Patient Mr. NCS is a 53 year old Chinese man with the height of 1.72m, and weighs 82kg where his BMI is 27.7kg/m2 (overweight). Patient runs his own business and is currently staying with his wife and 3 children. He claims that he does not smoke and does not drink at all. According to the patient, the paternal side of his family has family history of hypertension and kidney failure where else for the maternal side, hypertension was known to be the family history. Patient has no known drug or food allergy.

Patient was known to have had hypertension 15 years ago and also a history of pulmonary tuberculosis 35 years ago. Patient denied of being diagnosed with diabetes mellitus in the past. As for drug history, patient was only on 10mg of lovastatin (tablet) once at night and according to the patient, he was compliant to the medication.

1.2 Clinical Progress

Patient was admitted into Accident and Emergency department and complained of shortness of breath (SOB) and mild giddiness. He also complained of having chest pain and a first episode of shortness of breath earlier before he was admitted into the hospital. On examination, he was found to be alert and conscious. Venous blood gas sampling was done and pH was found to be 7.306 (low), pCO2 was 44.2mmHg, pO2 was 45.8mmHg and HCO3 was 24.7mmol/L. Blood pressure was found to be 157/95mmHg, pulse rate was 72bpm, SPO2 was 97%, body temperature was 35.4°C and respiratory rate was 21 breaths per minute. Reflo value was also obtained and it was found to be 17.1mmol/L and blood ketone was 0.9. Lungs were clear and abdominal was soft and non tender. Cardiovascular testing was done and it showed dual rhythm no murmur. The initial impression of this patient by the general practitioner in the hospital was impending diabetes ketoacidosis. Patient was immediately given 6 units Actrapid subcutaneously and the GP also planned to give O2 3L/min and to prescribe GTN 1/1 subcutaneously and Aspirin 1/1.

Later on day 1 of admission, patient complained of increased in sweating, shortness of breath, body weakness and vomiting for 3 times in the morning. Patient’s blood pressure was 123/76, pulse rate was 82bpm, SPO2 was 99% and respiratory rate was 20 breaths per minute. When patient was asked, he mentioned that he has not done body check up and blood pressure measurement for at least 5 years now. Later in the afternoon, patient complained of excessive sweating and lack of appetite for the past 3 days. Patient then denied of having any chest discomfort or shortness of breath, headache and abdominal pain. Besides that, patient also complained of having polyuria and needed to wake up more than 3 times at night for micturation. He also complained of having polydypsia, lethargic and vomiting for 2 times in the morning. Patient was examined and he was found to be alert and conscious where he responded fully to Glasgow Coma Scale (GCS). Patient was also found to have good hydration and his capillary refill time (CRT) was less than 2 seconds. Vital signs were obtained and temperature was back to normal, 37°C, blood pressure was 151/69, SPO2 was 97%, pulse rate was 88bpm and reflo value was 14.6. The management plan by the local GP was to continue monitoring the reflo value, prescribe 10mg lovastatin (tablet) once at night and 10mg amlodipine (tablet) once daily and have the patient to rest in bed. As patient was able to tolerate orally, IV drip was off and patient was allowed to take fluid orally.

On day 2, patient was found to be comfortable. However, patient complained of having poor oral intake and that he was sweating profusely. He was still feeling mild giddiness and lethargic but no more chest or abdominal pain. Vital signs were observed and temperature was 37°C, blood pressure was 128/84, pulse rate was 96bpm and reflo was 14.9mmol/L. Fundoscopy was also done and patient was found to not have any signs of retinopathy and chest X-ray was found to be clear. The management plan for day 2 was to continue 10mg amlodipine once daily, allow fluid intake orally, continue reflo monitoring 4 hourly and to trace and review the fasting blood sugar (FBS). On examination, patient was found to be alert and responded well to the GCS with the score of 15/15. Blood pressure was taken and it was 145/100 when patient was lying down and 130/90 when patient was standing. Renal profile was normal except for low potassium level of 3.0mmol/L. Impression for this patient was newly diagnosed diabetes mellitus.

Further management plan for this patient was to conduct a stress test on patient after discussing with the specialists and to monitor patient’s blood pressure for both lying down and standing up position 4 hourly for a day. Further plan was to start 500mg metformin (tablet) twice daily, 150mg aspirin (tablet) once daily, 20mg lovastatin (tablet) once at night, trace urine full examination microscopic examination and to refer the patient for diabetic counseling. Besides that, local GP also decided to off amlodipine and to change it to 4mg perindopril (tablet) once daily.

Table 1 : Patient’s laboratory findings on Day 2.

