Assessment of Drug Therapy Problems Among Type 2 Diabetes Patients with Hypertension Comorbidity in Indonesia

Type 2 diabetes mellitus (T2DM) is a major chronic disease that affects a large number of people worldwide. Hypertension is a common disease comorbidity among T2DM patients, and often those patients received polypharmacy and complex treatment in long term duration. This condition may lead to an increased risk of drug therapy problems (DTPs). This study aimed to assess and determine potential drug therapy problems in type 2 diabetic patients with hypertension comorbidity. Retrospective cross-sectional design was conducted in a hospital setting, especially data sources from the prescription of ambulatory T2DM patients with hypertension. A total of 190 patients were studied. More than half of the participants were female (53.68%). The majority age range of participants was 50-59 years (46.84%). Almost all antidiabetic agents were prescribed as polypharmacy (73.16%). Metformin was the most antidiabetic agent prescribed as monotherapy and combination therapy (63.16%). Almost all antihypertensive agents were prescribed as polypharmacy (63.26%). Amlodipine was the most antihypertensive agent prescribed as monotherapy and combination therapy (34.74%). Among the study participants, 56.84% have at least one of DTPs. Adverse drug reaction was the most frequent (47.22%), followed by ineffective drug therapy (29.63%). Since the potential of DTPs in T2DM patients with hypertension comorbidity is relatively high, early identifying, resolving, and preventing drug therapy problems by the pharmacist is needed to achieve goals of treatment.


INTRODUCTION
Diabetes Mellitus (DM) has become a popular chronic disease worldwide. The prevalence of DM is 8.8% globally and 8.6% in Southeast Asia. It has been increasing rapidly in low-and middle-income countries (Dunning et al., 2014). Uncontrolled DM treatment is a serious problem that might be caused by microvascular and macrovascular complications (Chawla et al., 2016;Cade, 2008) and death (American Diabetes Association, 2015). Cardiovascular disease (CVD) is the leading cause of death in patients with diabetes mellitus (Benjamin et al., 2017). Health problems in many developing countries are in epidemiology transition where chronic Non-Communicable Diseases (NDCs) are major public health concerns due to the enormous financial burden associated with these diseases. Diabetes mellitus and hypertension were top the list of NDCs, these two chronic diseases are the most important risk factor for cardiovascular diseases (Bolarinwa et al., 2018).
Hypertension is the most common disease comorbidity with diabetes. The presence of hypertension with diabetes increases in mortality and drug therapy problems worldwide, with a greater risk in developing countries (Petrie et al., 2018;James et al., 2014).
Hypertension and type 2 diabetes mellitus (T2DM) called "lethal duo" which increases the risk of cardiovascular disease 2-to 4-fold over both diseases themselves, such as heart attack, stroke, ischemic heart disease, and microvascular complications (Farský et al., 2018).
Multiple medical conditions have been shown to contribute to drug therapy problems (DTPs) (Gangwar et al., 2014). Similarly, T2DM patients with hypertension often use polypharmacy medication and this may lead to the occurrence of drug therapy problems. Studies show that the number of DTPs per patient linearly increases with the increase in the number of medicines used (Abdulmalik et al., 2019).
In Indonesia, hypertension is a common comorbidity in T2DM patients. However, Indonesia has no adequate and comprehensive studies on DTPs, particularly among T2DM patients with hypertension comorbidity. The aims of this study are to determine pattern prescription of antidiabetic and antihypertensive agents, to assess the prevalence of potential drug therapy problems, and to identify determine of drug therapy problems among T2DM patients with hypertension comorbidity.  (Cipolle et al., 2012).

MATERIALS AND METHODS
This study was performed a descriptive analysis of demographic characteristics, pattern prescriptions antidiabetic and antihypertensive agents, as well as type and cause of DTPs.
These results were in the line with Zazuli et al. (2017) and Ayele et al. (2018) who reported majority T2DM patients with hypertension comorbidity were female and age range under 56 years old. Contrasting to Yimama et al. (2018) and Argaw et al. (2019) Table I   This drug is used for normotensive T2DM patients for albuminuria, retinopathy, and stroke prevention (Farský et al., 2018).

