Dr Glynis Magee MD FRCP, Consultant Diabetologist and Endocrinologist, tackles the major treatment issues surrounding type 2 diabetes, including management options and some of the newer and less prescribed agents available.
The myriad of agents available for the treatment of type 2 diabetes have ensured that those not managing the condition all the time would be in danger of getting left behind. Following Metformin, we now regularly have a choice of six classes of therapeutic agent, which, although giving more choice to the clinician and the person living with diabetes, can be confusing.
New to these guidelines is the important concept of ‘rescue treatment’. This means that it may be necessary to temporarily break from guidelines for a short period if the patient becomes symptomatically hyperglycaemic, and use insulin or a sulfonylurea until the blood glucose control is achieved, before resorting back to the guidelines. This commonly is required during inter-current illnesses, steroid use, or at diagnosis, especially if the patient is thin and may have presented as insulinopenic, such as in the case of LADA (Latent Autoimmune Diabetes of the Adult). This concept is supported by the theory of glucose toxicity which implies that β cell exposure to hyperglycaemia over time leads to an adverse ability of the cells to function. (1)
Being aware of the pathophysiology of the disease and taking into consideration the individual needs and preferences of the patient, specific drug tolerances, and HbA1c targets hoping to be achieved, are all vital in disease management. The newest 2015 NICE guidelines assist in the decision-making process and take account of all these factors. (2)
Individualised targets should be set based on the needs of the patient and at each stage of the management process, when HbA1c results may have exceeded the target, time should be taken to check compliance and enforce lifestyle, before intensifying treatment.
The treatment guidelines are shown in figure 1, and the pros and cons of the treatment in table 1.
With previous adverse events in diabetes medications e.g. Rosiglitazone (3), it is no longer acceptable for all new diabetes medications to simply perform at improving the surrogate endpoint of HbA1c; they are now expected to demonstrate safety in major adverse cardiovascular events (MACE). Pioglitazone, DPP4is, GLP1 analogues and the newest oral agents SGLT2is have all been stringently examined with regard to this. Some of the newer agents will be discussed here. In this short review, I will concentrate on some of the newer or less prescribed agents available, the evidence behind them, and when to use them.
SODIUM GLUCOSE 2 CO-TRANSPORTER INHIBITORS (SGLT2I)
The kidney, a very important and previously neglected organ in the diabetes world, is essential in the regulation of glucose homeostasis via two main ways, through glucose production with gluconeogenesis, and processing through glomerular filtration and reabsorption in the proximal tubule. The majority (90 per cent) of the glucose filtered by the kidneys is reabsorbed by Sodium Glucose Co-transporters (SGLTs). (4)
Inhibiting the SGLT2 receptor with pharmacological agents SGLT2 inhibitors is a game-changer in the management of type 2 diabetes mellitus. These agents enable additional glucose to be excreted in the urine, thus reducing hyperglycaemia and increasing urinary glucose excretion and thus calories. Results of several placebo-controlled randomised clinical trials of up to two years duration have shown significant reductions in HbA1c, administered as monotherapy or in addition to other glucose-lowering therapies, including insulin in patients with T2DM with additional weight loss benefits. In head-to-head trials of up to two years, SGLT2 inhibitors exerted similar glucose-lowering activity to metformin, Sulphonylureas or DPP4is. (5)
The National Institute of Clinical Excellence (NICE) has approved three of these agents (table 2). Worldwide, other SGLT2 inhibitors have been approved for use, mainly in Japan; Ipragliflozin (Suglat ®), Tofogliflozin (Apleway ®, Deberza ®) and Luseogliflozin (Lusefi ®).
Cardiovascular outcome studies looking at the agents compared to 3 point MACE are underway for Canigloflozin and Dapagliflozin. The Empagliflozin cardiovascular outcomes study, EMPA-REG (6), has already reported. The results of the study, where over 7,000 patients at high risk of cardiovascular disease were observed over a three-year period, showed a significant reduction in rates of cardiovascular events and death from any cause when the drug was added into standard care. There was a 32 per cent relative risk reduction in the risk of death from all causes in the pooled Empagliflozin group, meaning that the number needed to treat to prevent one death over a three-year period was 39 patients.
2 diabetes mellitus. These agents enable additional glucose to be excreted in the urine, thus reducing hyperglycaemia and increasing urinary glucose excretion and thus calories. Results of several placebo-controlled randomised clinical trials of up to two years duration have shown significant reductions in HbA1c, administered as monotherapy or in addition to other glucose-lowering therapies, including insulin in patients with T2DM with additional weight loss benefits. In head-to-head trials of up to two years, SGLT2 inhibitors exerted similar glucose-lowering activity to metformin, Sulphonylureas or DPP4is. (5)
The National Institute of Clinical Excellence (NICE) has approved three of these agents (table 2). Worldwide, other SGLT2 inhibitors have been approved for use, mainly in Japan; Ipragliflozin (Suglat ®), Tofogliflozin (Apleway ®, Deberza ®) and Luseogliflozin (Lusefi ®).