Sodium

129 mmol/L ↓ [135 – 145mmol/L]

Potassium

3.0 mmol/L [ 3.5 – 5.0mmol/L]

Creatinine

83 µmol/L [27 – 62 µmol/L]

Glucose fasting

14.1 mmol/L [3.9-5.0mmol/L]

Total Cholesterol

5.7

HDL

0.82

Triglycerides

6.7

AST

24 IU/I [10-37IU/I]

ALT

45 IU/I [10-65IU/I]

Bilirubin

11 µmol/L [2-24 µmol/L]

INR

1.03

Trop I

0.02

CKMB

0.5

Disease Overview and Pharmacological Basis of Drug Therapy.

Disease Background

The prevalence of diabetes mellitus (DM) varies vastly from population to population and throughout the whole wide world. In United Kingdom (UK) itself, diabetes prevalence increased from 2.8% in the year of 1996 to 4.3% in the year of 2005. The incidence of type 2 DM showed an increase from 2.60/1000 person-years in 1996 to 4.31/1000 person-years in 20059. As much as the incidence of DM is increasing, it was estimated that up to half a million more have not had their condition diagnosed and treated10.

Diabetes mellitus (DM) is a disorder in which blood glucose level is persistently above the normal range. This hyperglycaemia is thought to be due to either deficiency of insulin secretion or resistance to the action of insulin, or it could also be a combination of these6,7.

DM is classified into four different types which include Type 1 DM, Type 2 DM, DM due to specific mechanisms and diseases and lastly, gestational DM8. Only type 2 DM will be discussed further here. Type 2 DM is normally caused by a combination of insulin resistance and decreased insulin secretion to overcome the resistance. It is the more common form of DM and it comprises of approximately 90-95% of the total DM cases8. The common risk factors associated with type 2 DM include increasing age, high caloric intake, overweight, central adiposity and sedentary lifestyle8. In type 2 DM patients, insulin secretory peaks every 5-10 minutes seen in normal subjects are hardly or absolutely not seen. In normal cases, when intravenous glucose is administered into a human’s body, this will stimulate normal insulin secretion and is illustrated by a biphasic pattern, with an initial peak rising immediately 3-5 minutes after the administration, and lasted for 10 minutes, then followed by a deliberate and more progressive phase, which lasts throughout the glucose infusion period. In type 2 DM, initial phase insulin secretion is not seen and the late phase occurs later and to a lesser extent11.

For the diagnosis of DM, hyperglycaemia must be established before confirming that the patient has DM. “Persistent” hyperglycaemia needs to be confirmed and in order to do so, at least two plasma glucose measurements must be taken on separate days. There are three different types of plasma glucose test that can be used which include casual plasma glucose, fasting plasma glucose and oral glucose tolerance test (OGTT). According to WHO, there are three main criteria to be met to confirm diabetes in patients. The first would be symptoms of diabetes which include thirst, polydipsia, loss of weight and polyuria are seen in patients and their casual plasma glucose ≥ 11mmol/L. The other two would be if patient’s fasting plasma glucose ≥ 7.0mmol/L and patient’s 2-hours plasma glucose ≥ 11.1mmol/L during OGTT being conducted by giving the patient 75g of glucose load6. OGTT is the most effective test to detect glucose metabolism disorder where it assesses the rate of glucose excretion after administration of glucose. OGTT is strongly recommended when fasting blood glucose is within 7.0-7.8 mmol/L in the diabetic range where OGTT is practical to clarify the diagnosis6,8.

Summary of Drugs Pharmacology

Aspirin

Aspirin with the dose of 150mg is used as an anti-platelet agent or as prophylaxis to cardiovascular events. The mechanism of action of aspirin as an anti-platelet agent is strongly associated with the permanent inactivation of prostaglandin synthase and cyclooxygenase12. It also inhibits the formation of thromboxane in the platelet concurrently. The common side effects of aspirin include bronchospasm, gastrointestinal haemorrhage and also other forms of haemorrhage13.

Lovastatin

Statin reduces the risk of cardiovascular disease events without taking into account of the serum cholesterol concentration and is often used as the drug of first choice in the primary and secondary prevention of cardiovascular disease. The mechanism of action of statins involves competitive inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, which is the enzyme involved in the synthesis of cholesterol13. As liver is the major site of cholesterol biosynthesis, it appears to be the main target organ for the statins14. Statins can cause several muscular adverse effects which include myositis and other side effects include gastrointestinal disturbances, sleep disturbances, dizziness, paraesthesia, fatigue, sexual dysfunction and alopecia13.

