Rapid Review: Diabetic retinopathy screening during the COVID-19 pandemic

May 12, 2020

Ehtasham Ahmad, Melanie J Davies, Kamlesh Khunti


BACKGROUND
People with diabetes (PWD) are included in the group at increased risk of severe illness from coronavirus (COVID-19) and have been advised to observe stringent social distancing measures.(1)  This creates a difficult situation for PWD and their Health Care Providers (HCP) as PWD require an annual review including retinal screening as part of their screening for complications, which involves a physical visit to a community or hospital facility or an eye clinic.

This rapid review addresses the following questions:

  • How can we help stratify annual retinal screening programmes for PWD during the COVID-19 pandemic?
  • Can we do remote retinal review for PWD?
  • What can we do to control the risk factors for development or progression of diabetic retinopathy during the COVID-19 pandemic?
  • Is hydroxycholoroquine safe to use in individuals with diabetic retinopathy?

SEARCH STRATEGY
We conducted a focused database search of  Medline for articles published in English without date restriction, using the search terms “diabetic retinopathy”, “mass screening”, retinal screening”, “screening of diabetic retinopathy”, “teleophthalmology” and “telemedicine”(alone and in combination). We also searched the reference lists of research articles, clinical guidelines, systematic reviews, and meta-analyses for relevant material. Google scholar was searched for terms “diabetes”, “Covid-19”, “coronavirus”, “pandemic” and “hydroxycholoroquine” (alone and in combination). Publications were selected on the basis of relevance irrespective of year of publication.

Burden of diabetes retinopathy:
The retinal screening programme has reduced the incidence of preventable blindness as a result of diabetes globally. (2, 3) PWD usually undergo annual retinal screening unless there is a reason for urgent referral to an ophthalmologist such as vitreous haemorrhage, retinal detachment, referable maculopathy or pre-proliferative retinopathy.

Duration of diabetes is the major risk factor associated with increased prevalence and progression of diabetic retinopathy. In a UK study, the prevalence of any diabetic retinopathy and sight threatening diabetic retinopathy in those with type 1 diabetes was 56.0% and 11.2%, respectively, and in type 2 diabetes, 30.3% and 2.9%, respectively. (4) The presence of diabetic retinopathy, non-sight-threatening and sight-threatening, was strongly associated with increasing duration of diabetes for either type 1 or type 2 diabetes. The major burden was type 2 diabetes in this study (94%).

In another study (5), the minority ethnic communities with type 2 diabetes in the UK were found to be more prone to diabetic retinopathy, including sight-threatening retinopathy and maculopathy compared to white Europeans.

Proliferative diabetic retinopathy develops in 2% of people with type 2 diabetes who have diabetes for less than 5 years and in 25% of patients who have diabetes for 25 years or more. (6)

How can we help stratify annual retinal screening programmes for PWD during the COVID 19 pandemic?
Although annual screening is still recommended by most for PWD, there is increasing evidence that this may not be required especially for those at low risk of progression of diabetic retinopathy. There is increasing emphasis on individualisation of care in PWD. This also holds true for retinal screening and it may not be essential for all individuals with diabetes to undergo retinal photograph annually especially in those at low risk groups defined as those with no retinopathy (R0) on two screening episodes (7). Data have demonstrated that people without diabetic retinopathy in either eye are at a low risk of progression to sight-threatening diabetic retinopathy over a 2-year period (event rate 4.8 per 1000 person years), irrespective of whether the screening method is one-field non-mydriatic or two-field mydriatic digital photography. (7)

An earlier study showed that annual incidence of sight-threatening diabetic retinopathy  in 3743 people with type 2 diabetes without retinopathy at baseline was 0.3% (95% CI 0.1–0.5) in the first year, rising to 1.8% (95% CI 1.2–2.5) in the fifth year. (8) The study concluded that a 3-year screening interval could be safely adopted for people with type 2 diabetes with R0.