COVID-19
At present, in the condition of the pandemic novel coronavirus 2019 (COVID-19), diabetic comorbidities are one of the risk factors for hospitalization and death due to COVID-19. Diabetes was a comorbidity in 22% of nonsurvivors in a study of 52 intensive care patients . Other comorbidities such as hypertension in about 20% of cases, cardiovascular disease (16%), and lung disease (6%) are other common comorbidities (Ruan et al., 2020;Wu et al., 2020;Li et al., 2020). In fact, patients with T2DM are at high risk for infection and suffer severe symptoms of COVID-19, including bacterial pneumonia which can be reduced through good blood glucose control (Critchley et al., 2018). Basalbolus insulin or insulin pump therapy will be preferred in T2DM patients to avoid hyperglycemia and ketoacidosis. It also requires monitoring of blood glucose levels and setting insulin doses to prevent hypoglycemia (Apicella et al., 2020).
The other most common comorbidities in COVID-19 patients besides diabetes are hypertension. Both of these diseases are often treated with ACE inhibitors and ARBs.

COVID-19 binds to target cells via angiotensin-
converting enzyme 2 (ACE2) expressed in epithelial cells in the lungs, blood vessels, and in the intestine (Wan et al., 2020). Patients treated with ACE inhibitors and ARBs showed an increase in the number of ACE2 (Li et al., 2017). Therefore, there are two hypothetical drugs of choice in comorbid hypertension in  infections. Hypothesis by Fang et al. (2020)

Drug therapy problems
Among the participants, more than half of the participants (56.84%) have at least one of DTPs. The number of DTPs finding is lower than Yimama et al. (2018) and Shareef et al. (2015), where 82% and 71.1% of participants at least had one of DTPs, respectively. A total of 108 DTPs was identified across the six categories as presented in Table III. Adverse drug reaction was the highest 51 cases (47.22%), followed by ineffective drug therapy 32 cases (29.63%), unnecessary drug therapy 19 cases (17.6%), as well as need additional therapy, dose too low, and dose too high, each of them with two cases (1.85%). These study findings supported by Nazilah et al. (2017), Lira et al. (2017), andHartuti et al. (2019), which highlighted adverse drug reaction and drug interaction as most common DTPs occurred during polypharmacy treatment prescribed. Potential adverse drug reaction event in the combination of medications treatment higher than single medication treatment. This study contrasting to another study who reported the most common drug therapy problems was the need for additional drug therapy (Yimama et al., 2018;Argaw et al., 2019;Hussen et al., 2017). Percentage of DTP events in this study is visualized in Figure 1.  (Baxter, 2009). The possible drug interactions that occur are presented in Table IV. In this study, ineffective drug therapy (29.63%) and unnecessary drug therapy (17.60%) were the second and third most potential DTPs, respectively. Ineffective drug therapy was found in 32 T2DM patients with hypertension who received furosemide because the antihypertensive treatment might be involved in glucose tolerance. Meanwhile, the drug of choice for hypertension with diabetes based on guidelines recommends the use of ACE inhibitors or ARBs or nondihydropyridine CCBs (James et al., 2014). Unnecessary drug therapy in 10 patients who received antibiotics and nine patients received gastrointestinal drugs without clear indications. Need additional therapy, the dose is too low, and the dose is too high, each only 1.85% of the total DTPs. This insignificant amount might be due to the study being conducted in patients who were hospitalized, where there are better care and collaboration of health professionals with supervised drug administration. Because of the retrospective data source in this study, non-compliance with treatment was excluded to be assessed in this study.
There are several limitations to this study. First, this study is not from an evaluation of prospective structures or interviews with patients. Second, this study did not assess treatment compliance among T2DM patients with hypertension. However, this study has several advantages, including this research which is a pioneer in the study of DTPs assessment in T2DM patients with hypertension. Besides, this study proposes insights for the drug of choice in T2DM patients and hypertension who are infected with COVID-19.

CONCLUSION
This study highlights the majority of T2DM patients with comorbid hypertension who have at least one drug therapy problem that might have an impact on treatment goals and treatment costs. The role of pharmacists in drug management by detecting, preventing, and solving drug therapy problems can be encouraged to deal with these problems.