg group), and 1.7% (15-mg group); hypoglycemia was reported in 0.4% of those who received semaglutide. Serious adverse events were reported in 5 to 7% of the patients who received tirzepatide and in 3% of those who received semaglutide. CONCLUSIONS: In patients with type 2 diabetes, tirzepatide was noninferior and superior to semaglutide with respect to the mean change in the glycated hemoglobin level from baseline to 40 weeks. (Funded by Eli Lilly; SURPASS-2 number, NCT03987919.).

Diabetes Mellitus, Type 2/drug therapy , Gastric Inhibitory Polypeptide/administration & dosage , Glucagon-Like Peptides/administration & dosage , Hypoglycemic Agents/administration & dosage , Blood Glucose/analysis , Diabetes Mellitus, Type 2/blood , Dose-Response Relationship, Drug , Drug Administration Schedule , Drug Therapy, Combination , Female , Gastric Inhibitory Polypeptide/adverse effects , Glucagon-Like Peptide-1 Receptor/agonists , Glucagon-Like Peptides/adverse effects , Humans , Hypoglycemic Agents/adverse effects , Hypoglycemic Agents/therapeutic use , Incretins/therapeutic use , Injections, Subcutaneous , Male , Metformin/therapeutic use , Middle Aged , Nausea/chemically induced , Weight Loss/drug effects
BMJ ; 375: n2938, 2021 11 26.
Article in English | MEDLINE | ID: covidwho-1537932

Adrenergic beta-Antagonists/adverse effects , Blood Pressure/drug effects , Diabetes Mellitus/prevention & control , Hypertension/drug therapy , Thiazides/adverse effects , Adrenergic beta-Antagonists/therapeutic use , Aminobutyrates/pharmacology , Aminobutyrates/therapeutic use , Angiotensin Receptor Antagonists/pharmacology , Angiotensin Receptor Antagonists/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Animals , Biphenyl Compounds/pharmacology , Biphenyl Compounds/therapeutic use , COVID-19/diagnosis , COVID-19/epidemiology , COVID-19/therapy , COVID-19/virology , Calcium Channel Blockers/adverse effects , Calcium Channel Blockers/therapeutic use , Cats , Diabetes Mellitus/etiology , Diabetes Mellitus, Type 2/drug therapy , Dogs , Drug Combinations , Gastric Inhibitory Polypeptide/adverse effects , Gastric Inhibitory Polypeptide/pharmacology , Gastric Inhibitory Polypeptide/therapeutic use , Heart Sounds/physiology , History, 20th Century , Humans , Hypertension/complications , Immunization, Passive/methods , Immunization, Passive/statistics & numerical data , Incretins/adverse effects , Incretins/pharmacology , Incretins/therapeutic use , Insulin Glargine/adverse effects , Insulin Glargine/history , Insulin Glargine/pharmacology , Insulin Glargine/therapeutic use , Meta-Analysis as Topic , Randomized Controlled Trials as Topic , SARS-CoV-2/genetics , Thiazides/therapeutic use , Valsartan/pharmacology , Valsartan/therapeutic use
Expert Opin Drug Saf ; 20(11): 1309-1315, 2021 Nov.
Article in English | MEDLINE | ID: covidwho-1366929


INTRODUCTION: A number of anti-diabetic treatments have been favored during the continuing spread of the current SARS-CoV-2 pandemic. Glucagon like peptide-1 receptor agonists (GLP1-RAs) are a group of antidiabetic drugs, the glucose reducing effect of which is founded on augmenting glucose-dependent insulin secretion with concomitant reduction of glucagon secretion and delayed gastric emptying. Apart from their glucose lowering effects, GLP1-RAs also exert a plethora of pleiotropic activities in the form of anti-inflammatory, anti-thrombotic and anti-obesogenic properties, with beneficial cardiovascular and renal impact. All these make this class of drugs a preferred option for managing patients with type 2 diabetes (T2D), and potentially helpful in those with SARS-CoV2 infection. AREAS COVERED: In the present article we propose a hypothetical molecular mechanism by which GLP1-RAs may interact with SARS-CoV-2 activity. EXPERT OPINION: The beneficial properties of GLP1-RAs may be of specific importance during COVID-19 infection for the most fragile patients with chronic comorbid conditions such as T2D, and those at higher cardiovascular and renal disease risk. Yet, further studies are needed to confirm our hypothesis and preliminary findings available in the literature.