Metformin

Metformin is so far the only biguanide available in the market now. It is an antihyperglycemic agent that improves glucose tolerance in patients with type 2 DM by decreasing both the intestinal absorption of glucose and the hepatic glucose production, and improves insulin sensitivity in the tissues. Metformin was also found to have potentially favourable effects on decreasing serum lipid levels and fibrinolytic activity15. Gastrointestinal side effects such as nausea, abdominal pain and diarrhoea are common with metformin and may persist in some patients13. Lactic acidosis due to metformin is rare, and the risk of this complication is higher in patients with renal impairment13,15.

Amlodipine

Amlodipine falls in the calcium channel blockers group which act by interfering with the inward entrance of calcium ions via slow channels present in the active cell membranes. They act mainly on the myocardial cells and the vascular smooth muscle cells which then lead to reduction of myocardial contractility. It affects both the electrical impulses and vascular tone within the heart where they may be depressed or diminished13.

2.2.5 Perindopril

Perindopril is an angiotensin converting enzyme (ACE) inhibitor where it acts by inhibiting the conversion of angiotensin I to angiotensin II. ACE inhibitors are the preferred initial drug to be used for hypertension13. ACE is the enzyme that converts angiotensin I to angiotensin II where angiotensin II causes increase blood pressure, systemic vasoconstriction, Na2+ and fluid retention and etc16. Thus, ACE inhibitors act by directly blocking the formation of angiotensin II and also increase the bradykinin level at the same time. This results in reduced vasoconstriction and increased vasodilation through the release of bradykinin. The common side effects of perindopril include profound hypotension, dry cough, angioedema, rash and gastrointestinal disturbances13.

Actrapid (Soluble Insulin)

Insulin plays an important role in the regulation of carbohydrate, protein and fat metabolism where it helps to increase the glucose utilization in human body. Actrapid, soluble insulin, is a short acting form of insulin where it is normally injected into patients 15 to 30 minutes pre-meal. Actrapid is normally given in emergency cases especially in patients suspected with diabetic ketoacidosis4. It is normally administered subcutaneously as it gives a rapid onset of action (30 to 60 minutes) and a longer duration of action of up to 8 hours. One of the potential problems of insulin is hypoglycaemia where patients can be advised on how to avoid it13.

2.2.7 Glyceryl Trinitrate (GTN)

Nitrate plays a key role in the prophylaxis and treatment of angina. It causes direct relaxation on vascular smooth muscles and also dilation of the coronary vessels which improves oxygen supply to the heart. Dilation of the blood vessels results in reduction of preload and afterload and thus, myocardial oxygen consumption is reduced17. Sublingual form of GTN is one of the most effective drugs to provide a fast symptomatic relief of chest pain but it is of short duration of action. Dose of 300mcg is appropriate as the starting dose for patients who have not used GTN before previously. Side effects of nitrates include postural hypotension, tachycardia, dizziness, throbbing headache and possible nausea, vomiting, flushing and heartburn13.

2.2.8 Oxygen

Oxygen is normally prescribed for patients experiencing hypoxia to raise the alveolar oxygen tension and to lessen the workload of breathing in patients. There are generally four types of oxygen therapy which include long term oxygen therapy, short burst oxygen therapy, emergency oxygen and ambulatory oxygen. It is commonly given in emergency cases to achieve oxygen saturation within the normal range, just like in this case. The administration of the correct oxygen concentration is important as inappropriate concentration of oxygen may result in serious or fatal outcomes13.

Evidence for Treatment of The Condition.

Metformin

Metformin is one of the main therapeutic drugs used in managing Type 2 DM and many clinical studies have been conducted to support the clinical use of metformin in the management of type 2 DM. In one of the Cochrane Review, it confirms that metformin as a single agent is one of the key therapeutic options for type 2 DM in patients with overweight or obesity problems, as it may prevent some cardiovascular complications events and mortality as well. Just as mentioned in this patient, he is a newly diagnosed diabetes patient who is overweight and he was given metformin 500 mg twice daily.

In the study, 29 trials with 5259 participants were included in the analysis, comparing metformin (2007 participants) with sulphonylureas (1167), placebo (702), diet (493), thiazolidinediones (132), insulin (439), meglitinides (208), and glucosidase inhibitors (111). Obese patients who are given metformin as blood glucose control agent showed a superior benefit than glibenclamide, chlorpropamide, or insulin for any diabetes-related consequences (P = 0.009), and for mortality (P = 0.03). Besides that, patients assigned to metformin as a single therapy showed a significant greater benefit for blood glucose control, weight, dyslipidaemia, and blood pressure18.

