Year : 2020 | Volume
: 25 | Issue : 1 | Page : 11--14
Paradigm shift in the pharmacological treatment of type 2 diabetes mellitus
Consultant Endocrinologist, Fortis Hiranandani and Apollo Hospitals, Navi Mumbai, Maharashtra, India
Dr. Tejal Lathia
Fortis Hospital, Sector 10A, Vashi, Navi Mumbai - 400 703, Maharashtra
The options for pharmacological management of type 2 diabetes mellitus have exploded over the last decade or so. Availability of a variety of new drugs, oral as well as injectable, has made the choice of treatment more complex and challenging. Over a decade or so ago, glycemic (glucometabolic) control was the main target of treatment in patients with type 2 diabetes mellitus – usually with metformin, sulfonylureas (SU), thiazolidinediones, and insulin (the traditional quartet). There is conflicting evidence on the cardiovascular (CV) effects of the traditional quartet of drugs. The almost serendipitous benefit of sodium-glucose transporter 2 (SGLT2) inhibitors on CVD and kidney disease in patients with type 2 diabetes mellitus has revolutionized the way we view the treatment of diabetes. . What the physician needs to remember when prescribing this drug is – right patient and right intent.
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Lathia T. Paradigm shift in the pharmacological treatment of type 2 diabetes mellitus.J Mahatma Gandhi Inst Med Sci 2020;25:11-14
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Lathia T. Paradigm shift in the pharmacological treatment of type 2 diabetes mellitus. J Mahatma Gandhi Inst Med Sci [serial online] 2020 [cited 2020 Dec 1 ];25:11-14
Available from: https://www.jmgims.co.in/text.asp?2020/25/1/11/282354
The options for pharmacological management of type 2 diabetes mellitus have exploded over the last decade or so. Availability of a variety of new drugs, oral as well as injectable, has made the choice of treatment more complex and challenging. Furthermore, there has been a paradigm shift from glucometabolic benefit of a particular drug to its vasculometabolic benefit. This has led to a distinct change in the treatment guidelines of type 2 diabetes mellitus by the American Diabetes Association (ADA)/European Association for the Study of Diabetes (EASD) in 2018.
In this article, I trace the journey of the newer drugs and discuss the challenges of applying the new ADA/EASD guidelines to the Indian patient with diabetes mellitus.
The Story So Far
Over a decade or so ago, glycemic (glucometabolic) control was the main target of treatment in patients with type 2 diabetes mellitus – usually with metformin, sulfonylureas (SU), thiazolidinediones, and insulin (the traditional quartet). Moreover, it was expected that good glycemic control alone would reduce the risk of micro- and macro-vascular complications. This was supported by the findings of the UK Prospective Diabetes Study which showed that tight glycemic control could prevent the onset and progression of diabetes-related microvascular but not macrovascular complications.
There is conflicting evidence on the cardiovascular (CV) effects of the traditional quartet of drugs. Metformin is CV safe with some possible benefits in CV disease (CVD) reduction in long-term follow-up (legacy effect), with an approximately 13% reduction in CVD. A shadow has always lingered over SU association with increased risk of CVD, which was recently dispelled by the CAROLINA trial (linagliptin vs. glimepiride), where other than expected hypoglycemia and weight gain there was no additional risk of CV events with glimepiride use. Although pioglitazone can be beneficial for the heart, there is indisputable evidence of the increased risk of heart failure and fractures with pioglitazone., Insulin (glargine) is neutral for CV events as proven by the ORIGIN.
There has long been need for a drug which not only gave glucometabolic benefit but did not cause weight gain or hypoglycemia and additionally offered added benefits such as heart and kidney protection – vasculometabolic benefit versus glucometabolic benefit alone.
Before 2008, CV outcome trials (CVOTs) were not mandatory for the approval of a diabetes medication. The change occurred when a meta-analysis on rosiglitazone suggested that it increased the risk of adverse CV events. The Food and Drug Administration (FDA) then made it mandatory for CV safety of a newly approved diabetes drug to be proven. This led to an avalanche of clinical trials – some beneficial, some adverse.
