Taking a snapshot of current diabetes research

The management of type 2 diabetes mellitus (T2DM) has changed enormously in recent decades. The UK Prospective Diabetes Study (UKPDS) shifted treatment from simply alleviating symptoms of hyperglycaemia to aiming to prevent or ameliorate the microvascular and macrovascular complications of diabetes, via establishment of good glycaemic control (generally as near normal as possible) as soon as possible after diagnosis.

The availability of new therapeutic classes of glucose-lowering agents has increased the opportunity for individualisation of strategies to achieve personalised optimal glycaemic targets. However, novelty has also raised controversy and in 2008 the US Food and Drug Administration (FDA) introduced new regulations that effectively required a fully-powered cardiovascular outcomes trial (CVOT) for new therapeutic agents for the management of diabetes.1 The European Medicines Agency (EMA) introduced similar requirements in 2012.2

A cardiovascular outcomes trial (CVOT) is now necessary to ensure that the new agent offers cardiovascular outcomes that are at least similar to (non-inferior) and ideally better (superior) than the current standard care. To date, these trials have demonstrated the cardiovascular safety of the new agents – the studies of dipeptidyl peptidase-4 (DPP-4) inhibitors were the first CVOTs to report – and further reductions in the risks of major adverse cardiovascular events (MACE) have been demonstrated with some glucagon-like peptide-1 receptor agonists (GLP-1RA) and sodium-glucose co-transporter (SGLT)2 inhibitors.3 These data have provided the first major evidence for cardiovascular protection since the reductions in macrovascular complications and mortality seen with metformin in the UKPDS.4

This article provides a brief review of two major, recent international congresses: the European Association for the Study of Diabetes (EASD) and International Diabetes Federation (IDF) held in September and December 2017 respectively. Most of the material presented at these conferences is available online, therefore, abstract and symposium/session numbers are provided to facilitate access to detailed information. 5,6 The main focus of this report is pharmacotherapy for T2DM (see a symposium at IDF P-001 – P-003), but we also take a brief look at developments in insulins and management of type 1 diabetes mellitus (T1DM).

Metformin

Metformin has been used in the treatment of T2DM for 60 years, and was the subject of a symposium, a dedicated session and a conference ‘newscast’ at EASD as well as publication of a special issue of Diabetologia.7-9 However, metformin only became the internationally recommended first-line pharmacological agent (contraindications permitting) this century.

In new-onset T2DM, 73% of patients were inadequately controlled (HbA1c ≥7.5%) on monotherapy by 1 year and higher baseline HbA1c predicted earlier need for therapy intensification (EASD #659). A 3-year multinational observational study found metformin was first-line treatment in 87% of patients, and the main reasons for discontinuation were side effects, onset of chronic kidney disease (CKD) and lack of health insurance, implying that even for this low-cost treatment there are issues with access to care in some health systems (EASD #906). Metformin DR is a novel delayed release formulation in development which may reduce requirements for drug discontinuation (EASD #243, #244).

 

Table 1: Clinical trial abbreviations

ACE: Acarbose Cardiovascular Evaluation trial
CANVAS: CANagliflozin CardioVascular Assessment Study
CANVAS- R: CANVAS - Renal
DEPICT: Dapagliflozin Evaluation in Patients with Inadequately Controlled Type 1 diabetes
DiRECT: Diabetes REmission Clinical Trial
DISCOVER: DISCOVERing treatment reality of type 2 diabetes in real world settings
EXSCEL: EXenatide Study of Cardiovascular Event Lowering
inTANDEM: Sotagliflozin in patients with type 1 diabetes who have inadequate glycemic control with insulin therapy alone
REMOVAL: Reducing with MetfOrmin Vascular Adverse Lesions in type 1 diabetes
SUSTAIN: Semaglutide once weekly (sc injection)
TOSCA.IT: Thiazolidinediones Or Sulfonylureas Cardiovascular Accidents Intervention Trial
UKPDS: United Kingdom Prospective Diabetes Study
VERTIS: eValuation of ERTugliflozin effIcacy and Safety

 

 

