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Pharmacological control of blood sugar
PHARMACOLOGY
Pharmacological control of blood sugar
Learning objectives After reading this article, you should be able to: C understand the different types of insulins used in clinical practice including their duration and actions C know the oral agents and newer glucose-lowering drugs used in type 2 diabetes C appreciate that long-term diabetes control can be challenging and that there is an increasing need for newer drugs with good safety profiles and benefits in long-term cardiovascular outcomes
Sudesna Chatterjee Melanie J Davies Giridhar Tarigopula
Abstract Diabetes is a chronic and progressive metabolic disorder characterized by hyperglycaemia. The two main types of diabetes are type 1 diabetes (T1DM) where there is complete lack of insulin and type 2 diabetes (T2DM) which may be due to a combination of insulin resistance and relative insulin deficiency due to impaired b-cell function. Good control of blood glucose near physiological limits is vital to reduce long-term microvascular and macrovascular complications of diabetes. Insulin replacement is a life-saving measure in individuals with T1DM whereas the mainstay of therapy in T2DM includes oral agents, non-insulin injectables (incretin mimetics) and insulin. In T2DM, the incretin mimetics and sodium glucose co-transporter 2 inhibitors have revolutionized recent treatment options by reducing blood glucose, promoting weight loss and improving b-cell function with improved cardiovascular outcomes associated with some of these agents. Despite the availability of several drugs to treat this chronic debilitating condition, the management of hyperglycaemia remains challenging. The role of diet, lifestyle changes and patient education is of paramount importance and should be pursued aggressively. This review will look at drugs currently used to optimize blood glucose control and briefly discuss the role of newer therapeutic agents.
Introduction Diabetes is one of the biggest health challenges faced by UK. There are an estimated 4.5 million people with diabetes in the UK and with current trends, by 2034 1 in 10 people will be diagnosed with type 2 diabetes.1,2 Optimal and sustained glycaemic control is essential in minimizing long-term complications. Type 1 diabetes (T1DM) is treated with insulin supplemented by educational and psychological support. Type 2 diabetes (T2DM) requires lifestyle interventions, combination of drugs and often use of insulin. Current and emerging glucose-lowering therapies for T1DM and T2DM are discussed below.
Insulin Insulin replacement therapy either regular daily injections by the subcutaneous route or continuously via an insulin pump is the mainstay of treatment for all patients with T1DM and for individuals with T2DM who do not achieve optimal glycaemic control despite the use of oral agents or non-insulin based injectable therapies. Hypoglycaemia and weight gain are the major problems associated with glucose-lowering therapies. Insulins are classified according to the preparations as described below or according to onset and duration of action (Figure 1).
Keywords Incretin mimetics; insulin; oral agents; sodiumeglucose transporter 2 inhibitors Royal College of Anaesthetists CPD Matrix: 1A02
Animal insulins
Sudesna Chatterjee MD FRCP(UK) is a Consultant Diabetologist at University Hospitals of Leicester and a Senior Clinical Researcher at University of Leicester, UK. Conflicts of interest: Dr Chatterjee has received speaker fees, educational funding or both from Janssen, Eli Lilly, Novo Nordisk, Astra Zeneca and Boehringer Ingelheim and has received grants in support of investigator-initiated trials from Boehringer Ingelheim and Janssen.
Animal insulins are derived from the pancreatic extracts of animals (e.g. cows and pigs) and were the earliest insulins used in the treatment of diabetes. However, due to problems with variable rates of insulin absorption, allergic reactions at injection sites and immunogenicity, they have been largely replaced by human insulins and insulin analogues.
Melanie J Davies MB ChB MD FRCP is Professor of Diabetes Medicine at the Department of Cardiovascular Sciences, University of Leicester, Leicester, UK. Conflicts of interest: Professor Davies has acted as consultant, advisory board member and speaker for Novartis, Novo Nordisk, Sanofi-Aventis, Lilly, Merck Sharp & Dohme, Servier, BMS and Roche. She has received grants in support of investigator and investigator initiated trials from Novartis, Novo Nordisk, Sanofi-Aventis, Lilly, Pfizer, Merck Sharp & Dohme, GlaxoSmithKline and Servier.
