Santo Domingo.- Four days after a tropical disturbance caused widespread damage in the Dominican Republic, over a million people in Greater Santo Domingo, San Cristóbal, Azua, and Duarte remain without access to drinking water. The National Institute of Drinking Water and Sewers (Inapa) reported that 66 of their aqueducts are still inoperative, affecting 1,015,924 users. The Santo Domingo Aqueduct and Sewer Corporation (Caasd) managed to restore service in three of its four affected aqueducts, except La Isabela.

The closure of Inapa’s aqueducts has impacted citizens across numerous provinces including Sánchez Ramírez, Duarte, Samaná, María Trinidad Sánchez, San José de Ocoa, San Cristóbal, Peravia, Azua, Barahona, Bahoruco, Independencia, Pedernales, San Juan, El Seibo, La Altagracia, Monte Plata, Hato Mayor, and San Pedro de Macorís. Both Inapa and Caasd have active brigades working to restore normal service in the systems impacted by the torrential rains.

The Emergency Operations Center (COE) reports that the disturbance, which brought a record 431 millimeters of water in 24 hours, resulted in 25 confirmed deaths, with field work by Diario Libre suggesting up to 30 fatalities. Twenty-two families lost their homes, 7,412 homes were affected, and 14 suffered partial damage. In response to the floods and soil saturation, 37,060 people moved to safer areas, and 965 are using the nine shelters set up by Civil Defense.

Electricity service has also been affected, with 1.62% of users experiencing interruptions. Electrical companies (Edes) have repaired most affected circuits, leaving only 16 branch circuits out of service.

The Ministry of Public Works is awaiting the receding of floods to assess damage to roads and bridges. Currently, 45 communities are cut off due to damage to eight roads and five bridges. Traffic on the 27 de Febrero Avenue tunnel overpass is suspended in the east-west direction following a deck collapse that caused nine fatalities.

With the reduction in rainy activity, the COE has lowered alert levels in several provinces. The National Institute of Hydraulic Resources (Indrhi) reports that dams are receiving significant inflows, with Sabana Yegua dam in Azua reaching 78.99% of its storage capacity.

In Santo Domingo Norte, Mayor Carlos Guzmán reported that 13,212 families in the Los Macos sector were affected. He emphasized the need for unity and has provided mattresses, food, and essential items, along with medical and psychological care to the affected residents. Sanitation and repair efforts are ongoing in various sectors.

DIABETIC RETINOPATHY is one of the most common complications of diabetes. It is an eye condition that affects blood vessels in the retina, the innermost layer lining the back of the eye. It occurs due to damage to the small capillaries that supply...

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(2) It has also been reported that South Asians are more susceptible to developing T2DM as compared to the Western population. (1)

Multi-Comorbidity Burden with Type 2 Diabetes Mellitus (T2DM)

The comorbidities and complications add to the burden of diabetes. Reportedly, 75% of patients have at least one additional comorbidity at the time of T2DM diagnosis, and 44% have at least two comorbidities. (3) Among Indian T2DM patients, high blood pressure (28.5%) is reported as a major comorbidity, followed by rheumatism (24.4%), retinopathy (21.8%), and cardiovascular diseases (19.5%). (4)

Therapeutic Approach in Type 2 Diabetes (T2DM): Overview

The latest American Diabetes Association 2023 guidelines recommend that a patient-centered approach should guide the choice of therapy. (5) Patient-related factors such as age, presence of comorbidities and cardiovascular (CV) risk, and treatment-related factors such as individualised glycemic targets, avoidance of hypoglycemia and weight gain, cardiorenal protection, minimal side effects of the medications, and treatment costs are important factors that must be considered when managing T2DM. (6)

Combination of Dipeptidyl Peptidase IV Inhibitors (DPP-4i) and Sodium-glucose Cotransporter-2 (SGLT2) Inhibitors (SGLT2i): Opinion from the Indian Experts