Results of 63,622 screening episodes among 20,788 PWD (predominantly type 2 diabetes) showed that 16,094 (25%) had any retinopathy, 3136 (4.9%) had referable retinopathy, and 384 (0.60%) had sight threatening retinopathy (defined as proliferative diabetic retinopathy or treatable maculopathy). (9)

A 10-year study showed that out of the 296 PWD (both type 1 and type 2 diabetes), 172 (58%) did not develop diabetic retinopathy during the 10-year observation period. (10) Ninety-six (32%) patients developed mild non-proliferative retinopathy, 6 (2%) developed clinically significant diabetic macular oedema, 23 (7.7%) developed pre-proliferative retinopathy, and 4 (1.3%) developed proliferative diabetic retinopathies during the 10-year observation period. All the patients who developed macular oedema or proliferative retinopathy had already been diagnosed as having mild non-proliferative retinopathy. The study concluded that screening for diabetic eye disease every other year seems to be safe and effective in PWD without retinopathy and such an approach will reduce the number of screening visits by more than 25%.

In a decade-long telemedicine screening program for diabetic retinopathy, in which colour fundus photos of PWD were acquired in two remote diabetes clinics and sent by intranet link to a reading centre, the incidence of sight threatening diabetic retinopathy in people with type 1 and type 2 diabetes and duration >10 years was 8.21% and 8.15%; in people with type 1 diabetes with duration <10 years was 5.5% and in those with type 2 diabetes and duration <10 years was 1.91%. (11) They advised that screening every 2.5-year in PWD with R0 at the first examination seems to be adequate.

A systematic review concluded that in people with type 2 diabetes without retinopathy at last screening, the incidence of severe sight-threatening retinopathy at the subsequent screening session was low. (12) This review supported lengthening of the screening interval of people with type 2 diabetes without retinopathy at last screening session although it did not specify minimum timescales between screening visits.

In 2016, Lund et al published a study to validate a mathematical algorithm that calculates the risk of diabetic retinopathy progression in a diabetic population with the UK staging of diabetic retinopathy. (13) A cohort of 9690, PWD (both type 1 and type 2) in England was followed for 2 years. The algorithms calculated the individual risk for development of pre-proliferative retinopathy (R2), active proliferative retinopathy (R3A), and diabetic maculopathy (M1) based on clinical data including consideration of duration of diabetes, HbA1c and blood pressure (BP).

They recommend following screening intervals based on their algorithms:

Average recommended screening intervals (months)
Type of diabetesWithout Pre-proliferative retinopathy, proliferative retinopathy, and maculopathyWith Pre-proliferative retinopathy, proliferative retinopathy, and maculopathy
Type 123.722.7
Type 220.313.5

According to these numbers, only individuals with type 2 diabetes who have underlying pre-proliferative and proliferative retinopathy, and those with maculopathy need annual retinal screening and rest can be followed with screening interval of 18 months to 24 months. It can also lead to 40-50% reduction in screening frequency with cost effectiveness.

So, based on the evidence it is reasonably safe to defer the routine retinal screening for PWD except for those individuals with type 2 diabetes with pre-proliferative retinopathy (R2) or higher retinopathy and such patients should be triaged earlier during the current pandemic. However, the published evidence suggests that it is safe to extend this screening practice even after the pandemic is over. This is especially true for PWD with R0, especially during early years after diagnosis of diabetes.

This idea is not new and in a large UK community‐based diabetic retinopathy screening programme spanning over 17 years, compared with screening intervals of 12–18 months, screening intervals of 19–24 months were not associated with increased risk of referable retinopathy (adjusted OR 0.93, 94% CI 0.82–1.05), but screening intervals of more than 24 months were associated with increased risk (OR 1.56, 95% CI 1.41–1.75). (9)

Such practices will help NHS prioritise service care for patients better during the current pandemic and as we emerge out of the pandemic. Fixed annual screening for all PWD, irrespective of risk of future visual loss, is not sustainable in the long-term. (14)

Can we do remote retinal review for PWD?
Telemedicine is care given to patients where the HCP and patient are separated by place, time, or both. Teleophthalmology makes use of technology including specialised imaging equipment which can be operated remotely rather than sitting in the same room or at a very closed distance to patient as in during the traditional slit lamp examination.

Ophthalmological telemedicine services have been in use and offers a possibility of remote assessment during the COVID-19 pandemic by mitigating the need for clinicians/technical staff and patients to be in the same place, it protects PWD by keeping them out of the hospital environment, and protects clinicians and technical staff by reducing the time they spend in close physical proximity with patients. (15)

With many clinics now running virtually during the pandemic, it is possible to realise that this will be a continuing practice in the future and has the potential for cost saving. However, it will require digitisation of services with quality checks.

