Systematic Review: Drug Interactions in the Treatment of

Hypertension with Diabetes Mellitus

Sofia Ngarso and Diana Laila Ramatillah

Faculty Pharmacy, University 17 August 1945 Jakarta, Jl. Sunter Permai Raya, Jakarta 14350, Indonesia

Keywords: Diabetes Mellitus, Drug, Hypertension, Interactions.

Abstract: Hypertension and diabetes are degenerative diseases that can cause a decrease in the body's physiological

functions. Regular monitoring of blood pressure and blood sugar levels, along with consistent treatment, can

help reduce physical complaints. However, it is important to be aware of potential drug interactions that may

affect the effectiveness of treatment and cause unwanted side effects. The objective of this study was to

evaluate drug interactions in the treatment of hypertension and diabetes mellitus. A systematic review was

conducted following the PRISMA (Preferred Reporting Items for Systematic Review) guidelines. Relevant

published articles were searched for to investigate the use and interactions of drugs in patients with

hypertension and diabetes. The literature search was conducted between July and August 2023 using Google

Scholar, National Library of Medicine, and Public Health Reviews. The results show that commonly used

treatments for hypertensive patients with diabetes mellitus include Amlodipine-Metformin, Furosemide-

Metformin, Captopril-Glimepiride, and Captopril-Metformin. It is important to note that the interaction of

various drugs can increase the risk of health problems and drug-drug interactions. The literature review's

conclusion highlights the significance of evaluating drug interactions in treating hypertension and diabetes

mellitus to ensure effective and appropriate treatment.

INTRODUCTION

Diabetes mellitus and hypertension are degenerative

diseases caused by various factors, such as age,

oxidative stress, and lifestyle, that lead to a decrease

in the body's physiological functions (Madania et al.,

2022). The prevalence of hypertension or high blood

pressure accompanied by complications of diabetes

mellitus, often referred to as the 'Silent Killer,'

continues to increase every year (Rosyadi, 2022).

The World Health Organization (WHO) reports

that 1.28 billion adults aged 30 to 79 worldwide suffer

from hypertension, with two-thirds of them residing

in low or middle income countries (WHO, 2023). The

number of people affected by hypertension continues

to rise annually across the globe. By 2025, it is

projected that 1.5 billion people will suffer from

hypertension, and 9.4 million people will die from

hypertension-related complications each year (Ganga

et al., 2022). In 2019, Paraguay, Dominican Republic,

Dominica, Argentina, Grenada, Jamaica, Saint Kitts

and Nevis, and Brazil had the highest prevalence of

hypertension, with rates exceeding 45% (PAHO,

2023). In 2018, Indonesia joined the list of Southeast

Asian countries with the highest incidence of

hypertension, affecting 34.1% of the population

(Pulungan et al., 2022).Hypertension is the

occurrence of increased blood pressure which is

characterized by systolic blood pressure >140 mmHg

and diastolic blood pressure >90 mmHg, where

symptoms can vary for each individual.

The most common symptoms of hypertension

include headache or heaviness in the nape of the neck,

vertigo, heart palpitations, fatigue, blurred vision,

tinnitus, and nosebleeds (Nurlinda et al., 2022).

Hypertension can lead to comorbidities, such as

diabetes mellitus, due to shared trigger factors like

diet, lack of physical activity, and impaired insulin

production in diabetes sufferers, which directly affect

blood pressure (Wati et al., 2021). Hypertension in

diabetes patients is caused by high blood glucose

levels, which lead to intravascular fluid resistance and

an increase in body fluid volume. Additionally,

damage to the vascular system increases peripheral

arterial resistance, resulting in hypertension

(Rasdianah & Pakaya, 2023).

Regular control of blood pressure and blood sugar

is necessary to reduce physical complaints, and

Ngarso, S. and Ramatillah, D.

Systematic Review: Dr ug Interactions in the Treatment of Hypertension with Diabetes Mellitus.