Human insulins The human insulins were introduced in the early 1980s and are synthetically derived using recombinant DNA technology from yeast and bacteria. They are grouped into short- and intermediateacting insulins according to their onset and duration of action. Short-acting insulins Short-acting human insulins (Human Actrapid, Humulin S) have a delayed onset of action of 20e30 minutes with duration of action lasting up to 6 hours. Hence they have to be administered
Giridhar Tarigopula FRCP (Lon) MRCP (Diabetes & Endocrinology) is a Consultant Physician in Diabetes & Endocrinology; Royal College Tutor DMH County Durham & Darlington NHS Foundation Trust, Darlington, UK. Conflicts of interest: no conflict of interest to declare.
ANAESTHESIA AND INTENSIVE CARE MEDICINE --:-
1
Ó 2017 Published by Elsevier Ltd.
Please cite this article in press as: Chatterjee S, et al., Pharmacological control of blood sugar, Anaesthesia and intensive care medicine (2017), http://dx.doi.org/10.1016/j.mpaic.2017.06.017
PHARMACOLOGY
(basal) insulins. They are also used as add-on therapy to oral hypoglycaemic agents in diabetes patients with inadequately controlled T2DM.
Types of insulin and duration of action (adapted from Nolte, 2009) Rapid acting: Intermediate acting: Insulin lispro, aspart or glulisine NPH Short acting: Regular insulin
Ultra-long-acting insulin (degludec) Degludec is a basal ultra-long-acting insulin with duration of action with a plasma half-life of around 42 hours. It also exhibits significantly lower day-to-day variability and more glucosestabilizing effect. A recent cardiovascular outcome trial has confirmed that safety and efficacy of degludec is non-inferior to glargine and degludec is associated with a much lower rate of severe hypoglycaemia.3
Insulin effect
Long acting: Insulin detemir Insulin glargine
Oral agents in the treatment of T2DM
0
5
10
15
20
Metformin Metformin belongs to a biguanide class of drugs and works by decreasing gluconeogenesis, reducing hepatic glucose output and increasing peripheral utilization of glucose by muscles. Metformin is recommended as a first-line drug in the treatment of T2DM alongside lifestyle interventions. The main side effects are gastrointestinal such as nausea, abdominal discomfort and diarrhoea. Rare side effects include lactic acidosis. Metformin should be used with caution when renal function is compromised (i.e. at estimated glomerular filtration rate (eGFR) 45 ml/minute/1.73 m2) and is contraindicated with an eGFR 30 ml/minute/1.73 m2.
25
Time (hours) Figure 1
30 minutes prior to a meal for optimal effect. The prolonged duration of action and variable absorption of this insulin results in early postprandial hyperglycaemia and higher rates of hypoglycaemia.
Sulfonylureas Sulphonylureas are insulin secretagogues and stimulate insulin production by the pancreas. Gliclazide is a short-acting Sulphonylureas while glipizide and glimepiride have a longer duration of action. Indications for use include add-on therapy to metformin when blood glucose is poorly controlled, as first-line therapy in non-obese T2DM patients or when metformin is contraindicated. Side effects include hypoglycaemia and weight gain.
Intermediate-acting insulins Intermediate-acting (basal) insulins (neutral protamine Hagedorn (NPH), lente, ultralente) have an onset of action of 1e2 hours and a peak action of 4e6 hours which can last up to 14 hours. Due to their differing profiles in peaks and duration of action they are not suitable as a basal insulin in all patients and nocturnal hypoglycaemia is commonly encountered in clinical use.
Postprandial regulators Postprandial regulator (repaglinide) stimulate insulin release by stimulating the pancreas. They are administered before a meal and reduce postprandial hyperglycaemia. They have a shorter duration of action with a lower incidence of hypoglycaemia. They are usually added to metformin therapy.