In UK, the best model of teleophthalmology, is successful implementation of UK National Diabetic Eye Screening Programme (DESP). First implemented in 2003, DESP has gradually evolved from a hospital-based, consultant-lead service, to an independent community-based, technician delivered service. The benefits of this teleophthalmology programme was realised almost a decade later, when in 2009-2010, for the first time in five decades, diabetic retinopathy was no longer the leading cause of blindness in England. (3)

Advances in imaging have also helped evolve telemedicine clinics. Virtual ophthalmology clinics have been piloted in UK, although they have not gained national success yet. (16)

An observational study in UK comparing utility of automated diabetic retinopathy image assessment software to manual imaging concluded that automated assessment appeared to be cost-effective alternative to manual grading approach. (17)

Moorefield Eye Hospital performed the world’s first teleophthalmology examination in 4K resolution using 5G broadband last year, which was streamed live to a conference hundreds of miles away.

A deep-learning algorithm for retinal images, which relies on large data sets to generate data representations, has also been shown to make referral recommendations for sight-threatening retinal diseases comparable to expert ophthalmologists. (18) The use of deep learning has led to substantial improvements in diabetic retinopathy detection, achieving significantly high sensitivity (87–90%) and specificity (98%). (19)

In a recent US study, the standard of the technology-based eye-care services protocol was found to be accurate when compared to a face-to-face examination for the detection of common eye diseases including diabetic retinopathy. (20) The technology-based eye-care protocol was fed details like chief complaint, ocular, medical, social, and family history and employed auto-refraction. Every patient also received a face-to-face comprehensive examination by an ophthalmologist. There was 98.4% agreement between the two examinations for the diagnosis of any stage of diabetic retinopathy.

For some chronic eye conditions, such as diabetic macular oedema (DME), there are also reliable mobile applications available from commercial healthcare partners, which enable monitoring of visual symptoms on a handheld mobile device and allow ophthalmologists to remotely monitor their patients. Bilong et al reported a study in 220 PWD using a smartphone to obtain retinal images and found that screening for diabetic retinopathy using a smartphone-based retinal camera has a satisfactory specificity at all stages of diabetes retinopathy (sensitivity 73.3% and specificity 90.5%) (21).  The sensitivity was high for stages of diabetic retinopathy, which required therapeutic intervention e.g. proliferative retinopathy or macular oedema.

However, despite all these advances it is important that patients should be advised of the symptoms to be aware of in case they may need expedited or urgent eye care.

The NHS plans to transform its services over the course of next few years including digitalisation of existing services and teleophthalmology appears to be a feasible target. But at present we know the services are limited within the UK, but the evidence suggests that it can be employed as a very useful tool to assess patients remotely where available to safeguard PWD and HCPs during this pandemic. Long-term success will depend on validated algorithm for detection of diabetic retinopathy (22), use of artificial intelligence and integrated IT systems to support the telemedicine.

What can we do to control the risk factors for development or progression of diabetic retinopathy during the COVID-19 pandemic?
Clinical trials and epidemiological studies have shown that the two key modifiable risk factors associated with developing diabetic retinopathy are blood glucose and blood pressure control. (23) Hence, achieving and maintaining an adequate individualised glycaemic control and BP control aiming for target of less than 140/90mmHg are the two most important steps to prevent the development or progression of retinopathy.

It is important to remember that rapid improvement in glycaemic control especially in those with previously poorly controlled diabetes can lead to some early deterioration in diabetic retinopathy as was evident from the Diabetes Control and Complications Trial (DCCT) which showed that early worsening was observed in significantly more patients assigned to receive intensive (13.1%) vs conventional (7.6%) treatment (P < 0.001). (24) However, subsequent improvement in diabetic retinopathy occurred in 51% and 55% of patients, respectively at the 18-month follow-up. Improvements in long-term was also confirmed in people with type 2 diabetes in the ACCORD eye study. (25) This study investigated whether intensive glycaemic control, combination therapy for dyslipidaemia and intensive BP control could limit diabetic retinopathy. Participants were randomly assigned to receive either intensive (target HbA1c <6.0%/<42 mmol/mol) or conventional (target HbA1c 7.0%‐7.9%/53‐63 mmol/mol) treatment for glycaemia, dyslipidaemia and BP. At 4 years, rates of progression of diabetic retinopathy were significantly lower at 7.3% with intensive glycaemic control vs 10.4% with standard control (adjusted OR 0.67, 95% CI 0.51 to 0.87, P=0.003). (25)