DOI: 10.5220/0012643000003821

Paper published under CC license (CC BY-NC-ND 4.0)

In Proceedings of the 4th International Seminar and Call for Paper (ISCP UTA ’45 JAKARTA 2023), pages 257-264

ISBN: 978-989-758-691-0; ISSN: 2828-853X

257

patients should undergo regular treatment

(Simanjuntak & Amazihono, 2023). The treatment

options for oral diabetes and hypertension include

Amlodipine-Metformin, Furosemide-Metformin,

Captopril-Glimepiride, and Captopril-Metformin

(Retnowati & Renha Lestari, 2022). It is important to

note that drug interactions can lead to unsuccessful

treatment of diabetes mellitus and increased blood

pressure. When patients take multiple medications,

treatment failure is a common problem that can lead

to increased toxicity or decreased efficacy of

concurrent medications (Abdulkadir et al., 2023).

Additionally, the use of multiple drugs increases the

risk of health problems and drug-drug interactions

(DDIs) (Madania et al., 2022). Drug interactions can

be a significant issue that affects patient clinical

outcomes. With the complexity of drugs used in

current treatments and the tendency for

polypharmacy to occur, the possibility of drug

interactions is increasing (Susanti, 2021).

METHODS

A systematic review was conducted to search for

published articles on drug use and drug interactions

in the treatment of hypertension and diabetes

mellitus. The search strategy involved using online

database facilities such as Google Scholar, National

Library of Medicine, and Public Health Reviews. The

search was limited to the years 2019 to 2023 and

included Public Health Reviews and the National

Library of Medicine. Researchers searched

international and national journals using the

keywords 'Drug Interactions in the Treatment of

Hypertension with Diabetes Mellitus' and 'Drug Use

and Drug Interactions in the Treatment of

Hypertension with Diabetes Mellitus' respectively. to

2023. English or Indonesian articles were selected

based on their relevance to the inclusion and

exclusion criteria. The inclusion criteria were limited

to articles published between 2019 and 2023 that

discuss treatment and treatment interactions, as well

as patient socio-demographics. The exclusion criteria

for this study are as follows: articles that are

incomplete or not written in English or Indonesian,

articles published before 2019, and articles that do not

have clear publications or research results that have

non-health impacts. The author employed a

systematic review method following the PRISMA

(Preferred Reporting Items for Systematic Review)

stages, which include identification, screening,

inclusion, and analysis of relevant article findings. To

record treatment and drug interactions, we reviewed

articles that met the inclusion criteria. The study

recorded and presented all identified risk factors,

along with a narrative explanation. Conclusions were

drawn based on the collected data on treatment and

drug interactions related to hypertension and diabetes

mellitus. A literature search was conducted using

Public Health Reviews, National Library of

Medicine, and Google Scholar, resulting in 7260

articles. However, only 26 articles met the inclusion

criteria and were included in the study.

Figure 1: Article collection using the PRISMA method.

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RESULTS AND DISCUSSION

The systematic review analysed several articles and

found evidence of drug use and interactions between

hypertension and diabetes mellitus treatments.

Respondent characteristics, such as age, gender,

antidiabetic treatment, and antihypertensive

treatment, were also studied. According to Susanti

(2021), the majority of patients diagnosed with

hypertension complicated by diabetes mellitus were

female (76%). Hormonal changes resulting from a

higher body mass index, premenstrual syndrome, and

menopause can cause fat to accumulate more easily

in the body. In women, the hormone estrogen is

unable to produce High Density Lipoprotein (HDL),

which can lead to increased blood pressure due to

atherosclerosis. According to research by Apristina et

al. (2023), the majority of respondents in the elderly

category (93.7%) exhibited these characteristics. As

age increases, changes occur that can make a person

more susceptible to various diseases, including

hypertension and diabetes mellitus.

Table 1: Interactions of hypertension and diabetes mellitus drugs.