Besides that, the Comparative Outcomes Study of Metformin Intervention versus Conventional (COSMIC) study was done to compare the incidence of serious adverse effects, mortality and hospitalization in patients receiving metformin and also those who are on other usual care treatments. Among the patients, 7,227 of them received metformin and another 1,505 of the patients received usual care. To the end of the study, there were only 89.7% of the metformin group and 76.9% of the usual care group remained receiving their initial intended treatment. Serious adverse events were reported in 10.3% of the metformin group and in 11.0% of the usual care group, where both the groups reported similar adverse events. Cardiovascular events were found to be the most ordinary cause of death in DM patients where 0.7% occurred in metformin group while 0.9% in usual care group19.

A population-based cohort study was also done to study on the mortality rates with the use of sulphonylureas compared to metformin. The mean age of the patients was 66.3±13.4 years old where 43.4% were female and their mean length of follow-up was 4.6±2.1 years. A greater risk of mortality was observed with higher daily doses of the first-generation sulfonylureas and glyburide but not metformin20.

3.2 Insulin secretagogues (Sulphonylureas and Meglitinides)

Sulphonylureas is another group of antidiabetic treatment used after metformin in Type 2 DM. Patient’s blood glucose level remained high on day 2 and thus should be monitored closely after administering metformin. If blood glucose level has not been brought down, addition of sulphonylureas or meglitinides should be considered. The sulphonylureas act by enhancing insulin secretion. The sulphonylureas act at the pancreatic β-cell membrane by causing closing of ATP-sensitive potassium (K+) channels. Closure of the channels occurred when sulphonylurea binds to the sulphonylurea receptor (SUR) subunit of the K+ channel. Meglitinides, which is not a sulphonylurea, act through the same mechanism where it also binds at the sulphonylurea binding site. Examples of sulphonylureas include tolbutamide, gliclazide, glibenclamide and glimepiride. Meglitinides is referred as an alternative to sulphonylureas as it does not cause additional stimulation of insulin excretion when patient failed to respond to maximal dosage of sulphonylureas. Examples of meglitinides include repaglinide and nateglinide21.

Adding on a sulphonylurea or meglitinide to metformin as a therapy to type 2 DM was found to have a better control of blood glucose level. 318 patients (61 from metformin group, 126 from glimepiride group and 131 from glimepiride + metformin group) completed the study to compare the effectiveness of metformin monotherapy, glimepiride monotherapy and the combination treatment in controlling blood glucose level. It was found that the greater efficacy of combination treatment in reducing HbA1c levels than either glimepiride alone (p < 0.001) or metformin alone (p < 0.001) was significant. However, there was no significant difference between metformin or glimepiride monotherapy in reducing HbA1c levels (p = 0.369). It was also found that combination treatment was also significantly better than either of the monotherapy in reducing fasting blood glucose (FBG) (p < 0.001) and postprandial plasma glucose (PPG) (p < 0.001)22.

Comparison was conducted in a study where 124 patients were randomly given either repaglinide 1 mg daily or glimepiride 1 mg daily. The dose of study drug was given over an 8 week titration duration, which then followed by a 12 months treatment length. FPG levels, HbAlc values and PPG levels significantly fall from baseline in both groups after 6 and 12 months of treatment. However, after 12 months, fasting plasma insulin (FPI) levels on the other hand were significantly increased in the repaglinide group (p < 0.05) while no significant changes were observed in the glimepiride group. Lipid levels were also observed and at 12 months, lipid levels were significantly decreased from baseline in both the groups (repaglinide [p<0.05], glimepiride [p<0.01])23.

So far, the most commonly reported adverse event in sulphonylureas was hypoglycaemia. 605 people over 34,052 person-years were diagnosed with hypoglycemia during sulphonylurea therapy, which equals to an annual risk of 1.8%24. There is also high risk of hypoglycaemia in diabetic patients who are taking ACE inhibitors at the same time. Therefore, the use of sulphonylureas in this patient should be used in caution as he is currently taking perindopril as his anti-hypertensive drug. Several studies suggested that there is an increase in mortality due to cardiac events in patients treated with sulphonylureas. In one of the studies, 120, 4138 and 1537 patients were given a first-generation sulfonylurea, glyburide monotherapy and metformin monotherapy respectively. 24.8% of the total deaths were found to be due to an acute ischaemic event. Those given first-generation sulfonylurea monotherapy had the highest mortality (67.6 deaths per 1000 person-years), compared with metformin monotherapy users (39.6 deaths per 1000 person-years). As higher doses are used, higher rates of death are observed as compared to those who are on lower doses20.

Other less common side effects of sulphonylureas include weight gain, nausea, diarrhoea, gastrointestinal pain and cutaneous reactions such as rashes, urticaria and pruritus21.