Cardiovascular outcome studies looking at the agents compared to 3 point MACE are underway for Canigloflozin and Dapagliflozin. The Empagliflozin cardiovascular outcomes study, EMPA-REG (6), has already reported. The results of the study, where over 7,000 patients at high risk of cardiovascular disease were observed over a three-year period, showed a significant reduction in rates of cardiovascular events and death from any cause when the drug was added into standard care.
There was a 32 per cent relative risk reduction in the risk of death from all causes in the pooled Empagliflozin group, meaning that the number needed to treat to prevent one death over a three-year period was 39 patients.
GLUCAGON LIKE PEPTIDE-1 RECEPTOR ANTAGONISTS (GLP-1 RA)
Over the last 10 years, the use of Glucagon like peptide-1 receptor antagonists (GLP-1 RA) has grown and there are several now available and approved for type 2 diabetes management. GLP-1 is a peptide hormone that increases insulin and decreases glucagon secretion from the pancreas in a glucose dependent manner. GLP1-RA provide supra-physiological levels of GLP-1 in a subcutaneous injection formulation, which, in addition to lower glucose levels, through the extra-pancreatic mechanisms of GLP-1 action, also delay gastric emptying and increase satiety assisting with weight reduction over time. The available GLP-1RAs have all been extensively evaluated in phase 3 clinic trials (table 3).
Newer agents were compared in general against Exenatide (first in class). When comparing HbA1C reduction, Dulaglutide once weekly was more efficacious at lowering A1C compared with Exenatide twice daily and was non-inferior to Liraglutide 1.8mg.
Weight loss was similar between Dulaglutide and Exenatide twice daily, but was greater with Liraglutide 1.8mg compared to Dulaglutide (7). It is important to note, however, that NICE has not approved the 1.8mg dose of Liraglutide 97and only recommends up to 1.2mg.
Much like the EMPA-REG study, in the LEADER study (8), patients in the Liraglutide group had a lower risk of death from all causes and cardiovascular death than the placebo group. The number needed to treat to prevent one outcome at three years was 66. Two studies on diabetes agents are now showing cardiovascular benefits. The EMPA-REG study demonstrated cardiovascular benefit at a much earlier stage than LEADER potentially due to a haemodynamic rather than mechanism rather than atherosclerotic modification, although precise mechanisms and the wonder as to class effect are still to be proven.
NEWER INSULIN AND INSULIN GLP1 RA COMBINATIONS
Insulin therapy may be required at any step in the type 2 diabetes management algorithm, either for a short period as rescue therapy, or long-term as part as treatment intensification. NICE will always recommend that the older, less expensive Neutral Protamine Hagedorn (NPH) insulins should be offered first-line, or, especially if the HbA1c is greater than 75mmol/mol, along with shorter-acting insulins or replaced with pre-mixed biphasic insulins.
Long-acting insulin analogues, e.g. Insulin Glargine (Lantus ®) and Insulin Detemir (Levemir ®), have been available either once or twice per day for some considerable time, but now newer higher concentrated insulins are now in general use, so knowledge of their characteristics and indications is essential for safe prescribing.
The standard international unit of insulin means that for a U-100 concentration, there are 100 units of insulin per millilitre (ml) of liquid. Newer higher concentrated insulins are available in u200 and u300 strengths. These insulins, although more expensive, have a more favourable basal insulin action without such an increased risk of hypoglycaemia and lower individual variability and the higher concentrations can help overcome severe insulin resistance and the associated high injection volume. Basal insulins available are Insulin Degludec (Tresiba ®) u100 and u200, Insulin Glargine u300 (Toujeo ®), and a combined preparation of Insulin Degludec u100 and Liraglutide (Xultophy®).
A recent meta-analysis found once daily Toujeo® non-inferior to once daily Lantus ® with an overall reduction in severe nocturnal hypoglycaemia (9); similar results have been seen with Insulin Degludec (10). These newer insulins are not bioequivalent to Lantus® so care and supervision have to be taken when converting from one to the other, although the dose prescribed is visible on the dose counter window of the pen device showing the number of units, due to the concentration difference the volume in the higher concentration insulin will be less. To minimise risk using these newer insulin, they are dispensed and should only be used in pre-filled insulin pens under supervision of a specialist team.
Finally, the last key update in insulin therapy is the launch of the first biosimilar insulin, Insulin Glargine biosimilar 100 units/ml (Abasaglar). Abasaglar has been shown not to have any clinically meaningful differences from the originator biological medicine (Glargine u100) in terms of quality, safety, and efficacy, but is 15 per cent less in cost than the cost of Lantus ®. (11)
Despite the ever-growing diabetes formulary, one must not lose track of the importance of patient-centred care and the need to empower those living with diabetes to self-manage themselves, as understanding of the disease and the rationale regarding medication and diet improve compliance, and ultimately control.