Hypertension

Medicine

Diabetes

Mellitus

Medicine

Effect Severity

Level

Reference Author

Amlodipine Metformin Amlodipine reduces the effects of

metformin by pharmacodynamic

antagonism and can cause

cemia

Moderate 1. Abdulkadir et al., (2023)

2. Rahmawaty & Pratiwi, (2022)

3. Murwati & Murtisiwi, (2021)

Ramipril Metformin Ramipril may increase the toxicity of

metformin by an undetermined

interaction mechanism that may

lea

to h

cemia

Moderate 1. Agus & Permana, (2023)

2. Rahman & Octavia, (2019)

Captopril Metfotmin Captopril can increase the effects

of metformin, thereby increasing

the ris

of h

cemia

Moderate 1. Rasdianah et al., (2021)

2. Ganga et al., (2022)

Furosemide Metformin Furosemide used with metformin

can cause an increase in metformin

levels in the blood, causing

hypoglycemia

Moderate 1. Muhammad Fajar et al., (2023)

2. Refdanita & Sukmaningsih, (2021)

3. Fitri et al., (2022)

4. (Susanti, 2021)

Captopril Glimepiride Captopril can increase the effects of

glimepiride, causing hypoglycemia

Moderate 1. Sa'adah et al., (2018)

2. Retnowati & Renha Lestari, (2022)

3. Risal et al., (2021)

Bisopropol Glimepiride Bisoporol used with glimepiride can

inhibit the ß-2 receptors in the

pancreas so that it can reduce the

effects of glimepiride and will

cause hyperglycemia.

Moderate 1. Iskandar et al., (2021)

2. Oktaverawati & Susanti, (2020)

3. Amellia & Sumiwi,

4. (2023)

Ramipril Candesartan This interaction has a

pharmacodynamic mechanism and

has a synergistic effect, so it will

potentiate each other's effects. Dual

inhibition of the renin- angiotensin

system may increase the risk of

hypotension, hyperkalemia and

renal impairment

Moderate 1. Oktianti et al., (2023)

2. Suri et al., (2022)

3. Effendi & Harimu, (2022)

4. Momuat & Annisaa', (2023)

Ciprofloxacin Glimepiride Ciprofloxacin increases the effect of

glimepiride synergistically so it is

necessary to monitor blood sugar

levels re

ularl

Major 1. Tanty et al., (2023)

Systematic Review: Drug Interactions in the Treatment of Hypertension with Diabetes Mellitus

259

Table 1: Interactions of hypertension and diabetes mellitus drugs (cont.).

Hypertension

Medicine

Diabetes

Mellitus

Medicine

Effect Severity

Level

Reference Author

Bisopropol Insulin

Lispro

The use of bisoprolol

(cardioselective beta blocker) with

insulin lispro can increase the risk

of hypoglycemia

Moderate 1. Timur et al., (2022)

2. Dungan et al., (2019)

Bisopropol Metformin Concomitant use of metformin and

iso

rolol can cause h

cemia

Moderate 1. Sormin & Salmaa Qoonitah, (2021)

(

Reskiani et al., 2023

)

DDI Between Amlodipine and Metformin

Combination therapy using Angiotensin II receptor

blocker (ARB) and Calcium-channel blocker (CCB)

is more effective in achieving blood pressure targets.

This therapy can be administered as monotherapy or

in combination. CCBs can cause arterial widening

and are commonly used as antihypertensive drugs.

Additionally, it has been found that it can reduce

resistance in blood vessels, leading to a decrease in

blood pressure (Rahmawaty & Pratiwi, 2022).

According to Abdulkadir et al., the interaction

between metformin and calcium channel blocker

drugs, such as amlodipine, can reduce the

effectiveness of metformin. This is due to a

pharmacodynamic interaction mechanism, which can

cause hypoglycemic effects. To avoid hypoglycemia

and potential drug interactions, it is necessary to

check blood sugar levels before administering this

drug and adjust the insulin dose accordingly

(Abdulkadir et al., 2023).

DDI Between Ramipril and Metformin

Metformin is an oral drug used to lower blood sugar

levels. Due to its cationic nature, it has a high

potential for drug interactions, which can occur via

organic cationic ion transporters in the kidney. When

used in combination with ramipril, metformin can

cause hypoglycemia due to an increase in its blood

sugar-lowering effect. The interaction mechanism

between ramipril and metformin is undetermined

(Agus & Permana, 2023). When administering both

drugs, it is necessary to monitor them closely to avoid

any potential adverse effects and maintain a safe

distance between them (Rahman & Octavia, 2019).