Compared to monotherapy, combination therapy improves treatment adherence and tackles several pathophysiologic defects in T2DM, enabling faster blood glucose control. Evidence from several clinical trials suggests that the SGLT2i+DPP4i combination is efficient and safe in controlling glycemic parameters in T2DM patients. (7) SGLT2 inhibitors have a unique insulin-independent mechanism of action and clinically proven weight lowering, blood pressure lowering, and cardiorenal-benefits. DPP4 inhibitors are weight-neutral; neither of these drug classes induce hypoglycemia. (8)

An expert opinion published on the optimal clinical approach to the combination use of SGLT2i + DPP4i in Indian diabetes settings suggests using SGLT2i+DPP4i fixed-dose combination in uncontrolled type 2 diabetes on Metformin with HbA1c >8.5% and among treatment-naive T2DM patients with HbA1c>8% in whom Metformin may be contraindicated or not tolerated. The SGLT2i+DPP4i combination may assist weight loss while providing benefits in T2DM patients with a higher predisposition to CV events and kidney disease. (7)

Linagliptin and Dapagliflozin: Applicability Across the Continuum of T2DM Care

Linagliptin is a DPP-4 inhibitor clinically useful for improving glycemic control in adults with T2DM. It offers a lower risk of hypoglycemia than other antidiabetic therapies and is weight-neutral. Importantly, it does not require dose modifications in a broad range of patient populations. It has a reassuring safety profile with robust evidence in T2DM, especially in cases of cardiac and renal comorbidities. (6)

Dapagliflozin is a highly selective SGLT2i that induces glucosuria by inhibiting glucose reabsorption in the kidney's proximal tubule. (9) In addition to potent blood glucose lowering effects, it has clinically established benefits beyond glycemic control, including lowering the rates of serious cardiovascular events, CV death, and hospitalisation for heart failure (HF) among T2DM with high CV risk. It also reduces the progression of CKD. (10)

Linagliptin & Dapagliflozin: Robust Glycemic Benefits

Linagliptin improves glycemic control in a varied T2DM population, including Asians, as established in several clinical trials and real-world evidence. (11) Treatment with Linagliptin reduces HbA1c level by 0.94%, fasting blood glucose (FBG) by 31.81 mg/dL (12), and postprandial glucose (PPG) by 33.5 mg/dl in T2DM patients. (13) Additionally, linagliptin treatment reduces the need for other glucose-lowering therapies, including insulin addition and up-titration. (11)

Dapagliflozin reduces glycemic fluctuations without increasing hypoglycemia episodes in patients newly diagnosed with T2DM. Treatment with dapagliflozin among T2DM patients has shown a reduction in HbA1c by 1.1%, FBG by 31.6 mg/dL, and PPG by 54.9 mg/dl. (9)

Linagliptin & Dapagliflozin: Reaping CV-CKD Benefits in Type 2 Diabetes

Linagliptin: Linagliptin reduces CV risk by 6.36% (P= 0.017), lowers triglyceride by 31.70 mg/dL [P=0.009] (12) and LDL-C by 41.9 mg/dL [P<0.05] (14). Treatment with Linagliptin also reduces albuminuria by 32% [P<0.05], indicating reno-protective benefits (15)

Dapagliflozin: Treatment with Dapagliflozin reduces CV death by 45%, hospitalization for HF by 36%, and all-cause mortality by 41% among T2DM with Heart Failure with reduced Ejection Fraction (HFrEF). (10) It also reduces the risk of ventricular arrhythmia, resuscitated cardiac arrest, or sudden death by 21%, (16) atrial fibrillations and atrial flutter events by 19% [ P=0.009] (17).

Dapagliflozin reduces albuminuria by 33.2% (95% CI −45.4, −18.2) in T2DM with hypertension (18). The subanalysis of the DECLARE-TIMI 58 trial has shown positive impact of Dapagliflozin on renal outcomes with no evidence of modification of treatment effect (P=0.28 and P=0.52). (19)

Linagliptin & Dapagliflozin: Effectiveness in T2DM Across Liver & Kidney Impairment & CVD :

Liver Safety:

