Risk Factors Analysis and Management of Cardiometabolic-Based Chronic Disease in Low- and Middle-Income Countries

Figures & data

Figure 1 Mitochondrial dysfunction plays a central role leading to metabolic perturbations in different organ systems, including skeletal muscle, heart, the liver, brain, adipose tissue, pancreas, and blood vessels. Metabolic disturbances, including insulin resistance, dysglycemia, dyslipidemia, and hypertension, act as a metabolic driver concurrently and independently to produce different stages of DBCD/ CMBCD. The four stages of DBCD and CMBCD are depicted at the bottom.

Notes: Adapted from: Kalra S, Unnikrishnan AG, Baruah MP, Sahay R, Bantwal G. Metabolic and Energy Imbalance in Dysglycemia Based Chronic Disease. Diabetes Metab Syndr Obes. 2021;14:165–184. doi: 10.2147/DMSO.S286888. © 2021 Kalra et al. Creative Commons Attribution – Non-Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/).⁷

Abbreviations: ATP, adenosine triphosphate, CMBCD, cardiometabolic-based chronic disease; DBCD, dysglycemia-based chronic disease ROS, reactive oxygen species; ETC, electron transport chain; VCAM, vascular cell adhesion molecule; ICAM, intracellular adhesion molecule.

Figure 2 The atherogenic lipoprotein consists of chylomicrons, VLDL-C, IDL-C, and LDL-C.

Abbreviations: HDL-C, high-density lipoprotein cholesterol; IDL-C, intermediate-density lipoprotein-cholesterol; LDL-C, low-density lipoprotein-cholesterol; VLDL-C, very low-density lipoprotein-cholesterol; nHDL-C, non-high-density lipoprotein-cholesterol.

Figure 3 Targets for nHDL modification to reduce cardiovascular risk. The nHDL targets should be 2.6 mmol/L (less than 100 mg/dL) and 3.3 mmol/L (less than 130 mg/dL) in those at very high and high total CV risk, respectively, as per the 2019 ESC/EAS Guidelines for the management of dyslipidemia.

Figure 4 JBS3 risk score (65%) identified the highest proportion of patients as “high risk,” ie, >20% 10-year cardiovascular risk vs ACC/AHA risk score (28.9%), FRS (46.3%), WHO risk score (21.3%).

Notes: Reprinted with permission from: Findlay SG, Kasliwal RR, Bansal M, Tarique A, Zaman A. A comparison of cardiovascular risk scores in native and migrant South Asian populations. SSM Popul Health. 2020;11:100594. doi:10.1016/j.ssmph.2020.100594. © 2020 The Author(s). Published by Elsevier Ltd. CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).⁴⁰

Abbreviations: FRS, Framingham Risk Score; JBS, Joint British Society; ACC/AHA, American College of Cardiology/American Heart Association; WHO, World Health Organisation.

Table 1 Summary of Medication Used for Treatment of Type 2 Diabetes Mellitus

Drug	Mechanism of Action	Clinical Effects	Side Effects
Metformin^Citation70	i. Exerts a weak and reversible selective inhibition of Complex-1 of mitochondrial respiratory chain leading to secondary activation of AMPK, regulating glucose and lipid metabolism.^Citation71 ii. Enhances peripheral muscle glucose uptake and utilization by increasing insulin sensitivity iii. Reduces hepatic gluconeogenesis and intestinal glucose absorption iv. Alters endocrine function in the pancreas	i. Reduces blood glucose (HbA1c) without causing hypoglycemia and weight gain. ii. Reduces CVD risk iii. Reduces LDL and increases HDL iv. Decreases food intake and body weight v. Modulates inflammatory markers	Lactic acidosis (rare), abdominal distention, diarrhea, nausea, vitamin B12 deficiency
SGLT-2 inhibitors^Citation72,Citation73	i. Inhibit glucose reabsorption in the proximal tubule of the kidney leading to diuresis and natriuresis Other potential mechanisms ii. Improve cardiac mitochondrial bioenergetics iii. Reduce inflammation	i.Reduce incidence of CV deaths and heart failure hospitalization in people with and without T2DM and those with and without prevalent heart failure. ii. Reduce blood glucose/HbA1c ii. Reduce in blood pressure iv. Increase HDL-C and TGs v. Reduce weight	Urinary tract infection, genital mycotic infection, Increased urination Dyslipidemia (increase in LDL-C)
Sulfonylureas^Citation74	i. Increase release of insulin through the stimulation of pancreatic beta cells by binding to a subunit of potassium ATP-dependent channels (sulphonylurea receptor). ii. Increase growth and sensitivity of insulin receptors on other tissues like adipocytes and triggering hepatic gluconeogenesis	i. Reduce blood glucose (HbA1c)	Hypoglycemia, weight gain
Thiazolidinediones^Citation75	Regulate gene expression through binding to peroxisome proliferator-activated receptor-gamma (PPAR-gamma) in skeletal muscle, adipose tissue, and hepatocytes, causing i. Decrease hepatic gluconeogenesis, ii. Increase insulin-dependent glucose uptake in skeletal muscle and adipose tissue. iii. Increase adiponectin levels	i. Reduce blood glucose (HbA1c) without causing hypoglycemia. ii. Improve insulin sensitivity in insulin-resistant individuals iii. Increase HDL-C iv. Reduce sdLDL and TGs v. Increases adiponectin vi. Reduces blood pressure vii. Reduces inflammation viii. Reduces procoagulant state ix. Preserves β-cell function	Edema, congestive heart failure (rosiglitazone), weight gain, fractures, risk of bladder cancer (pioglitazone, rare)
DPP-4 inhibitor^Citation76	i. Prevents the degradation of glucagon-like peptide-1 and enhances its insulinotropic effects	i. Reduces fasting and postprandial blood glucose (HbA1c) without causing hypoglycemia ii. Weight neutral	Increase the risk of acute pancreatitis (rare). Isolated cases of arthralgia and bullous pemphigoid
GLP-1 receptor agonist^Citation77,Citation78	i. Regulates the expression of beta-cell genes by inhibiting beta-cell apoptosis, preventing beta-cell glucolipotoxicity, and improving beta-cell function, causing ii. Improves insulin sensitivity iii. Decreases glucagon iv. Slows gastric emptying v. Increases satiety vi. Reduces free fatty acid	i. Reduces fasting and postprandial blood glucose (HbA1c) without causing hypoglycemia ii. Reduces bodyweight iii. Reduces systolic blood pressure iv. Reduction in LDL-C and total cholesterol. v. Reduces cardiovascular and microvascular complications	Common: Gastrointestinal symptoms, including nausea, vomiting, diarrhea. Others: Headache and nasopharyngitis
Alpha glycosidase inhibitor^Citation79	i. Inhibits the absorption of carbohydrates from the small intestine, competitively inhibit an enzyme that converts complex carbohydrates to simple	i. Reduces postprandial blood glucose (HbA1c)	Gastrointestinal: Flatulence, diarrhea, abdominal pain