Advent of Newer Drugs
There was initially some evidence of how DPPIV inhibitors would probably have beneficial effect on the heart over and above glycemic benefit. The SAVOR-TIMI trial, however, raised the question of increased risk of hospitalization heart failure in the initial 6 months after drug initiation. The other DPPIV inhibitors such as sitagliptin and linagliptin were declared safe or CV neutral (TECOS and CARMELINA),, but no benefit could be demonstrated.
A small glimmer of hope on the horizon came with the LEADER study, showing a 13% reduction in CVD in the primary prevention cohort using the GLP1 analog liraglutide. Dulaglutide also has shown similar promise for CV protection in the recently released REWIND study at the ADA, 2019. However, the main concern with GLP1 analogs in daily practice is the cost, restricting its usage in countries where patients pay out of pocket without any reimbursement. They remain out of reach of a large part of the diabetes population around the world.
New Kids on the Block
The almost serendipitous benefit of sodium-glucose transporter 2 (SGLT2) inhibitors on CVD and kidney disease in patients with type 2 diabetes mellitus has revolutionized the way we view the treatment of diabetes. SGLT2 inhibitors are novel because they have no direct effects on pancreas, insulin secretion, or action but work by preventing glucose reuptake in the kidney by blocking sodium-glucose channels. As a result, glycosuria ensues and blood glucose levels decrease.
The first SGLT2 inhibitor, empagliflozin, made an entry onto the global diabetes stage with a remarkable reduction in risk of CV mortality, heart failure, and chronic kidney disease (CKD) progression (~30%) in patients with preexisting CVD (99% of the study population) in the EMPAREG trial.
Canagliflozin followed closely with somewhat similar results, though in the CANVAS study 60% of patients only suffered from preexisting CVD. However, there was a signal of increase in the risk of amputations (great toe) in this trial, especially in patients with a prior history of amputations, peripheral vascular disease, or neuropathy. Further, the FDA issued an advisory regarding the risk of diabetic ketoacidosis with SGLT2 inhibitors. There was also a suggestion of increased risk of fractures with SGLT2 inhibitors.
Then, the DECLARE trial debuted. This trial with the drug dapagliflozin included a much smaller number of patients with established CVD ~ 40%. It was not better in reducing CV mortality as compared to placebo, though the benefit for heart failure and kidney disease was evident.
The ADA/EASD has since reworked their guidelines. They now advocate the categorization of patients according to whether they have:
Established CVDNeed to lose weight or avoid weight gain
For both these categories, SGLT2 inhibitors and GLP1 analogs are the drug of choice.
For both these categories, SGLT2 inhibitors are the drugs of choice.
Risk of hypoglycemia – SGLT2 inhibitors/GLP1 analogs/DPPIV inhibitors/pioglitazoneFinancial constraints – SU or pioglitazone.
The latest gliflozin trial to make an impact in the diabetes world is CREDENCE. This trial restored the reputation of canagliflozin as it did not show any evidence of increased amputation in very high risk patients. This trial recruited patients with established CVD and macro-albuminuria (albumin: creatinine ratio >300 mg/g) and showed a dramatic benefit in reducing CV mortality, kidney disease progression, as well as reducing heart failure.
To summarize, DPPIV is a safe option but does not offer any additional benefits for heart or kidney. Both GLP1 analogs and SGLT2 inhibitors reduce CVD, cause weight loss, and have low risk of hypoglycemia, but only SGLT2 inhibitors reduce risk of heart failure and kidney disease progression. The SU and insulin seem to have fallen by the wayside at least in the guidelines, though not in real-world practice, in spite of being the most potent in reducing HBA1C.
There are several dilemmas when it comes to the application of the current ADA/EASD guidelines.
Extrapolation of results to routine outpatient department care
SGLT2 inhibitors perform remarkably well in patients with preexisting heart disease for reduction in three-point MACE and CV mortality, but can the results really be extrapolated to general routine outpatient care as of yet?