Linagliptin: Linagliptin can be safely used in T2DM patients with mild to moderate liver dysfunction as opined by 87% Indian HCPs in a recent position paper on Linagliptin in T2DM management. (6) A pooled analysis of 17 randomized trials (n=7009, 39% Asians) showed that the adjusted mean change in HbA1c from baseline in those with hepatic disorders (hepatic steatosis, hepatitis C) was −0.75% ± 0.05 with linagliptin and − 0.20% ± 0.08 with placebo (P<0.0001) over 24 weeks. These suggest that linagliptin is effective and safe in people with T2DM and liver disease. (20)

Dapagliflozin: Dapagliflozin is well tolerated and associated with improvements in body composition and visceral fat, as well as improvements in liver parameters (serum concentrations of aspartate aminotransferase and alanine aminotransferase) and metabolic variables such as FPG, insulin, HbA1c, HDL-C, LDL-C, and triglycerides in patients with NASH associated with T2DM. (21)

Kidney Safety:

Linagliptin: Linagliptin is the only gliptin to have renal safety evidence, with demonstrated effectiveness across the spectrum of CKD in T2DM. (6) The KDIGO (Kidney Disease: Improving Global Outcomes) 2022 guidelines noted the favourable effects of linagliptin and recommended its use as no dose modifications are required. (22)

Dapagliflozin: Dapagliflozin has renal protection function and controls the progression of diabetic nephropathy by enhancing glomerular and renal tubular function and decreasing the release of TNF- and IL-6 inflammatory factors. (23) The KDIGO 2022 guideline recommended initiation of an SGLT2i for patients with T2DM and CKD who have eGFR ≥20 mL/min/1.73 m2 (a change from ≥30 mL/min/1.73 m2 in the 2020 guideline), and the ADA has also updated this threshold to ≥20 mL/min/1.73 m2 in its Standards of Care (from ≥25 mL/min/1.73 m2 in the initial issue of the 2022 Standards of Care). (22)

CV Safety- Established in Asian T2DM Patients

Linagliptin: A subgroup analysis of the CARMELINA trial (N=6979, 8.0% Asian) assessed the CV safety of linagliptin among Asian T2DM. During a median follow-up of 2.2 years, 3-point MACE (first occurrence of CV death, non-fatal MI, or nonfatal stroke) occurred in 29/272 (10.7%) and 33/283 (11.7%) of linagliptin and placebo groups, respectively (HR]0.90 P=0.3349). This suggests the CV safety of linagliptin among Asian T2DM patients. (24)

Another subgroup analyses of the CAROLINA trial showed that linagliptin showed fewer 3P-MACE (first occurrence of CV death, non-fatal MI, or non-fatal stroke events) during 6.2 years of median follow-up (9.5% linagliptin vs 11.1% glimepiride, HR 0.85, There were no significant differences between groups for other outcomes, including CV death (HR 0.73), non-CV mortality (HR 0.76) and hospitalization for heart failure (HR 0.89). Hypoglycemia adverse events occurred in 13.1% of linagliptin patients versus 42.1% of glimepiride patients (HR 0.25; P<0.0001) despite similar glycemic control. Body weight was slightly lower with linagliptin relative to glimepiride. (25)

Dapagliflozin: Dapagliflozin is well tolerated and safe in a wide spectrum of T2DM including patients with poorly controlled diabetes, the elderly, heart failure (NYHA class II or higher), or patients with CV risk factors. It decreases body weight and SBP (systolic blood pressure) in patients with poorly managed hypertension and pre-existing CVD without affecting CV safety. (26)

Clinical Takeaways

• Diabetes is growing alarmingly, and the increasing comorbidities add to the disease burden. Glucose-lowering medications with long-term durability, as well as CV, hepatic, and renal safety, are relevant and important for streamlining T2DM management.
• Linagliptin has a reassuring safety profile with robust evidence across the T2DM continuum.
• Linagliptin has been proven efficacious in the Asian T2DM population, with demonstrated cardiovascular (CV) and renal safety, improvement in the metabolic profile, and enhanced adherence due to once-a-day dosing without the need for dose modifications.
• Dapagliflozin is effective in reducing the risk of hospitalisation for HF, CV deaths, and renal disease progression.
• Dapagliflozin is well-tolerated and safe across T2DM patient population groups, including poorly controlled diabetes with high CV risk and CKD.

