Diabetes Drug Notes E-Book

• Herausgeber: John Wiley & Sons
• Kategorie: Fachliteratur
• Sprache: Englisch

Seitenzahl: 767

Veröffentlichungsjahr: 2022

Beschreibung

DIABETES DRUG NOTES Diabetes is becoming more common in both older and younger generations and in keeping with this escalation in cases, there are an ever increasing number of drugs and drug classes that are suitable to treat hyperglycaemia. In a unique blend of diabetes practice, clinical pharmacology, and cardiovascular medicine, Diabetes Drug Notes describes the principles of clinical pharmacology with regards to diabetes prescribing. Each drug class for the treatment of diabetes is covered in detail, along with the effect on the cardiovascular and renal systems caused by each drug. Building upon the success of their "Drug Notes" series for Practical Diabetes and their "Drugs for Diabetes" series in the British Journal of Cardiology, the team of experts focuses on the glycaemic management of type 1 and type 2 diabetes, with other effects of antidiabetic drugs covered as well. Diabetes Drug Notes also includes: * Comprehensive and up-to-date coverage of the drugs for the glycaemic management of patients with type 1 or type 2 diabetes * Expert reflection on prescribing considerations for special groups, as well as common pitfalls in prescribing * Detailed case histories to illustrate relevant information * Summaries of recent guidelines related to diabetic intervention Diabetes Drug Notes is a user-friendly guide for a general diabetes medical, nursing, and pharmacology readership, as well as those who support them.

Leseprobe

Diabetes Drug Notes

Edited by

MILES FISHER, GERARD A. MCKAY, AND ANDREA LLANO

Glasgow Royal Infirmary, Glasgow, UK

This edition first published 2022

© 2022 John Wiley & Sons Ltd

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The contents of this work are intended to further general scientific research, understanding, and discussion only and are not intended and should not be relied upon as recommending or promoting scientific method, diagnosis, or treatment by physicians for any particular patient. In view of ongoing research, equipment modifications, changes in governmental regulations, and the constant flow of information relating to the use of medicines, equipment, and devices, the reader is urged to review and evaluate the information provided in the package insert or instructions for each medicine, equipment, or device for, among other things, any changes in the instructions or indication of usage and for added warnings and precautions. While the publisher and authors have used their best efforts in preparing this work, they make no representations or warranties with respect to the accuracy or completeness of the contents of this work and specifically disclaim all warranties, including without limitation any implied warranties of merchantability or fitness for a particular purpose. No warranty may be created or extended by sales representatives, written sales materials or promotional statements for this work. The fact that an organization, website, or product is referred to in this work as a citation and/or potential source of further information does not mean that the publisher and authors endorse the information or services the organization, website, or product may provide or recommendations it may make. This work is sold with the understanding that the publisher is not engaged in rendering professional services. The advice and strategies contained herein may not be suitable for your situation. You should consult with a specialist where appropriate. Further, readers should be aware that websites listed in this work may have changed or disappeared between when this work was written and when it is read. Neither the publisher nor authors shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidental, consequential, or other damages.

Library of Congress Cataloging-in-Publication Data Names: Fisher, Miles, editor. | McKay, Gerard A., editor. | Llano, Andrea, editor. Title: Diabetes drug notes / edited by Miles Fisher, Gerard A. McKay, Andrea Llano. Description: Hoboken, NJ : Wiley-Blackwell, 2022. | Includes bibliographical references and index. | Contents: Clinical pharmacology of antidiabetic drugs / Andrea Llano, Gerry McKay, and Ken Paterson -- Metformin / Joseph Timmons and James Boyle -- Sulfonylureas and meglitinides -- Joseph Timmons and James Boyle -- DPP-4 inhibitors / Sharon Mackin and Gemma Currie -- SGLT2 inhibitors / Miles Fisher, Andrea Llano, and Gerry McKay -- GLP-1 receptor agonists / Catherine Russell and John Petrie -- Animal and human insulin / Ken Paterson -- Short-acting insulin analogues / Kate Hughes and Gerry McKay -- Long-acting Insulin Analogues / Robert Lindsay -- Devices / David Carty -- Acarbose and alpha glucosidase inhibitors / Miles Fisher -- Glitazones and glitazars / Miles Fisher -- Other antidiabetic drugs / Maroria Oroko, Andrea Llano, and Miles Fisher -- Future antidiabetic drugs / Emma Johns and Miles Fisher -- Guidelines / Miles Fisher and Russell Drummond -- Prescribing antidiabetic drugs / Andrea Llano, Gerry McKay, Frances McManus, Catriona McClements, Joyce McKenzie, and Deborah Morrison. Identifiers: LCCN 2022020904 (print) | LCCN 2022020905 (ebook) | ISBN 9781119785002 (paperback) | ISBN 9781119785019 (pdf) | ISBN 9781119785026 (epub) | ISBN 9781119785033 (ebook) Subjects: MESH: Hypoglycemic Agents--pharmacology | Glycoside Hydrolase Inhibitors--pharmacology | Insulins-- pharmacology | Diabetes Mellitus--drug therapy Classification: LCC RC661.I6 (print) | LCC RC661.I6 (ebook) | NLM WK 825 | DDC 616.4/62061--dc23/ eng/20220608 LC record available at https://lccn.loc.gov/2022020904 LC ebook record available at https://lccn.loc.gov/2022020905