Insulin analogues Insulin analogues or ‘designer insulins’ are derived by modifying the structure of the insulin molecule resulting in improved pharmacokinetics and pharmacological profiles. Based on their onset and duration of action, they are further divided into rapidacting and long-acting insulin analogues.
Thiazolidinediones Thiazolidinediones (TZDs) (pioglitazone and rosiglitazone) belong to the peroxisome proliferator-activated receptors (PPARs) agonist group of drugs. TZDs decrease the peripheral insulin resistance thereby reducing blood glucose, and can be used singly, added to metformin, sulfonylureas or to a combination of metformin and insulin. TZDs are associated with weight gain and fluid retention and should not be used in patients with heart failure. Studies suggest a link with osteoporosis by these agents and a possible association with cardiac ischaemia by rosiglitazone. Hence, an agent of this class, rosiglitazone (Avandia, Avandamet), has been withdrawn.4
Rapid-acting analogues Rapid-acting analogues lispro (Humalog), insulin aspart (Novorapid), glulisine (Apidra) mimic the physiologic action of endogenous prandial insulin release. They can be administered prior, with or just after the meal. They have a peak onset of action of 2 hours and duration of action lasting up to 5 hours. This offers a distinctive advantage in terms of greater freedom and flexibility to inject at variable meal times. Long-acting analogues The long-acting (basal) insulin analogues include glargine and detemir. Their duration of action lasts up to 20e24 hours. These are used as background insulins alongside rapid-acting or shortacting insulins. They have a lower risk of hypoglycaemia especially nocturnal hypoglycaemia when compared to human
ANAESTHESIA AND INTENSIVE CARE MEDICINE --:-
Acarbose Acarbose inhibits the digestive enzyme a-glucosidase thus reducing glucose uptake by the intestines resulting in reduction
2
Ó 2017 Published by Elsevier Ltd.
Please cite this article in press as: Chatterjee S, et al., Pharmacological control of blood sugar, Anaesthesia and intensive care medicine (2017), http://dx.doi.org/10.1016/j.mpaic.2017.06.017
PHARMACOLOGY
of postprandial glucose. It is commonly added to other oral agents to improve glycaemic control. Common side effects include bloating, flatulence and diarrhoea.
Conclusion A number of oral and injectable therapies are available to optimize glucose control and prevent disease progression. However, several drug therapies either singly or in combination often fail to achieve blood glucose targets and their use is limited by undesirable side effects. New therapies offer hope but can be associated with undesirable side effects requiring careful monitoring and evaluation. Furthermore potential benefits in cardiovascular disease require assessment in long-term outcome trials. A
DPP-4 inhibitors: (incretin enhancers including saxagliptin, sitagliptin and vildagliptin) These drugs inhibit the enzyme dipeptidylpeptidase-4 (DPP-4) which prolongs the action of endogenous glucagon-like peptide (GLP-1).This augments insulin secretion and decreases glucagon. They are weight neutral and can be used as monotherapy or as add-on therapy to oral agents. Clinical trials have shown reductions in HbA1c ranging from 0.7% to 0.9% when gliptins were combined with oral agents like metformin or sulfonylureas.5e7
