We investigated maximum dosage RAASi use in a real-life routine care setting of complicated type 2 diabetes patients. Only a third of these patients receive maximum dose treatment, which is in line with a previously reported proportion of 19-26 percent, found in a population of 195,327 patients with chronic kidney disease, diabetes and/or heart failure (15).
When we tried to find the reasons for not using maximum RAASi dosage, it appeared that a considerable number of patients (23%) had a previous history of at least one measurement of hyperkalemia but this percentage was not different between the maximal (mRAASi) and submaximal (smRAASi) group. This, and the finding that the actual prevalence of hyperkalemia at baseline was 2%, suggests that other considerations must play a role, e.g., a clinical judgement of likelihood of reoccurrence. It should be emphasized however, that reducing the RAASi dose is not necessarily the primary option to prevent hyperkalemia. Reducing dietary potassium intake and/or the use of oral potassium binders are effective measures that should be taken into consideration as a first step in this respect.
Another potential factor limiting the use of RAASi is the occurrence of acute kidney injury (AKI) prior to baseline. We found that almost 20% of the patients had a history of AKI and that the occurrence of which was strongly associated with the use of submaximal dose RAASi instead of maximal dose. The occurrence of AKI, regardless of the cause, is often an important reason to pause RAASi to restore glomerular filtration pressure. However, in follow-up after AKI, persistent RAASi use is associated with decreased mortality, although the risk for hospitalization due to renal causes is higher(17). As in our population, AKI prior to baseline did not occur after initiation or increasing dose of RAASi, and as current severe renal impairment eGFR <30 ml/min/1.73m2 was rare (4% of patients), carefully monitored increase of RAASi dosage in patients with previous AKI could be attempted.
Finally, low blood pressure can be a limiting factor for maximal dosing of RAASi. We found that 1% of the patients had documented hypotension defined as a systolic blood pressure below 100 mmHg. Notably, the prevalence of difficult to treat hypertension was very high, as the majority of patients did not reach the target blood pressure (58%), and the median number of used antihypertensive agents was 2. When patients use an antihypertensive drug with limited renal and cardiovascular preventive effects, compared to RAASi, it could be considered to cease these agents, in order to initiate, or increase, RAASi therapy.
Taken together, there is ample opportunity to increase the dosage of RAASi in this population of patients with advanced type 2 diabetes, as 1) hyperkalemia occurs in a minority of patients and is manageable with alternative strategies; 2) hypotension is rare; 3) Previous AKI is relatively highly frequent and important to consider when maximizing RAASi treatment, but should not be a reason to forego RAASi optimization.
Because this was a retrospective and observational study, we cannot guarantee 100% correct adverse effects documentation in the patient files. On the other hand, to our knowledge, it is extremely rare that patients have a contraindication limiting the use of any RAASi, and if this were the case, it would be extremely unlikely that this would not be documented in the files.
Apart from contraindications, which are patient related factors, physicians may have preferences -in general and in specific situations- that are likely to influence the penetrance of maximal RAASi dosing. First, alternative antihypertensive drug classes could be preferred in certain situations due to competing indications, e.g., beta blockers or calcium channel blockers when CHD coincides with type 2 diabetes. Our finding that TIA/CVA was a negative predictor of mRAASi compared to smRAASi, could be a reflection of such a phenomenon. The guidelines on secondary stroke prevention recommend lowering blood pressure with combination therapy of multiple antihypertensives in a low dose, rather that maximizing RAASi(18). Also, in hypertension treatment, an approach of combining drugs at submaximal doses has been advocated as a strategy to treat hypertension with less side-effects(19). This strategy does not seem to be adopted here, as is indicated by our finding that the number of used antihypertensives was strongly positively associated with mRAASi.
The most important patient characteristics associated with mRAASi were the presence of moderately increased albuminuria, and difficult to treat hypertension. The former was an expected finding, as albuminuria is a very important indication for initiation of RAASi. However, even in patients with albuminuria, mRAASi use was still 46%, although ideally all patients should receive mRAASi, as it is associated with a decrease in hard cardiovascular and renal endpoints(11). Our finding that difficult to treat hypertension is strongly associated with mRAASi suggests that clinicians often do increase RAASi dosage in the scope of blood pressure treatment. Surprisingly, coronary heart disease, which is a very important indication for RAASi, was not associated with mRAASi compared to smRAASi. Although these patients also use other agents which act on blood pressure and possibly renal function, our data demonstrated that the prevalence of unequivocal contraindications for increasing RAASi dosage is low, which suggests that there is enough possibility to increase RAASi dosage.
Reduction of dietary sodium intake is an additional well-established method to increase RAASi effectivity(20). In our population, only 13% of patients adhered to the guideline on sodium intake of <100 mmol/day. Therefore, next to increasing RAASi dosage, reducing dietary sodium could be a good strategy to increase RAASi efficacy.
This study has several strengths. First, it represents a real-life population of patients with complicated type 2 diabetes, and therefore provides important insights on implementation of pharmacological treatment in routine care. Also, our data on pharmacological drug use was extensively verified by review of the electronic patient files and by collection of drug delivery-data from local pharmacies. Furthermore, we extracted an ample amount of laboratory data on potassium and creatinine measurements prior to baseline to investigate the association between previous adverse events and current RAASi dosing.
This study also has some limitations. Because of the retrospective nature, the reasons not to choose maximum dose RAASi were not systematically registered in the patient files and neither was is information on side-effects. For the same reason, any relation between previous AKI or hyperkalemia and RAASi should be considered as hypothesis-generating. Additionaly, this was a single-center study performed in the Netherlands, therefore extrapolation to other populations should be done with caution.
In conclusion, we found that in a real-life population of patients with type 2 diabetes in routine clinical care, only a third of patients used maximum dosage RAASi. Although the prevalence of contraindications for maximal RAASi, such a hyperkalemia and AKI, is considerable, they are usually relative in nature. These findings suggest that, to improve renoprotection and cardiovascular risk management in type 2 diabetes, it is worthwhile to explore strategies aimed at maximizing RAASi while circumventing the alleged contraindication.