DDI Between Captopril and Metformin

Ganga et al. (2022) suggest that in hypertensive

patients with diabetes, ACEI monotherapy

(Captopril) is the preferred primary therapy due to its

long-term safety and lack of metabolic side effects.

Additionally, ACEI therapy is commonly used

because it provides kidney protection by causing

vasodilation in the renal efferent arterioles and

reducing proteinuria. The combination of metformin

and captopril can increase the risk or severity of lactic

acidosis and hypokalemia. Patients should monitor

their blood glucose levels and recognize early

symptoms of hypoglycemia. Rasdianah et al. (2021)

suggest this solution.

DDI Between Furosemide and Metformin

Furosemide is an antihypertensive drug that can be

combined with metformin. However, this

combination can cause hypoglycemia as furosemide

can increase the plasma concentration of metformin

by 22%. Conversely, metformin can decrease the

concentration of furosemide and its elimination half-

life by 31% and 32%, respectively (Refdanita &

Sukmaningsih, 2021). Metformin belongs to the

biguanide class of drugs and is the first-line treatment

for diabetes. Furosemide, on the other hand, is a loop

diuretic. The two drugs have a minor interaction that

can increase metformin levels, although the

mechanism is not yet understood. It is important to

monitor patients to prevent loss of blood glucose

control. When discontinuing the drug in patients

taking metformin, it is important to monitor their

blood glucose levels to prevent hypoglycemia (Fitri

et al., 2022). To manage the interaction between these

two drugs, the dose should be adjusted and the patient

should be closely monitored for potential irregular

heartbeat issues (Fajar et al., 2023).

DDI Between Captrpril and Glimepiride

The concurrent use of glimepiride and captropil may

have a moderate interaction effect, potentially leading

to changes in the patient's clinical status, additional

treatment, hospitalization, and/or prolonged length of

hospital stay. This is due to the potential for drug

interactions when using antidiabetic and

antihypertensive medications simultaneously, which

can be exacerbated by the patient's overall health

condition. Drug absorption requires monitoring

during use to anticipate unwanted reactions. When

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administering the drug captropil with glimepride, an

ACE inhibitor interaction mechanism can increase

glucose uptake by increasing capillary blood flow in

skeletal muscle. Therefore, the use of captopril can

enhance the effect of glimepiride (Sa'adah et al.,

2018). The combination of these two drugs does not

have a synergistic effect and instead produces a

combination effect that is lower than the effect of

each drug individually (Risal et al., 2021).

DDI Between Bisoprolol and Glimepiride

Administration of beta blockers that selectively

inhibit β-1 is a better choice when given to

hypertensive patients with diabetes or peripheral

circulatory disorders. The use of carvedilol and

bisoprolol is beneficial and recommended for the

treatment of heart failure in combination with ACE

inhibitors, as stated in JNC VI and VII (Iskandar et

al., 2021). Glimepiride is a sulfonylurea drug, and

bisoprolol is a beta-blocker drug. These two drugs

interact through pharmacodynamic mechanisms. The

interaction between these two drugs can cause

hypoglycemia in patients. Beta blockers inhibit

insulin-induced glycogenesis in patients with

diabetes mellitus and delay the recovery of normal

blood glucose levels, leading to a decrease in insulin

secretion. To manage this interaction, it is

recommended to monitor the patient's glucose levels

or replace the antihypertensive with a different class

of drug (Oktaverawati & Susanti, 2020).

DDI Between Candesartan and Ramipril

Suri et al. state that ACE inhibitor drugs and

angiotensin receptor blockers (ARB), including

candesartan and ramipril, have been shown to be

effective in treating hypertension in patients with

complications such as atherosclerosis and diabetes.

Monotherapy may be more effective than

combination therapy in improving blood pressure,

renal function, insulin resistance, and plasma

adipocytokine profile (Suri et al., 2022).

Additionally, the combination of ACEI/ARB with

potassium-sparing diuretics may increase blood

potassium levels and lead to hyperkalemia (Effendi &

Harimu, 2022).