REFERENCES 1 Quality and Outcomes Framework. Diabetes Prevalence Model 2016 (Public Health England) and 2012 APHO Diabetes Prevalence Model 2014/2015. 2 Public Health England. NHS Diabetes Prevention Programme (NHS DPP). Non-diabetic hyperglycaemia 2015. Produced by National Cardiovascular Intelligence Network (NCVIN). 3 Marso SP, McGuire DK, Zinman B, et al. DEVOTE Study Group. Efficacy and safety of degludec versus glargine in type 2 diabetes. N Engl J Med 2017; http://dx.doi.org/10.1056/NEJMoa1615692. 4 Medicines and Healthcare products Regulatory Agency (MHRA) recommends the withdrawal of rosiglitazone (Avandia, Avandamet) for treatment of diabetes 24.09.10. 5 Hollander P, Li J, Allen E, Chen R. CV181-013 Investigators. Saxagliptin added to a thiazolidinedione improves glycemic control in patients with type 2 diabetes and inadequate control on thiazolidinedione alone. J Clin Endocrinol Metab 2009; 94: 4810e9. 6 Charbonnel B, Karasik A, Liu J, Wu M, Meininger G. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone. Diabetes Care 2006; 29: 2638e43. 7 Aschner P, Kipnes M, Lunceford J, Mickel C, Davies M, Williams-Herman D. Sitagliptin monotherapy improved glycemic control in the fasting and postprandial states and beta-cell function after 24 weeks in patients with type 2 diabetes. Diabetes 2006; 55: A462. 8 Amori RE, Lau J, Pittas AG. Efficacy and safety of incretin therapy in type 2 diabetes: systematic review and meta-analysis. J Am Med Assoc 2007; 298: 194e206. 9 Drucker DJ, Buse JB, Taylor K, et al. Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: a randomised, open-label, non-inferiority study. Lancet 2008; 372: 1240e50. 10 Marso SP, Daniels GH, Brown-Frandsen K, et al. LEADER Trial Investigators. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016; 375: 311e22. 11 Zhang L, Feng Y, List J, Kasichayanula S, Pfister M. Dapagliflozin treatment in patients with different stages of type 2 diabetes mellitus: effects on glycaemic control and body weight. Diabetes Obes Metab 2010; 12: 510e6. 12 List F, Woo V, Morales E, Tang W, Fiedorek FT. Sodiumeglucose cotransport inhibition with dapagliflozin in type 2 diabetes. Diabetes Care 2009; 32: 650e7.
Injectable therapies in T2DM GLP-1 agonists: (incretin mimetics including exenatide and liraglutide) The glucagon-like peptide-1 (GLP-1) agonists (exenatide, and liraglutide, lixisenatide, dulaglutide) are currently licensed injectable therapies for T2DM. They stimulate the pancreas to release the insulin and decrease the glucagon secretion. They delay gastric emptying, suppress appetite and promote weight loss. Exenatide has to be injected twice daily in view of its shorter half-life. However, liraglutide is injected once daily and dulaglutide once weekly. Most studies show reductions of HbA1c up to 0.9% and weight loss of 3e4 kg with these drugs.8,9 Liraglutide is associated with improved cardiovascular outcomes.10
Oral/injectable therapies for type 2 diabetes Sodiumeglucose co-transporter 2 (SGLT2) inhibitors This new class of drugs primarily inhibits absorption of glucose in the proximal tubules of kidneys, thus promoting glycosuria and hence decreasing blood glucose levels. Dapagliflozin, canagliflozin and empagliflozin belong to the class of SGLT2 inhibitors. Clinical trials with dapagliflozin have demonstrated lowering of HbA1c ranging from 0.5% to 0.9% and weight loss of 2.5e3.4 kg independent of dosage.11,12 Empagliflozin and canagliflozin are associated with improved cardiovascular and renal outcomes. Common side effects include genito-urinary infections. There is an association with euglycaemic ketoacidosis and SGLT2 inhibitors should be discontinued during acute illness and/or hospitalization. Other less common adverse effects include increased risk of lower limb amputations, acute kidney injury and bony fractures. Oral GLP-1 agonists/analogues and SGLT1/2 inhibitors Semaglutide, a GLP-1 agonist available in both oral and injectable formulation, is currently being investigated in phase 3 clinical trials. Sotaliflozin, a combined SGLT1/2 inhibitor which also reduces glucose absorption from the gastrointestinal tract, is also in phase 3 trials for treatment of both type 1 and types 2 diabetes.
ANAESTHESIA AND INTENSIVE CARE MEDICINE --:-
3
Ó 2017 Published by Elsevier Ltd.