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Contents

Cover

Title page

Copyright

FOREWORD

PREFACE

EDITORS AND CONTRIBUTORS

Introduction

1 Clinical Pharmacology of Antidiabetic Drugs

Introduction

Clinical Pharmacology

Introduction

Pharmacodynamics

Action on a Receptor

Action on an Enzyme

Membrane Channels

Cytotoxic

Dose–Response Relationship

Pharmacokinetics

Absorption

Distribution/Plasma Protein Binding

Clearance

Drug Metabolism and Elimination

Enzyme Induction and Inhibition

Renal Excretion

Drug Development and Clinical Trials

Introduction

Preclinical Development

Regulatory Approval

Clinical Trials

Microdosing

Phase 1 Trials

Phase 2 Trials

Phase 3 Trials

Phase 4 Trials

Drug Licensing of Antidiabetic Drugs

Cardiovascular Outcome Trials

Marketing Authorisation

Development and Licensing of Insulin

Insulin Regulatory Approval

Development and Approval of Biosimilar Insulin

Introduction

Insulin Production

Biosimilar vs. Generic Drugs

Regulatory Considerations for Biosimilars

Safety of Biosimilars

Interchangeability and Substitution

Prescribing Considerations for Biosimilars

Pharmacovigilance

Passive Pharmacovigilance

Active Pharmacovigilance

Pharmacoeconomics

Introduction

Utility Values

Health Economic Modelling

Sensitivity Analysis

Discounting

Indirect Comparison and Network Meta-analysis

Future Developments in Diabetes Clinical Pharmacology

Drug Development

Pharmacovigilance

Pharmacoeconomics

2 Metformin

Introduction

History of Biguanides

Phenformin and Lactic Acidosis

Pharmacology

Mechanism of Action

Inhibition of Hepatic Glucose Production

Reduced Insulin Resistance

Intestinal Effects

Pharmacokinetics

Prescribing in Renal Impairment

Prescribing in Liver Disease

Prescribing in Heart Failure

Prescribing in Pregnancy

Glycaemic Efficacy

Safety and Side Effects

Lactic Acidosis

Outcome Trials

Cardiovascular Outcome Trials

UKPDS

HOME Study

SPREAD-DIMCAD

Renal Effects

Prevention of Type 2 Diabetes

DPP

IDPP

CANOE

Metformin in Type 1 Diabetes

REMOVAL

Place of Metformin in Current and Future Practice

3 Sulfonylureas and Meglitinides

Introduction

History of Sulfonylureas

Pharmacology

Insulin Secretion from Beta Cells

Mechanism of Action

Insulin Secretion

Extra-pancreatic Actions

Pharmacokinetics

Gliclazide

Glimepiride

Glycaemic Efficacy

ADOPT

UKPDS

GRADE Study

Safety and Side Effects

Weight Gain

Hypoglycaemia

Other Side Effects

Outcome Trials

Cardiovascular Safety and Sulfonylureas

UGDP

UKPDS

ADVANCE

CAROLINA

TOSCA. IT

Meglitinides

Nateglinide

Repaglinide

Outcome Trials

NAVIGATOR

Place of Sulfonylureas and Meglitinides in Current and Future Practice

4 DPP-4 Inhibitors

Introduction

Pharmacology

Structure and Function of Dipeptidyl Peptidase-4

Mechanism of Action

Pharmacodynamics and Pharmacokinetics

Sitagliptin

Saxagliptin

Vildagliptin

Alogliptin

Linagliptin

Other DPP-4 Inhibitors

Glycaemic Efficacy

VERIFY

GRADE

Safety and Side Effects

Side Effects

Pancreatitis and Pancreatic Cancer

Hepatic Side Effects of Alogliptin

Outcome Trials

Cardiovascular Outcome Trials

SAVOR-TIMI 53

EXAMINE

TECOS

CARMELINA and CAROLINA

Vildagliptin Meta-analysis

Summary of Cardiovascular Outcome Trials

Renal Outcomes

Saxagliptin

Alogliptin

Sitagliptin

Linagliptin

Summary of Renal Effects

The Place of DPP-4 Inhibitors in Current and Future Practice

5 SGLT2 Inhibitors

Introduction

Pharmacology

Physiology of Sodium-dependent Glucose Transporters

Mechanism of Action

Pharmacodynamics and Pharmacokinetics

Dapagliflozin

Canagliflozin

Empagliflozin

Ertugliflozin

Sotagliflozin

Other SGLT2 Inhibitors

Glycaemic Efficacy

Comparisons of SGLT2 Inhibitors with GLP-1 Receptor Agonists

Additional Effects of SGLT2 Inhibitors

Body Weight

Blood Pressure

Side Effects and Safety

Genitourinary Infections

Diabetic Ketoacidosis

Amputation

Other Adverse Effects

Outcome Trials

Cardiovascular Outcome Trials in Diabetes

EMPA-REG OUTCOME

The CANVAS Program

DECLARE-TIMI 58

VERTIS CV

Meta-analysis of Cardiovascular Outcome Trials

Real-world Evidence of Cardiovascular Benefits

Renal Outcome Trials

CREDENCE

DAPA-CKD

SCORED

Empagliflozin

Ertugliflozin

Meta-analysis of Renal Outcomes

Real-world Evidence of Renal Benefit

Heart Failure Outcome Trials

DAPA-HF

The EMPEROR Trials Program

SOLOIST-WHF

Canagliflozin and Ertugliflozin

Meta-analysis of DAPA-HF and EMPEROR-Reduced

SGLT2 Inhibitors in Type 1 Diabetes

Dapagliflozin in Type 1 Diabetes

Sotagliflozin in Type 1 Diabetes

Efficacy and Safety of Other SGLT2 Inhibitors in Type 1 Diabetes

Diabetic Ketoacidosis

Regulatory Approval in Type 1 Diabetes

Use of SGLT2 Inhibitors in Other Diseases

DARE-19

Place of SGLT2 Inhibitors in Current and Future Practice

Type 2 Diabetes

Chronic Kidney Disease and Heart Failure

Type 1 Diabetes

6 GLP-1 Receptor Agonists

Introduction

Pharmacology

Glucagon-like Peptide-1 and the Incretin Effect

Mechanism of Action

Pancreatic Actions

Extra-pancreatic Actions

Pharmacodynamics and Pharmacokinetics

Exenatide

Lixisenatide

Liraglutide

Dulaglutide

Semaglutide

Other GLP-1 Receptor Agonists

Glycaemic Efficacy and Effect on Weight

Comparisons within Class

Comparisons with Other Antidiabetic Drugs

DPP-4 Inhibitors

SGLT2 Inhibitors

Insulin

Other Antidiabetic Drugs

Efficacy of Combinations of GLP-1 Receptor Agonists with Insulin

Other Effects of GLP-1 Receptor Agonists

Cardiovascular System

Lipids

Side Effects and Safety

Side Effects

Safety

Thyroid Cancer

Pancreatitis and Pancreatic Cancer

Cholelithiasis

Outcome Trials

Cardiovascular Outcome Trials

ELIXA

LEADER

SUSTAIN-6

EXSCEL

REWIND

Harmony Outcomes

PIONEER 6

AMPLITUDE-O

Meta-analysis of Cardiovascular Outcome Trials

Summary of Cardiovascular Outcome Trials

Renal Outcomes

Renal Outcomes from Cardiovascular Outcome Trials

Meta-analysis of Renal Outcomes from Cardiovascular Outcome Trials

Use of GLP-1 Receptor Agonists in Other Diseases

Overweight and Obesity

Nonalcoholic Fatty Liver Disease

Place of GLP-1 Receptor Agonists in Current and Future Practice

7 Animal and Human Insulins

Introduction

Insulin Structure

Insulin Receptors

Insulin Physiology

Production and Pharmacokinetic Modifications

Improved Purification

Time Action Prolongation

Insulin Zinc Suspension

Protamine Zinc Insulin

Isophane or Neutral Protamine Hagedorn Insulin

Biphasic Insulins

Unified Formulation

Sources of Insulin

Beef Insulin

Pork Insulin

Human Insulin

Hypoglycaemia and Human Insulin

Limitations of Older Insulins

Short-acting Insulins

Intermediate and Long-acting Insulins

Time–Action Profile

Morning (Fasting) Hyperglycaemia

Variability

Intensified Insulin Therapy

DCCT and EDIC

UKPDS

Side Effects of Intensified Insulin Therapy

Hypoglycaemia

Weight Gain

Place of Human Insulin in Current and Future Therapy

Insulin Therapy in Type 1 Diabetes

Insulin Therapy in Type 2 Diabetes

8 Short-acting Insulin Analogues

Introduction

Factors Affecting Absorption and Metabolism of Short-acting Insulin

Manufacturing Insulin Analogues

Short-acting Insulin Analogues

Insulin Lispro

Insulin Aspart

Insulin Glulisine

Meta-analysis of Short-acting Insulin Analogues

Biosimilar Short-acting Insulin Analogues