The combination treatment of linagliptin and dapagliflozin may be a reasonable choice as a potential ‘evergreen duo’ for managing a wide spectrum of T2DM. This is due to their complementary actions, robust glycemic control, and the associated benefits of metabolic improvement, weight and blood pressure reduction. Moreover, this combination offers cardiovascular and renal safety and can be administered once daily without the need for dose modifications, benefiting a broad range of T2DM patients.

References:

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2. Anjana RM, Unnikrishnan R, Deepa M, Pradeepa R, Tandon N, Das AK, Joshi S, Bajaj S, Jabbar PK, Das HK, Kumar A, Dhandhania VK, Bhansali A, Rao PV, Desai A, Kalra S, Gupta A, Lakshmy R, Madhu SV, Elangovan N, Chowdhury S, Venkatesan U, Subashini R, Kaur T, Dhaliwal RS, Mohan V; ICMR-INDIAB Collaborative Study Group. Metabolic non-communicable disease health report of India: the ICMR-INDIAB national cross-sectional study (ICMR-INDIAB-17). Lancet Diabetes Endocrinol. 2023 Jul;11(7):474-489. doi: 10.1016/S2213-8587(23)00119-5. Epub 2023 Jun 7.

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9. Ji L, Ma J, Li H, Mansfield TA, T'joen CL, Iqbal N, Ptaszynska A, List JF. Dapagliflozin as monotherapy in drug-naive Asian patients with type 2 diabetes mellitus: a randomized, blinded, prospective phase III study. Clin Ther. 2014 Jan 1;36(1):84-100.e9. doi: 10.1016/j.clinthera.2013.11.002. Epub 2013 Dec 28.

10. Verma S, McMurray JJV. The Serendipitous Story of SGLT2 Inhibitors in Heart Failure. Circulation. 2019 May 28;139(22):2537-2541. doi: 10.1161/CIRCULATIONAHA.119.040514. Epub 2019 Mar 18.

11. Vlado Perkovic, Robert Toto, Mark E. Cooper, Johannes F.E. Mann, Julio Rosenstock, Darren K. McGuire, Steven E. Kahn, Nikolaus Marx, John H. Alexander, Bernard Zinman, Egon Pfarr, Sven Schnaidt, Thomas Meinicke, Maximillian von Eynatten, Jyothis T. George, Odd Erik Johansen, Christoph Wanner; on behalf of the CARMELINA investigators, Effects of Linagliptin on Cardiovascular and Kidney Outcomes in People With Normal and Reduced Kidney Function: Secondary Analysis of the CARMELINA Randomized Trial. Diabetes Care 1 August 2020; 43 (8): 1803–1812. https://doi.org/10.2337/dc20-0279

12. Poonchuay N, Wattana K, Uitrakul S. Efficacy of linagliptin on cardiovascular risk and cardiometabolic parameters in Thai patients with type 2 diabetes mellitus: A real-world observational study. Diabetes Metab Syndr. 2022 May;16(5):102498. doi: 10.1016/j.dsx.2022.102498. Epub 2022 May 13.

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14. Naoto Kamatani et al, Comparison between the clinical efficacy of linagliptin and sitagliptin, Journal of Diabetes & Endocrinology 2013;4(4): 51-54

15. Groop PH, Cooper ME, Perkovic V, Emser A, Woerle HJ, von Eynatten M. Linagliptin lowers albuminuria on top of recommended standard treatment in patients with type 2 diabetes and renal dysfunction. Diabetes Care. 2013 Nov;36(11):3460-8. doi: 10.2337/dc13-0323. Epub 2013 Sep 11.

16. Curtain JP, Docherty KF, Jhund PS, et al. Effect of dapagliflozin on ventricular arrhythmias, resuscitated cardiac arrest, or sudden death in DAPA-HF. Eur Heart J. 2021;42(36):3727-3738. doi:10.1093/eurheartj/ehab560

17. Zelniker TA, Bonaca MP, Furtado RHM, Mosenzon O, Kuder JF, Murphy SA, Bhatt DL, Leiter LA, McGuire DK, Wilding JPH, Budaj A, Kiss RG, Padilla F, Gause-Nilsson I, Langkilde AM, Raz I, Sabatine MS, Wiviott SD. Effect of Dapagliflozin on Atrial Fibrillation in Patients With Type 2 Diabetes Mellitus: Insights From the DECLARE-TIMI 58 Trial. Circulation. 2020 Apr 14;141(15):1227-1234. doi: 10.1161/CIRCULATIONAHA.119.044183. Epub 2020 Jan 27.