Please cite this article in press as: Chatterjee S, et al., Pharmacological control of blood sugar, Anaesthesia and intensive care medicine (2017), http://dx.doi.org/10.1016/j.mpaic.2017.06.017
Pharmacological control of blood sugar
Learning objectives After reading this article, you should be able to: C understand the different types of insulins used in clinical practice including their duration and actions C know the oral agents and newer glucose-lowering drugs used in type 2 diabetes C appreciate that long-term diabetes control can be challenging and that there is an increasing need for newer drugs with good safety profiles and benefits in long-term cardiovascular outcomes
Sudesna Chatterjee Melanie J Davies Giridhar Tarigopula
Abstract Diabetes is a chronic and progressive metabolic disorder characterized by hyperglycaemia. The two main types of diabetes are type 1 diabetes (T1DM) where there is complete lack of insulin and type 2 diabetes (T2DM) which may be due to a combination of insulin resistance and relative insulin deficiency due to impaired b-cell function. Good control of blood glucose near physiological limits is vital to reduce long-term microvascular and macrovascular complications of diabetes. Insulin replacement is a life-saving measure in individuals with T1DM whereas the mainstay of therapy in T2DM includes oral agents, non-insulin injectables (incretin mimetics) and insulin. In T2DM, the incretin mimetics and sodium glucose co-transporter 2 inhibitors have revolutionized recent treatment options by reducing blood glucose, promoting weight loss and improving b-cell function with improved cardiovascular outcomes associated with some of these agents. Despite the availability of several drugs to treat this chronic debilitating condition, the management of hyperglycaemia remains challenging. The role of diet, lifestyle changes and patient education is of paramount importance and should be pursued aggressively. This review will look at drugs currently used to optimize blood glucose control and briefly discuss the role of newer therapeutic agents.
Introduction Diabetes is one of the biggest health challenges faced by UK. There are an estimated 4.5 million people with diabetes in the UK and with current trends, by 2034 1 in 10 people will be diagnosed with type 2 diabetes.1,2 Optimal and sustained glycaemic control is essential in minimizing long-term complications. Type 1 diabetes (T1DM) is treated with insulin supplemented by educational and psychological support. Type 2 diabetes (T2DM) requires lifestyle interventions, combination of drugs and often use of insulin. Current and emerging glucose-lowering therapies for T1DM and T2DM are discussed below.
Insulin Insulin replacement therapy either regular daily injections by the subcutaneous route or continuously via an insulin pump is the mainstay of treatment for all patients with T1DM and for individuals with T2DM who do not achieve optimal glycaemic control despite the use of oral agents or non-insulin based injectable therapies. Hypoglycaemia and weight gain are the major problems associated with glucose-lowering therapies. Insulins are classified according to the preparations as described below or according to onset and duration of action (Figure 1).
Keywords Incretin mimetics; insulin; oral agents; sodiumeglucose transporter 2 inhibitors Royal College of Anaesthetists CPD Matrix: 1A02
Animal insulins
Sudesna Chatterjee MD FRCP(UK) is a Consultant Diabetologist at University Hospitals of Leicester and a Senior Clinical Researcher at University of Leicester, UK. Conflicts of interest: Dr Chatterjee has received speaker fees, educational funding or both from Janssen, Eli Lilly, Novo Nordisk, Astra Zeneca and Boehringer Ingelheim and has received grants in support of investigator-initiated trials from Boehringer Ingelheim and Janssen.
Animal insulins are derived from the pancreatic extracts of animals (e.g. cows and pigs) and were the earliest insulins used in the treatment of diabetes. However, due to problems with variable rates of insulin absorption, allergic reactions at injection sites and immunogenicity, they have been largely replaced by human insulins and insulin analogues.
Melanie J Davies MB ChB MD FRCP is Professor of Diabetes Medicine at the Department of Cardiovascular Sciences, University of Leicester, Leicester, UK. Conflicts of interest: Professor Davies has acted as consultant, advisory board member and speaker for Novartis, Novo Nordisk, Sanofi-Aventis, Lilly, Merck Sharp & Dohme, Servier, BMS and Roche. She has received grants in support of investigator and investigator initiated trials from Novartis, Novo Nordisk, Sanofi-Aventis, Lilly, Pfizer, Merck Sharp & Dohme, GlaxoSmithKline and Servier.