Second-generation Ultrafast-acting Insulin Analogues

Fast-acting Insulin Aspart

Ultra-rapid Insulin Lispro

Other Attempts to Improve Insulin Absorption and Inhaled Insulin

Technosphere Inhaled Insulin

Place of Short-acting Insulin Analogues in Current and Future Practice

Intensive Insulin Therapy

Structured Education

Alternative Routes of Insulin Delivery

9 Long-acting Insulin Analogues

Introduction

Older Strategies to Extend the Action of Insulin

Factors Affecting the Absorption and Action of Insulin

Development of Long-acting Insulin Analogues

Strategies to Modify the Action of Long-acting Insulin Analogues

Long-acting Insulin Analogues

Insulin Glargine

Glycaemic Efficacy and Risk of Hypoglycaemia with Glargine

ORIGIN

Insulin Detemir

Glycaemic Efficacy and Risk of Hypoglycaemia with Detemir

4-T

Insulin Degludec

Glycaemic Efficacy and Risk of Hypoglycaemia with Degludec

DEVOTE

U300 Glargine

Glycaemic Efficacy and Risk of Hypoglycaemia with U300 Glargine

Biosimilar Long-acting Insulin Analogues

Other Long-acting Insulin Analogues

Combinations of Long- and Short-acting Insulin Analogues

Meta-analysis of Glycaemic Efficacy of Long-acting Insulin Analogues

Type 1 Diabetes

Type 2 Diabetes

Safety of Long-acting Insulin Analogues

The Place of Long-acting Insulin Analogues in Current and Future Practice

Advantages of Insulin Analogues

Patterns of Insulin Administration

Future Long-acting Insulin Analogues

10 Devices

Introduction

Insulin Pens

History

Modern Insulin Pens

Insulin Pumps

History

Modern Insulin Pumps

Glycaemic Efficacy of Insulin Pumps

Safety of Insulin Pumps

Potential Disadvantages of Pump Therapy

Self-monitoring of Blood Glucose

Blood Glucose Monitors

Continuous Glucose Monitoring

Intermittently Scanned (Flash) Continuous Glucose Monitoring

Real-time Continuous Glucose Monitoring

Accuracy of Continuous Glucose Monitoring

Ambulatory Glucose Profiles

Time in Range

Efficacy of Continuous Glucose Monitoring

Linkage of Continuous Glucose Monitoring to Insulin Pumps

Low-glucose Suspend

Hybrid Closed Loop

Efficacy of Closed Loop Systems

DIY Closed Loop

Guidelines on the Use of Devices

Insulin Pumps

Continuous Glucose Monitoring

Place of Devices in Current and Future Practice

11 Acarbose and Alpha Glucosidase Inhibitors

Introduction

Pharmacology

Mechanism of Action

Acarbose

Other Alpha Glucosidase Inhibitors

Glycaemic Efficacy

Safety and Side Effects

Outcome Trials

Prevention of Type 2 Diabetes

STOP-NIDDM

Voglibose Ph-3 Study

Cardiovascular Outcome Trials

Meta-analysis of Cardiovascular Events with Acarbose

ACE

Meta-analysis of Cardiovascular Events with Alpha Glucosidase Inhibitors

Place of Alpha Glucosidase Inhibitors in Current and Future Practice

12 Glitazones and Glitazars

Introduction

Pharmacology

Mechanism of Action

Pharmacokinetics

Pioglitazone

Glycaemic Efficacy

ADOPT

Other Effects of Glitazones

Safety and Side Effects

Side Effects

Safety

Cardiovascular Safety

Heart Failure

Bone Fractures

Bladder Cancer

Outcome Trials

Cardiovascular Outcome Trials

RECORD

TIDE

PROactive

IRIS

TOSCA. IT

Prevention of Type 2 Diabetes

DREAM

Other Trials on the Prevention of Diabetes

Glitazars

Aleglitazar

Saroglitazar

Place of Glitazones and in Current and Future Practice

Type 2 Diabetes

Prevention of Diabetes

13 Other Antidiabetic Drugs

Introduction

Pramlintide

Pharmacology

Glycaemic Efficacy

Efficacy in Type 1 Diabetes

Efficacy in Type 2 Diabetes

Safety

Colesevelam

Pharmacology

Glycaemic Efficacy

Cardiovascular Safety

Bromocriptine

Pharmacology

Glycaemic Efficacy

Cylcoset Safety Trial

Hydroxychloroquine

Pharmacology

Glycaemic Efficacy

Antiobesity Drugs

Orlistat

Pharmacology

Glycaemic Efficacy

XENDOS

Naltrexone/Bupropion

Pharmacology

Efficacy

Cardiovascular Safety

Phentermine and Phentermine/Topiramate

Pharmacology

Efficacy

Cardiovascular Safety

Place of Other Drugs in Current and Future Practice

Type 1 Diabetes

Type 2 Diabetes

14 Future Antidiabetic Drugs

Introduction

Dual and Triple Agonists

Physiology

GLP-1

GIP

Glucagon

Pharmacology of Multiagonist Therapies

GLP-1/GIP Receptor Dual Agonists

Tirzepatide

NNc1490-2746

GLP-1/Glucagon Receptor Dual Agonists

Cotadutide

Bamadutide

GLP-1/Glucagon Receptor Dual Agonists in Non-alcoholic Fatty Liver Disease

Triple Agonists

Imeglimin

Pharmacology

Mechanism of Action

Pharmacokinetics

Glycaemic Efficacy and Safety

Regulatory Status

Place of New Antidiabetic Drugs in Future Practice

15 Guidelines on Antidiabetic Drugs

Introduction

Evidence-based Guidelines

Consensus Reports

Common Approaches and HbA1c Targets

Guidelines on the Use of Antidiabetic Drugs in Type 2 Diabetes

NICE

SIGN

ICGP

EASD and ADA Consensus Reports

ESC

IDF

Guidelines on the Management of Type 1 Diabetes

NICE

SIGN

ADA

ADA/ESD Consensus Report on the Management of Type 1 Diabetes in Adults

Special Patient Groups

Use of Antidiabetic Drugs in Pregnancy

Use of Antidiabetic Drugs in Patients with Kidney Disease

KDIGO

ABCD

Use of Antidiabetic Drugs during Ramadan

Use of Antidiabetic Drugs in Under-resourced Countries

Place of Guidelines in Current and Future Practice

16 Prescribing Antidiabetic Drugs

Introduction

Why Prescribe?

Therapeutic Inertia

Introduction

Causes of Therapeutic Inertia

Clinician-related Factors

Patient-related Factors

Healthcare System Factors

Overcoming Inertia

Polypharmacy

Introduction

Detecting and Managing Polypharmacy

Nonadherence

Introduction

Improving Adherence

The Patient with Problematic Hypoglycaemia

Introduction

Problematic Hypoglycaemia

Management of Problematic Hypoglycaemia

Identify and Characterise Hypoglycaemia

Review Risk Factors for Problematic Hypoglycaemia

Review Patient Education and Behaviour

Review Insulin

Prescribing in Renal Impairment

Introduction

Reduced Absorption

Increased Bioavailability

Reduced Renal Clearance

Metformin

Pioglitazone

Acarbose

Sulfonylureas and Meglitinides

Incretin-based Therapies

SGLT2 Inhibitors

Insulin

Prescribing in Liver Disease

Introduction

Liver Disease and Diabetes

Reduced Drug Absorption

Increased Volume of Distribution

Altered Protein Binding

Reduced Metabolism

Hepatic Blood Flow

Reduced Excretion

Metformin

Pioglitazone

Sulfonylureas and Meglitinides

Incretin-based Therapies

SGLT2 Inhibitors

Insulin

Acarbose

Prescribing in Cardiovascular Disease

Diabetes and Coronary Artery Disease

Glycaemic Control

Choosing Antidiabetic Drugs with Cardiovascular Benefit

Management of Other Cardiovascular Risk Factors

Blood Pressure Management

Lipid Management

Antiplatelet Therapy

Acute Coronary Syndromes

Diabetes and Heart Failure

Pioglitazone

Saxagliptin

GLP-1 Receptor Agonists

SGLT2 Inhibitors

Prescribing in Pregnancy

Introduction

Antidiabetic Drugs in Pregnancy

Other Drugs Used in Pregnancy

Breastfeeding

Prescribing in the Young

Prescribing in the Elderly

Introduction

Hypoglycaemia in the Elderly

The Patient with Type 1 Diabetes: a Therapeutic Journey (an Illustrative Case)

The Patient with Type 2 Diabetes: a Therapeutic Journey (an Illustrative Case)

Future Developments in Prescribing in Diabetes

APPENDIX

INDEX

End User License Agreement

List of Illustrations

Chapter 1

FIGURE 1.1 Dose–response relationships for...

