Severe hypoglycaemia and cardiovascular disease: systematic review and meta-analysis with bias analysis
BMJ 2013; 347 doi: https://doi.org/10.1136/bmj.f4533 (Published 30 July 2013) Cite this as: BMJ 2013;347:f4533
All rapid responses
Rapid responses are electronic comments to the editor. They enable our users to debate issues raised in articles published on bmj.com. A rapid response is first posted online. If you need the URL (web address) of an individual response, simply click on the response headline and copy the URL from the browser window. A proportion of responses will, after editing, be published online and in the print journal as letters, which are indexed in PubMed. Rapid responses are not indexed in PubMed and they are not journal articles. The BMJ reserves the right to remove responses which are being wilfully misrepresented as published articles or when it is brought to our attention that a response spreads misinformation.
From March 2022, the word limit for rapid responses will be 600 words not including references and author details. We will no longer post responses that exceed this limit.
The word limit for letters selected from posted responses remains 300 words.
Dear Editor(s),
I read with interest metanalysis by Gotto et al.
I was not able to find answers to certain questions that came in my mind while reading this article:
a. What was the cutoff point taken for severe hypoglycemia and were the same cut off points used in all studies included?
b. Was the number of severe hypoglycemic events in any way associated with cardiovascular disease?
c. Were the criteria used to label cardiovascular disease uniform in all the studies and if so what were the criteria used?
An important prospective study by Gruden et al concluded that although severe hypoglycemia occurs more commonly in people with type 1 diabetes than those with type 2 diabetes, cardiovascular disease events are relatively rare among young people with type 1 diabetes(1). Therefore, it is either duration of diabetes or associated insulin resistance which in my opinion is the responsible factor for development of cardiovascular disease. And severe hypoglycemia by initiating sympathetic stimulation and associated cascade leads to cardiovascular events.
Reference:
1. Gruden G, Barutta F, Chaturvedi N, Schalkwijk C, Stehouwer CD, Witte DR, et al. Severe hypoglycemia and cardiovascular disease incidence in type 1 diabetes: the EURODIAB Prospective Complications Study. Diabetes Care 2012;35:1598-604
Competing interests: No competing interests
Abnormal glycation, hypercoagulability and changes in hemodynamic properties may result in micro- and macro-angiopathy in diabetics. Therefore, diabetes itself is a risk factor for coronary artery disease. The sudden fluctuations between hyperglycemia and hypoglycemia due to fluctuations in diet, therapy and stress remain the cause and concern for each diabetic patient. The need for a much disciplined life style and strict adherence to therapy creates a dysfunctional metabolic state in contrast to the resilience of normal metabolic machinery.
Hypoglycemia is only a part of a diabetic story which could physiologically aggravate cardiac function. It is normal for clinicians and researchers to understand the implications of hypoglycemic episode in diabetic patients. A diabetic patient with little medical knowledge of diabetes believes strongly that he has to control his blood sugar from shooting up to a non-manageable level. For him to understand how hypoglycemia can be adverse to his cardiac function when he is told to manage hyperglycemia may come as a surprise or sometimes a shock. Therefore patient education and awareness will play a vital role to influence the diabetic mind that is troubled by high blood glucose levels.
Competing interests: No competing interests
Re: Severe hypoglycaemia and cardiovascular disease: systematic review and meta-analysis with bias analysis
Title:
Patient education on proper adherence of diet chart, life style modifications by diabetologists, daily aerobic & physical exercises, brisk walking daily for half an hour as routine, awareness about identifying minor symptoms & providing guideline of prevention of hypoglycemia play a vital role in influencing the diabetic mind in the community – instead of prescribing very costly newer but not time tested OHA agents like Pioglitazone / Rosiglitazone/ gliptins/ or Dipeptidyl peptidase-4 inhibitors [long term effects of this drugs are still unknown] and Metformin is the time tested drug to treat Type-2 Diabetics with least chance of hypoglycemia
Severe hypoglycemia is a well established potential risk factor for cardiovascular diseases resulting in silent Acute Myocardial Infraction and fatal cardiac arrhythmia in people with type 2 DM without other comorbid conditions and risk factors like older age, sex, cigarette smoking, hyperlipidimia, obesity, microalbuminia, hyperuricimia, diabetic nephropathy & metabolic syndromes and poorly controlled glycemic index. Many RCT trials also cautioned us that intensive glucose control with Insulin or various modern newer OHA Sulphonurias (SU), including recently withdrawn from USA market Rosiglitazone & Pioglitazone by FDA, was associated with risk of fatal myocardial infarction in people with type 2 DM. The ACCORD study[1] or ADVANCE study in 2011 [2] or VADT study [3] also provided us information since 2010 onwards on relative increased risks (22% as per ACCORD) for CVS mortality in Type2 DM when associated with hypoglycemia and indicated that severe hypoglycemia was strongly associated with a higher risk of cardiovascular disease and mortality. Intensive & tight glucose control thus must not be the main goal of controlling of HBA1c at non diabetic level [HBA1c 5%-6%] and it is rather better to maintain HbA1c between 6.5 % to <7% by the clinicians, giving advice to his patients accordingly. Education of common public in community is thus important in this regard. Severe hypoglycemia has acute effects on sympatho-adrenal activation, inflammation, and endothelial dysfunction, all of which have potential adverse cardiovascular effects including enhanced atherosclerosis. In addition, cardiac ischemia or fatal arrhythmias occuring during hypoglycemia may be responsible for the increased risk of cardiovascular death among patients with severe hypoglycemia. Avoiding hypoglycemia is thus very important to prevent cardiovascular death, and less stringent glycemic control targets may be thus considered for people with type 2 DM who are at high risk of hypoglycemia and aged more than 60 years.