Human insulins The human insulins were introduced in the early 1980s and are synthetically derived using recombinant DNA technology from yeast and bacteria. They are grouped into short- and intermediateacting insulins according to their onset and duration of action. Short-acting insulins Short-acting human insulins (Human Actrapid, Humulin S) have a delayed onset of action of 20e30 minutes with duration of action lasting up to 6 hours. Hence they have to be administered
Giridhar Tarigopula FRCP (Lon) MRCP (Diabetes & Endocrinology) is a Consultant Physician in Diabetes & Endocrinology; Royal College Tutor DMH County Durham & Darlington NHS Foundation Trust, Darlington, UK. Conflicts of interest: no conflict of interest to declare.
ANAESTHESIA AND INTENSIVE CARE MEDICINE --:-
1
Ó 2017 Published by Elsevier Ltd.
Please cite this article in press as: Chatterjee S, et al., Pharmacological control of blood sugar, Anaesthesia and intensive care medicine (2017), http://dx.doi.org/10.1016/j.mpaic.2017.06.017
PHARMACOLOGY
(basal) insulins. They are also used as add-on therapy to oral hypoglycaemic agents in diabetes patients with inadequately controlled T2DM.
Types of insulin and duration of action (adapted from Nolte, 2009) Rapid acting: Intermediate acting: Insulin lispro, aspart or glulisine NPH Short acting: Regular insulin
Ultra-long-acting insulin (degludec) Degludec is a basal ultra-long-acting insulin with duration of action with a plasma half-life of around 42 hours. It also exhibits significantly lower day-to-day variability and more glucosestabilizing effect. A recent cardiovascular outcome trial has confirmed that safety and efficacy of degludec is non-inferior to glargine and degludec is associated with a much lower rate of severe hypoglycaemia.3
Insulin effect
Long acting: Insulin detemir Insulin glargine
Oral agents in the treatment of T2DM
0
5
10
15
20
Metformin Metformin belongs to a biguanide class of drugs and works by decreasing gluconeogenesis, reducing hepatic glucose output and increasing peripheral utilization of glucose by muscles. Metformin is recommended as a first-line drug in the treatment of T2DM alongside lifestyle interventions. The main side effects are gastrointestinal such as nausea, abdominal discomfort and diarrhoea. Rare side effects include lactic acidosis. Metformin should be used with caution when renal function is compromised (i.e. at estimated glomerular filtration rate (eGFR) 45 ml/minute/1.73 m2) and is contraindicated with an eGFR 30 ml/minute/1.73 m2.
25
Time (hours) Figure 1
30 minutes prior to a meal for optimal effect. The prolonged duration of action and variable absorption of this insulin results in early postprandial hyperglycaemia and higher rates of hypoglycaemia.
Sulfonylureas Sulphonylureas are insulin secretagogues and stimulate insulin production by the pancreas. Gliclazide is a short-acting Sulphonylureas while glipizide and glimepiride have a longer duration of action. Indications for use include add-on therapy to metformin when blood glucose is poorly controlled, as first-line therapy in non-obese T2DM patients or when metformin is contraindicated. Side effects include hypoglycaemia and weight gain.
Intermediate-acting insulins Intermediate-acting (basal) insulins (neutral protamine Hagedorn (NPH), lente, ultralente) have an onset of action of 1e2 hours and a peak action of 4e6 hours which can last up to 14 hours. Due to their differing profiles in peaks and duration of action they are not suitable as a basal insulin in all patients and nocturnal hypoglycaemia is commonly encountered in clinical use.
Postprandial regulators Postprandial regulator (repaglinide) stimulate insulin release by stimulating the pancreas. They are administered before a meal and reduce postprandial hyperglycaemia. They have a shorter duration of action with a lower incidence of hypoglycaemia. They are usually added to metformin therapy.