Abbreviations: ATP, adenosine triphosphate; CVD, cardiovascular disease; DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1; HbA1c, glycated hemoglobin; HDL-C, high-density lipoprotein-cholesterol; LDL-C, low-density lipoprotein-cholesterol; sdLDL-C, small density low-density lipoprotein-cholesterol; SGLT-2, sodium-glucose cotransporter 2 inhibitor; TG, triglyceride.

Kalra S, Unnikrishnan AG, Baruah MP, Sahay R, Bantwal G. Metabolic and energy imbalance in dysglycemia-based chronic disease. Diabetes Metab Syndr Obes. 2021;14:165–184. doi:10.2147/DMSO.S286888

 Web of Science ®Google Scholar

Findlay SG, Kasliwal RR, Bansal M, Tarique A, Zaman A. A comparison of cardiovascular risk scores in native and migrant South Asian populations. SSM Popul Health. 2020;11:100594.

 Web of Science ®Google Scholar

Pernicova I, Korbonits M. Metformin—mode of action and clinical implications for diabetes and cancer. Nat Rev Endocrinol. 2014;10:143–156. doi:10.1038/nrendo.2013.256

 PubMed Web of Science ®Google Scholar

Zhou G, Myers R, Li Y, et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest. 2001;108:1167–1174. doi:10.1172/JCI13505

 PubMed Web of Science ®Google Scholar

Lopaschuk GD, Verma S. Mechanisms of cardiovascular benefits of Sodium Glucose Co-Transporter 2 (SGLT2) inhibitors. JACC Basic Transl Sci. 2020;5:632–644. doi:10.1016/j.jacbts.2020.02.004

 PubMedGoogle Scholar

Halimi S, Vergès B. Adverse effects and safety of SGLT-2 inhibitors. Diabetes Metab. 2014;40(S28–S34):S28–S34. doi:10.1016/S1262-3636(14)72693-X

 Web of Science ®Google Scholar

Costello RA, Nicolas S, Shivkumar A. Sulfonylureas. In: StatPearls. StatPearls Publishing; 2021.

 Google Scholar

Lebovitz HE. Thiazolidinediones: the forgotten diabetes medications. Curr Diab Rep. 2019;19(151). doi:10.1007/s11892-019-1270-y

 Web of Science ®Google Scholar

Deacon CF. Dipeptidyl peptidase 4 inhibitors in the treatment of type 2 diabetes mellitus. Nat Rev Endocrinol. 2020;16:642–653. doi:10.1038/s41574-020-0399-8

 PubMed Web of Science ®Google Scholar

Tran KL, Park YI, Pandya S, et al. Overview of glucagon-like peptide-1 receptor agonists for the treatment of patients with type 2 diabetes. Am Health Drug Benefits. 2017;10:178–188.

 PubMed Web of Science ®Google Scholar

Hinnen D. Glucagon-like peptide 1 receptor agonists for type 2 diabetes. Diabetes Spectr. 2017;30:202–210. doi:10.2337/ds16-0026

 PubMedGoogle Scholar

van de Laar FA, Lucassen PL, Akkermans RP, et al. α-Glucosidase inhibitors for patients with type 2 diabetes: results from a Cochrane systematic review and meta-analysis. Diabetes Care. 2005;28:154–163. doi:10.2337/diacare.28.1.154

 PubMed Web of Science ®Google Scholar