Based on the Scottish Diabetes Survey 20081, nearly 220,000 people (4.3% of the Scotland population) with diagnosed diabetes were registered on the National Health Service (NHS) boards and half of them were obese (body mass index ≥30 kg/m2). There is 0.3% of increment compared to year 2007 as the incidence of diabetes increases constantly every year. Reasons behind the increment are believed to be the aging problem, obesity, latest definition of diabetes with lower fasting blood glucose diabetic range, life extension due to better control of disease, improved identification in asymptomatic patients and better documentation with computer system1. Approximate 87% of people diagnosed diabetes was suffered from diabetes mellitus (DM), also known as type 2 diabetes or non-insulin dependent DM previously.
DM is defined by the World Health Organisation as constantly high blood glucose accompanied with the disrupted metabolism of nutrition caused by the faulty in the secretion of insulin, the activity of insulin or sometime both2. The control of blood sugar is regulated by insulin, an endogenous hormone. The equilibrium relationship between insulin secretion and insulin activity with normal function islet β cells is important to sustain the normal level of blood glucose3. Islet β cells malfunction reduces their sensitivity towards insulin activity, causes insulin resistance and thus retard the termination of hepatic glucose production. Besides that, in obese patients, insulin activity is found to be decreased causes the compensation by increasing β cells. Nonetheless, the blood glucose concentration is still elevated which then leads to glucose toxicity and causes β cell malfunction3. Therefore, the malfunction of islet β cells play vital role in the pathophysiology of DM. Long term untreated or uncontrolled DM can lead to many complications for example retinopathy, nephropathy, neuropathy, diabetic foot disease and also increase cardiovascular disease risk. The classic symptoms that present in people with diabetes are polyuria especially at night, dry mouth, visual disturbance, tiredness, prolonged wound healing and unidentified weight loss2. There are two ways to diagnose DM; if a person presented with symptoms and his/her blood glucose result that falls into the diabetic range (table 1), he/she is considered diabetic. However, in asymptomatic person, a minimum of two blood glucose results that falls into the diabetic range (preferably fasting blood glucose) taken at different day should be obtained before the diagnosis is made2.
Diabetic range (meet either one of the reading shown below)2:
• Random blood glucose concentration ≥11.1mmol/L
• A fasting blood glucose concentration ≥7.0mmol/L
• Post 2 hours blood glucose concentration ≥ 11.1mmol/L
[after 75g glucose load orally in an oral glucose tolerance test (OGTT)]
Table 1: Diabetic range that used in the diagnosis of DM
The main pharmacological treatments include insulin and insulin analogues as well as oral hypoglycaemic agents (OHAs) such as biguanides, sulphonylureas, thiazolidinediones, acarbose, meflitanides, exenatide, sitagliptin and vildagliptin. However, only insulin, biguanides and sulphonylureas will be further discussed as they are related to the case study.
Exogenous insulin is introduced to mimic the action of endogenous insulin in the blood circulation. It is commonly used and has enhanced glucose lowering effects in combination with OHA especially insulin sensitisers3. Sulphonylureas bind to the specific membrane receptors on the surface of islet ᵦ-cells then cause the blockade of adenosine-5V-triphosphate (ATP)-dependent K+ (KATP) channels4. This results the influx of calcium and thus stimulate the insulin secretion from the storage granules4. Overall, sulphonylureas could cause 1.5-2 % mean reduction in HbA1c with 3.3-3.9mmol/L mean fall in fasting blood glucose5. Gliclazide used in this case study is a short acting sulphonylurea that act specifically on the potassium channel at islet β cells and the binding is reversible4. On the other hand, metformin, the only used biguanide, is found to be inhibit the hepatic glucose production by induce the expression of small heterodimer partner (SHP) gene through the protein kinase activated by adenosine monophosphate(MOA)6. Besides that, metformin improve insulin sensitivity by promoting uptake of glucose into hepatic and muscle tissues which is useful in obesity patient5. However, metformin is not effective if there is no normal function islet β cell or no insulin available. The mean reduction of HbA1c by metformin is approximately 1.5-2% and 3.3-4.4mmol/L for fasting blood glucose5. Although both gliclazide and metformin are OHA, they have different glucose-lowering mechanism thus they are not used interchangeably.
According to the National Institute for Health and Clinical Excellence (NICE) guideline in the primary and secondary care for management of type 2 diabetes, when DM is not controlled by lifestyle modification, metformin monotherapy should be initiated in obese or overweight patient. In addition, metformin is also recommended as one of the first-line OHA choices besides sulphonylureas in normal weight patient by NICE7.