18. Heerspink HJ, Johnsson E, Gause-Nilsson I, Cain VA, Sjöström CD. Dapagliflozin reduces albuminuria in patients with diabetes and hypertension receiving renin-angiotensin blockers. Diabetes Obes Metab. 2016 Jun;18(6):590-7. doi: 10.1111/dom.12654.

19. Furtado RHM, Raz I, Goodrich EL, Murphy SA, Bhatt DL, Leiter LA, McGuire DK, Wilding JPH, Aylward P, Dalby AJ, Dellborg M, Dimulescu D, Nicolau JC, Oude Ophuis AJM, Cahn A, Mosenzon O, Gause-Nilsson I, Langkilde AM, Sabatine MS, Wiviott SD. Efficacy and Safety of Dapagliflozin in Type 2 Diabetes According to Baseline Blood Pressure: Observations From DECLARE-TIMI 58 Trial. Circulation. 2022 May 24;145(21):1581-1591. doi: 10.1161/CIRCULATIONAHA.121.058103. Epub 2022 May 5.

20. Inagaki N, Sheu WH, Owens DR, Crowe S, Bhandari A, Gong Y, Patel S. Efficacy and safety of linagliptin in type 2 diabetes patients with self-reported hepatic disorders: A retrospective pooled analysis of 17 randomized, double-blind, placebo-controlled clinical trials. J Diabetes Complications. 2016 Nov-Dec;30(8):1622-1630. doi: 10.1016/j.jdiacomp.2016.07.002. Epub 2016 Jul 15.

21. Tobita H, Sato S, Miyake T, Ishihara S, Kinoshita Y. Effects of Dapagliflozin on Body Composition and Liver Tests in Patients with Nonalcoholic Steatohepatitis Associated with Type 2 Diabetes Mellitus: A Prospective, Open-label, Uncontrolled Study. Curr Ther Res Clin Exp. 2017;87:13-19. Published 2017 Jul 8. doi:10.1016/j.curtheres.2017.07.002

22. de Boer IH, Khunti K, Sadusky T, et al. Diabetes Management in Chronic Kidney Disease: A Consensus Report by the American Diabetes Association (ADA) and Kidney Disease: Improving Global Outcomes (KDIGO). Diabetes Care. 2022;45(12):3075-3090. doi:10.2337/dci22-0027

23. Huang, Y., Lu, W. & Lu, H. The clinical efficacy and safety of dapagliflozin in patients with diabetic nephropathy. Diabetol Metab Syndr 14, 47. 2022. https://doi.org/10.1186/s13098-022-00815-y

24. Inagaki N, Yang W, Watada H, et al. Linagliptin and cardiorenal outcomes in Asians with type 2 diabetes mellitus and established cardiovascular and/or kidney disease: subgroup analysis of the randomized CARMELINA® trial. Diabetol Int. 2019;11(2):129-141. Published 2019 Oct 22. doi:10.1007/s13340-019-00412-x

25. Kadowaki T, Wang G, Rosenstock J, Yabe D, Peng Y, Kanasaki K, Mu Y, Mattheus M, Keller A, Okamura T, Johansen OE, Marx N. Effect of linagliptin, a dipeptidyl peptidase-4 inhibitor, compared with the sulfonylurea glimepiride on cardiovascular outcomes in Asians with type 2 diabetes: subgroup analysis of the randomized CAROLINA® trial. Diabetol Int. 2020 Jun 27;12(1):87-100. doi: 10.1007/s13340-020-00447-5.

26. Saleem F. Dapagliflozin: Cardiovascular Safety and Benefits in Type 2 Diabetes Mellitus. Cureus. 2017;9(10):e1751. Published 2017 Oct 5. doi:10.7759/cureus.175

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