Type 2 Diabetes Mellitus: A Review

Type 2 Diabetes Mellitus: A Review


Type 2 diabetes (T2DM) is a complex metabolic disease which can be life threatening if not managed optimally. It has a high prevalence of co-morbidities such as; hypertension, dyslipidaemia, obesity as well as its metabolic implications. It’s not surprising to say that T2DM has reached an epidemic globally as mentioned by Zimmet (2003), so the need to understand the effective management and wider implications of poor glycaemic management in T2DM is essential to improving the quality of life for patients. This review will discuss the multitude of approaches used to manage blood glucose levels in T2DM patients and will also critically appraise past and present research relevant to T2DM management today and briefly discuss emerging medical therapies that may become the cornerstone of treatment in the future. The key focus will revolve around discussing glycaemic management.

T2DM is managed entirely by medical intervention through the use of pharmacological agents, patient self-management, dietary measures and exercise (Molitch, 2013), (Ripsin, 2009), (Levesque, 2011), and (NICE, 2009). However, research shows that surgical intervention has its place in managing hyperglycaemia and a means to a state of remission according to Dixon (2011).
Insulin resistance, reduced insulin secretion and elevated hepatic glucose output are the hallmarks of T2DM. Therefore, the main management principles revolve around controlling hyperglycaemia. Hyperglycaemia is defined as 6.5 percent A1C or above (NICE, 2009). Currently, there is a huge pharmacological armamentarium of treatment options for T2DM which forms part of standard therapy. There are several well-known oral anti-hyperglycaemic agents (OHA) available for aiding glycaemic control. The first of them Metformin (biguanides), secondly; Sulphonylureas (SU), thirdly; Meglitinides, fourthly; Thiazolodinediones (TZDs), fifthly; Alpha-glucosidase inhibitors, sixthly; Dipeptidyl peptidase-4 inhibitors (DPP4i), seventhly; Glucogon-like peptide-1 agonists (GLP-1) as stated by Molitch (2003). These clinical agents are used in a stepwise manner to achieve glycaemic control as explained by Ripsin (2009), (NICE, 2009), and (Molitch, 2003). Typically metformin monotherapy is initiated as a first line for patients who are overweight without contraindications. Conversely, SUs may be initiated first line as monotherapy where marked hyperglycaemic symptoms present in the non-obese patient. Thereafter, combinations of metformin with SUs can be used and where inadequate glycaemic control is observed additional agents such as TZDs, DPP4is, GLP-1 agonists and insulin can be added in a stepwise approach in a bid to achieve optimal glycaemic control (Molitch 2003; Ripsin 2009; NICE 2009; Levesque 2011). Despite the currently available treatment options Molitch (2003) states that glycaemic control remains poor. There are several reasons for sub-optimal glycaemic control including; clinical inertia, financial issues, cultural issues, patient beliefs, adverse effects associated with pharmacotherapy and the individuality of patient management (Molitch, 2003) and (Weller, 2013). However, Ripsin (2009) argues that each of the mentioned pharmacotherapies reduce A1C by 0.5 to 2.5 percent and with that in mind a further question is to be asked as to why then does inadequate hyperglycaemic control exist in patients and what can be done to tackle this issue? It may be suggestive of beta cell failure or reduced number of functioning beta cells resulting in decreased levels of insulin systemically coupled with increased insulin resistance as the disease process progresses. With this in mind it seems that insulin treatment is essentially delayed either by the physician due to personal beliefs and risk of hypoglycaemia or the patient due to personal and/or social circumstances.

Following on from standard treatment of T2DM there has been significant research on the effects of intensive management of glycaemic control. Ray (2009) and colleagues conducted one of the largest meta-analyses. They found that a decrease in HbA1C from 7.5% – 6.6% (0.9%) was associated with a reduction in myocardial infarction events (non-fatal) by 17%, stroke risk reduction, coronary events reduced by 15% and no heterogeneity was observed. There was no significant difference between standard and intensive regimes on mortality and heart failure (Ray, 2009). Boussageon (2011) also found that intensive glucose lowering resulted in improved microalbuminuria, a reduction in the progression of retinopathy thereby showing positive outcomes on microvascular end points. The ACCORD trial results showed that intensive management led to increased hypoglycaemic attacks and all cause mortality (Riddle, 2010). One of the reasons for an increase in all cause mortality is due to patients HbA1C remaining > 7%. Patients in the intensive arm of the trial were switched to the standard arm and this will of course have negative effects on outcomes data due to change in study design part way through the trial. Major hyperglycaemia is associated with cardiac ischaemia or arrhythmia secondary to catecholamine secretion. This could be the causal factor related to increased mortality and more research needs to be done to answer this question. (Preiss 2011; Riddle 2010; Gerstein 2008).