The REMOVAL study, which initially reported at ADA 2017, was the subject of an EASD satellite symposium.10,11 This study in patients with established T1DM showed that the addition of metformin treatment improved cardiovascular risk factors as well as eGFR (eGFR increased 4·0 mL/min per 1·73m2; p<0·0001). Post hoc analyses presented at EASD supported the original observation and suggested that improved eGFR, including a 37% reduction in time to onset of microalbuminuria, is due to a direct effect of metformin on the kidney.10

Inhibitors of SGLT

The CANVAS program (amalgamation of data from CANVAS and CANVAS-R) was initially reported at ADA 2017. This CVOT was the focus of a dedicated session at EASD (S44).12 Treatment with canagliflozin was superior to usual care, with a significant 14% reduction in the risk of the primary outcome of 3-point MACE (a composite of cardiovascular death, non-fatal MI or non-fatal stroke). The strict hierarchical statistical analysis resulted in all other endpoints being considered exploratory and a 13% reduction in all-cause mortality just failed to reach statistical significance. In the discussion of the results it was apparent that there was a consensus amongst leading physicians that cardiovascular protection is a class effect of SGLT2 inhibitors.

Other EASD sessions devoted to SGLT inhibitors were S07, S27, OP07, OP31 .There were several presentations on the VERTIS studies with ertugliflozin – the most recent SGLT2 inhibitor to receive regulatory approval in Europe (January 2018) for treating T2DM - (EASD #38, #41 and #878- #881 and IDF OP-0104). S27 and S07 focussed on the potential use of dapagliflozin (the DEPICT studies13) and the investigational drug sotagliflozin (inTANDEM studies) respectively, as adjuncts to insulin treatment in T1DM.

SGLT2 inhibitory activity has been associated with euglycaemic DKA, notably in patients with lower basal insulin and a longer duration of diabetes (EASD #892). It must be remembered that insulin is necessary for cellular uptake and utilisation of glucose, and inhibition of fat breakdown whereas SGLT2 inhibitors only stop excess glucose re-entering the circulation.

GLP-1 receptor agonists

The CVOT trial, EXSCEL, reported at a dedicated EASD symposium (S29). The trial with once-weekly (QW) exenatide met its primary endpoint of non-inferiority versus usual care with regard to 3-point MACE, and there was a significant 14% reduction in all-cause mortality (a secondary endpoint).14

A once weekly injectable formulation of the GLP-1RA semaglutide has received regulatory approval in Europe (February 2018). The phase 3 trials SUSTAIN (1-6) have shown marked weight loss and superior effects on glycaemia versus comparators (e.g. EASD #4, #812, #817, #821; IDF P-0521, P-0526, P-0528, P-0529). An oral formulation of semaglutide is in development (EASD #147, #148, #786–792), but its bioavailability is low and absorption is variable.

 

Metformin only became the internationally recommended first-line pharmacological agent (contraindications permitting) this century

Novel insulins

Basal insulins with longer (“flatter”) plasma concentration-time profiles have equivalent efficacy to other basal insulins, but cause fewer hypoglycaemic events: for example, degludec versus glargine (e.g. IDF OP-0169) or glargine U300 compared with glargine U100 (EASD #78, IDF P-0172). Glargine biosimilars are now available and others are in development (IDF P-0256, P-0272). A very long-acting derivative of glargine (BC glargine) has been developed which is suitable for ‘fixed ratio’ combination with liraglutide (BC GlaLira) and dulaglutide (BC GlaD) (EASD #793). An oral basal insulin is in development (EASD #74) – but it has low bioavailability. It is absorbed in the stomach, so like oral semaglutide patients must take their morning dose on an empty stomach and not eat for at least 30 minutes.

Elsewhere, fast-acting aspart (e.g. EASD #690, IDF P-0363, P-0364) provides slightly earlier postprandial glucose control and may be useful in artificial pancreas systems. A new fast-acting formulation of insulin lispro has also been described (EASD #192).