Insulin analogues Insulin analogues or ‘designer insulins’ are derived by modifying the structure of the insulin molecule resulting in improved pharmacokinetics and pharmacological profiles. Based on their onset and duration of action, they are further divided into rapidacting and long-acting insulin analogues.
Thiazolidinediones Thiazolidinediones (TZDs) (pioglitazone and rosiglitazone) belong to the peroxisome proliferator-activated receptors (PPARs) agonist group of drugs. TZDs decrease the peripheral insulin resistance thereby reducing blood glucose, and can be used singly, added to metformin, sulfonylureas or to a combination of metformin and insulin. TZDs are associated with weight gain and fluid retention and should not be used in patients with heart failure. Studies suggest a link with osteoporosis by these agents and a possible association with cardiac ischaemia by rosiglitazone. Hence, an agent of this class, rosiglitazone (Avandia, Avandamet), has been withdrawn.4
Rapid-acting analogues Rapid-acting analogues lispro (Humalog), insulin aspart (Novorapid), glulisine (Apidra) mimic the physiologic action of endogenous prandial insulin release. They can be administered prior, with or just after the meal. They have a peak onset of action of 2 hours and duration of action lasting up to 5 hours. This offers a distinctive advantage in terms of greater freedom and flexibility to inject at variable meal times. Long-acting analogues The long-acting (basal) insulin analogues include glargine and detemir. Their duration of action lasts up to 20e24 hours. These are used as background insulins alongside rapid-acting or shortacting insulins. They have a lower risk of hypoglycaemia especially nocturnal hypoglycaemia when compared to human
ANAESTHESIA AND INTENSIVE CARE MEDICINE --:-
Acarbose Acarbose inhibits the digestive enzyme a-glucosidase thus reducing glucose uptake by the intestines resulting in reduction
2
Ó 2017 Published by Elsevier Ltd.
Please cite this article in press as: Chatterjee S, et al., Pharmacological control of blood sugar, Anaesthesia and intensive care medicine (2017), http://dx.doi.org/10.1016/j.mpaic.2017.06.017
PHARMACOLOGY
of postprandial glucose. It is commonly added to other oral agents to improve glycaemic control. Common side effects include bloating, flatulence and diarrhoea.
Conclusion A number of oral and injectable therapies are available to optimize glucose control and prevent disease progression. However, several drug therapies either singly or in combination often fail to achieve blood glucose targets and their use is limited by undesirable side effects. New therapies offer hope but can be associated with undesirable side effects requiring careful monitoring and evaluation. Furthermore potential benefits in cardiovascular disease require assessment in long-term outcome trials. A
DPP-4 inhibitors: (incretin enhancers including saxagliptin, sitagliptin and vildagliptin) These drugs inhibit the enzyme dipeptidylpeptidase-4 (DPP-4) which prolongs the action of endogenous glucagon-like peptide (GLP-1).This augments insulin secretion and decreases glucagon. They are weight neutral and can be used as monotherapy or as add-on therapy to oral agents. Clinical trials have shown reductions in HbA1c ranging from 0.7% to 0.9% when gliptins were combined with oral agents like metformin or sulfonylureas.5e7