As discussed, the magnitude of benefits decrease as the number of patients with preexisting CVD reduce – EMPAREG 99%, CANVAS 65%, and DECLARE 40%.,, The recently published DISCOVER study (prospective, observational study, n = 16,000) found that patients with type 2 diabetes mellitus seen in outpatient care are most likely to be included in the DECLARE trial which had the least number of patients with established CVD (40%). Hence, the generalizability of the results of trials with very high-risk patients is less, and thus, the magnitude of benefits likely to be accrued is also diminished
Age and ethnic considerations
How many of these trials included Asian Indians in their study populations? Very few of these randomized clinical trials have any significant number of Indian patients, maximum in the CREDENCE trial which had 144 patients out of 4401 (3.3%), whereas India represents the second largest population of diabetes in the world. Similarly, the average age of patients in these trials was ~ 63 years,,, whereas our patient population is much younger. There was much greater inclusion of US Hispanic/Latino participants in the major CVOTs (18.5%) which was proportionate to the population of Hispanic/Latino in the US population, but their characteristics (age, gender, and weight) differed from native Hispanic participants.
The cardinal rule of evidence based medicine is that type of patients included in trial must match the population to extrapolate the results. Of course, the drugs may turn out to be more effective in Asian Indians. This can only be confirmed in studies done in Asian Indian populations or by real-world data.
Risk of urogenital infections
There is known increase in the risk of urogenital infections with SGLT2 inhibitors. Whenever a patient is started an SGLT2 inhibitor, the patient needs to be counseled regarding the need for perineal hygiene and frequent bladder emptying. Given the current state of sanitation in our country – lack of adequate toilets, poor hygiene standards, and lack of clean water, how does this impact the risk of urogenital infections that arise as a result of SGLT2 inhibitors? Physicians also see large numbers of patients in busy outpatient practice, how much patient education can be accomplished in this limited time is doubtful.
How are most of our patients going to be able to afford these drugs as most of our patients pay out of pocket rather than being financed by insurance?
SGLT2 inhibitors are a welcome addition to our therapeutic armamentarium for type 2 diabetes mellitus and are here to stay. What the physician needs to remember when prescribing this drug is – right patient and right intent.
Right patient means making sure patient does not have any clinical history which precludes its safe use such as history of recurrent urinary infections or prior foot ulceration or amputations. We must eschew its use at times of infection, dehydration, or perioperative.
Right intent means whether we are using it for glucometabolic control or we are using it for vasculometabolic control. Glucometabolic benefits will be evident quickly with improved glycemic control, whereas the vasculometabolic benefits will accrue over time.
This is the time for stakeholders – clinicians, public health policy experts, and patient representatives to come together, and envision a path for diabetes management in the country so that all patients with diabetes may enjoy the glucometabolic as well as vasculometabolic benefits of the newer drugs.