FIGURE 1.2 Steady–state concentration...

FIGURE 1.3 Drug development and...

FIGURE 1.4 Health benefits of...

Chapter 2

FIGURE 2.1 Mechanism of action...

FIGURE 2.2 Event rates (events...

FIGURE 2.3 Total events comparing...

Chapter 3

FIGURE 3.1 Mechanism of action...

FIGURE 3.2 Event rates comparing...

Chapter 4

FIGURE 4.1 Mechanism of action...

FIGURE 4.2 Hospitalisation for heart...

Chapter 5

FIGURE 5.1 Mechanism of action...

FIGURE 5.2 Major adverse cardiovascular...

FIGURE 5.3 Hospitalisation for heart...

FIGURE 5.4 Tubuloglomerular feedback...

Chapter 6

FIGURE 6.1 Mechanism of action of...

FIGURE 6.2 Structure of GLP-1 receptor...

Chapter 7

FIGURE 7.1 Insulin structure. Preproinsulin...

FIGURE 7.2 Insulin receptors. Binding...

FIGURE 7.3 Physiological insulin profile...

Chapter 8

FIGURE 8.1 Structures of short...

Chapter 9

FIGURE 9.1 Structures of glargine...

FIGURE 9.2 Six year event rates...

FIGURE 9.3 24 month event rates...

Chapter 10

FIGURE 10.1 Freestyle Libre flash...

FIGURE 10.2 Time in range is a...

Chapter 11

FIGURE 11.1 Mechanism of action...

FIGURE 11.2 Cardiovascular events (total...

FIGURE 11.3 Cardiovascular event rate...

Chapter 12

FIGURE 12.1 Mechanism of action...

FIGURE 12.2 Event rates (%) comparing...

FIGURE 12.3 Event rates (%) comparing...

FIGURE 12.4 Event rates (%) comparing...

Chapter 13

FIGURE 13.1 Structure of pramlintide...

Chapter 14

FIGURE 14.1 The two main types...

FIGURE 14.2 Structure of tirzepatide...

List of Boxes

Chapter 1

Box 1.1 Prescribing considerations...

Box 1.2 2Examples of...

Box 1.3 Example of...

Chapter 5

Box 5.1 Possible mechanisms...

Box 5.2 Strategies to...

Chapter 6

Box 6.1 Derivation of...

Box 6.2 Side effects...

Box 6.3 NICE recommendations...

Chapter 7

Box 7.1 1Actions of...

Box 7.2 Currently available...

Box 7.3 Symptoms, signs...

Chapter 10

Box 10.1 Glossary of...

Chapter 14

Box 14.1 Structure and...

Chapter 15

Box 15.1 Recommendations on...

Box 15.2 Recommendations on...

Box 15.3 SIGN recommendations...

Box 15.4 Consensus recommendations...

Box 15.5 Changes to...

Box 15.6 Recommendation on...

Box 15.7 Recommendation on...

Box 15.8 NICE recommendations...

Box 15.9 Recommendations on...

Box 15.10 Therapeutic recommendations...

Box 15.11 Recommendations on...

Box 15.12 Key recommendations...

Chapter 16

Box 16.1 Good prescribing...

Box 16.2 Therapeutic inertia...

Box 16.3 The STOPP...

Box 16.4 Polypharmacy clinical...

Box 16.5 Glucagon...

Box 16.7 Prescribing points...

Box 16.8 The patient...

Box 16.9 The patient...

List of Tables

Chapter 1

TABLE 1.1 The main regulatory...

TABLE 1.2 Dapagliflozin timeline as...

TABLE 1.3 Proposed glucose levels...

TABLE 1.4 Comparison of biosimilar...

TABLE 1.5 The numbers of patients...

Chapter 2

TABLE 2.1 Cardiovascular trials with...

TABLE 2.2 Studies on the...

Chapter 3

TABLE 3.1 Cardiovascular trials with...

Chapter 4

TABLE 4.1 Prescribing considerations for...

TABLE 4.2 Prescribing considerations for...

TABLE 4.3 Glycaemic efficacy of...

TABLE 4.4 Glycaemic efficacy and...

TABLE 4.5 Side effects associated...

TABLE 4.6 Meta-analysis of pancreatitis...

TABLE 4.7 Summary of cardiovascular...

Chapter 5

TABLE 5.1 Studies comparing the...

TABLE 5.2 Cardiovascular outcome trials...

TABLE 5.3 Cardiorenal outcome trials...

TABLE 5.4 Heart failure outcome...

TABLE 5.5 Efficacy and safety of SGLT2...

Chapter 6

TABLE 6.1 Summary of head...

TABLE 6.2 Cardiovascular outcome trials...

Chapter 7

TABLE 7.1 Insulin time–action...

Chapter 8

TABLE 8.1 Approximate onset, peak...

TABLE 8.2 Fixed mixtures containing...

TABLE 8.3 Biosimilar short-acting...

Chapter 9

TABLE 9.1 Comparison of glargine...

TABLE 9.2 Cardiovascular outcome trials...

TABLE 9.3 Currently available fixed...

TABLE 9.4 Meta-analysis of the...

Chapter 10

TABLE 10.1 Currently commercially available...

Chapter 11

TABLE 11.1 Outcome trials with...

Chapter 12

TABLE 12.1 Cardiovascular outcome trials...

TABLE 12.2 Diabetes prevention trials...

Chapter 13

TABLE 13.1 Cycloset cardiovascular safety...

Chapter 14

TABLE 14.1 Tirzepatide phase 3 clinical...

Chapter 15

TABLE 15.1 NICE [1], SIGN [2]...

Chapter 16

TABLE 16.1 Factors associated with...

TABLE 16.2 Establishing the risk...

TABLE 16.3 Prescribing in renal...

TABLE 16.4 Determination of Child...

TABLE 16.5 Prescribing in liver...

TABLE 16.6 Risk factors associated...

TABLE 16.7 Landmark trials of...

TABLE 16.8 Long-term epidemiological...

TABLE 16.9 Blood glucose targets...

TABLE 16.10 Pharmacokinetic changes in...

Guide

Cover

Title page

Copyright

Table of Contents

Foreword

Preface

EDITORS AND CONTRIBUTORS

Begin Reading

Appendix

Index

End User License Agreement

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Foreword

As the prevalence of diabetes continues to escalate, the delivery of individualised, effective, and well-tolerated treatment has become ever more prescient. Achieving adequate glycaemic control is a fundamental therapeutic objective across the spectrum of diabetes presentations in order to defer and address complications and co-morbidities. Type 2 diabetes accounts for the majority of people with diabetes, and the management of this disease is made particularly difficult by its heterogeneity and variable natural history. Type 1 diabetes requires the fine-tuning of insulin replacement to maintain quality and quantity of life. Recent years have seen the availability of an increasing range of therapies that target different aspects of the pathophysiology, but how can these drugs be used to best effect?