REFERENCES 1 Quality and Outcomes Framework. Diabetes Prevalence Model 2016 (Public Health England) and 2012 APHO Diabetes Prevalence Model 2014/2015. 2 Public Health England. NHS Diabetes Prevention Programme (NHS DPP). Non-diabetic hyperglycaemia 2015. Produced by National Cardiovascular Intelligence Network (NCVIN). 3 Marso SP, McGuire DK, Zinman B, et al. DEVOTE Study Group. Efficacy and safety of degludec versus glargine in type 2 diabetes. N Engl J Med 2017; http://dx.doi.org/10.1056/NEJMoa1615692. 4 Medicines and Healthcare products Regulatory Agency (MHRA) recommends the withdrawal of rosiglitazone (Avandia, Avandamet) for treatment of diabetes 24.09.10. 5 Hollander P, Li J, Allen E, Chen R. CV181-013 Investigators. Saxagliptin added to a thiazolidinedione improves glycemic control in patients with type 2 diabetes and inadequate control on thiazolidinedione alone. J Clin Endocrinol Metab 2009; 94: 4810e9. 6 Charbonnel B, Karasik A, Liu J, Wu M, Meininger G. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone. Diabetes Care 2006; 29: 2638e43. 7 Aschner P, Kipnes M, Lunceford J, Mickel C, Davies M, Williams-Herman D. Sitagliptin monotherapy improved glycemic control in the fasting and postprandial states and beta-cell function after 24 weeks in patients with type 2 diabetes. Diabetes 2006; 55: A462. 8 Amori RE, Lau J, Pittas AG. Efficacy and safety of incretin therapy in type 2 diabetes: systematic review and meta-analysis. J Am Med Assoc 2007; 298: 194e206. 9 Drucker DJ, Buse JB, Taylor K, et al. Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: a randomised, open-label, non-inferiority study. Lancet 2008; 372: 1240e50. 10 Marso SP, Daniels GH, Brown-Frandsen K, et al. LEADER Trial Investigators. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016; 375: 311e22. 11 Zhang L, Feng Y, List J, Kasichayanula S, Pfister M. Dapagliflozin treatment in patients with different stages of type 2 diabetes mellitus: effects on glycaemic control and body weight. Diabetes Obes Metab 2010; 12: 510e6. 12 List F, Woo V, Morales E, Tang W, Fiedorek FT. Sodiumeglucose cotransport inhibition with dapagliflozin in type 2 diabetes. Diabetes Care 2009; 32: 650e7.
Injectable therapies in T2DM GLP-1 agonists: (incretin mimetics including exenatide and liraglutide) The glucagon-like peptide-1 (GLP-1) agonists (exenatide, and liraglutide, lixisenatide, dulaglutide) are currently licensed injectable therapies for T2DM. They stimulate the pancreas to release the insulin and decrease the glucagon secretion. They delay gastric emptying, suppress appetite and promote weight loss. Exenatide has to be injected twice daily in view of its shorter half-life. However, liraglutide is injected once daily and dulaglutide once weekly. Most studies show reductions of HbA1c up to 0.9% and weight loss of 3e4 kg with these drugs.8,9 Liraglutide is associated with improved cardiovascular outcomes.10
Oral/injectable therapies for type 2 diabetes Sodiumeglucose co-transporter 2 (SGLT2) inhibitors This new class of drugs primarily inhibits absorption of glucose in the proximal tubules of kidneys, thus promoting glycosuria and hence decreasing blood glucose levels. Dapagliflozin, canagliflozin and empagliflozin belong to the class of SGLT2 inhibitors. Clinical trials with dapagliflozin have demonstrated lowering of HbA1c ranging from 0.5% to 0.9% and weight loss of 2.5e3.4 kg independent of dosage.11,12 Empagliflozin and canagliflozin are associated with improved cardiovascular and renal outcomes. Common side effects include genito-urinary infections. There is an association with euglycaemic ketoacidosis and SGLT2 inhibitors should be discontinued during acute illness and/or hospitalization. Other less common adverse effects include increased risk of lower limb amputations, acute kidney injury and bony fractures. Oral GLP-1 agonists/analogues and SGLT1/2 inhibitors Semaglutide, a GLP-1 agonist available in both oral and injectable formulation, is currently being investigated in phase 3 clinical trials. Sotaliflozin, a combined SGLT1/2 inhibitor which also reduces glucose absorption from the gastrointestinal tract, is also in phase 3 trials for treatment of both type 1 and types 2 diabetes.
ANAESTHESIA AND INTENSIVE CARE MEDICINE --:-
3
Ó 2017 Published by Elsevier Ltd.
Please cite this article in press as: Chatterjee S, et al., Pharmacological control of blood sugar, Anaesthesia and intensive care medicine (2017), http://dx.doi.org/10.1016/j.mpaic.2017.06.017