We would like to acknowledge and thank Dr. Sanjay Kalra and Dr. Unnikrishnan for review of this article and their valuable comments and suggestions.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
|1||Davies MJ, D'Alessio DA, Fradkin J, Kernan WN, Mathieu C, Mingrone G, et al. Management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 2018;41:2669-701.|
|2||King P, Peacock I, Donnelly R. The UK Prospective Diabetes Study (UKPDS): Clinical and therapeutic implications for type 2 diabetes. Br J Clin Pharmacol 1999;48:643-8.|
|3||Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008;359:1577-89.|
|4||Azoulay L, Suissa S. Sulfonylureas and the risks of cardiovascular events and death: A methodological meta-regression analysis of the observational studies. Diabetes Care 2017;40:706-14.|
|5||Full Data from CAROLINA® Cardiovascular Outcome Trial,Press. Available from: https://www.boehringer-ingelheim.com/press-release/CAROLINA-full-data. [Last accessed on 2019 Jun 30].|
|6||de Jong M, van der Worp HB, van der Graaf Y, Visseren FLJ, Westerink J. Pioglitazone and the secondary prevention cardiovascular disease. A meta-analysis of randomized-controlled trials. Cardiovasc Diabetol 2017;16:134.|
|7||Erdmann E, Charbonnel B, Wilcox RG, Skene AM, Massi-Benedetti M, Yates J, et al. Pioglitazone use and heart failure in patients with type 2 diabetes and preexisting cardiovascular disease: Data from the PROactive study (PROactive 08). Diabetes Care 2007;30:2773-8.|
|8||Viscoli CM, Inzucchi SE, Young LH, Insogna KL, Conwit R, Furie KL, et al. Pioglitazone and risk for bone fracture: Safety data from a randomized clinical trial. J Clin Endocrinol Metab 2017;102:914-22.|
|9||ORIGIN Trial Investigators, Gerstein HC, Bosch J, Dagenais GR, Díaz R, Jung H, et al. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med 2012;367:319-28.|
|10||Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007;356:2457-71.|
|11||Research C for DE and. Diabetes Mellitus–Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes. U.S. Food and Drug Administration. 2019. Available from: http://www.fda.gov/regulatory-information/search-fda-guidance-documents/diabetes-mellitus-evaluating-cardiovascular-risk-new-antidiabetic-therapies-treat-type-2-diabetes. [Last accessed on 2019 Jul 06].|
|12||Pala L, Rotella CM. The role of DPP4 activity in cardiovascular districts:In vivo and in vitro evidence. J Diabetes Res 2013;2013:590456.|
|13||Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 2013;369:1317-26.|
|14||Green JB, Bethel MA, Armstrong PW, Buse JB, Engel SS, Garg J, et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med 2015;373:232-42.|
|15||Rosenstock J, Perkovic V, Johansen OE, Cooper ME, Kahn SE, Marx N, et al. Effect of linagliptin versus placebo on major cardiovascular events in adults with type 2 diabetes and high cardiovascular and renal risk: The CARMELINA randomized clinical trial. JAMA 2019;321:69-79.|
|16||Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016;375:311-22.|
|17||Gerstein HC, Colhoun HM, Dagenais GR, Diaz R, Lakshmanan M, Pais P, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): A double-blind, randomised placebo-controlled trial. Lancet 2019;394:121-30.|
|18||Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117-28.|
|19||Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017;377:644-57.|
|20||Matthews DR, Li Q, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, et al. Effects of canagliflozin on amputation risk in type 2 diabetes: The CANVAS Program. Diabetologia 2019;62:926-38.|
|21||U.S. Food and Drug Administration. Drug Safety Communication: FDA warns that SGLT2 Inhibitors for Diabetes May Result in a Serious Condition of Too Much Acid in the Blood; 15 May, 2015. Available from: http://www.fda.gov/downloads/Drugs/DrugSafety/UCM446954.pdf. [Last accessed on 2019 Jul 06].|
|22||Tarentino AL, Maley F. A comparison of the substrate specificities of endo-beta-N-acetylglucosaminidases from streptomyces griseus and diplococcus pneumoniae. Biochem Biophys Res Commun 1975;67:455-62.|
|23||Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2018;380:347-57.|
|24||Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJ, Charytan DM, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med 2019;380:2295-306.|
|25||Pintat S, Fenici P, Hammar N, Ji L, Khunti K, Medina J, et al. Eligibility of patients with type 2 diabetes for sodium-glucose cotransporter 2 inhibitor cardiovascular outcomes trials: A global perspective from the DISCOVER study. BMJ Open Diabetes Res Care 2019;7:e000627.|
|26||Kelley AT, Mizokami-Stout K, O'Brien MJ, Bowen ME, Sussman J. Hispanic representation in diabetes cardiovascular outcomes trials. BMJ Open Diabetes Res Care 2019;7:e000656.|
|27||Liu J, Li L, Li S, Jia P, Deng K, Chen W, et al. Effects of SGLT2 inhibitors on UTIs and genital infections in type 2 diabetes mellitus: A systematic review and meta-analysis. Sci Rep 2017;7:2824.|