The management of T2DM discussed thus far have been with current treatments. Newer, novel and emerging agents shed a promising light on the future management of T2DM with several drugs currently under study and one pharmacological agent which has been made available recently; these are 11β-HSD-1 inhibitors, GP inhibitors (Glycogen Phosphorylase), PTP-1B inhibitors (Protein Tyorsine Phosphatase), GK activators (GlucoKinase) and GPR119 agonists (G-Protein Receptor), and finally SGLT-2 inhibitors (Sodium Glucose Transporter) which are currently prescribable. Newer agents that are currently being studied take a metabolic approach to managing A1C as opposed to directly manipulating glycaemic levels. Glucose homeostasis involves three organs; the liver, pancreas and kidney (DeFronzo, 2012). This leads to the use of SGLT-2 inhibitors which manipulate the sodium glucose transporter pathway to prevent the reabsorption of glucose which equates to 90% excreted in the kidneys Rochester (2014). Canagliflozin and Dapagliflozin are available in Europe and USA for prescribing. An RCT (Randomised Controlled Trial), double blind, placebo-controlled, 52 week trial conducted by Wilding (2013) looked at adding in SGLT-2 inhibitors as a third line after maximal doses of metformin and SUs had been prescribed. They observed an A1C reduction of -0.85% – 1.06% at 26 weeks from baseline on 100mg to 300mg of canagliflozin, this trend was maintained to the 52nd week compared to placebo (Rochester, 2014). From an adverse effects view point the main concern was an increased incidence of genital mycotic infections, the most important point being that the infections were treated successfully without treatment interruption (Wilding, 2013). Also canagliflozin showed superior A1C reduction (-1.03% vs -0.66%) when compared with sitagliptin in an RCT which had similar inclusion criteria to the previously mentioned study (Wilding, 2014). Another vital observation was the increased achievement of A1C <7% in the canagliflozin group when compared to the sitagliptin group (Schernthaner, 2013). Dapagliflozin as monotherapy was not superior to metformin but when combined showed an extensive reduction in A1C making it a worthwhile option for the T2DM patient (Henry, 2012). From a safety perspective side effects were similar to canagliflozin. When there is a reluctance to initiate insulin based on clinical or social grounds and when poor glycaemic control is maintained despite intervention with standard pharmacotherapy agents SGLT-2 inhibitors are a definite 2nd or 3rd line option and have proven efficacy and existing safety data. Because high levels of glucocorticoids in systemic circulation have been linked hyperglycaemia (CDC, 2011). Two isozymes of 11β-HSD are responsible for inactivating and storing cortisol as cortisone and vice versa. 11β-HSD-1 activates inactive cortisone to active cortisol and 11β-HSD-2 works antagonistically thereby inactivates circulating cortisol by converting it cortisone and storing it in adipocytes. (CDC 2011 and St-Pierre 2012). Research on white mice suggests that inhibiting 11β-HSD-1 is the key to reducing central obesity, insulin resistance and hyperglycaemia because 11β-HSD-1 expression shows a clear link to formation of central obesity and insulin resistance leading to a hyperglycaemic metabolic state. Administering 11β-HSD-1 inhibitors to T2DM patients for two weeks has shown a lower fasting plasma glucose, in clinical studies (Rosenstock, 2010). Rosenstock (2010) observed a reduced A1C of -0.38% – -0.47% on 100 or 200mg groups on INCB13739. A greater A1C reduction was seen in obese patients and those with an A1C >8%. Rosenstock (2010) also made an important observation which included good safety outcomes and dose dependent statistically significant Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) reduction. This suggested that the INCB13739 200mg triggered an insulin sensitising mechanism of action and therefore needs further study to examine its therapeutic effect in T2DM patients (Rosenstock, 2010). GP inhibitors are being studied for potential use in T2DM patients. GP inhibitors work by inhibiting the breakdown of glycogen from the liver thereby reducing glucose levels in the circulation. Studies in white mice have shown positive outcomes in reducing hyperglycaemia (Martin, 1998). However, concerns exist with regards to intense exercise and inhibition of glycogenolysis due to one of the GP analogues studied (CP-316819-A) which lacks hepatic specifity and therefore may effect skeletal muscle especially during intense exercise. Baker (2005) argues that these concerns are unfounded in his study with rats, even when skeletal muscle effects were exhibited clearly. More work needs to be done on this potential class of agents from a safety view point, despite Baker’s (2005) claims. PTP-1B inhibitors are another class of agents being studied to gauge their suitability for use in T2DM and obesity patients. By suppressing leptin signalling via PTP-1B inhibition it is hoped that leptin manipulation will lead to increased energy release, food intake suppression, and increased insulin receptor sensitivity thereby reducing hyperglycaemia. This was observed in diabetes mice but not in humans as of yet. Further preclinical studies are needed for safety before proceeding to human subjects (Johnson 2002 and Chen 2013). G-Protein-coupled receptor 119 (GPR119) has been studied and as a consequence shows clear involvement in glucose homeostasis. The location of GPR119 is primarily in the Islets of Langerhans (Soga 2005; Bonini 2002; Chu 2008). GPR119 activation has shown release of insulin from the beta-cells of the pancreas. Likewise, it causes the release of GLP-1 and glucose-dependent insulinotropic peptide from the intestinal tract (Soga 2005; Bonini 2002; Chu 2008). Strikingly, several studies have failed to show any beneficial end points (glycaemic lowering) due to the loss of pharmacological effect of several related agents of GPR119 (Kang, 2013). The lack of end points observed with this class of agents in preclinical and early clinical trials have been poor and therefore further study and manipulation of GPR119 is needed to present a plausible, effective and safe related therapeutic agent that has a sustained clinical effect to be of any real benefit. Finally, Glucokinase activators (GKAs) have shown to lower glucose in preclinical and early clinical trials (Meininger, 2011). The role of GKA is impaired in patients with T2DM and therefore is an essential enzyme in glucose regulation and is responsible for glucose stimulated insulin secretion, regulation of glucose metabolism; gluconeogenesis, glycolysis, and glycogen synthesis, glucose oxidation and lipogensis as stated by Matschinsky (2011). GK is heavily involved in the major processes of hepatoglucose regulation. Unfortunately clinical trials studies in diabetes have been stopped prematurely due to side effects such as hyperlipidaemia, vascular hypertension and total therapy failure as highlighted by Meininger (2011). Further manipulation of GKA molecules are required to rid the side effects which have been observed in studies. GKAs raise blood pressure and lipids and are currently counterproductive in the management of T2DM despite effective glycaemic control. Standard treatments currently are more advantageous from an efficacy, safety and outcomes perspective due to their long standing experience of use in the clinical community. Although, newer emerging therapies that have been discussed are promising and shed a light on future management of diabetes there is a long way to go before they are seen in wide clinical use. There is no doubt that newly studied therapies will shape the future management of T2DM.
A not so obvious treatment that has shown positive results when used in T2DM patients particularly with obesities, is Laparoscopic Adjustable Gastric Banding (LAGB). LAGB has shown to reduce weight and achieve a state of remission in the hyperglycaemic T2DM patient. However, surgical intervention with LAGB has shown downward trends as time progresses as stated by Dixon (2011). Even though the initial impact and up to 2 years post LAGB show reduction of A1C from 7.8% to 6.2% the state of remission is time dependent, there is no obvious explanation for this and was put down to the progression of diabetes by Dixon (2011). Dixon (2011) also states the omissions of clearly defined sets of criteria for classing patients as remitted or not. He admits the lack of reporting of HbA1c values in the studies that he has reported on. Without HbA1c values it is hard to make a comparison positive or negative outcomes from a statistical viewpoint. From the data presented positive outcomes are clear in the first 24 months, thereafter remission subsides according to Dixon (2011). Dixon (2011) claims that LAGB are the safest of the bariatric surgical procedures but fails to mention pre and post-surgical risks to patients regardless of how small a surgical procedure may be. In summary, LAGB generally showed positive results but costs outweigh any potential for use in standard clinical practice as part of mainstream treatment.