This book explains the rationale that underpins the selection of antidiabetic drugs and offers clear practical know-how advice to guide healthcare professionals through the pharmacotherapy of diabetes. Each class of antidiabetic drug receives comprehensive coverage, supported by evidence from key clinical trials and ‘real-world’ usage. The text is conveniently structured for a duality of purpose, such that it successfully provides detailed pharmacology for the specialist while also offering straightforward clinical pointers for the non-specialist.

Optimising the management of diabetes requires clinicians to take full advantage of the variety of antidiabetic drugs, and this book brings a much welcomed informative and authoritative resource to serve this need.

Clifford J. BaileyProfessor emeritusAston University, Birmingham, UK

Preface

At Glasgow Royal Infirmary historically diabetes and clinical pharmacology were linked with specialists in each discipline contributing to one of the medical units in the provision of general medical care to the inhabitants of the east of Glasgow whilst delivering specialist expertise. A few miles north of the Royal Infirmary, Stobhill Hospital in its prime had physicians delivering care who were also delivering academic excellence in the Department of Materia Medica at the University of Glasgow. In 2011 the two hospitals in the northeast of Glasgow merged to provide in patient care on one site and in doing so brought together the prospect of having a combined Department of Diabetes, Endocrinology and Clinical Pharmacology.

In addition to having a long-standing reputation for recruiting patients to commercial studies, the Royal Infirmary has strong links with the University of Glasgow, with senior academics continuing to provide both general and specialist patient care, and the University of Strathclyde Institute of Pharmacy and Biomedical Sciences, specifically around training independent pharmacy prescribers.

Education and training have been hallmarks of the department and in 2008 a series of Drug Notes was established for Practical Diabetes, covering drugs used in those with diabetes but not necessarily ones for lowering blood glucose, encouraging trainees to be first authors. The series is still going, suggesting that an understanding of drugs is an essential part of being a healthcare provider with an interest in diabetes. Antidiabetic drugs were covered in two separate series for the British Journal of Cardiology, again with trainees aspiring to be specialists in diabetes and endocrinology being first authors and to consider clinical pharmacology as a key knowledge skill.

With the emergence of new therapies for diabetes that are now providing benefits beyond glycaemic control, it seemed like the right time to bring together one definitive text that provides the prescriber with the background information and evidence that will help underpin their practice. We chose to ask colleagues in our department to contribute with the help of trainees working on a formula that has worked before but also because the clinical expertise within our department has specialists in both fields and contributed significantly to the Scottish Intercollegiate Guideline Network (SIGN) guideline for diabetes (SIGN116) but also to the Clinical Pharmacological update for type 2 diabetes in 2017 owing to the emergence of new classes of drugs to treat type 2 diabetes (SIGN154).

We are grateful to colleagues and trainees in the Department of Diabetes, Endocrinology and Clinical Pharmacology for taking on the challenge of contributing to this book. As is often the case when taking on a task like this, it became incredibly time consuming, particularly as we neared completion, and therefore we owe a debt of gratitude to our families for their patience, understanding and support.

Miles FisherAndrea LlanoGerry McKay

Editors and contributors

Editors

Miles Fisher, MBChB, MD, FRCP

Formerly Consultant Physician, Department of Diabetes, Endocrinology and Clinical Pharmacology, Glasgow Royal Infirmary, 84 Castle Street, Glasgow G4 0SF, UK

Honorary Professor, University of Glasgow, Glasgow, UK

[email protected]

Gerard A. McKay, BSc (Hons), MBChB, FRCP, FBPhS

Consultant Physician, Department of Diabetes, Endocrinology and Clinical Pharmacology, Glasgow Royal Infirmary, 84 Castle Street, Glasgow G4 0SF, UK

Honorary Clinical Associate Professor, University of Glasgow, Visiting Professor, University of Strathclyde, Glasgow, UK

[email protected]

Andrea Llano, BSc (Hons), MBChB, MRCP

Consultant Physician, Department of Diabetes, Endocrinology and Clinical Pharmacology, Glasgow Royal Infirmary, 84 Castle Street, Glasgow G4 0SF, UK

Honorary Clinical Lecturer, University of Glasgow, Glasgow, UK

[email protected]

Contributors

James G. Boyle, MBChB, MD, MSc, FRCP

Consultant Physician, Department of Diabetes, Endocrinology and Clinical Pharmacology, Glasgow Royal Infirmary, 84 Castle Street, Glasgow G4 0SF, UK

Honorary Clinical Associate Professor, University of Glasgow, Glasgow, UK

David Carty, MBChB, PhD, FRCP

Consultant Physician, Department of Diabetes, Endocrinology and Clinical Pharmacology, Glasgow Royal Infirmary, 84 Castle Street, Glasgow G4 0SF, UK

Honorary Clinical Senior Lecturer, University of Glasgow, Glasgow, UK

Gemma E. Currie, MBChB, MRCP, PhD

Consultant Physician, Department of Diabetes, Endocrinology and Clinical Pharmacology, Glasgow Royal Infirmary, 84 Castle Street, Glasgow G4 0SF, UK

Honorary Clinical Senior Lecturer, University of Glasgow, Glasgow, UK

Russell S. Drummond, BSc (Hons), MBChB, MD, FRCP

Consultant Physician, Department of Diabetes, Endocrinology and Clinical Pharmacology, Glasgow Royal Infirmary, 84 Castle Street, Glasgow G4 0SF, UK

Honorary Clinical Associate Professor, University of Glasgow, Glasgow, UK

Miles Fisher, MBChB, MD, FRCP

Formerly Consultant Physician, Department of Diabetes, Endocrinology and Clinical Pharmacology, Glasgow Royal Infirmary, 84 Castle Street, Glasgow G4 0SF, UK

Honorary Professor, University of Glasgow, Glasgow, UK

Katherine A. Hughes, MBChB, MRCP, PhD

Consultant Physician, Department of Diabetes, Endocrinology and Clinical Pharmacology, Glasgow Royal Infirmary, 84 Castle Street, Glasgow G4 0SF, UK

Emma C. Johns, MBChB, MRCP, PhD

Specialty Trainee in Diabetes and Endocrinology, Department of Diabetes, Endocrinology and Clinical Pharmacology, Glasgow Royal Infirmary, 84 Castle Street, Glasgow G4 0SF, UK

Robert Lindsay, BSc, MBChB, PhD, FRCP

Reader in Diabetes and Endocrinology, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK

Honorary Consultant Physician, NHS Greater Glasgow and Clyde, Glasgow, UK

Andrea Llano, BSc (Hons), MBChB, MRCP

Consultant Physician, Department of Diabetes, Endocrinology and Clinical Pharmacology, Glasgow Royal Infirmary, 84 Castle Street, Glasgow G4 0SF, UK

Honorary Clinical Lecturer, University of Glasgow, Glasgow, UK

Sharon T. Mackin, MBChB (Hons), MRCP (Diabetes and Endocrinology), MD

Consultant Physician, Department of Diabetes, Endocrinology and Clinical Pharmacology, Glasgow Royal Infirmary, 84 Castle Street, Glasgow G4 0SF, UK

Honorary Clinical Senior Lecturer, University of Glasgow, Glasgow, UK

Catriona McClements, MBChB

Senior Clinical Fellow, Department of Diabetes, Endocrinology and Clinical Pharmacology, Glasgow Royal Infirmary, Glasgow, UK

Gerard A. McKay, BSc (Hons), MBChB, FRCP, FBPhS

Consultant Physician, Department of Diabetes, Endocrinology and Clinical Pharmacology, Glasgow Royal Infirmary, 84 Castle Street, Glasgow G4 0SF, UK