The UK Prospective Diabetes Study (UKPDS) reported the beneficial effect of BP control on diabetic retinopathy progression and the development of maculopathy, suggesting that tight BP control may reduce the risk of diabetic retinopathy complications. (26) After 4.5 years, there was a significant difference in microaneurysms between the intense BP control group and the less‐tight BP control group (23.3% vs 33.5%; RR 0.7, 99% CI 0.51-0.95; p= 0.003). This effect continued to 7.5 years. In addition, there were fewer cotton-wool spots in the intense BP control group. (27)

Besides glycaemic control, BP and dyslipidaemia, microalbuminuria is the other major risk factors for the development and progression of diabetic retinopathy. (28) So, we recommend that PWD are on appropriate medications including statins and ACE inhibitors or ARBs where indicated to reduce the risk of deterioration of pre-existing diabetic retinopathy. The legacy benefits of multiple risk factor lowering comprising of blood glucose, BP and lipid control in PWD are well established for both microvascular (including diabetic retinopathy) and macrovascular complications and long-term mortality. (29)

Smoking cessation is also important to halt the progression of retinopathy and PWD should be encouraged and supported to abstain from smoking particularly during the COVID-19 pandemic. A meta-analysis looking at association of smoking with diabetic retinopathy found that in individuals with type 1 diabetes, compared to non-smokers, the risk of diabetic retinopathy significantly increased in smokers (RR 1.23, 95% CI 1.14-1.33, P < 0.001), however, in individuals with type 2 diabetes, compared with non-smokers, the risk of diabetic retinopathy significantly decreased in smokers (RR 0.92, 95% CI 0.86-0.98, p= 0.02). (30) The authors still emphasized not change the importance of smoking cessation for public health in general. This is especially relevant during the current pandemic when individuals with COPD and other lung conditions who smoke are more likely at greater risk of serious COVID-19 infection.

In summary, good glycaemic and BP control, management of dyslipidaemia and other modifiable risk factors like smoking cessation are some of the steps PWD can take to reduce the chances of developing or progression of the diabetes related eye problems when health services are fully stretched to their limits with focus on managing more acutely unwell patients and non-urgent services are either put on hold or run via virtual clinics including many diabetes clinics.

Is hydroxycholoroquine safe to use in individuals with diabetic retinopathy?
There has been recent media interest on the use of hydroxychloroquine to treat the coronavirus infection with conflicting information emerging. There is an ongoing RECOVERY trial in UK as well in which hydroxychloroquine will be given to one group of patients with COVDI-19 infection.  (31)

Hydroxycholoroquine associated retinopathy is a rare but well-established side effect of hydroxycholoroquine use and Royal College of Ophthalmologists has recently published clinical guidelines on screening for chloroquine and hydroxychloroquine retinopathy. (32)

Because of its glucose lowering properties, hydroxycholoroquine is used as a 3rd or 4th line agent in the treatment of type 2 diabetes in many parts of the world (33) however, we recommend exercising caution when considering use of hydroxychloroquine for treatment of COVID-19 in PWD who have advanced diabetic retinal disease especially active pre-proliferative retinopathy.

CONCLUSIONS

  1. We recommend that PWD who have stable diabetic retinopathy with no urgent or referable indication can have retinal screening at 18-24 months interval during the COVID-19 pandemic. There is a possibility that this may become a routine practice post-pandemic in near future based on the current evidence available and with the rise in prevalence of diabetes.
  2. Teleophthalmology, although not widely practiced, may offer an alternate option where available during the COVID-19 pandemic.
  3. The main stay of treatment during the pandemic to halt or slow the progression of diabetic retinopathy should be optimisation of diabetes control albeit gradually, BP control, use of statins to control hyperlipidaemia and ACE inhibitors/ARB for albuminuria. Smoking cessation is also important. This optimisation of diabetes care will likely continue to happen remotely via virtual clinics in most instances during the current pandemic.
  4. Although hydroxychloroquine is prescribed for various indications e.g. rheumatoid arthritis and treatment of malaria and occasionally in PWD, we recommend caution when using high doses of hydroxycholoroquine for treatment of COVID-19 in those with pre-existing advanced retinal disease including when recruiting PWD for trials like RECOVERY, where hydroxycholoroquine is included in one of the active arms.