Self-management of diabetes is imperative, a concept which is a chief player in the overall management of diabetes because it’s entirely in the control of patients. Educating patients and physicians alike is important in bridging the differences in knowledge when comparing patients to physicians. Weller (2012) concluded that the disparity between physician and patient beliefs of diabetes exists and this no doubt is a factor that could lead to sub-optimal glycaemic control (Weller, 2012). Weller (2012) discovered that congruence of beliefs between Mexican patients and physicians led to improved glycaemic control and selfmanagement practices. Comparing these findings to a multi-cultural city such as Bradford/Leeds in England, United Kingdom isn’t the same, this is due to physicians being exposed to languages other than the native language. Personal observations on a series of patients during level 1 diabetic reviews in Asian patients has shown failed consultations simply due to language barriers and practitioners poor understanding of patients cultures, lifestyle and background. No doubt, this is clear treatment failure and often results in elevated glycaemia with poor outcomes. More work needs to be done to improve patients understanding of diabetes to bring it line with true evidence based views of the condition. Perhaps, creating education centres in England specifically designed to school new diagnoses may pave the way for robust selfmanagement (Forjuoh, 2014), delayed microvascular and macrovascular disease and a reduction in economic impact of managing diabetes complications. In America The Chronic Disease Self-Management Programme (CDSMP) created by Stanford University has shown improvements in chronic disease but a more specific programme for T2DM needs to be investigated to see if observable evidence exists to show improvement of micro and macrovascular end-points (Brady 2011; Barlow 2005; Kennedy 2007; Goeppinger 2007; Lorig 2013; Ory 2013; Altman 2001; Forjuoh 2014; Sevick 2007). A recent RCT, double blind, 24 week study looked in to methods of improving glycaemic control through self-management namely, exercising using a computer console (Wii Fit Plus®) in middle-aged to elderly patients (Kempf and Martin, 2013). Important observations were made and this included a decrease in A1C levels in the intervention arm from 7.1% to 6.8% A1C while no significant reduction was seen in the control arm 6.8% to 6.7% A1C (Kempf and Martin, 2013). The intervention arm reached a goal of A1C <7% (+9% increase) from baseline (Kempf and Martin, 2013). This study by Kempf and Martin (2013) did not test the actual effect of physical exercise on glucometabolic control rather a test of general improvement in A1C, exercise activity and weight loss was tested. A systematic review that supports Kempf and Martin’s (2013) study shows that lifestyle interventions in the elderly improve general health.