Honorary Clinical Associate Professor, University of Glasgow, Visiting Professor, University of Strathclyde, Glasgow, UK

Joyce McKenzie, BSc, MBChB, MD

Specialty Doctor in Diabetes, Department of Diabetes and Endocrinology, New Stobhill Hospital, Glasgow, UK

Frances McManus, BSc (MedSci), MBChB, MRCP, PhD

Consultant Physician, Consultant Physician, Department of Diabetes, Endocrinology and Clinical Pharmacology, Glasgow Royal Infirmary, 84 Castle Street, Glasgow G4 0SF, UK

Deborah Morrison, MBChB, MRCP, PhD, MRCGP

General Practitioner with a special interest in diabetes, Department of Diabetes and Endocrinology, New Stobhill Hospital, Glasgow, UK

Honorary Clinical Lecturer, University of Glasgow, Glasgow, UK

Maroria Oroko, BSc (Hons), MBChB, MRCP

Specialty Trainee in Diabetes and Endocrinology, Department of Diabetes, Endocrinology and Clinical Pharmacology, Glasgow Royal Infirmary, 84 Castle Street, Glasgow G4 0SF, UK

Kenneth Paterson, MBChB, FRCP, FFPM, FBPhS

Formerly Consultant Physician, Department of Diabetes, Endocrinology and Clinical Pharmacology, Glasgow Royal Infirmary, 84 Castle Street, Glasgow G4 0SF, UK

Honorary Senior Research Fellow, University of Glasgow, Glasgow, UK

John R. Petrie, BSc (Hons), MBChB, PhD, FRCP

Professor of Diabetic Medicine, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK

Honorary Consultant Physician, Department of Diabetes, Endocrinology and Clinical Pharmacology, Glasgow Royal Infirmary, 84 Castle Street, Glasgow G4 0SF, UK

Catherine Russell, MBChB, MRCP

Specialty Trainee in Diabetes and Endocrinology, Department of Diabetes, Endocrinology and Clinical Pharmacology, Glasgow Royal Infirmary, Glasgow, UK

Joseph G. Timmons, BMSc (Hons), MBChB (Hons), MRCP

Clinical Lecturer in Diabetes and Endocrinology, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK

Honorary Specialty Trainee in Diabetes and Endocrinology, NHS Greater Glasgow and Clyde, Glasgow, UK

Introduction

Diabetes Drug Notes is an expansion of the approach that we used for the Drug Notes series in Practical Diabetes. That series features drugs used in people with diabetes to manage cardiovascular disease, diabetic complications, and other effects of diabetes, but not the management of glycaemia. Each note in Practical Diabetes had a short introduction, a description of the pharmacology, evidence for efficacy and safety, any specific evidence for use in people with diabetes, and a short discussion. Three or four key points summarised the review, and references are kept to a minimum. Diabetes Drug Notes follows a broadly similar approach with key points, short introductions, sections on pharmacology, evidence for glycaemic efficacy and safety, results from outcome trials in diabetes, and refences that are focussed on glycaemic efficacy and outcome trials.

In Chapter 1 we describe the basic principles of clinical pharmacology with a focus on how these principles apply to antidiabetic drugs (we have adopted this term as it is used in the British National Formulary, which will be familiar to many readers, rather than alternatives such as ‘glucose-lowering agents’ or ‘hypoglycaemic agents’).

In Chapters 2–14, following a short introduction, we describe the pharmacology of the drugs, including descriptions of the mechanisms of action, relevant pharmacokinetic considerations, and doses for drugs that are available in the UK. Glycaemic efficacy is described, including in comparison with other antidiabetic drugs, followed by safety and side effects. We then detail outcome trials with the drugs, covering cardiovascular outcome trials, renal outcome trials, and other outcome trials such as the prevention of diabetes or use in overweight and obesity. For metformin, sulfonylureas and animal and human insulin we also include information about the history of the drugs. Each chapter finishes with a discussion of the place of the drug/s in current and future clinical practice. Detailed references are provided for efficacy and outcome trials, but other sections have minimal referencing.

Chapter 15 on guidelines focusses on the drugs rather than wider aspects of diabetes care. For patients with type 2 diabetes there are many guidelines dedicated to antidiabetic drugs, but for patients with type 1 diabetes, and for diabetes and pregnancy, information has been extracted from more comprehensive guidelines. Chapter 16 describes how antidiabetic drugs are prescribed in patients with diabetes depending on clinical features and comorbidities and includes patient journeys for a patient with type 1 diabetes and a patient with type 2 diabetes.

It is not the intention that the book should be read in order from first to last chapter, and we have provided detailed cross-referencing within the chapters. For example, a reader might start with the chapter on DPP-4 inhibitors, go to Chapter 1 to understand why the cardiovascular outcome trials were conducted, dip into Chapter 12 on glitazones for more information on the rosiglitazone controversy, move on to Chapter 6 to see how GLP-1 receptor agonists compare with DPP-4 inhibitors, see what guidelines say about these drugs in Chapter 15, and finish with prescribing issues for them in Chapter 16.

Miles Fisher

Andrea Llano

Gerry McKay

CHAPTER 1 Clinical Pharmacology of Antidiabetic Drugs

Andrea Llano, Gerry McKay and Ken Paterson

KEY POINTS

Clinical pharmacology studies the relationship between drugs and the body and has a crucial role in the development of new therapies.

Pharmacodynamics describes how a drug exerts its actions and pharmacokinetics is the processes a drug undergoes (absorption, distribution, metabolism and excretion).

The drug development and regulatory process is lengthy and new medicines need to demonstrate safety, efficacy and quality. In addition, drugs intended to be used in diabetes require demonstration of cardiovascular safety.

Pharmacoeconomics allows the provision of cost-effective therapies to those who need them and is an important tool when there is an increasing demand for healthcare and limited resource.

Introduction

Clinical pharmacology describes all aspects of the relationship between drugs and humans. An understanding not only allows for the discovery and development of new drugs that influence the course of disease, but also a better understanding of how drugs work can aid the prescriber in partnership with the patient to ensure that the most appropriate drug is chosen. This is relevant for prescribing in diabetes given the increase in antidiabetic drugs that are now available for glucose lowering, many with additional benefits. Choosing the correct antidiabetic drug (‘antihyperglycaemic’ and ‘oral hypoglycaemic’ are other terms used) is complicated in many cases by the need for wider cardiovascular risk management and the polypharmacy that can result from managing established complications and other co-morbidities. Before getting to the individual with diabetes, antidiabetic drugs have to go through a lengthy development process underpinned by the requirement to show safety, efficacy and quality.

A serendipitous approach to drug discovery and development based on observations and careful measurement of response has been replaced by a deeper understanding of biochemical and pathophysiological processes that influence disease. This has led to the synthesis of specific agents (chemical or biological) with specific actions. Measurement of drug concentrations in plasma and correlation with effect have aided drug development. The development of genomics and proteomics has added further sophistication such that individualisation of drug choice is a much more realistic prospect.

Clinical Pharmacology

Introduction

The dose–response relationship within an individual is a measure of sensitivity to a drug. This has two components: pharmacokinetics and pharmacodynamics. Pharmacokinetics describes the dose–concentration relationship, and pharmacodynamics describes the concentration–effect relationship. Understanding pharmacodynamics and pharmacokinetics is fundamental to the process of drug development, e.g. selecting the appropriate dose to ensure that the concentration of drug at the site of action is likely to have a therapeutic effect. Understanding pharmacokinetics and pharmacodynamics is relevant to clinical practice as it allows optimisation of therapeutic interventions for the individual being treated [1].