Some interesting trials

In TOSCA.IT (EASD S13) no differences in cardiovascular outcomes were observed when comparing pioglitazone versus a sulphonylurea (gliclazide 50%, glimepiride 48%, glibenclamide 2%) as add-on to metformin for a median of 4.8yrs.15

In DiRECT (IDF 192-194), obese people with T2DM were assigned to usual care or a weight loss programme which included a meal replacement diet (~800kcal/day for 3–5 months) followed by food re-introduction over 2-8 weeks. After 1 year, 46% of the intervention group and 4% of control subjects achieved diabetes remission. Diabetes remission in the whole study population occurred in 86% of people who lost >15kg, 57% who lost 10–15kg, 34% who lost 5–10kg and 7% who maintained a weight loss of <5kg.16 Weight loss decreases intra-organ fat, thereby reducing hepatic insulin resistance and permitting a return to normal pancreatic function – including β-cell differentiation and reappearance of 1st phase insulin secretion. However, β-cell dysfunction increases with diabetes duration, thus earlier intervention to reduce weight and relieve insulin resistance and gluco/lipotoxicity increases the likelihood of β-cell recovery.

DISCOVER is a global observational study in 14,000 T2DM patients in 37 countries to investigate current diabetes care strategies, especially with respect to the use of antidiabetic therapies (IDF 186-191). Metformin monotherapy was the most commonly prescribed first-line treatment and for intensification sulphonylureas and DPP-4 inhibitors were the commonest combination partners. Lower educational attainment and higher HbA1c predicted addition of a sulphonylurea rather than a DPP-4 inhibitor.

 

Basal insulins with longer (“flatter”) plasma concentration-time profiles have equivalent efficacy to other basal insulins, but cause fewer hypoglycaemic events

 

A high prevalence of clinical inertia has been revealed in DISCOVER: about 50% of patients had an HbA1c >8%, and 30% had an HbA1c >9%, before intensification to combination therapy. Delayed treatment intensification, has also been shown in other ‘real-world’ studies (EASD #783, IDF P-0362).

Antidiabetic therapies in development

ITCA650 is novel drug-device combination. Continuous subcutaneous release of the GLP-1RA exenatide, for up to 12 months from a sub-dermally-located removable osmotic mini-pump improved glycaemic control and reduced the incidence of treatment intensification (e.g., EASD #784, #785).

The development of peptide-based therapies has provided an opportunity to generate chimeric single protein structures that elicit an agonist action at more than one receptor. This approach is being investigated using GLP-1 and other enteral hormones, such as glucose-dependent insulinotropic peptide (GIP), which is a potent stimulator of insulin secretion. LY3298176, a long-acting GLP-1/GIP dual agonist, caused marked weight loss and improved multiple cardiometabolic parameters in diabetic rats (EASD #862) and HM15211 (a GIP/GLP-1/glucagon triple agonist) has shown benefits in the treatment of obesity and fatty liver disease in rodents (EASD #109).

 

Lifestyle strategies are key to diabetes prevention – but one size doesn’t fit all

 

MED14166 is a fusion molecule of an antibody (a PCSK9 inhibitor) and a GLP-1RA. Administration to T2DM patients demonstrated dose-dependent PCSK9 inhibition, but GLP-1 activity was only achieved at the higher dose (EASD #114). This highlights the challenge of obtaining the optimal balance of effects in fusion molecules.

Imeglimin, a tetrahydrotriazine compound which improves both insulin secretion and insulin sensitivity, reduced the main liver enzymes, fasting glucose and HbA1c, in a Phase 2 study in T2DM patients. There was no reported hypoglycaemia and no change in body weight (EASD #843). The main tolerability issue was gastrointestinal side-effects at the highest drug dosage.

Pancreatic β-cells and entero-endocrine cells, including L-cells which produce GLP-1, express the G-protein coupled fatty acid receptors, GPR40 (FFAR1) and GPR119. A novel GPR40 agonist, HD-6277, improved metabolic control in diabetic rats (IDF P-0546; EASD #846), and a GPR119 agonist, DS 8500a, improved glycaemia and lipids in a Phase 2 study in T2DM patients (EASD #847).