Based on the review by Cochrane by Saenz A at el.8, metformin has shown superior glucose-lowering effect and also other cardiovascular protective effects in 29 trials which have a total of 5259 patients. Metformin improved diabetes-linked consequences (P = 0.009) and reduced any-cause death (P = 0.03) compared to insulin or long acting sulphonylureas in strict management of blood glucose for obesity. Besides that, this review has compared the efficacy of metformin usage in obesity and other conventional treatment in overweight patients. Metformin has found to have significant improvement in diabetes-linked consequences (P = 0.004) and death (P = 0.03). The further proofs that support the initiation of metformin in obesity are metformin has excellent blood glucose control than restricted diet control and placebo as well as greater effect on blood glucose, lipid or weight control compared to sulphonylureas. Therefore, this review concluded that metformin should used in obese or overweight DM patients before consider other conventional OHAs.
Sulphonylureas is another choice in first line therapy if patient has normal weight and an alternative for patient who cannot tolerate or contra-indicated with the use of metformin7. The rationale for not using sulphonylureas in obese patients is sulphonylureas are known to cause weight gain. This might associate with the effect of sulphonylureas on appetite or metabolism of peripheral glucose9.
If the blood glucose is not well-controlled (HbA1c ≥ 6.5%) by metformin monotherapy even after dose titration until the maximum, an add-on therapy is required to achieve better control. Any OHA can be added into the monotherapy with appropriate dose adjustment. The addition of sulphonylureas into metformin monotherapy is the most commonly used and it is recommended by the NICE guideline. This recommendation is supported by the meta-analysis carried out by Monami at el.10 by comparing the efficacy of OHA that added into metformin monotherapy after monotherapy failed. They have identified 27 clinical trials which included 16 placebo-controlled studies and 11 direct comparisons between different drugs that combine with metformin (sulphonylureas, acarbose, thiazolidinediones, meglinides and glucagon-like peptide-1 agonist) in this review. The results of placebo-controlled studies showed significant decrease of the plasma HbA1c by sulphonylureas (0.85%), acarbose (0.61%) and thiazolidinediones (0.42%). However, when compared to placebo, the decrease of plasma HbA1c was significant better (P<0.05) in sulphonylureas-metformin instead of thiazolidinediones-metformin. Besides that, there were no significant differences between acarbose-metformin and sulphonylureas-metformin as well as between acarbose-metformin and thiazolidinediones-metformin. On the other hand, the result in direct comparisons between sulphonylureas-metformin and thiazolidinediones-metformin indicates that the efficacy of sulphonylureas-metformin in reducing the plasma HbA1c was significant greater (P < 0.05) than thiazolidinediones-metformin. Nonetheless, the efficacy of sulphonylureas-metformin was no significant difference than insulin-metformin. The combination of both results showed that sulphonylureas-metformin has the best reduction of plasma HbA1c.This review has concluded that there is a similar reduction in plasma HbA1c between sulphonylureas-metformin and acarbose-metformin and also suggested acarbose could be an option as an add-on therapy however there is no direct comparison of efficacy between acarbose-metformin and sulphonylureas-metformin and lack of standardise studies thus making this suggestion inappropriate yet.
In a randomised, double blinded, parallel group clinical trial was carried out by Ristic S at el.11 for 6 months to compare the efficacy between nateglinide-metformin and gliclazide-metformin in 262 DM patients where their blood glucose level are not controlled at the highest doses of metformin monotherapy. Both nateglinide and gliclazide are sulphonylureas and both combinations have shown significant baseline reduction of plasma HbA1c. There was no significant difference between both combinations even though gliclazide-metformin has better baseline reduction (0.57%) compared to nateglinide-metformin (0.41%). However, the postprandial insulin control was significantly better in nateglinide-metformin (P < 0.05). Another study was conducted by Tessier D at el.12 to compare the blood glucose control and the frequency of side effect particularly on hypoglycaemia between the long acting (glibenclamide) and short acting sulphonylureas (gliclazide). The results showed that the blood glucose controls in both groups were similar but hypoglycaemic events occurred significantly more in glibenclamide.