Pharmacodynamics

The effect that a drug has on the body can often be explained through a specific mechanism of action. This can be through action on specific receptors, enzymes or membrane ionic channels or by a direct cytotoxic action.

Action on a Receptor A receptor is normally a protein situated on the cell membrane or within the cell. Drugs bind to the receptors and can act in three ways:

An agonist stimulates the receptor to produce an effect.

An antagonist blocks the receptor from being activated by an agonist.

A partial agonist stimulates the receptor to a limited extent but blocks it from being stimulated by naturally occurring agonists.

For antidiabetic drugs the main type of effect seen at receptors is an agonist effect. This can be seen for sulfonylureas, which bind to SU receptors on beta cells, and PPAR gamma agonists, which act on nuclear receptors to increase transcription of insulin-sensitive genes.

Action on an Enzyme Enzymes are proteins that, through interaction with substrates, result in activation or inhibition. Although the mechanism of action of metformin is poorly understood, part of its effect in diabetes is through activated AMP kinase. Another diabetes class acting through an effect on enzymes is DPP-4 inhibitors. These drugs inhibit the action of dipeptidyl peptidase-4, allowing for the prolongation of the action of endogenous incretins GLP-1 and GIP.

Membrane Channels Some drugs exert their action through an effect on membrane channels. SGLT 2 inhibitors work by blocking the sodium glucose co-transporter 2, resulting in the loss of glucose and sodium in urine.

Cytotoxic This mechanism of action is more relevant to drugs used to treat cancer.

Dose–Response Relationship When thinking about drugs an understanding of dose response is important. Dose–response relationships can be steep or flat (Figure 1.1). In the treatment of diabetes with insulin, a flat dose–response curve is desirable for background insulin, but a steep dose–response curve is desirable for prandial insulin. In clinical practice the maximum therapeutic effect might not be achieved because of the emergence of undesirable effects. In drug development, if too high a dose is chosen it may be that the success of the drug is hampered by the side effects, e.g. in the case of the DPP-4 inhibitor vildagliptin, at a higher dose liver function tests need to be monitored, which is not the case for other drugs in the class. It is very important to consider this in drug development both for the desired effect and for adverse effects. This leads to the concept of therapeutic range. The difference between the concentration causing a desired effect and the concentration causing an adverse effect is termed the therapeutic index, a measure of a drug’s safety.

FIGURE 1.1 Dose–response relationships for drugs. Schematic examples of a drug (a) with a steep dose– (or concentration–) response relationship in the therapeutic range, and (b) a flat dose– (or concentration–) response relationship within the therapeutic range.

Dose–response curves can be influenced by genetics, environment and disease, and have two components: dose–plasma concentration and plasma concentration–effect. The ability to develop assays to measure drug concentration has allowed a better understanding of the variability in response between individuals but also for some drugs with a narrow therapeutic index the ability to perform therapeutic drug monitoring.

Pharmacokinetics

Absorption After drugs have been given orally, they can be considered to have an absorption rate and bioavailability. By slowing absorption, the dose–concentration relationship can be smoothed out, giving a more sustained effect and minimising side effects, e.g. Glucophage SR® (slow-release metformin). Subcutaneous absorption of insulin can also be manipulated to provide the desired effect, both to make absorption quicker, which is desirable for prandial insulin, and to make it slower, which is desirable for basal insulin. Bioavailability is a term used to describe the fraction of drug that gets into the systemic circulation. GLP-1 receptor agonists like most peptide-based drugs generally cannot be given orally owing to them being digested, so they need to be given parenterally to get sufficient quantities into the systemic circulation. However, one oral preparation of GLP-1 receptor agonist is now available that relies on a sophisticated delivery method and at a much higher dose than the parenteral preparation to achieve sufficient systemic exposure for the desired clinical effect (see Chapter 6). Other orally administered drugs can undergo extensive first-pass metabolism in the liver, resulting in a significant reduction in systemic exposure and clinical effect.

Distribution/Plasma Protein Binding When a drug gets into the systemic circulation it is then distributed to the tissues. This process will be dependent on the properties of the drug, in particular protein binding and lipid solubility factors. In practice protein binding has little in the way of clinical relevance, but if a drug has low protein binding and is highly lipid soluble, it will have only a small amount in the circulation and thus will be considered to have a high volume of distribution. In real terms this has more of an impact on drug development.

Clearance Clearance is the sum of all of the drug eliminated from the body and mostly depends on hepatic metabolism and renal excretion. If a drug is given by intravenous infusion or repeated doses orally, there will come a point at which a balance is reached between the drug entering and the drug leaving the body. This results in a steady-state concentration in the plasma or serum (Css). A constant-rate intravenous infusion will yield a constant Css, while a drug administered orally at regular intervals will result in fluctuation between peak and trough concentrations (Figure 1.2). Clearance depends on the liver and/or kidneys eliminating a drug and will be affected by diseases that affect these organs either directly or via blood flow to these organs. In stable clinical conditions when clearance remains constant it is directly proportional to dose rate, so-called first-order or linear kinetics. Few drugs show zero-order kinetics, e.g. alcohol when eliminating enzymes become saturated. Following a single intravenous bolus dose, it is possible to work out the time that it takes for elimination to result in half the original concentration of the drug being present (the half-life or t1/2) and through a number of complex equations, the time at which steady state will be achieved after starting a regular treatment schedule or after any change in dose can be predicted. Generally this takes four to five half-lives.

FIGURE 1.2 Steady-state concentration–time profile for an oral dose (—) and a constant rate intravenous infusion (- - - - -).

Drug Metabolism and Elimination Drugs that are already water soluble are generally excreted unchanged by the kidney. Lipid-soluble drugs are not easily excreted by the kidney because, following glomerular filtration, they are largely reabsorbed from the proximal tubule. The first step in the elimination of such lipid-soluble drugs is metabolism to more polar (water-soluble) compounds. This is achieved mainly in the liver.

Metabolism generally occurs in two phases:

Phase 1

. Mainly oxidation, but also reduction or hydrolysis to a more polar compound. Oxidation can occur in various ways at carbon, nitrogen or sulfur atoms and

N

- and

O

-dealkylation. These reactions are catalysed by the cytochrome P450-dependent system of the endoplasmic reticulum. Knowledge of P450, which exists as a superfamily of similar enzymes (isoforms), has increased greatly recently, and it is divided into a number of families and subfamilies. Although numerous P450 isoforms are present in human tissue, only a few of these have a major role in the metabolism of drugs. These enzymes, which display distinct but overlapping substrate specificity, include CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4.

Phase 2

. Conjugation usually by glucuronidation or sulfation to make the compound more polar. This involves the addition of small endogenous molecules to the parent drug, or to its phase 1 metabolite, and almost always leads to abolition of pharmacological activity. Multiple forms of conjugating enzymes are also known to exist, although these have not been investigated to the same extent as the P450 system.

Enzyme Induction and Inhibition Enzyme induction or inhibition can result in a pharmacokinetic drug interaction diminishing clinical efficacy or resulting in side effects, respectively. Induction is the result of a drug prolonging the action and activity of drug-metabolising enzymes. In clinical practice rifampicin, carbamazepine and phenytoin are potent enzyme inducers, as is ‘over the counter’ St John’s Wort. These agents increase the activity of drug metabolising enzymes and increase the metabolism of medicines metabolised by the same route. Inhibition reduces metabolism and prolongs the action of a drug. In clinical practice macrolide antibiotics (e.g. clarithromycin) can inhibit cytochrome P450, prolonging the action of some drugs that are commonly used in diabetes patients, e.g. simvastatin, which should be stopped whilst on macrolide treatment.