Diabetes Mellitus, Type 2/drug therapy , Glucagon-Like Peptide-1 Receptor/agonists , Hypoglycemic Agents/therapeutic use , Incretins/therapeutic use , Animals , COVID-19/epidemiology , COVID-19/metabolism , COVID-19/virology , Diabetes Mellitus, Type 2/epidemiology , Diabetes Mellitus, Type 2/metabolism , Glucagon-Like Peptide-1 Receptor/metabolism , Humans , Hypoglycemic Agents/adverse effects , Incretins/adverse effects , Signal Transduction , Treatment Outcome
Expert Opin Pharmacother ; 22(2): 229-240, 2021 Feb.
Article in English | MEDLINE | ID: covidwho-861954


INTRODUCTION: Diabetes mellitus is one of the most prevalent comorbidities identified in patients with coronavirus disease 2019 (COVID-19). This article aims to discuss the pharmacotherapeutic considerations for the management of diabetes in hospitalized patients with COVID-19. AREAS COVERED: We discussed various aspects of pharmacotherapeutic management in hospitalized patients with COVID-19: (i) susceptibility and severity of COVID-19 among individuals with diabetes, (ii) glycemic goals for hospitalized patients with COVID-19 and concurrent diabetes, (iii) pharmacological treatment considerations for hospitalized patients with COVID-19 and concurrent diabetes. EXPERT OPINION: The glycemic goals in patients with COVID-19 and concurrent type 1 (T1DM) or type 2 diabetes (T2DM) are to avoid disruption of stable metabolic state, maintain optimal glycemic control, and prevent adverse glycemic events. Patients with T1DM require insulin therapy at all times to prevent ketosis. The management strategies for patients with T2DM include temporary discontinuation of certain oral antidiabetic agents and consideration for insulin therapy. Patients with T2DM who are relatively stable and able to eat regularly may continue with oral antidiabetic agents if glycemic control is satisfactory. Hyperglycemia may develop in patients with systemic corticosteroid treatment and should be managed upon accordingly.

COVID-19/therapy , Diabetes Mellitus, Type 1/drug therapy , Diabetes Mellitus, Type 2/drug therapy , Hypoglycemic Agents/therapeutic use , Insulin/therapeutic use , Adrenal Cortex Hormones/adverse effects , Blood Glucose/metabolism , COVID-19/complications , Comorbidity , Deprescriptions , Diabetes Mellitus, Type 1/complications , Diabetes Mellitus, Type 1/metabolism , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/metabolism , Dipeptidyl-Peptidase IV Inhibitors/adverse effects , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Disease Susceptibility , Glycemic Control , Hospitalization , Humans , Hyperglycemia/chemically induced , Hyperglycemia/drug therapy , Incretins/adverse effects , Incretins/therapeutic use , Metformin/adverse effects , Metformin/therapeutic use , Monitoring, Physiologic , Patient Care Planning , SARS-CoV-2 , Sodium-Glucose Transporter 2 Inhibitors/adverse effects , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use , Thiazolidinediones/adverse effects , Thiazolidinediones/therapeutic use
J Cardiovasc Pharmacol Ther ; 25(6): 494-496, 2020 11.
Article in English | MEDLINE | ID: covidwho-630976


The current coronavirus disease 2019 (COVID-19) pandemic has led the scientific community to breach new frontiers in the understanding of human physiology and disease pathogenesis. It has been hypothesized that the human dipeptidyl peptidase 4 (DPP4) enzyme receptor may be a functional target for the spike proteins of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). Since DPP4-inhibitors are currently used for the treatment of patients with type-2 diabetes (T2DM), there is currently high interest in the possibility that these agents, or incretin-based therapies (IBTs) in general, may be of benefit against the new coronavirus infection. Diabetes is associated with increased COVID-19 severity and mortality, and accumulating evidence suggests that IBTs may favorably alter the clinical course of SARS-CoV-2 infection due to their inherent mechanisms of action. Further research into prognostic variables associated with various antidiabetic treatment regimens, and in particular the IBT, in patients with T2DM affected by the COVID-19 pandemic is therefore warranted.

Coronavirus Infections/drug therapy , Coronavirus Infections/epidemiology , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/epidemiology , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Incretins/therapeutic use , Pneumonia, Viral/drug therapy , Pneumonia, Viral/epidemiology , Betacoronavirus , COVID-19 , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Glucagon-Like Peptide-1 Receptor/metabolism , Humans , Hypoglycemic Agents , Incretins/pharmacology , Inflammation Mediators/metabolism , Pandemics , SARS-CoV-2 , Severity of Illness Index