ACKNOWLEDGMENTS
We acknowledge the support from the National Institute for Health Research (NIHR) Applied Research Collaboration East Midlands (ARC EM) and the NIHR Leicester Biomedical Research Centre. The views expressed are those of the author(s).

REFERENCES

  1. GOV.UK. Guidance on social distancing for everyone in the UK March 2020 [Available from: https://www.gov.uk/government/publications/covid-19-guidance-on-social-distancing-and-for-vulnerable-people/guidance-on-social-distancing-for-everyone-in-the-uk-and-protecting-older-people-and-vulnerable-adults.
  2. Scanlon PH. The English National Screening Programme for diabetic retinopathy 2003-2016. Acta Diabetol. 2017;54(6):515-25.
  3. Liew G, Michaelides M, Bunce C. A comparison of the causes of blindness certifications in England and Wales in working age adults (16-64 years), 1999-2000 with 2009-2010. BMJ Open. 2014;4(2):e004015.
  4. Thomas RL, Dunstan FD, Luzio SD, Chowdhury SR, North RV, Hale SL, et al. Prevalence of diabetic retinopathy within a national diabetic retinopathy screening service. Br J Ophthalmol. 2015;99(1):64-8.
  5. Sivaprasad S, Gupta B, Gulliford MC, Dodhia H, Mohamed M, Nagi D, et al. Ethnic variations in the prevalence of diabetic retinopathy in people with diabetes attending screening in the United Kingdom (DRIVE UK). PLoS One. 2012;7(3):e32182.
  6. Klein R, Klein BE, Moss SE, Davis MD, DeMets DL. The Wisconsin epidemiologic study of diabetic retinopathy. III. Prevalence and risk of diabetic retinopathy when age at diagnosis is 30 or more years. Arch Ophthalmol. 1984;102(4):527-32.
  7. Scanlon PH. Screening Intervals for Diabetic Retinopathy and Implications for Care. Curr Diab Rep. 2017;17(10):96.
  8. Younis N, Broadbent DM, Vora JP, Harding SP. Incidence of sight-threatening retinopathy in patients with type 2 diabetes in the Liverpool Diabetic Eye Study: a cohort study. Lancet. 2003;361(9353):195-200.
  9. Misra A, Bachmann MO, Greenwood RH, Jenkins C, Shaw A, Barakat O, et al. Trends in yield and effects of screening intervals during 17 years of a large UK community-based diabetic retinopathy screening programme. Diabet Med. 2009;26(10):1040-7.
  10. Olafsdottir E, Stefansson E. Biennial eye screening in patients with diabetes without retinopathy: 10-year experience. Br J Ophthalmol. 2007;91(12):1599-601.
  11. Vujosevic S, Pucci P, Casciano M, Daniele A, Bini S, Berton M, et al. A decade-long telemedicine screening program for diabetic retinopathy in the north-east of Italy. J Diabetes Complications. 2017;31(8):1348-53.
  12. Groeneveld Y, Tavenier D, Blom JW, Polak BCP. Incidence of sight-threatening diabetic retinopathy in people with Type 2 diabetes mellitus and numbers needed to screen: a systematic review. Diabet Med. 2019;36(10):1199-208.
  13. Lund SH, Aspelund T, Kirby P, Russell G, Einarsson S, Palsson O, et al. Individualised risk assessment for diabetic retinopathy and optimisation of screening intervals: a scientific approach to reducing healthcare costs. Br J Ophthalmol. 2016;100(5):683-7.
  14. Vujosevic S, Aldington SJ, Silva P, Hernández C, Scanlon P, Peto T, et al. Screening for diabetic retinopathy: new perspectives and challenges. Lancet Diabetes Endocrinol. 2020;8(4):337-47.
  15. Sim D, Thomas P, C. C. Tackling COVID-19 with Telemedicine 03/19/2020 [Available from: https://theophthalmologist.com/subspecialties/tackling-covid-19-with-telemedicine.
  16. Sim DA, Mitry D, Alexander P, Mapani A, Goverdhan S, Aslam T, et al. The Evolution of Teleophthalmology Programs in the United Kingdom: Beyond Diabetic Retinopathy Screening. J Diabetes Sci Technol. 2016;10(2):308-17.
