Are We Hitting the Sweet Spot with Medications for Type 2 Diabetes?
Ian Jackson
Former National Health Service (NHS) Prescribing Adviser and Senior Lecturer in Clinical Pharmacology and Therapeutics at a UK Medical/Pharmacy School. Director Green Pill Training Ltd.
Contact: ian.pharmacist@gmail.com
There have been numerous new treatments for type 2 diabetes introduced over the past ten to fifteen years. They all lower blood glucose levels but we need to consider whether these drugs actually reduce the risk of macrovascular events and deaths.
In 2008, the US Food and Drug Administration (FDA) issued guidance on the demonstration of cardiovascular safety for all new medicines developed for glycaemic control in type 2 diabetes. This was driven by the withdrawal of rosiglitazone that was shown in studies to increase the rates of heart attacks and strokes even though it lowered blood glucose levels. This is why it is important to focus on robust randomised controlled studies that measure outcomes and not just lowering of surrogate markers such as HbA1c. It is important to note that the guidance talks about cardiovascular safety and not a reduction in events. Studies now have to measure a composite end point of major adverse cardiac events (MACE). These events include cardiovascular death, nonfatal myocardial infarction, and stroke. (1)
The question we need to ask is whether these newer drugs for treating type 2 diabetes represent an improvement compared to more established therapies such as metformin in terms of reducing macrovascular events and all-cause mortality?
Is Metformin Still Storming?
Goats Rue (Galega officinalis) has been used in herbal medicine for centuries and contains the phytochemical guanidine which was the foundation of biguanide group of drugs such as metformin.
Ó Epibase
The mainstay of any treatment of type 2 diabetes is metformin.and has been available in the UK since 1958. Metformin can cause weight loss which is an ideal property given the fact that many type 2 diabetics are overweight and hypoglycaemia is very rarely associated with this drug.
Lactic acidosis is a rare but potentially fatal condition that can occur with metformin. A Cochrane review of 347 trials found no cases of fatal or nonfatal lactic acidosis in 70,490 patient-years of metformin use. (2) There is a greater risk of metformin induced lactic acidosis when there is a reduction in renal function due to dehydration. Cases studies have highlighted the importance of stopping metformin treatment during illnesses associated with dehydration. (3)
One compelling reason for prescribing metformin first line is the fact that it has been shown to reduce macrovascular events. UKPDS 34 was a randomised controlled trial involving 1704 overweight patients with type 2 diabetes. (4) The three arms of the study were conventional therapy with diet alone, intensive therapy with metformin (dose 1700 to 2550mg daily), or intensive therapy with a sulfonylurea (chlorpropamide, glibenclamide) or insulin. The median follow-up was 10.7 years.
UKPDS 34 provided us with some outstanding primary endpoint data for metformin. The all-cause mortality, after 10 years, for metformin was 15% compared to 22% for conventional therapy giving an absolute risk reduction of 7% and an NNT of 14 (8 to 67). This means that for every fourteen patients taking intensive therapy with metformin you prevent one death over 10 years compared to conventional therapy.
From the UKPDS 34 outcomes, it is easy to see why metformin has become the first-line drug for type 2 diabetes.
A few points need to be considered. The UKPDS 34 study had relatively small numbers of patients on metformin, just 342, compared to future larger studies on diabetes and that sulfonylureas used in UKPDS 34 tend to have longer half lives compared to those used in practice today, such as gliclazide. These have a higher risk of hypoglycaemia and we know this increases cardiovascular risk. The average age of the patients in the UKPDS 34 study was 53 years of age, which is hardly reflective of clinical practice where nearly half of patients with type 2 diabetes are 65 or over.
A Cochrane review in 2005 confirmed the benefits of metformin monotherapy (5) but one issue that was raised by the UKPDS 34 study, was that when a combination of metformin and sulfonylurea were given for glycaemic control, there was a significantly increased risk of diabetes-related death and all-cause mortality. A meta-analysis of studies in 2008 found that the combination therapy of metformin and sulfonylurea significantly increased the composite endpoint of cardiovascular hospitalisation or mortality (fatal and nonfatal events) (RR 1.43; 1.10–1.85) but not all cause or cardiovascular mortality. (6)
A meta-analysis of thirteen randomised controlled trials (2012) involving 13,110 patients (9560 taking metformin) found that metformin did not significantly affect the primary outcomes all-cause mortality or cardiovascular mortality. (7)
A more recent meta-analysis (2019) which included 40 studies comprising 1,066,408 patients showed that metformin reduced cardiovascular mortality, all-cause mortality and cardiovascular events in coronary artery disease patients. (8)
Conclusions:
UK’s Clinical Practice Research Datalink (CPRD) indicated that metformin is prescribed to >70% of type 2 diabetics patients with or without CVD. This is not surprising given metformin’s safety profile and the results of UKPDS. An ongoing trial is comparing CV benefits of metformin versus dapagliflozin in 4300 patients with type 2 diabetes with the results due in 2025. The results of this could help us confirm or challenge metformin’s position as the first-line treatment.
References:
- Smith R, et al. Evaluating the Cardiovascular Safety of New Medications for Type 2 Diabetes: Time to Reassess? Diabetes Care 2016;39:738–742.
2) Salpeter S, et al. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Syst Rev. 2010 Jan 20;(1):CD002967. doi: 10.1002/14651858.CD002967.pub3.
3) Fitzgerald E, et al. Metformin associated lactic acidosis. BMJ 2009;339:b3660.
4) Turner R, et al. UK Prospective Diabetes Study Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998;352:854-65.
5) Saenz A, et al. Metformin monotherapy for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2005 Jul 20;(3):CD002966.
6) Rao A, et al. Is the Combination of Sulfonylureas and Metformin Associated With an Increased Risk of Cardiovascular Disease or All-Cause Mortality? Diabetes Care 2008 Aug; 31(8): 672–1678.
7) Boussageon R, et al. Reappraisal of Metformin Efficacy in the Treatment of Type 2 Diabetes: A Meta-Analysis of Randomised Controlled Trials. PLOS Medicine 2012; 9(4): e1001204. https://doi.org/10.1371/journal.pmed.1001204
8) Han Y, et al. Effect of metformin on all-cause and cardiovascular mortality in patients with coronary artery diseases: a systematic review and an updated meta-analysisCardiovasc Diabetol, 18 (1) (2019), pp. 1-16