However, sulphonylureas is well-known to cause hypoglycaemia (blood glucose < 3 mmol/L). There is a short report by Ng JM at el.13 where 76 patients who experienced serious hypoglycaemia that required medical attention were examined to identify therapy that causes this problem. Although the majority (80%) was caused by insulin therapy, 15% of them were taking sulphonylureas either alone or in combination either with metformin, thiazolidinediones or insulin. Thus, among all the OHAs, sulphonylureas has greatest potential of causing hypoglycaemic. Therefore, NICE guideline suggested thiazolidinediones as the alternative in combination with metformin if the hypoglycaemia is troublesome in patient. A randomized, one year-double blinded trial has been carried out by Matthews at el.14 to compare the tolerability and efficacy between the metformin-pioglitazone (one of the thiazolidinediones) combination therapy and metformin-gliclazide combination therapy in uncontrolled DM. The results have shown that the efficacy of metformin-pioglitazone is not only similar compared to metformin-gliclazide but also well-tolerated and has extra benefits on lipid levels. In addition, another substudy carried out by Charbonnel at el.15 has shown 2 years improvement of blood glucose control and also suggested the capability of pioglitazone in lipid control. However, NICE advises on the chances of the development of oedema and prohibit the usage in proven heart failure or patient in greater fracture risk as well as to consider the latest recommendation by related regulatory agency, tolerability and cost matters.
The further step on treatment if DM is still not controlled (HbA1c ≥ 7.5% or depends on patient condition), is triple OHAs therapy (addition of thiazolidinediones) or add insulin into the current dual-therapy7. Exenatide can be used as alternative add on therapy if patient's body mass index > 35kg/m2 which causes some specific clinical problems and HbA1c still ≥ 7.5% after dual-therapy with conventional OHAs7. However, Exenatide is not licensed for routine use in DM yet as this is a recent OHA used. It also much more costly compared to older OHAs and has less knowledge about its side effects and efficacy. If triple OHAs therapy is used and the HbA1c still remains more than 7.5% or to achieve a better control, insulin-metformin-sulphonylureas combination with dose adjustment especially insulin due to the numerable regimes, is recommended in NICE guideline.
There are two studies on direct comparison of efficacy, safety15 and an addition parameter (quality of life) in one of the studies16 between insulin add on therapy and rosiglitazone (thiazolidinediones) add on therapy. The results of both studies has showed similar efficacy (has similar reduction in HbA1c form baseline) in blood glucose control however insulin triple therapy has showed better improvement (P < 0.05 compared to thiazolidinediones) when HbA1c ≥ 9.5% at baseline. Besides that, both studies preferred the insulin add on therapy as insulin also has greater reduction in fasting blood glucose (P = 0.001 compared to thiazolidinediones), little weight gain, no incidence of oedema, lower cost and beneficial lipid control as well as significant improvement in overall health-linked quality of life. The only downside of insulin in the studies was the incidence of hypoglycaemia is more frequent.
Besides that, if insulin therapy was to be initiated, NICE guideline has also suggested the continuous used of previous OHAs regardless mono- or dual-therapy. However, if hypoglycaemic events happen, metformin can still be continued but sulphonylureas shall be shopped immediately7. There is a study conducted by Chow CC at el.18 which involved the analysis of the effects, safety and quality of life between patients who were taking insulin therapy only and patients who used the combination of insulin with OHAs that have been used formerly. The results in this analysis showed that the blood glucose control both groups were similarly good. There were no significant difference between both groups on the reduction of fasting blood glucose, HbA1c and fructosamine. Besides that, there were no serious hypoglycaemic events and similar incidence of side effects occurred in both groups. Moreover, both groups showed well-tolerated and have significant improvement in quality of life. However, the combination of insulin with OHAs should be initiated first before switching to fully insulin therapy as the combination groups showed little weight gain and the mean insulin doses used were lower than insulin monotherapy to achieve the similar blood glucose control.
The sequence of therapeutic management of patient in this case study was inappropriate according to the algorithms recommended by NICE guideline. Although patient (obese) was on metformin previously before admitted to the hospital due to uncontrolled DM, insulin was initiated alone without the continuous used of metformin. A OHAs combination preferably metformin and sulphonylureas should be used first before the initiation of insulin and insulin should be used in conjunction with the metformin that has been used previously as suggested. However, insulin was only used for one day in this case to produce rapid fall of blood glucose. Metformin was restarted with the introduction of sulphonylureas. The addition of short acting sulphonylureas, gliclazide into metformin was a wise choice. As mentioned above, gliclazide has similar efficacy comparable with nateglinide (another type of insulin stimulator) but gliclazide is more cost-effective and has better compliance. Besides that, when gliclazide was compared with the long acting sulphonylureas (glibenclamide), gliclazide has favourable side effect profile especially less hypoglycaemic events. As a result, patient's DM was well controlled by the combination of metformin and gliclazide without the need to step up treatment.