  17. Tufail A, Kapetanakis VV, Salas-Vega S, Egan C, Rudisill C, Owen CG, et al. An observational study to assess if automated diabetic retinopathy image assessment software can replace one or more steps of manual imaging grading and to determine their cost-effectiveness. Health Technol Assess. 2016;20(92):1-72.
  18. De Fauw J, Ledsam JR, Romera-Paredes B, Nikolov S, Tomasev N, Blackwell S, et al. Clinically applicable deep learning for diagnosis and referral in retinal disease. Nat Med. 2018;24(9):1342-50.
  19. Wong TY, Bressler NM. Artificial Intelligence With Deep Learning Technology Looks Into Diabetic Retinopathy Screening. Jama. 2016;316(22):2366-7.
  20. Maa AY, Medert CM, Lu X, Janjua R, Howell AV, Hunt KJ, et al. Diagnostic Accuracy of Technology-based Eye Care Services: The Technology-based Eye Care Services Compare Trial Part I. Ophthalmology. 2020;127(1):38-44.
  21. Bilong Y, Katte JC, Koki G, Kagmeni G, Obama OPN, Fofe HRN, et al. Validation of Smartphone-Based Retinal Photography for Diabetic Retinopathy Screening. Ophthalmic Surg Lasers Imaging Retina. 2019;50(5):S18-s22.
  22. Gulshan V, Peng L, Coram M, Stumpe MC, Wu D, Narayanaswamy A, et al. Development and Validation of a Deep Learning Algorithm for Detection of Diabetic Retinopathy in Retinal Fundus Photographs. Jama. 2016;316(22):2402-10.
  23. Flaxel CJ, Bailey ST, Fawzi A, Lim JI, Adelman RA, Vemulakonda GA, et al. Diabetic Retinopathy PPP 2019, AAO PPP Retina/Vitreous Committee, Hoskins Center for Quality Eye Care American Academy of Ophthalmology; October 2019 [Available from: https://www.aao.org/preferred-practice-pattern/diabetic-retinopathy-ppp.
  24. Group TDCaCTR. Early worsening of diabetic retinopathy in the Diabetes Control and Complications Trial. Arch Ophthalmol. 1998;116(7):874-86.
  25. Chew EY, Ambrosius WT, Davis MD, Danis RP, Gangaputra S, Greven CM, et al. Effects of medical therapies on retinopathy progression in type 2 diabetes. N Engl J Med. 2010;363(3):233-44.
  26. Group UPDS. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group. Bmj. 1998;317(7160):703-13.
  27. Matthews DR, Stratton IM, Aldington SJ, Holman RR, Kohner EM. Risks of progression of retinopathy and vision loss related to tight blood pressure control in type 2 diabetes mellitus: UKPDS 69. Arch Ophthalmol. 2004;122(11):1631-40.
  28. Ghamdi AHA. Clinical Predictors of Diabetic Retinopathy Progression; A Systematic Review. Curr Diabetes Rev. 2020;16(3):242-7.
  29. Khunti K, Kosiborod M, Ray KK. Legacy benefits of blood glucose, blood pressure and lipid control in individuals with diabetes and cardiovascular disease: Time to overcome multifactorial therapeutic inertia? Diabetes Obes Metab. 2018;20(6):1337-41.
  30. Cai X, Chen Y, Yang W, Gao X, Han X, Ji L. The association of smoking and risk of diabetic retinopathy in patients with type 1 and type 2 diabetes: a meta-analysis. Endocrine. 2018;62(2):299-306.
  31. [Available from: https://www.recoverytrial.net/.
  32. Ophthalmologists TRCo. Hydroxychloroquine and Chloroquine Retinopathy: Recommendations on Monitoring January 2020 [Available from: https://www.rcophth.ac.uk/wp-content/uploads/2020/02/HCR-Recommendations-on-Monitoring.pdf.
  33. Singh AK, Singh A, Shaikh A, Singh R, Misra A. Chloroquine and hydroxychloroquine in the treatment of COVID-19 with or without diabetes: A systematic search and a narrative review with a special reference to India and other developing countries. Diabetes Metab Syndr. 2020;14(3):241-6.