Renal Excretion Glomerular filtration is the most common route of renal elimination. Free drug is cleared by filtration and the protein-bound drug remains in the circulation. Active secretion in the proximal tubule, which can affect both weak acids and weak bases, has specific secretory sites in proximal tubular cells and can also be a mechanism for elimination and also passive reabsorption in the distal tubule. If renal function is impaired, for example by disease or old age, then the clearance of drugs that normally undergo renal excretion is decreased. The effect of reduced renal excretion on dose for antidiabetic drugs is summarised in Chapter 16, Table 16.3.

Drug Development and Clinical Trials

Introduction

The development of drugs for therapeutic use is complex and lengthy and necessarily subject to extensive regulatory requirements. The three pillars of drug development are safety, efficacy and quality. Safety and efficacy of an investigational product are required to be shown in well-designed and robust clinical trial programmes before regulatory approval is granted so that a drug can be marketed. This is governed by Good Clinical Practice. Quality needs to be shown in manufacturing processes and is governed by Good Manufacturing Practice. Drugs intended for use in patients with type 2 diabetes are also required to demonstrate their cardiovascular safety using outcomes such as cardiovascular mortality, myocardial infarction and stroke. There have been many changes in the development process and its regulation over the last century. The process of drug development and approval is summarised in Figure 1.3. It can take more than 12 years to take a drug into the market, at a considerable cost (>£1 billion).

FIGURE 1.3 Drug development and approval. clinical development consists of Phase 0, Phase I (or 1), Phase II (or 2) and Phase III (or 3). Phase IV (or 4) is part of post-marketing.

Preclinical Development

Historically, remedies and treatments were derived from plants and herbs, and many drugs were discovered serendipitously. The use of Galega officianalis (biguanide) to treat symptoms of hyperglycaemia has been documented as far back as medieval times. Sulfonylureas were initially investigated for use in the treatment of typhoid and incidentally found to cause hypoglycaemia. SGLT2 inhibitors were derived from phlorizin, a compound derived from apple tree bark that was initially used in fever but was found to also cause glycosuria.

Advances in the understanding of the pathological processes involved in disease at the cellular and molecular levels have led to more sophisticated methods of drug discovery and a more methodical approach to drug development. Biological targets are first selected and compounds which are active at this site are identified. These compounds can be designed according to the target’s chemical structure or selected from a pharmaceutical research organisation’s extensive compound library. Several thousand molecules are usually identified at the beginning of this process. Candidate drug molecules then enter a process known as lead optimisation where they undergo further selection and/or modification to achieve the desired pharmacological activity. Preclinical testing involves extensive in vivo studies undertaken to determine a compound’s affinity and selectivity in cell disease models. This period takes 2–10 years and approximately 50% of lead compounds do not progress beyond this point. Various animal models are used to establish the compound’s pharmacokinetic characteristics (absorption, distribution, metabolism and excretion). In vivo toxicology studies are used to determine the maximum nontoxic dose of the drug and establish reproductive toxicity (adverse effects on fertility, foetal development and lactation).

This is a crucial stage in drug development as the costs increase exponentially once a drug gets into clinical development in humans. If a drug shows potential toxicity in animal studies, it is important to understand that this is generally at higher concentrations than would be used clinically and does not necessarily result in it not getting tested in humans. An example of this is the GLP-1 receptor agonist liraglutide, which was shown to increase the risk of thyroid cancer in mice and rat models, but at doses 8 times higher than what humans would receive. In subsequent clinical trials the risk of developing medullary thyroid cancer, which is very rare, has not been shown. However, the animal results have meant that this potential side effect has been highlighted as something to look out for in subsequent clinical trials in the development programme.

Chemical properties such as stability and formulation are also established, and manufacturing processes developed to ensure that the lead compound can be produced in sufficient quantity and quality for clinical studies. Towards the end of this period, applications to regulatory bodies are prepared to proceed to investigation in humans [2].

Regulatory Approval

Prior to the 1960s there was no formal process of drug approval or regulation, and it was not a legal requirement to demonstrate the efficacy or safety of a drug. Thalidomide was first marketed in 1956 as a sedative and hypnotic and was used as a treatment for nausea and vomiting associated with pregnancy. No formal clinical trials or reproductive toxicology studies had been carried out prior to its marketing. It was soon noted to cause an increase in birth defects and was banned in 1961.

These findings prompted regulatory reformations necessitating that a drug’s safety and efficacy be vigorously demonstrated. The Food and Drug Administration (FDA) produced the Drug Amendments Act of 1962 in the US, and the Medicines Act 1968 in the UK set down the legal framework by which medicines are licensed and controlled. These amendments ensure that manufacturers demonstrate a drug’s safety and efficacy using controlled clinical studies in appropriate study participants and that post-marketing surveillance is carried out.

Prior to testing in humans, regulatory approval must be obtained from the relevant regulatory authority, including the European Medicines Agency (EMA) in Europe and the FDA in the US (Table 1.1). Along with the third large regulatory authority in Japan, the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) was established and continues to meet to bring together the regulatory authorities and pharmaceutical industry to discuss scientific and technical aspects of drug registration.

TABLE 1.1 The main regulatory authorities and their functions

Regulatory authority

Function

Medicines and Healthcare Regulatory products Agency (MHRA)

Formed in 2003. Functions include: regulation of clinical trials, assessment and authorisation of medicinal products in the UK; operates post-marketing drug surveillance. It will have a new role post Brexit operating separately from the EMA

European Medicines Agency (EMA)

Established in 1995. Coordinates the evaluation and supervision of the new medicinal products, grants opinion on licensing and oversees pharmacovigilance across member states

Food and Drug Administration (FDA)

Established in 1927. Responsible for regulation and supervision of drug safety: drug assessment and authorisation, post-marketing surveillance

On 31 January 2020, the UK formally left the European Union and entered a transition period that ended on 1 January 2021. Following Brexit, the regulation of all medicines and devices has transferred from the EMA to the UK’s Medicines and Healthcare Products Regulatory Agency (MHRA) [3]. This is likely to prove challenging as previously many of the submissions to the EMA were contracted out to the MHRA. Therefore, more work will be required as a consequence of its new status as a stand-alone regulatory body, but without the external resources coming in from the EMA. The other complicating factor is that its regulatory role only relates to approval in England, Scotland and Wales, not Northern Ireland. However, there are mechanisms in place to ensure mutual recognition, particularly given the harmonisation of regulatory approach, which may allow a more responsive process with the potential advantage of marketing authorisations being fast tracked, particularly for drugs with clear potential benefits. This process has been clearly illustrated through the granting of marketing authorisations for COVID-19 vaccines.

All clinical trials must be registered in a clinical trials database and have ethics approval. Trials must be conducted in line with Good Clinical Practice, a set of international standards covering the design, conduct, recording and reporting of clinical trials, and manufactured in line with Good Manufacturing Practice, a set of international standards ensuring the quality of the investigational product.

Clinical Trials

Once the efficacy and safety of a drug have been determined in preclinical studies, it can move into investigation in the human population. Drugs progress through different stages of clinical trials prior to gaining regulatory approval and entering clinical use. Although these stages are described separately, in practice they often overlap [2].

Microdosing Microdosing was introduced in 2003 to improve the efficiency of drug development. It aims to improve the selection of preclinical candidate drugs by assessing in vivo