Methionine aminopeptidase 2 (MetAP2) inhibitors reduce fat biosynthesis, increase fat oxidation and lipolysis and are associated with weight loss and reduced hunger. In a 28-day dose evaluation study subcutaneous injection of the MetAP2 inhibitor, ZGN-1061, significantly reduced body weight and tended to improve lipid parameters in 39 healthy subjects (EASD #850).

Diabetes prevention

Lifestyle strategies are key to diabetes prevention – but one size doesn’t fit all. A 1-year structured lifestyle programme in obese T2DM patients resulted in about one third losing >10% of their initial body weight and experiencing multiple metabolic benefits (EASD #762), while a workplace-delivered programme led to half of participants losing >5% of their initial body weight (EASD #327). However, a 1-year lifestyle intervention in Europe only delivered modest weight loss, but improved quality of life in several domains (EASD #313). In the ACE study, which reported at EASD (S15), addition of acarbose (50mg tid ) to the usual cardiovascular care of patients in China who also had impaired glucose tolerance did not reduce the risk of major cardiovascular events, but it did reduce the incidence of type 2 diabetes (p=0.005).17

References

  1. US FDA, December 2008. Guidance for Industry Diabetes Mellitus — Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes. Available at https://www.fda.gov/downloads/Drugs/Guidances/ucm071627.pdf [last accessed July 2018]
  2. European Medicines Agency. Committee for Medicinal Products for Human Use (CHMP). EMA May 2012. CPMP/EWP/1080/00 Rev. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC500129256.pdf
  3. Bailey AV, Day C. Clinical Pharmacist 2018;10:113-120.
  4. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998; 352; 854-65.
  5. EASD meeting 2017. Available at https://www.easd.org/virtualmeeting/home.html [last accessed July 2018]
  6. IDF congress 2017. Available at https://www.idf.org/our-activities/congress/programme-and-abstracts.html [last accessed July 2018]
  7. Campbell IW, Howlett HCS, Holman RR, Bailey CJ (eds). Metformin. 60 Years of Clinical Experience. Addendum to the Scientific Handbook. Weinheim, Germany: Wiley, 2017 (ISBN: 978-3-527-34449-9).
  8. Clifford Bailey and Sally Marshall. EASD 2017. Available at https://www.youtube.com/watch?v=SO73Z7aJyhw [last accessed April 2018]
  9. 60 years of metformin use: a glance at the past and a look to the future. Diabetologia. Special Issue, September 2017. Available at http://www.diabetologia-journal.org/webpages/metformin.html [last accessed July 2018]
  10. REMOVAL: a randomized controlled trial of metformin in adults with type 1 diabetes. Satellite symposim, Sunday 12 September, EASD, 2017. Available at https://www.easd.org/removal.html [last accessed July 2018]
  11. Petrie JR, Chatuverdi N, Ford I, et al, for the REMOVAL Study Group. Lancet 2017;5:597–609.
  12. Neal B, Perkovic V, Mahaffey KW et al for the CANVAS program collaborative group. New Engl J Med. 2017; 377:644-657.
  13. Dandona P, Mathieu C, Phillip M, et al. Lancet Diabetes Endocrinol 2017;5: 864–76.
  14. Holman RR, Bethel A, Mentz RJ et al. N Engl J Med 2017; 377:1228-1239 DOI: 10.1056/NEJMoa1612917
  15. Vaccaro O, Masulli M, Nicolucci A et al, for the Thiazolidinediones Or Sulfonylureas Cardiovascular Accidents Intervention Trial (TOSCA.IT) study group. Lancet Diabetes Endocrinol 2017;5:887-97.
  16. Lean MEJ, Leslie WS, Barnes AC et al. Lancet, 2018;391;541-51.
  17. Holman RR, Colemena RL, Chan JCN, et al. Lancet Diabetes Endocrinol. 2017; 5: 877-86.

Dr Mike Gwilt

GT Communications, Shrewsbury, UK mikegwilt@gtcomm.myzen.co.uk

Dr Caroline Day

School of Life and Health Sciences Aston University, Birmingham, UK