DDI Between Ciprofloxacin and Glimepiride

The combination of ciprofloxacin and glimepiride

can cause severe hypoglycemia, which may lead to

coma or death, particularly in elderly patients and

those with kidney problems. It is important to avoid

using Glimepiride with quinolone class antibiotics. If

therapy cannot be avoided, closely monitoring blood

sugar levels when starting therapy with quinolone

class drugs is necessary (Tanty et al., 2023).

DDI Between Bisoprolol and Insulin Linspro

The moderate severity category suggests that the

effects may be moderate and could lead to organ

damage that requires additional therapy (Timur et al.,

2022). When using selective beta blockers with

insulin, the risk of hypoglycemia is higher than when

using non-selective beta blockers with insulin.

Therefore, monitoring of sugar levels is necessary.

Spacing between bisoprolol and insulin lispro can be

used to minimize the occurrence of hypoglycemia

(Dungan et al., 2019).

10.

DDI Between Metformin and Bisoprolol.

Concomitant use of metformin and bisoprolol may

lead to hypoglycemia. Therefore, it is necessary to

monitor glucose levels or adjust the antidiabetic dose

if required (Sormin & Salmaa Qoonitah, 2021).

Bisoprolol has a positive effect on the pathogenic

mechanisms of arterial hypertension and metabolic

syndrome. Similarly, metformin improves

carbohydrate and lipid metabolism. However, it may

also lower blood pressure and slow the heart rate,

which can cause dizziness (Reskiani et al., 2023).

Pharmacodynamic interactions can often be

extrapolated to other drugs in the same class because

drugs are classified based on their pharmacodynamic

effects. This means that the drug acts on the same

receptor, site of action, or physiological system with

additive, synergistic, or antagonistic effects without

changing plasma levels or other pharmacokinetic

profiles (Murwati & Murtisiwi, 2021). Osoro, Amir,

Vohra, and Sharma (2023) state that patient

compliance is the most significant factor influencing

drug-drug interactions. Monitoring is necessary as

moderate interaction effects can cause changes in

clinical conditions. Moderate interaction events can

occur at any age, but they are more likely to occur in

older patients due to age-related changes in

physiology, increased risk of chronic diseases, and

the use of multiple medications (Abdulkadir et al.,

2023). Regular and routine medication adherence is

crucial for maintaining stable blood pressure and

reducing or preventing physical symptoms,

ultimately improving the patient's quality of life.

Regular and routine medication adherence is crucial

for maintaining stable blood pressure and reducing or

preventing physical symptoms, ultimately improving

the patient's quality of life. It is important to note that

subjective evaluations have been excluded from this

text. Regular and routine medication adherence is

crucial for maintaining stable blood pressure and

reducing or preventing physical symptoms,

Systematic Review: Drug Interactions in the Treatment of Hypertension with Diabetes Mellitus

261

ultimately improving the patient's quality of life.

Tarigan et al. (2022) identified several factors that

influence treatment adherence, including knowledge,

attitudes, information from mass/electronic media,

and family support.

CONCLUSIONS

According to the results of a systematic review, the

treatments most commonly used for hypertensive

patients with diabetes mellitus are amlodipine

metformin, metformin ramipril, metformin

bisoprolol, metformin captopril, glimepiride

captopril, furosemide-metformin, bisoprolol-insulin

lispro, and ciprofloxacin glimepiride. Of these,

ciprofloxacin-glimepiride has the greatest potential

effect on hypoglycemia. Meanwhile, the combination

of glimepiride and bisoprolol may lead to

hyperglycemic effects.

To prevent this interaction, a time lag can be

provided when taking the medication. Drug

interactions can occur at any age, but are more likely

in old age due to changes in physiology, increased

risk of chronic diseases, and the need for multiple

medications. Follow the instructions closely to ensure

uniformity in the volume (Moore and Lopes, 1999).

ACKNOWLEDGEMENTS

I would like to express my gratitude to Professor for

their guidance and knowledge throughout this

research project. Their insights have been invaluable

in expanding my understanding and skills in this field.

I am fortunate to have had Professor as my advisor,

and their contributions have been instrumental in

guiding me towards achieving my academic goals.

Thank you for your dedication and patience

throughout this journey. I wish Professor continued

success and happiness in their academic and

professional pursuits.

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