Glucose lowering drugs with a low propensity to induce hypoglycemia (for example, best drug according to me is metformin) should be considered as first line choice to avoid hypoglycemia. Metformin has been prescribed for the type2 diabetic patients for more than 50 years if not more & it is time tested best drug. Long term studies and data with Metformin are also completely now available. Metformin has minimal GI side effects like nausea & vomiting, diarrhea, and it lowers appetite. It lowers the body weight also. It is also the drug of choice for impaired Glucose tolerance patients too. In most patients if started slowly or extended release Metformin is given as first line drug. The cost of treatment is also low in India. Importantly, severe hypoglycemic episodes are preceded by only change in food intake. However caution must be taken when creatinine level >130mg and eGFr less than 45.
The Second line of Drug is DPP4 inhibitors [Dipeptidyl peptidase-4 inhibitors-100 mg daily as sitagliptin] along with Metformin for adults. Meta-analysis of DPP-4 inhibitors agonists does not increase cardiac mortality or serious adverse events, GI intolerances like nausea, vomiting, diarrhea during its short term studies, it does not cause weight gain, it lowers HbA1c [DPP-4 inhibitors monotherapy are actually associated with a smaller decline in HbA1c], does not cause hypoglycemia, but it may cause nasopharyngitis, UTI and URTI and the drug is very costly in Indian market. Pioglitazone also significantly reduces HBA1c while achieving no positive impact on cardiovascular outcomes, but rather it increases the risk of heart failure. Rosiglitazone also reduces HbA1c but it also increases heart failure and increases risk of myocardial infarction and cardiovascular death. If one’s goals include fewer adverse outcomes, reduced cardiovascular mortality, and a reduction in complications from diabetes, I personally see no advantage of prescribing habit and in Indian diabetologists trend is to prescribe these agents over less expensive pharmacologic options like metformin for some unknown reason.
Fewer hypoglycemia episodes can be expected with DPP-4 inhibitors when these drugs are compared with other sulfonylureas, but not compared with the drug metformin. This group of drugs may be effective alternatives for patients with type 2 diabetes for whom weight gain is a de-motivating factor or who are troubled by hypoglycemic episodes .Also, this helps to postpone the use of insulin in patients who are intolerant to metformin or in whom metformin becomes failure or is contraindicated as most of the DPP-4s are licensed for use in low eGFR. Though US-FDA has approved this group of drugs in patients with type-2 DM [please note that DPP-4 inhibitors have not been included in the 2009 American Diabetes Association and the European Association for the study of Diabetes consensus algorithm], the exact position of these drugs in treatment of type-2 DM is still undefined. The exact long term effects of these drugs are still unknown. The National Institute for Health and Clinical Excellence (NICE)[4] clinical guideline for type 2 diabetes suggests adding a DPP-4 inhibitor instead of a sulfonylurea as second line treatment to first line metformin when there is a considerable risk for hypoglycemia or if a sulfonylurea is contraindicated or not tolerated by patient] .
Glycemic control with gliptins like sitagliptin[50 to 100 mg daily dose], vildagliptin, saxagliptin, and linagliptin may look slightly inferior to metformin for glycemic control, but weight neutrality and almost nil hypoglycemia makes this group of drugs superior to SUs on balance. GLP-1 analogue seems to be most promising second line drug after metformin failure. One of the serious side effects cautioned currently with sitagliptin is pancreatitis - the severe forms, hemorrhagic or necrotizing pancreatitis in patients using sitagliptin and pancreatic cancer. US FDA has approved the use of sitagliptin in combination with metformin marketed in India as trade name JANUMET.
But to me the best treatment options for type2 diabetes interventions are diet [Fiber containing low calorie diet], daily aerobic exercise, yoga, brisk walking on road or manual workers, control of BMI, weight and medications with Metformin.
Finally, study should be done with effect of hypoglycemia and risk of cardiovascular mortality in type 1 DM also.
References
1] Bonds DE, Miller ME, Bergenstal RM, Buse JB, Byington RP, Cutler JA, et al. The association between symptomatic, severe hypoglycemia and mortality in type 2 diabetes: retrospective epidemiological analysis of the ACCORD study. BMJ 2010;340:b4909.
2] Zoungas S, Patel A, Chalmers J, de Galan BE, Li Q, Billot L, et al. Severe hypoglycemia and risks of vascular events and death. N Engl J Med 2010;363:1410-8.
3]Duckworth WC, Abraira C, Moritz TE, Davis SN, Emanuele N, Goldman S, et al. The duration of diabetes affects the response to intensive glucose control in type 2 subjects: the VA Diabetes Trial.
J Diabetes Complications2011;25:355-61
4]Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, et al. Management of hyper-glycemia in type 2 diabetes: a patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia 2012;55:1577-96
Competing interests: No competing interests