Further Management

Thiazolidinediones, gliptins (GLP-1) mimetic, also known as exenatide and insulin administrations are the further management in type 2 DM if the above oral anti-diabetic agents are not able to control the high blood glucose level.

Pioglitazone and rosiglitazone are examples of thiazolidinediones where they are the newer oral anti-diabetic agents which are more expensive but present better adverse effects profiles. A thiazolidinedione can be added on instead of a sulfonylurea as second-line therapy if sulphonylurea is contraindicated or not well tolerated or it can be added on to the sulphonylurea therapy if metformin is contraindicated. Another recommendation is to add on a thiazolidinedione to metformin plus sulphonylurea when the blood glucose is not well controlled and the use of insulin therapy is not suitable25. Two randomised trials were conducted and in the first study, 317 patients who are already on metformin received an add-on therapy of pioglitazone at the dose 15-45 mg/day and another 313 patients received gliclazide at the dose 80-320 mg/day instead. In the second study, 319 patients who are already on sulphonylurea therapy were randomly assigned to receive add-on therapy of pioglitazone at the dose 15-45 mg/day and another 320 with metformin at the dose of 850-2,550 mg/day. After 2 years, the mean reduction in HbA1c from baseline was found to be 0.89% for pioglitazone and 0.77% for gliclazide addition to metformin. The reduction in mean FBG after 2 years was statistically significant between the two add-on therapies where a decrease of 1.8 mmol/L for pioglitazone and a decrease of 1.1 mmol/L for gliclazide was seen (p<0.001)26.

Another option is adding on a GLP-1 mimetic agent as third-line therapy to first-line metformin and a second-line sulfonylurea25. Effectiveness of exenatides in bringing down the blood glucose level in type 2 DM patients was extensively studied. One of the studies includes patients at the age of 22-76 years old and had type 2 DM treated with at least the maximally effective dose of a sulfonylurea as monotherapy for at least 3 months. After a 4 weeks single-blind, placebo period, 377 patients were randomized (60% men, age 55±11 years, BMI 33±6 kg/m2, HbA1c 8.6±1.2%) and began either at 5 µg subcutaneous exenatide twice daily(before breakfast and dinner; arms A and B) or placebo for 4 weeks. Patients in arm B were then increased to 10 µg bd of exenatide. At week 30, HbA1c changes from baseline were -0.86±0.11, -0.46±0.12, and 0.12±0.09% (±SE) in the 10-µg, 5-µg, and placebo arms respectively (p ≤ 0.001). FPG values also showed a significant reduction in the 10-µg arm compared to the placebo arm (P ≤ 0.05) 28.

If all else fails to control blood glucose, insulin therapy should be introduced in patients with poorly controlled type 2 DM. It was believed that there is possibility that the oral anti-diabetic agents mentioned above might be useful in combination with insulin therapy in enhancing better blood glucose control, reducing insulin dose requirement, or minimizing side effects of insulin therapy. A study was conducted to compare the efficacy of adding once-daily basal insulin with switching to twice-daily premixed insulin in type 2 DM patients uncontrolled by oral anti-diabetic agents (OADs). It was a 24 weeks period clinical trial where 371 patients with poor glycaemic control (FBG ≥120 mg/dl, HbA1c 7.5-10.5%) were randomized to once-daily morning insulin glargine plus glimepiride and metformin or to only 30% regular/70% human NPH insulin (70/30) twice daily without any OADs. It was found that mean HbA1c decrease from baseline was significantly better in the presence of OADs than the one without OADs (p = 0.0003). More patients reached HbA1c ≤7.0% without confirmed nocturnal hypoglycemia (45.5 vs. 28.6%, p = 0.0013) with glargine plus OAD than with only 70/30 NPH insulin. In addition, decrease in FPG was greater with glargine plus OAD (p < 0.0001), and more patients reached target FBG of less than 100 mg/dl (31.6 vs. 15.0%, p = 0.0001) with glargine plus OAD than with 70/30. Besides that, patients on glargine plus OADs also had fewer confirmed hypoglycemic episodes than those patients taking only 70/30 NPh insulin (p < 0.0001)29.

Conclusion

In this patient, he was newly diagnosed with type 2 DM and was given metformin 500mg twice daily initially to control his high blood glucose level, which was appropriate according to the guideline. If blood glucose is still not well controlled, changing of medication or further management as above should be considered. As hypertension and overweight are risk factors of DM, hypertension should be well managed in this patient and the patient should be advised on complying with his medication. Besides that, patient should also be advised on healthy diet and lifestyle to control his weight.