The economic impact of T2DM places an enormous burden on health systems. Marx (2013) explains that the economic burden on the US health system is set to increase in the next couple of decades as prevalence increases and this will effect healthcare costs proportionally. The same could be said for countries with large T2DM populations and prevalence data. Further implications suggested by Marx (2013) are directed at costs related to medical errors, non-adherence and possibly avoidable ADRs. It’s arguable that good prescribing practice can largely rule out ADRs and medical errors but non-adherence is a challenge for clinicians because it’s directly in the control of the patient and as mentioned previously aligning beliefs and demystifying pre-conceptions are vital in delivering cost-effective healthcare and improving patients’ quality of life.

In conclusion T2DM is a complex disease and the management of hyperglycaemia is complicated due to the individuality of care required for each patient. Despite the huge treatment options from a medical management viewpoint, currently, T2DM patients are not reaching sufficient A1C goals and for this reason the microvascular and macrovascular progression of disease is manifesting much earlier than expected than with an otherwise well controlled T2DM patient. Current therapies are adequate in maintaining normoglycaemia in patients but there are clear limitations in the reduction of A1C from baseline. Contraindications and side effects such as major or frequent minor hypoglycaemic attacks are all a precursor for poor management, poor adherence and concordance to pharmacotherapies which are the mainstay of treatment. Patients beliefs are important and a major factor in successful management of T2DM owing to the huge importance of self-management in this condition. Therefore, patient education is a key factor into closing the gap between patient and physician knowledge of the management of diabetes mellitus. The way forward for successful hyperglycaemic management is by the manipulation of metabolic homeostatic mechanisms particularly glucose homeostasis through emerging treatments previously mentioned which are currently under investigation rather than direct manipulation of pancreatic cells, cortisone manipulation in adipose tissues by manipulating 11β-HSD-1 inhibition and reducing central obesity via bariatric surgery such as LAGB are a promising find that should be included in the routine management of the T2DM patient.

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